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"abstract": "Multiple myeloma (MM) is a malignancy of plasma cells, with a median survival of 6 years. Despite recent therapeutic advancements, relapse remains mostly inevitable, and the disease is fatal in the majority of patients. A major challenge in the treatment of patients with relapsed MM is the timely identification of treatment options in a personalized manner. Current approaches in precision oncology aim at matching specific DNA mutations to drugs, but incorporation of genome-wide RNA profiles has not yet been clinically assessed.\nWe have developed a novel computational platform for precision medicine of relapsed and/or refractory MM on the basis of DNA and RNA sequencing. Our approach expands on the traditional DNA-based approaches by integrating somatic mutations and copy number alterations with RNA-based drug repurposing and pathway analysis. We tested our approach in a pilot precision medicine clinical trial with 64 patients with relapsed and/or refractory MM.\nWe generated treatment recommendations in 63 of 64 patients. Twenty-six patients had treatment implemented, and 21 were assessable. Of these, 11 received a drug that was based on RNA findings, eight received a drug that was based on DNA, and two received a drug that was based on both RNA and DNA. Sixteen of the 21 evaluable patients had a clinical response (ie, reduction of disease marker ≥ 25%), giving a clinical benefit rate of 76% and an overall response rate of 66%, with five patients having ongoing responses at the end of the trial. The median duration of response was 131 days.\nOur results show that a comprehensive sequencing approach can identify viable options in patients with relapsed and/or refractory myeloma, and they represent proof of principle of how RNA sequencing can contribute beyond DNA mutation analysis to the development of a reliable drug recommendation tool.",
"affiliations": ", and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.;, and , Icahn School of Medicine at Mount Sinai, New York, NY; and , Cancer Genetics, Rutherford, NJ.",
"authors": "Laganà|Alessandro|A|;Beno|Itai|I|;Melnekoff|David|D|;Leshchenko|Violetta|V|;Madduri|Deepu|D|;Ramdas|Dennis|D|;Sanchez|Larysa|L|;Niglio|Scot|S|;Perumal|Deepak|D|;Kidd|Brian A|BA|;Miotto|Riccardo|R|;Shaknovich|Rita|R|;Chari|Ajai|A|;Cho|Hearn Jay|HJ|;Barlogie|Bart|B|;Jagannath|Sundar|S|;Dudley|Joel T|JT|;Parekh|Samir|S|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1200/PO.18.00019",
"fulltext": "\n==== Front\nJCO Precis Oncol\npo\npo\nPO\nJCO Precision Oncology\n2473-4284 American Society of Clinical Oncology \n\n1800019\n10.1200/PO.18.00019\n20BIOSTATISTICS AND CLINICAL TRIAL METHODOLOGY20.200Bioinformatics20.300Clinical Trials40.800TRANSLATIONAL ONCOLOGY460.400Gene Expression and ProfilingOriginal Report\nPrecision Medicine for Relapsed Multiple Myeloma on the Basis of an Integrative Multiomics Approach\nLaganà Alessandro Beno Itai Melnekoff David Leshchenko Violetta Madduri Deepu Ramdas Dennis Sanchez Larysa Niglio Scot Perumal Deepak Kidd Brian A. Miotto Riccardo Houldsworth Jane Shaknovich Rita Chari Ajai Cho Hearn Jay Barlogie Bart Jagannath Sundar Dudley Joel T. Parekh Samir Alessandro Laganà, Itai Beno, David Melnekoff, Violetta Leshchenko, Deepu Madduri, Dennis Ramdas, Larysa Sanchez, Scot Niglio, Deepak Perumal, Brian A. Kidd, Riccardo Miotto, Ajai Chari, Hearn Jay Cho, Bart Barlogie, Sundar Jagannath, Joel T. Dudley, and Samir Parekh, Icahn School of Medicine at Mount Sinai, New York, NY; and Jane Houldsworth and Rita Shaknovich, Cancer Genetics, Rutherford, NJ.\nA.L. and I.B. contributed equally to this work.\n\nS.P. and J.T.D. contributed equally to this work.\n\nCorresponding author: Alessandro Lagana, 770 Lexington Avenue, 14-12 New York, NY 10065; Twitter:@alagana1; e-mail: [email protected].\n2018 \n8 8 2018 \n8 8 2018 \n2 PO.18.00019© 2018 by American Society of Clinical Oncology2018American Society of Clinical OncologyLicensed under the Creative Commons Attribution 4.0 License: https://creativecommons.org/licenses/by/4.0/Purpose\nMultiple myeloma (MM) is a malignancy of plasma cells, with a median survival of 6 years. Despite recent therapeutic advancements, relapse remains mostly inevitable, and the disease is fatal in the majority of patients. A major challenge in the treatment of patients with relapsed MM is the timely identification of treatment options in a personalized manner. Current approaches in precision oncology aim at matching specific DNA mutations to drugs, but incorporation of genome-wide RNA profiles has not yet been clinically assessed.\n\nMethods\nWe have developed a novel computational platform for precision medicine of relapsed and/or refractory MM on the basis of DNA and RNA sequencing. Our approach expands on the traditional DNA-based approaches by integrating somatic mutations and copy number alterations with RNA-based drug repurposing and pathway analysis. We tested our approach in a pilot precision medicine clinical trial with 64 patients with relapsed and/or refractory MM.\n\nResults\nWe generated treatment recommendations in 63 of 64 patients. Twenty-six patients had treatment implemented, and 21 were assessable. Of these, 11 received a drug that was based on RNA findings, eight received a drug that was based on DNA, and two received a drug that was based on both RNA and DNA. Sixteen of the 21 evaluable patients had a clinical response (ie, reduction of disease marker ≥ 25%), giving a clinical benefit rate of 76% and an overall response rate of 66%, with five patients having ongoing responses at the end of the trial. The median duration of response was 131 days.\n\nConclusion\nOur results show that a comprehensive sequencing approach can identify viable options in patients with relapsed and/or refractory myeloma, and they represent proof of principle of how RNA sequencing can contribute beyond DNA mutation analysis to the development of a reliable drug recommendation tool.\n\n SJS Export v1\n==== Body\nINTRODUCTION\nMultiple myeloma (MM) is a mostly incurable malignancy of terminally differentiated plasma cells that affects 6.5 per 100,000 people per year in the United States, making it the second most common hematologic malignancy.1 Typically, the trajectory of MM is characterized by a pattern of recurrent remissions and relapses, with patients becoming increasingly refractory to treatment. Hallmarks of MM include chromosomal translocations and copy number alterations (CNA).2 However, the causal drivers of MM pathogenesis are still unclear, and treatment is administered empirically on the basis of recurrence risk rather than genetic events. High-throughput DNA sequencing of patients with MM has revealed wide and remarkable heterogeneity of the mutational spectrum across patients and a complex subclonal structure,3,4 suggesting that the use of a personalized therapeutic approach is likely to improve the outcomes for myeloma.5\n\nIn the past 4 years, we have focused on the design and development of a computational platform for personalized therapy of relapsed and/or refractory MM, on the basis of a comprehensive patient profile generated from DNA and RNA sequencing. Many institutions have now started precision medicine programs aimed at identifying viable therapeutic options for patients with cancer on the basis of specific targetable mutations. This is leading to a landmark paradigm shift in cancer therapy, in which treatment may be administered on the basis of the specific genomic alterations observed in a patient’s tumor, rather than on the tumor histology or tissue type.\n\nOur approach to precision medicine of relapsed MM critically incorporates RNA sequencing–based drug repurposing. In this article, we present our platform and the results obtained from a precision medicine clinical trial with 64 patients with relapsed MM seen at Mount Sinai. We show that our comprehensive approach can benefit patients beyond an approach that is based on mutations alone. Importantly, although our pipeline is designed and tailored for the specific needs of MM therapy, it can provide a general framework for incorporating RNA sequencing–based drug repurposing in oncology.\n\nMETHODS\nProtocol Approvals and Patient Enrollment\nThe patients were physician referred. Enrollment criteria, which included relapsed myeloma, lack of Food and Drug Administration (FDA)–approved therapeutic options, and a prognosis of 6 months of survival, were approved by the Mount Sinai institutional review board (IRB). Informed written consent was obtained from each patient. As part of the IRB-approved genomics protocol, genomics findings were returned to the patient and treating physician in a standardized report to provide interpretative assistance. Patient enrollment started in February 2014 and ended in February 2016. The study was concluded in September 2017.\n\nSample Processing and Sequencing\nBone marrow (BM) aspirates and peripheral blood (PB) were obtained from patients with MM in the study. Tumor genomic DNA and RNA were obtained from CD138+ cells isolated from BM (Data Supplement). Normal genomic DNA (control) was obtained from granulocytes isolated from PB. Whole-exome sequencing (WES) and RNA sequencing libraries were submitted to Illumina HiSeq2500 for paired-end sequencing (100 base pairs). Targeted sequencing was performed using the Lymphoma Extended targeted next-generation sequencing panel from Cancer Genetic, Rutherford, NJ; Data Supplement). Raw sequencing data are available at National Center for Biotechnology Information Sequence Read Archive (accession number: PRJNA474747).\n\nData Processing and Bioinformatics Analysis\nWe designed and implemented a software framework for the definition and execution of data analysis workflows. The DNA workflow processes raw data from paired tumor and normal samples to detect, annotate, and prioritize somatic mutations and CNA and to identify actionable alterations. The RNA workflow processes RNA sequencing (RNAseq) data from tumor samples to identify outlier genes, determine pathway activation, and perform drug repurposing. Extended methods are provided in the Data Supplement.\n\nRESULTS\nOverview of the Study and Patient Characteristics\nWe developed a computational platform for personalized therapy of relapsed and/or refractory MM, on the basis of a comprehensive patient profile generated from DNA sequencing and RNAseq data (Fig 1). We evaluated the feasibility and effectiveness of our approach in an IRB-approved precision medicine clinical trial with 64 participants treated at Mount Sinai (See Methods and Table 1). The study included 39 men (61%) and 25 women (39%), and the median age was 59 years (range, 40 to 85 years). Forty-three patients (67%) had high-risk cytogenetics features such as t(4;14), t(14;16), del(13q), del(17p), and gain of 1q (Data Supplement). Overall, the patients had received a median of seven lines of therapy, with 13 patients (20%) having received > 10 lines of therapy.\n\nFig 1. Schema of the analysis pipeline. Left panel (orange) illustrates the DNA processing flow. DNA is extracted from CD138+ tumor cells from bone marrow and CD3+ or granulocytes (GRN) from peripheral blood as a control. Whole-exome and/or targeted panel sequencing (seq) is performed, and the obtained reads are mapped to the reference genome and analyzed for the identification of somatic mutations and copy number alterations, which are then prioritized on the basis of their actionability. Right panel (blue) illustrates the RNA processing flow. RNA is extracted from CD138+ tumor cells, and RNA seq is performed. The obtained reads are mapped to the reference genome and summarized at the gene level. Gene expression analysis is then performed to calculate outlier genes, pathway activation, and drug repurposing through inverse match with drug-induced gene expression profiles. DNA- and RNA-based drug recommendations are then summarized in reports. CIViC, Clinical Interpretations of Variants in Cancer (https://civicdb.org).\n\nTable 1. Patient Characteristics\n\nGenomic Landscape of Patients With Relapsed MM and Actionable Findings\nWe obtained DNA data, either WES or targeted sequencing or both, for 55 patients (86%; Data Supplement). The pipeline identified a total of 21,166 somatic mutations in 10,403 genes in 54 of the 55 patients with DNA data available (Data Supplement). The mutational burden, quantified for the 41 patients with WES data and defined as the total number of mutations, ranged from 113 to 1,423, with an average of 527.5 mutations per patient (Fig 2A). Mutations were distributed among 14 different categories according to their nature and position in the genome, the majority of them being located in introns (57%; Fig 2B). Among the mutations with a potential pathogenic impact, missense mutations were the most numerous (17%), followed by nonsense, splice site, and start codon mutations (< 3%), for a total of 4,013 potentially pathogenic mutations in 3,163 genes (Data Supplement). We used the Clinical Interpretations of Variants in Cancer database (https://civicdb.org) to identify actionable mutations (ie, those associated with sensitivity to one or more drugs in one or more cancer types6; Fig 2C; Data Supplement). Among the most frequently mutated genes, KRAS, TP53, NRAS, BRAF, ATM, and APC had actionable mutations. Only the BRAF V600E mutation was associated specifically with MM. The other actionable mutations detected were associated with other hematologic malignancies or with solid cancers.\n\nFig 2. Summary of DNA findings. (A) Distribution of mutational burden (ie, number of total mutations per megabase [Mb] detected; n = 41 patients with whole-exome sequencing [WES] data available). (B) Pie chart illustrates the percentage of nonintronic mutations found per category. Bold print indicates categories of potentially pathogenic mutations. (C) Top 30 mutated genes (n = 55 patients with mutation data available from WES and/or targeted sequencing). (*) Gene carried actionable mutations (according to Clinical Interpretations of Variants in Cancer [https://civicdb.org]). (D) Genes with actionable copy number alterations (according to CIViC) found in the 41 patients with WES data available. The colors indicate that the corresponding gene had mostly gain of copies (red) or loss of copies (blue). IGR, intergenic region; lincRNA, long intergenic noncoding RNA.\n\nCNA constitute another important category of abnormalities observed frequently in MM, as well as in other cancers. We estimated CNA for the 41 patients with WES data and summarized them at the gene level. Overall, we found a total of 3,541 genes affected by CNA in at least one patient and identified 31 actionable alterations (Fig 2D; Data Supplement). We assessed concordance of WES-based CNA with fluorescent in situ hybridization and cytogenetics for detection of the most recurrent and clinically relevant CNA in MM (del[1p], del[13q], del[17p], and gain[1q21]) and observed a 69% overlap.\n\nAnalysis of the MM Transcriptome for the Identification of Actionable Variations\nRNAseq data were available for 60 patients (94%) and were used to determine outlier genes and pathway activation and to perform RNA drug repurposing (Data Supplement). We defined deregulated genes (over- or underexpressed) as actionable if they were reported as predictive of sensitivity to at least one drug in CIViC. We identified a total of 28 actionable genes, 17 over- and 11 underexpressed (Fig 3A; Data Supplement). We then calculated pathway activation by single-sample gene set variation analysis7 on a set of actionable pathways relevant in MM: XBP1s activation, mammalian target of rapamycin signaling, histone deacetylase (HDAC), DNA repair, interleukin-6 signaling, PI3K/AKT activation, Hedgehog signaling, fibroblast growth factor receptor 3, and mitogen-activated protein kinase (MAPK). Figure 3B presents pathway activation scores calculated for the 60 patients, whereas Figure 3C illustrates the distribution of activated pathways in the cohort. Each pathway is associated with specific targeted drugs (Data Supplement).\n\nFig 3. Summary of RNA findings. (A) Actionable outlier genes (according to Clinical Interpretations of Variants in Cancer [https://civicdb.org]). The colors indicate that the corresponding gene was mostly overexpressed (red) or underexpressed (blue). (B) Pathway activation calculated by gene set variation analysis for the 60 patients with RNA sequencing data available. (C) Distribution of activated pathways (ie, positive score) for the 60 patients with RNA sequencing data available. (D) Drugs recommended by RNA-based drug repurposing on the basis of inverse matching of patient gene expression profiles with drug-induced profiles from L1000. FGFR3, fibroblast growth factor receptor 3; HDAC, histone deacetylase; IL-6, interleukin-6; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; P13K AKT, phosphoinositide 3-kinase; XBP1s, Xbox binding protein 1 spliced.\n\nFinally, we performed RNA-based drug repurposing by matching each patient’s RNA profile (z scores) with gene expression profiles induced by different drugs from the L1000 project, using the L1000CDS2 method, which is based on characteristic direction signatures.8,9 The rationale behind this approach is that a drug inducing a gene expression profile that is opposite to a patient’s profile might be able to revert the disease-associated signature and the phenotype. This approach has been demonstrated successfully in several published cases.10-12\nFigure 3D presents the distribution of FDA-approved cancer drugs selected by our analysis in the cohort. The Data Supplement summarizes FDA-approved noncancer drugs options that were selected for at least one patient.\n\nImplemented Recommendations and Response to Therapy\nOur pipeline generated recommendations for 63 of 64 patients (98%). Recommended drugs were prioritized on the basis of their specific association with MM, according to the available evidence in CIViC (Data Supplement). Of the 63 patients with recommendations, 26 received at least one of the suggested drugs (42%). The most prescribed drugs were trametinib (n = 16 [61%]), venetoclax (n = 8 [30%]), and panobinostat (n = 6 [23%]). Trametinib was recommended because of mutations in either NRAS or KRAS; venetoclax was recommended because of high BCL2 expression in the context of all the patients analyzed (Data Supplement); panobinostat was recommended on the basis of RNAseq analysis indicating activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat. Other prescribed drugs were dabrafenib, prescribed because of concurrent BRAF and RAS mutations, and etoposide, selected by RNA-based drug repurposing (Table 2).\n\nTable 2. Summary of Implemented Therapies With Responses, Previous Line of Therapy, and Toxicities\n\nOf the 26 treated patients, 21 were evaluable for response (81%). Of these, 11 (52%) received a drug on the basis of RNA profiling, eight (38%) on the basis of DNA profiling, and two (10%) on the basis of both RNA and DNA profiling. Five patients received our recommended drugs alone, whereas for 16 patients, the drugs were either added to previous treatment (n = 10) or administered in combination with other drugs on the basis of physician discretion (n = 6). The clinical benefit rate was 76% (minimal response or greater; Fig 4A). In particular, of the 21 evaluable patients, one (5%) achieved CR; three (14%), very good partial response; and 10 (47%), PR, to give an overall response rate of 66%. Two patients (10%) had minimal response, three (14%) had stable disease, and two (10%) had progressive disease. The median duration of response was 131 days (range, 37 to 372 days). Five patients had still ongoing responses at the end of the study (September 1, 2017), with response durations of 235, 182, 150, 172, and 99 days, respectively (Fig 4B). Significant (≥ grade 3) nonhematologic toxicities were seen in five patients (24%); these included neutropenic fever, diarrhea, fatigue, and cardiomyopathy (Table 2).\n\nFig 4. Depth of response and timeline of treatments. (A) Chart shows depth of response as the percentage change from baseline (start of therapy), for patients who received our recommended drugs. Response was determined after the International Myeloma Working Group criteria. Patients ISMMS42 and ISMMS09 received two different drugs at different times; thus, their responses are shown as two separate bars. Colors indicate the source data used to generate the recommendation, either DNA or RNA or both (see legend). The arrow indicates that the patient had an ongoing response at the end of the study. (B) Each bar indicates the time that each patient was receiving our recommended treatment. Each color represents a different drug, coded as follows: trametinib (light blue), venetoclax (dark gold), panobinostat (dark blue), dabrafenib (salmon), and etoposide (dark red). Multicolored portions of the bars indicate time receiving a drug combination on the basis of our recommendation. Triangle indicates discontinuation of treatment, where reasons are color coded as follows: disease progression (gold), physician’s choice (green), adverse event (pink), and remission achieved (white). Red diamond indicates death of the patient. (+) Additional drugs were used in the specific time frame (see Table 2 for details). Gray bars indicate time receiving a different treatment outside of our recommendation. Red arrow indicates patient had an ongoing response at the end of the study.\n\nCase Studies\nCase 1: Patient ISMMS05 (RNA-Based Recommendation: Panobinostat Plus Venetoclax).\nA 73-year-old woman was diagnosed with IgG lambda MM in November 2007. She received lenalidomide and dexamethasone as front-line treatment, then relapsed and received multiple lines of chemotherapy (Data Supplement). Her CD138+ cells were then collected and sequenced. Our pipeline revealed activation of the HDAC pathway through RNA analysis and, concordantly, identified the HDAC inhibitor vorinostat through drug repurposing. Moreover, gene expression analysis revealed a high expression of BCL2 compared with that of the other patients analyzed (Data Supplement). On the basis of these findings, she was administered venetoclax 400 mg PO once daily, the HDAC inhibitor panobinostat 20 mg Monday, Wednesday, and Friday, 2 weeks on, 1 week off, and, in addition, pomalidomide 2 mg Monday to Friday, 3 weeks on, 1 week off. Notably, the patient had been treated previously with pomalidomide. Before therapy, IgG was elevated to 2,910 mg/dL and free lambda, 141. IgG has decreased to as low as 785 mg/dL and free lambda light chains to 19.16 mg/dL (Data Supplement). The patient remains receiving treatment.\n\nCase 2: Patient ISMMS23 (WES-Based Recommendation: Trametinib).\nA 72-year-old man was diagnosed with IgA kappa plus kappa MM, Durie-Salmon stage IIB in April 2011. After relapsing after receiving multiple treatments including pomalidomide 2 mg (immediate preceding regimen), his CD138+ cells and PB samples were sent for sequencing (Data Supplement). The pipeline identified an NRAS G12S mutation, and the patient was administered the MEK inhibitor trametinib. Before treatment, his IgA and free kappa light chains measured 661 mg/dL and 576 mg/L, respectively (free kappa/lambda ratio, 19·32). Three months after treatment began, his IgA had reached a nadir of 94 mg/dL, whereas his free kappa light chains had decreased to 109 mg/L. The patient relapsed 5 months later, with free kappa light chains rising to 390 mg/L (IgA, 187 mg/dL; Data Supplement).\n\nCase 3: Patient ISMMS40 (WES + RNA-Based Recommendation: Trametinib Plus Venetoclax).\nA 55-year-old man was diagnosed with IgG kappa MM in April 2008. The patient was initially administered lenalidomide and dexamethasone, which resulted in relapse and, after multiple failed regimens, his CD138+ cells and PB were sent for sequencing (Data Supplement). WES analysis identified a KRAS Q22K mutation. Concordantly, RNA analysis showed activation of the MAPK pathway. Gene expression analysis revealed a high expression of BCL2 compared with that of the other patients analyzed (Data Supplement). He was administered the BH3-mimetic venetoclax 400 mg Monday to Friday and trametinib 2 mg Monday, Wednesday, Friday. It has been shown that the combination of BH3-mimetic and MEK inhibition upregulates the proapoptotic Bcl-2 family member Bim and can have a synergistic anticancer activity.13 The patient’s free kappa/lambda ratio decreased from 13.2 to 0.251, and he responded well to therapy. However, he eventually developed grade 3 fatigue, and treatment was held. After relapse, the patient was challenged with venetoclax 400 mg Monday to Friday, trametinib 2 mg Monday, Wednesday, Friday, and carfilzomib 20/27 mg/m2. This showed tumor response, with an M spike decrease from 6.08 g/dL to 4.86 g/dL and an IgG decrease from 7,321 mg/dL to 4,818 mg/dL. Notably, the patient was previously refractory to carfilzomib. The patient has been continuing this regimen for 3 months (Data Supplement).\n\nDISCUSSION\nHere, we reported our integrated multiomics approach for personalized therapy of MM and its application in a pilot precision medicine clinical trial with 64 patients with relapsed MM seen at Mount Sinai. As patients with MM progress through advanced disease and receive multiple lines of therapy, they are left with fewer and fewer treatment options. The results of our study show how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium in MM. Our pipeline generated recommendations from a larger pool of FDA-approved cancer drugs (MM and non-MM) for 63 of 64 patients in the trial (98%; Fig 5).\n\nFig 5. Schematic of the trial with results, limitations, and proposed solutions. We recruited 64 patients (pts) with relapsed and/or refractory multiple myeloma (MM) treated at the Mount Sinai hospital. We obtained RNA sequencing (RNAseq) for 94%, whole-exome sequencing (WES) for 64%, and targeted DNA panel data for 53% of the pts. Sequencing (Seq) data were analyzed by our pipeline (see Fig. 1), and drug recommendation reports were produced. Treatment was implemented in 40% of the pts, and 81% of these were evaluable (see Table 2). According to IMWG criteria, 76% of the pts had a clinical response (MR and above, where MR = minimal response and corresponds to a 25% reduction of disease marker), whereas 24% of the pts had stable disease (SD) or worse. Problems to address to improve recommendations include assessment of clonal heterogeneity, analysis of bone marrow microenvironment, and extension of reference data to include MM-specific drug profiles from in vitro and in vivo models. Treatment was not implemented in 60% of the pts, because either no drugs were identified, because insurance denied the proposed drugs, or because of rapid progression of the patient before the results of sequencing were available. CyTOF, mass cytometry; scRNA, single-cell RNA.\n\nTreatment was implemented in 40% of patients, and 81% of these were evaluable (Table 2). Remarkably, 62% of the evaluable patients received a drug on the basis of RNA profiling. Two drugs that we repurposed successfully from other cancers in our study were trametinib and venetoclax, the former selected on the basis of DNA and the latter on the basis of RNA findings. Trametinib is a MEK1/2 inhibitor approved by the FDA in combination with dabrafenib for unresectable or metastatic melanoma and non–small-cell lung cancer carrying mutations in BRAF (V600E/V600K). Recent studies have shown activating mutations in NRAS, KRAS, and BRAF in MM, making the MAPK pathway a significant therapeutic target also in MM.3-5 A retrospective study has demonstrated clinical activity of trametinib in patients with MM with RAS-mutated tumors.14 Eleven of 21 evaluable patients in our study received trametinib, either alone or in combination with other drugs. Six of them had clinical response, with a median progression-free survival of 110 days, and two patients had ongoing responses at the end of the study. Venetoclax is a BH3 mimetic that acts as a Bcl-2 inhibitor and is approved only for patients with chronic lymphocytic leukemia carrying deletion of 17p.15 Phase I clinical trials reported the efficacy of venetoclax in relapsed and/or refractory MM, where patients with high BCL2 expression had a higher ORR than did patients with low BCL2 expression.16-18 Our pipeline selected venetoclax for eight patients on the basis of BCL2 expression, and all of them showed clinical response, with a median progression-free survival of 161 days, and five patients had ongoing responses at the end of the study. Overall, these results compare favorably to the efficacy seen in several novel agents for MM, including pomalidomide, daratumumab, and elotumumab, as well as targeted precision medicine approaches such as the NCI-MATCH (National Cancer Institute Molecular Analysis for Therapy Choice) trial, in which patients with specific solid tumors received treatment on the basis of actionable DNA mutations.19\n\nOur trial also identified the challenges in implementing NGS-based recommendations in a real-world setting. In 60% of the patients with recommendations, treatment was not implemented, either because of insurance denial of the drug or because of rapid progression of disease before sequencing results were available. Insurance denial represents a significant limitation in the implementation of personalized therapy that is based on genomic findings. Our results suggest a need for specialty pharmacies and insurers to evolve with the technology to optimally help patients. \n\nThe second limiting factor in our study was the time required for sequencing. The average turnaround time from sample collection to sequencing data was 6 weeks. However, most patients with relapsing MM experience rapid progression and need immediate treatment. To address this, we are now using rapid-run sequencing, which provides results in a few days. This may be more expensive initially but may become cost effective with greater use.\n\nOf the 21 treated patients who were evaluable, five did not respond to the recommended therapy. Multiple factors should be considered to improve the accuracy of treatment prediction. One key factor is clonal heterogeneity. MM is characterized by a branching pattern of clonal evolution, in which distinct subclonal tumor populations may evolve by selective pressure of therapy.5,20,21 We have recently started to investigate the impact of clonal heterogeneity on therapy selection, by extending our analysis to include clonality assessment on the basis of WES and/or single-cell RNA sequencing (scRNAseq). Integration of both WES and scRNAseq may provide a more comprehensive profile of a patient’s tumor, enabling drug repurposing at the subclonal level.\n\nAnother key factor in optimal therapy prediction is the BM microenvironment. MM cells are strongly dependent on the surrounding microenvironment, which promotes their homing, growth, survival, and migration, as well as their resistance to drugs.22 Therapies targeting both the cellular and the noncellular BM compartments are available and are currently used in MM, although not in a targeted manner. Profiling the microenvironment by scRNAseq and/or mass cytometry, which allows simultaneous measurements of up to 50 markers at single-cell resolution, may help dissect the nontumor compartment and better inform targeted therapy. We are currently investigating the feasibility of including this feature in the next generation of our platform. In particular, the use of scRNAseq in clinical precision oncology is limited by several challenges, including increased cost compared with bulk sequencing (approximately 10 times higher), high sensitivity to sample purity, and dropouts (ie, undetected transcripts due to low amounts of RNA sequenced within individual cells), as well as data processing and interpretation. In fact, the analysis of scRNAseq data requires the use of specialized tools, which are still in their development stage. Nevertheless, scRNAseq represents a promising and powerful technology that will likely complement current precision medicine strategies in the near future.\n\nA third key factor to consider concerns the accuracy of the predictions. This involves sequencing data, reference data in the knowledge base, and the algorithms used. We are working on extending our knowledge base to incorporate MM-specific data, including transcriptional effects of novel agents, to quickly and effectively translate robust research findings into clinical practice. To further improve drug recommendations, we are implementing validation of the in silico findings using both in vitro (micro-C3) and in vivo (PDX) models.23,24 This will also contribute to reducing both the costs and the toxicities associated with ineffective treatments. Finally, we are going to equip our platform with a machine learning flow, which will implement interactive learning techniques to refine the predictions on the basis of therapy outcome and physician’s opinion.\n\nIn conclusion, here we have described our sequencing-based precision medicine platform for relapsed and/or refractory MM and reported the results of a pilot clinical trial to assess the feasibility and usefulness of this approach. The trial has allowed us to test and reveal the accuracy of our platform and to understand the pitfalls and limitations of the approach, laying the foundation for our next-generation precision medicine framework. Overall, the results demonstrate feasibility and early efficacy, providing a basis for expanding NGS-guided personalized therapy integrating RNA- and DNA-based drug repurposing for patients with cancer.\n\nSupported by funds from the National Institutes of Health/National Cancer Institute (R21: 1R21CA209875-01A1), the Tisch Cancer Institute (National Cancer Institute Support Grant P30 CA196521), and the Multiple Myeloma Philanthropic Fund.\n\nACKNOWLEDGMENT\nWe thank the Genomics Core Facility at the Icahn Institute and the Department of Genetics and Genomic Sciences at Mount Sinai, the Mount Sinai Hematological Malignancies Tissue Bank (HMTB), and the Human Immune Monitoring Core (HIMC) for their support. We thank Archna Jariwala for providing data on insurance approvals. We also thank Scientific Computing at the Icahn School of Medicine at Mount Sinai for their computational resources and staff expertise.\n\nAUTHOR CONTRIBUTIONS\nConception and design: Alessandro Laganà, Joel T. Dudley, Samir Parekh\n\nProvision of study materials or patients: Ajai Chari, Hearn-Jay Cho, Deepu Madduri, Bart Barlogie, Sundar Jagannath, Samir Parekh\n\nCollection and assembly of data: Alessandro Laganà, Violetta Leshchenko, Deepu Madduri, Dennis Ramdas, Larysa Sanchez, Scot Niglio, Deepak Perumal, Ajai Chari, Hearn Jay Cho, Bart Barlogie, Sundar Jagannath\n\nData analysis and interpretation: Alessandro Laganà, Itai Beno, David Melnekoff, Brian A. Kidd, Riccardo Miotto, Jane Houldsworth, Rita Shaknovich\n\nManuscript writing: All authors \n\nFinal approval of manuscript: All authors \n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.\n\nAlessandro Laganà\nNo relationship to disclose\n\nItai Beno\nNo relationship to disclose\n\nDavid Melnekoff\nNo relationship to disclose\n\nVioletta Leshchenko\nNo relationship to disclose\n\nDeepu Madduri\nEmployment: Roivant Sciences (I)\n\nLeadership: Roivant Sciences (I)\n\nStock and Other Ownership Interests: Roivant Sciences (I)\n\nHonoraria: Abbvie\n\nConsulting or Advisory Role: Abbvie\n\nSpeakers' Bureau: Baxalta/Shire\n\nPatents, Royalties, Other Intellectual Property: Roivant Sciences (I)\n\nDennis Ramdas\nEmployment: Eli Lilly (I)\n\nStock and Other Ownership Interests: Eli Lilly (I)\n\nSpeakers' Bureau: Janssen Pharmaceuticals, Sanofi, Takeda Pharmaceuticals (I)\n\nLarysa Sanchez\nNo relationship to disclose\n\nScot Niglio\nNo relationship to disclose\n\nDeepak Perumal\nNo relationship to disclose\n\nBrian A. Kidd\nNo relationship to disclose\n\nRiccardo Miotto\nNo relationship to disclose\n\nRita Shaknovich\nEmployment: CGIX\n\nLeadership: CGIX\n\nStock and Other Ownership Interests: CGIX\n\nConsulting or Advisory Role: AstraZeneca\n\nTravel, Accommodations, Expenses: AstraZeneca\n\nAjai Chari\nConsulting or Advisory Role: Array BioPharma, Celgene, Novartis, Millennium Pharmaceuticals, Amgen, Janssen Oncology, Adaptive Biotechnologies, Bayer AG, Seattle Genetics\n\nResearch Funding: Array BioPharma, Celgene, Millennium Pharmaceuticals, Novartis, Onyx Pharmaceuticals, Janssen Pharmaceuticals, Pharmacyclics, Acetylon Pharmaceuticals (Inst), Biotest (Inst), Bristol-Myers Squibb (Inst)\n\nTravel, Accommodations, Expenses: Takeda Pharmaceuticals, Celgene, Novartis, Amgen, Janssen Oncology, Bristol-Myers Squibb\n\nHearn Jay Cho\nHonoraria: Genentech/Roche\n\nConsulting or Advisory Role: Janssen Research & Development, Genentech, Bristol-Myers Squibb\n\nResearch Funding: Agenus, Janssen Research & Development, Bristol-Myers Squibb\n\nTravel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb\n\nBart Barlogie\nNo relationship to disclose\n\nSundar Jagannath\nHonoraria: Celgene, Karyopharm Therapeutics\n\nConsulting or Advisory Role: Celgene, Bristol-Myers Squibb, Janssen Pharmaceuticals, Novartis, Karyopharm Therapeutics\n\nResearch Funding: Celgene (Inst), Karyopharm Therapeutics (Inst), Bristol-Myers Squibb (Inst)\n\nJoel T. Dudley\nConsulting or Advisory Role: Janssen Pharmaceuticals, Allergan\n\nResearch Funding: AstraZeneca (Inst)\n\nSamir Parekh\nConsulting or Advisory Role: Foundation Medicine\n==== Refs\nREFERENCES\n1. Siegel RL Miller KD Jemal A Cancer statistics, 2017\nCA Cancer J Clin 67 7 30\n2017 28055103 \n2. Morgan GJ Walker BA Davies FE The genetic architecture of multiple myeloma\nNat Rev Cancer 12 335 348\n2012 22495321 \n3. Chapman MA Lawrence MS Keats JJ et al Initial genome sequencing and analysis of multiple myeloma\nNature 471 467 472\n2011 21430775 \n4. Lohr JG Stojanov P Carter SL et al Widespread genetic heterogeneity in multiple myeloma: Implications for targeted therapy\nCancer Cell 25 91 101\n2014 24434212 \n5. Bolli N Avet-Loiseau H Wedge DC et al Heterogeneity of genomic evolution and mutational profiles in multiple myeloma\nNat Commun 5 2997 2014 24429703 \n6. Griffith M Spies NC Krysiak K et al CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer\nNat Genet 49 170 174\n2017 28138153 \n7. Hänzelmann S Castelo R Guinney J GSVA: Gene set variation analysis for microarray and RNA-seq data\nBMC Bioinformatics 14 7 2013 23323831 \n8. Campillos M Kuhn M Gavin AC et al Drug target identification using side-effect similarity\nScience 321 263 266\n2008 18621671 \n9. Duan Q Reid SP Clark NR et al L1000CDS2: LINCS L1000 characteristic direction signatures search engine\nNPJ Syst Biol Appl 2 16015 2016 28413689 \n10. Chen B Ma L Paik H et al Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets\nNat Commun 8 16022 2017 28699633 \n11. Dudley JT Deshpande T Butte AJ Exploiting drug-disease relationships for computational drug repositioning\nBrief Bioinform 12 303 311\n2011 21690101 \n12. Dudley JT Sirota M Shenoy M et al Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease\nSci Transl Med 3 96ra76 2011 \n13. Hendrickson AW Meng XW Kaufmann SH Anticancer therapy: Boosting the bang of Bim\nJ Clin Invest 118 3582 3584\n2008 18949061 \n14. Heuck CJ Jethava Y Khan R et al Inhibiting MEK in MAPK pathway-activated myeloma\nLeukemia 30 976 980\n2016 26228812 \n15. Roberts AW Davids MS Pagel JM et al Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia\nN Engl J Med 374 311 322\n2016 26639348 \n16. Touzeau C Dousset C Le Gouill S et al The Bcl-2 specific BH3 mimetic ABT-199: A promising targeted therapy for t(11;14) multiple myeloma\nLeukemia 28 210 212\n2014 23860449 \n17. Kumar S Kaufman JL Gasparetto C et al Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma\nBlood 130 2401 2409\n2017 29018077 \n18. Moreau P Chanan-Khan A Roberts AW et al Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM\nBlood 130 2392 2400\n2017 28847998 \n19. Brower V NCI-MATCH pairs tumor mutations with matching drugs\nNat Biotechnol 33 790 791\n2015 26252121 \n20. Bianchi G Ghobrial IM Biological and clinical implications of clonal heterogeneity and clonal evolution in multiple myeloma\nCurr Cancer Ther Rev 10 70 79\n2014 25705146 \n21. Brioli A Melchor L Cavo M et al The impact of intra-clonal heterogeneity on the treatment of multiple myeloma\nBr J Haematol 165 441 454\n2014 24580032 \n22. Andrews SW Kabrah S May JE et al Multiple myeloma: The bone marrow microenvironment and its relation to treatment\nBr J Biomed Sci 70 110 120\n2013 24273897 \n23. Pak C Callander NS Young EW et al MicroC(3): An ex vivo microfluidic cis-coculture assay to test chemosensitivity and resistance of patient multiple myeloma cells\nIntegr Biol 7 643 654\n2015 \n24. Pauli C Hopkins BD Prandi D et al Personalized in vitro and in vivo cancer models to guide precision medicine\nCancer Discov 7 462 477\n2017 28331002\n\n",
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"abstract": "OBJECTIVE\nDexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients.\nData was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected.\n\n\nRESULTS\nData of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis.\n\n\nCONCLUSIONS\nDexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.",
"affiliations": "Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Pediatrics, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea.;Department of Pediatrics, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea.;Department of Pediatrics, Korean Cancer Center Hospital, Seoul, Korea.;Department of Pediatrics, Hanyang University Medical Center, Hanyang University College of Medicine, Seoul, Korea.;Department of Pediatrics, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.;Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University School of Medicine, Hwasun, Korea.;Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University School of Medicine, Hwasun, Korea.;Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea.;Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea.;Department of Pediatrics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.;Department of Pediatrics, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Korea.;Department of Pediatrics, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.;Department of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Korea.;Department of Pediatrics, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea.;Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea.;Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Kim|Hyery|H|;Kang|Hyoung Jin|HJ|;Park|Kyung Duk|KD|;Koh|Kyung-Nam|KN|;Im|Ho Joon|HJ|;Seo|Jong Jin|JJ|;Lee|Jae Wook|JW|;Chung|Nack-Gyun|NG|;Cho|Bin|B|;Kim|Hack Ki|HK|;Lee|Jae Min|JM|;Hah|Jeong Ok|JO|;Lee|Jun Ah|JA|;Lee|Young Ho|YH|;Park|Sang Kyu|SK|;Baek|Hee Jo|HJ|;Kook|Hoon|H|;Kim|Ji Yoon|JY|;Kim|Heung Sik|HS|;Kim|Hwang Min|HM|;Chueh|Hee Won|HW|;Park|Meerim|M|;Yoon|Hoi Soo|HS|;Lee|Mee Jeong|MJ|;Choi|Hyoung Soo|HS|;Ahn|Hyo Seop|HS|;Kawano|Yoshifumi|Y|;Park|Ji Won|JW|;Hahn|Seokyung|S|;Shin|Hee Young|HY|",
"chemical_list": "D018943:Anthracyclines; D002316:Cardiotonic Agents; D064730:Dexrazoxane",
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2017.457",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 2976411710.4143/crt.2017.457crt-2017-457Original ArticleRisk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients Kim Hyery MDPhD12Kang Hyoung Jin MDPhD1Park Kyung Duk MDPhD1Koh Kyung-Nam MDPhD2Im Ho Joon MDPhD2Seo Jong Jin MDPhD2Lee Jae Wook MDPhD3Chung Nack-Gyun MDPhD3Cho Bin MDPhD3Kim Hack Ki MDPhD3Lee Jae Min MDPhD4Hah Jeong Ok MDPhD45Lee Jun Ah MDPhD6Lee Young Ho MDPhD7Park Sang Kyu MDPhD8Baek Hee Jo MDPhD9Kook Hoon MDPhD9Kim Ji Yoon MDPhD1011Kim Heung Sik MDPhD10Kim Hwang Min MDPhD12Chueh Hee Won MDPhD13Park Meerim MDPhD14Yoon Hoi Soo MDPhD15Lee Mee Jeong MDPhD16Choi Hyoung Soo MDPhD17Ahn Hyo Seop MDPhD117Kawano Yoshifumi MDPhD18Park Ji Won MS19Hahn Seokyung PhD19Shin Hee Young MDPhD1\n1 Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea\n2 Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea\n3 Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea\n4 Department of Pediatrics, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Korea\n5 Department of Pediatrics, Daegu Fatima Hospital, Daegu, Korea\n6 Department of Pediatrics, Korean Cancer Center Hospital, Seoul, Korea\n7 Department of Pediatrics, Hanyang University Medical Center, Hanyang University College of Medicine, Seoul, Korea\n8 Department of Pediatrics, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea\n9 Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University School of Medicine, Hwasun, Korea\n10 Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea\n11 Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea\n12 Department of Pediatrics, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea\n13 Department of Pediatrics, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Korea\n14 Department of Pediatrics, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea\n15 Department of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Korea\n16 Department of Pediatrics, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea\n17 Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea\n18 Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan\n19 Medical Research Collaborating Center, Seoul National University Hospital, Seoul, KoreaCorrespondence: Hee Young Shin, MD, PhD Division of Hematology/Oncology, Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: 82-2-2072-2917 Fax: 82-2-743-3455 E-mail: [email protected] 2019 14 5 2018 51 1 357 367 26 9 2017 11 5 2018 Copyright © 2019 by the Korean Cancer Association2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nDexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients.\n\nMaterials and Methods\nData was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected.\n\nResults\nData of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis.\n\nConclusion\nDexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.\n\nDexrazoxaneChildhoodCancerAnthracyclinesRisk factorsSecond neoplasm\n==== Body\nIntroduction\nAnthracycline plays an important role in chemotherapy of various cancer types, including breast cancer, leukemia, and sarcoma so that about 50% of pediatric cancer patients are receiving anthracycline based chemotherapy [1]. However, cardiotoxicity is well known side effect of anthracycline, and leaves permanent cardiac damage in certain patients. The likelihood of anthracycline-related cardiotoxicity is reported to be up to 57%, and mortality rate due to these heart problems is reported as 8.2 times higher than that of the normal people [2]. In particular, the risk of late onset cardiotoxicity is reported to be higher in patients younger at the time of anthracycline administration, and received higher total cumulative anthracycline dose.\n\nBecause it is important to prevent late anthracycline induced cardiac event due to irreversibility, various attempts to prevent cardiac toxicity of anthracyclines were tried, such as changing administration methods or co-infusion of candidate cardio-protective agents. However, those methods were not effective in preventing cardiac toxicity only except dexrazoxane (Cardioxane) [1].\n\nDexrazoxane has been widely used to prevent cardiac toxicity after anthracycline administration including pediatric cancer patients, and showed clinically significant cardio-protective effects [3,4]. However, in a previous prospective study of Hodgkin’s disease, there was a claim that dexrazoxane might have increased the incidence of myelodysplastic syndrome (MDS) and secondary cancers [5].\n\nHowever, on the contrary to the report with Hodgkin’s disease, following studies with various diseases and large numbers of patients showed that there was no difference in the occurrence of secondary malignancies (SMN) between patients administered dexrazoxane and the others [6-8]. In addition, there was no previous report about risk factor analysis including multivariate factors influencing the development of SMN. It is needed to verify whether SMN occurs in patients who received dexrazoxane, and whether other risk factors are associated with SMN. This study intended to analyze cardioprotective efficacy and SMN development related to dexrazoxane, and find out risk factors for SMN in Korean patients who received dexrazoxane.\n\nMaterials and Methods\n1. Study population\nThis nationwide study was conducted in 15 institutions in Korea. The subjects for this study were selected from all pediatric cancer patients whose treatment was ended at the time of study initiation (November 2012). Among those, patients who had received anthracycline during their chemotherapy and did not receive hematopoietic stem cell transplantation were finally selected for the analysis. The patients were divided into two groups: (1) patients who used dexrazoxane with anthracyclines, and (2) patients who did not use the dexrazoxane. For the comparison with control group, patients who had received dexrazoxane with every dose of anthracyclines during their treatment regardless of the preceding risk factors for cardiotoxicity were included, and those who were administered dexrazoxane intermittently or only during selected schedules were excluded.\n\n2. Data collection\nVarious clinical and laboratory data were collected, which included patients’ demographics, diagnosis, chemotherapy history, dexrazoxane related data (total dose, date of first and last administration), any cardiac event, survival status and other late effects at the last follow up. Data reported to be risk factors of SMN were also collected including any congenital condition or hereditary syndrome, granulocyte colony-stimulating factor (G-CSF) administration and the details of radiation therapy. Irradiation on the thoraxinvolved fields (thorax, lung, craniospinal, mediastinum, etc.) might influence late cardiac function, thus radiation in those locations was considered as an independent factor for the analysis of late cardiac function. Cumulative doses of various chemotherapeutic agents including anthracyclines (daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone), etoposide and cyclophosphamide were calculated. All anthracycline doses were converted to doxorubicin equivalent doses with the formula using doxorubicin equivalent dose conversion [9].\n\nAll the information was obtained using the electronic case report form developed by the Medical Research Collaborating Center (MRCC) in Seoul National University of Medicine, and was inputted by a designated researcher at each hospital. Data-management experts at MRCC performed quality-control checks to ensure accuracy of the recorded data, and audits were conducted thoroughly.\n\n3. Statistical analysis\nBaseline and demographic characteristics were summarized by standard descriptive statistics. Cumulative doses of chemotherapeutic agents and data related to dexrazoxane were summarized by descriptive statistics. For continuous data, basic statistical values were obtained, and T-test for parametric data and Wilcoxon rank sum test for nonparametric data were conducted. In case of categorical data, the frequencies and percentages were obtained, and Pearson's chi-square test or Fisher exact test were conducted for comparison between groups.\n\nEvents were defined as any relapse, death, or SMN. Cardiac events were defined as any cardiac abnormalities detected during and after the administration of anthracyclines including sudden cardiac death, and early cardiac toxicity. We defined early cardiotoxicity as which developed during treatment or first year after treatment completion, whereas late cardiotoxicity as which developed at least one year after therapy in cancer survivors [10,11]. Probabilities of event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier method, and survival differences were analyzed with log-rank test. Cox proportional hazard regression model was made after being adjusted for baseline and other factors which might influence on the outcome variables. Cardiac EFS was separately calculated for four groups which were divided according to each quartile values of the cumulative doses of anthracyclines and dexrazoxane.\n\nThe incidence of SMN and death in the two groups and unadjusted odds ratios were estimated with 95% confidence intervals. Considering the competing risks for death or relapse, cumulative incidence curves were calculated, and Fine and Gray models were used for the analysis of the difference between two groups. In addition, competing risk analysis with Fine and Gray model was conducted for the evaluation of risk factors for SMN. The correction factors for competing risk analysis were age, sex, diagnosis, G-CSF administration, hereditary or genetic syndrome, cumulative doses of chemotherapeutics, irradiation history, duration of anthracycline administration, duration between first anthracycline and last echocardiography, and total duration of chemotherapy.\n\nAll the statistical analysis was performed by biostatistics specialists at the MRCC in Seoul National University of Medicine, and SAS ver. 9.4 (SAS Institute Inc., Cary, NC) was used as a statistics program.\n\n4. Ethical statement\nThis study has been approved by the Institutional Review Board of Seoul National University Hospital (H-1212-107-453), and each participating hospital with a waiver of informed consent.\n\nResults\n1. Characteristics of the patients\nData of total 1,788 patients from 15 institutions were collected, and data of total 1,453 patients were analyzed for the study (S1 Fig., S2 Table). The date of initial diagnosis of all patients were ranged from August 1996 to September 2012. Dexrazoxane group (D group) included 1,035 patients, and non-dexrazoxane group (non-D group) included 418 patients. Median age at diagnosis was 5 years in non-D group, and 6 years in D group (Table 1). Age and sex proportions were not statistically different between two groups, but follow-up duration was longer in non-D group, as median 124.3 months comparing with 59.4 months in D group (p < 0.01).\n\nDiagnosis of patients was various as shown in Table 1. In D group, there were acute lymphoblastic leukemia (26.5%), non-Hodgkin's lymphoma (16.0%), and osteosarcoma (12.2%) in the order of proportion, and acute lymphoblastic leukemia (42.6%), non-Hodgkin's lymphoma (18.7%) and neuroblastoma (6.5%) in non-D group. The distribution of diagnosis was statistically different between two groups (p < 0.01).\n\nWe collected data of hereditary syndrome or genetic disease in all subjects (Table 1). There were 12 patients who were diagnosed with hereditary syndrome or genetic diseases; two (0.5%) patients in non-D group and 10 (1.0%) patients in D group, respectively.\n\n2. Chemotherapy and dexrazoxane\nCumulative doses of chemotherapeutic agents are shown in Table 2. The median cumulative doses of etoposide were 1,830 mg/m2 in non-D group and 1.82 g/m2 in D group (p=0.52). Cumulative doses of cyclophosphamide were significantly higher in the D group, as median cumulative doses were 4,030 mg/m2 in D group and 2,570 mg/m2 in non-D group (p < 0.01). The data about anthracyclines doses was collected in 1,443 patients, and the dose of total cumulative anthracyclines was significantly higher in D group, as 210 mg/m2 in D group and 150 mg/m2 in non-D group, respectively (p < 0.01). Among anthracyclines, cumulative doses of doxorubicin and idarubicin were significantly higher in the D group.\n\nThe median duration of entire chemotherapy was 652 days in non-D group and 366 days in D group, and total duration of chemotherapy was significantly longer in non-D group (p < 0.01) (Table 2), and the median total duration of anthracycline administration was 161 days in non-D group and 168 days in D group (p=0.90). The median age of first anthracycline administration was 5 years in non-D group and 6 years in D group, respectively (p=0.73). The median dose of dexrazoxane was 2,390 mg/m2, and the median total duration of dexrazoxane administration was 167 days (range, 1 to 2,974 days).\n\nRoutine G-CSF administration during neutropenia was more frequent in D group (86.0%) than in non-D group (71.2%) (p < 0.01), and more patients in non-D group (32.1%) received radiotherapy (p < 0.01) (Table 2). The total dose of radiation was significantly higher in D group (p=0.01); however, radiation fields were various and the number of patients who received radiation therapy on thorax-related fields was not significantly different between two groups (p=0.48).\n\n3. Efficacy of dexrazoxane\nCardiac events in 1,452 patients until the time of data collection were collected. A total of 75 cardiac events occurred, and there were 16 cases (3.8%) in non-D group, and 59 cases (5.7%) in D group (p=0.24) (S3 Table). Among all cardiac events, asymptomatic ventricular dysfunction in echocardiography was the most common cardiac manifestation (3 cases in non-D group, 26 cases in D group). According to the time of cardiotoxicity, early cardiotoxicity occurred in 13 cases of non-D group, and 52 cases of D group.\n\nThe cardiac EFS rate was 95.4% in non-D group, and 93.4% in D group. There was no significant difference in EFS after considering the corrections factors (p=0.09) (Fig. 1A). According to the total anthracyclines cumulative doses, there were 204 patients who received more than 400 mg/m2 of anthracyclines (32 patients in non-D group, 172 patients in D group). There were 6 cardiac events in non-D group, and 12 events in D group (S4 Table). When analyzing the cardiac EFS rates according to the total cumulative anthracycline doses, there was significant difference between non-D group and D group of patients who received more than 400 mg/m2, as 80.1% and 91.2% (p=0.04) (Fig. 1B).\n\n4. Secondary malignancy and survival\nData of SMN was available in 1,224 patients (non-D group 344 patients and D group 880 patients), and there were 4 and 12 patients who developed SMN or MDS in non-D group and D group, respectively (Table 3). The median latency from initial diagnosis to SMN was 5.7 years (range, 1.3 to 13.9 years). The most common SMN was acute myeloid leukemia (AML), as total five patients developed AML, and osteosarcoma was developed in three patients. The follow up duration of both groups were significantly different, so the cumulative incidence of both groups were compared at the same time points. The 6-year cumulative incidence rate of SMN in all patients was 0.67±0.24%. The rates of SMN were 0.52%±0.37% in non-D group and 0.60%±0.28% in D group, respectively (Fig. 2A), and the cumulative incidence rate after considering correction factors was not statistically different between two groups (p=0.55). When patients with Hodgkin lymphoma were analyzed (non-D group 12 patients, and D group 34 patients), the 6-year cumulative incidence rate of SMN was 0% in non-D group and 3.1%±2.9% in D group, and the difference between two groups was not significant (p=0.56) (Fig. 2B).\n\nThe OS in D group was 87.4%, and that in non-D group was 86.3% (Fig. 3A). The EFS was 80.3% in D group and 80.4% in non-D group (Fig. 3B). The survival rates were not significantly different between two groups (OS, p=0.06; EFS, p=0.64).\n\n5. Risk factor for secondary malignancy\nRisk factors affecting the occurrence of SMN after considering relapse and death as competing risks were analyzed with Fine and Gray model, and the results are shown in Table 4. According to the univariate analysis with significant level of 5%, irradiation history, higher cumulative doses of etoposide, cyclophosphamide and anthracyclines, longer duration of anthracycline, shorter time after last anthracycline, and longer duration of chemotherapy were related with statistically significant higher hazard ratio of the occurrence of SMN. The result of multivariate analysis showed that the incidence of SMN was not increased due to dexrazoxane, but increased approximately 1.05 times in response to every 1-month prolongation of anthracycline administration (p < 0.01) (Table 4). Whereas, the incidence of SMN was reduced by about 0.99 times as every month after last anthracycline went by (p < 0.01).\n\nDiscussion\nIn this study, multivariate analysis for assessing risk factors of SMN in pediatric cancer patients who received dexrazoxane was conducted, and there was no increased incidence or risk of SMN in those patients.\n\nThe mechanism of anthracycline’s early cardiotoxicity is known to be related to free radical injury, contributing to the formation of reactive oxygen species and leading to the apoptosis of cardiomyocyte and intracellular damage [12]. On the other hand, the mechanism of delayed cardiotoxicity in the long-term survivors is multifactorial including myocardial mitochondria related apoptosis which results in metabolic remodeling of heart [13]. However, delayed cardiotoxicity presents as overt clinical manifestations such as heart failure only in extreme cases, and only slowly progressing ventricular abnormalities are detected in many cases [13].\n\nFor assessing cardiotoxicity in pediatric cancer patients, cardiac event has been counted as one of the markers for cardiotoxicity [3,14]. A cumulative dose of anthracycline has been known as the most significant risk factor for cardiac dysfunction. The incidence of heart failure was approximately 3.0% in patients receiving a cumulative dose of doxorubicin of 400 mg/m2, 7.5% at doses of 550 mg/m2, and 18.0% at doses of 700 mg/m2 [15]. In our study, although there was no significant difference in EFS between two groups and the median follow up duration was significantly longer in non-D group, patients who received more than 400 mg/m2 of cumulative anthracyclines and dexrazoxane showed a slightly higher cardiac EFS than the other patients without dexrazoxane. These results might be related to the relatively low incidence of clinical cardiologic events in patients with less than 400 mg/m2 of anthracycline, thus the protective effect would be apparent only in patients receiving higher amounts of anthracyclines. Longer follow-up would be needed considering late cardiotoxicity especially in patients with short treatment off period.\n\nDespite of the cardioprotective effects of dexrazoxane, dexrazoxane was reported to be related with increased risk of SMN. Tebbi et al. [5] reported the results of the Pediatric Oncology Group study with Hodgkin lymphoma, in which patients were randomly assigned to receive dexrazoxane to evaluate its cardiopulmonary protective effect. The authors found an increased incidence of SMN after a median follow-up time of 4.8 years, especially AML or MDS, in the dexrazoxane-received patients.\n\nHowever, many refutations against the Tebbi’s report have been followed. Since in that article, risk factors of SMN such as cumulative doses of etoposide, cyclophosphamide, and doxorubicin or G-CSF administration were not considered as confounding factors in the analysis. Also, many studies in other patient groups have not shown the same results [6-8,13].\n\nIn our study, multiple risk factors known to affect SMN development were collected. In the multivariate analysis, longer duration of anthracycline, and shorter time after last anthracycline were related with statistically significant higher hazard ratio of the occurrence of SMN. There was no significant risk factor related to AML or MDS, specifically. There was no data related to the association of SMN and duration of certain chemotherapeutic agents. Considering the final adjusted hazard ratios in our study were relatively low as 1.05 and 0.99, our final multivariate factors could not be the most powerful risk factors for SMN. Further analysis could elucidate more influential risks factors for SMN in these patients group.\n\nRisk factors for SMN are known to be multifactorial. Chemotherapy agents known to be carcinogenic are the alkylating agents, topoisomerase II agents, and anthracyclines [16]. In addition, the cumulative dose, the schedule of chemotherapy administration, and the use of multiple drugs all significantly impact the risk of developing SMN [16]. In our study, patient No. 2 in Table 3 developed papillary thyroid cancer within radiation fields. Although there were cases where the irradiated fields and location of SMN were not related, radiation itself has been reported as one of the risk factors for SMN in childhood cancer patients [17-19]. Secondary osteosarcoma was developed in three retinoblastoma patients. The risk of secondary bone tumors in retinoblastoma survivors is higher in patients with bilateral disease or germline mutations in RB gene. In addition, radiation therapy could also increase the risk of secondary osteosarcoma in retinoblastoma patients [20].\n\nWhen patients with Hodgkin disease were analyzed separately, dexrazoxane was not a significant risk factor for SMN and the cumulative incidence of SMN was not significantly different regardless of dexrazoxane. In the study of the Childhood, Adolescent and Young Adult Cancer Survivors Research Program of British Columbia which analyzed long term results of 442 Hodgkin lymphoma survivors, radiation therapy (hazard ratio, 2.7), and female sex (hazard ratio, 1.8) were significant risk factors for SMN in multivariate analysis [21]. To analyze risk factors for SMN in Hodgkin disease, many factors other than dexrazoxane should be considered.\n\nThis study has several limitations. First, there would be possibility of selection bias due to retrospective design although data management and analysis were conducted by medical statistics specialists. Second, the follow up duration was variable, and there were patients with insufficient follow-up duration for late complication analysis. Especially, the follow up duration of D group was significantly shorter than non-D group so that cardiac events or SMN results might be changed after longer follow-up. Third, there could be other risk factors for SMN development such as cancer predisposing genetic factors and other alkylating agents including ifosfamide. In addition, specific medical conditions which might cause cardiac events other than anthracycline could not be considered because of the limitation of retrospective design.\n\nIn conclusion, dexrazoxane had an efficacy in the prevention of lowering cardiac EFS rates in patients with higher cumulative anthracyclines. According to the multivariate analysis, the occurrence of SMN was not related to dexrazoxane. Given the efficacy of dexrazoxane as a cardioprotectant, dexrazoxane could be used in anthracycline-containing pediatric regimens.\n\nConflict of interest relevant to this article was not reported.\n\nThis research was supported by a grant (12172MFDS231) from the Ministry of Food and Drug Safety, Republic of Korea.\n\nElectronic Supplementary Material\nSupplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).\n\n Fig. 1. Cardiac event-free survival (EFS) of all patients (A), patients who received more than 400 mg/m2 of total cumulative anthracyclines (B). (A) The cardiac EFS rate was 95.4% in non-dexrazoxane group (non-D group) (n=416), and 93.4% in dexrazoxane group (D group) (n=1,034) (p=0.09), (B) but there was significant difference in cardiac EFS between non-D group (n=32) and D group of patients (n=172) who received more than 400 mg/m2, as 80.1% and 91.2% (p=0.04).\n\nFig. 2. The 6-year cumulative incidence rate of secondary malignancy in all patients (n=1,224) (A), patients with Hodgkin disease (n=46) (B). (A) The 6-year cumulative incidence rate of secondary malignancies (SMN) in all patients was 0.67±0.24%. The rates of SMN were 0.52%±0.37% in non-dexrazoxane group (non-D group) (n=880) and 0.60%±0.28% in dexrazoxane group (D group) (n=344) (p=0.55). (B) When patients with Hodgkin lymphoma were analyzed, the rates of SMN was 0% in non-D group (n=12) and 3.1%±2.9% in D group (n=34) (p=0.56).\n\nFig. 3. Survival rates of all patients. (A) Overall survival rate of 1,035 patients in dexrazoxane group (D group) was 87.4%, and that of 418 patients in non-dexrazoxane group (non-D group) was 86.3% (p=0.06). (B) Event-free survival rate was 80.3% in D group (n=1,035) and 80.4% in non-D group (n=418) (p=0.64).\n\nTable 1. Clinical characteristics of all patients\n\nCharacteristic\tNon-dexrazoxane (n=418)\tDexrazoxane (n=1,035)\tp-value\t\nAge at diagnosis (yr)\t5 (0-26)\t6 (0-21)\t0.10\t\nSex\t\t\t\t\n Female\t174 (41.6)\t411 (39.7)\t0.50\t\n Male\t244 (58.4)\t624 (60.3)\t\t\nFollow-up duration (mo)\t124.3 (0-209.2)\t59.4 (0-182.1)\t< 0.01\t\nDiagnosis\t\t\t\t\n Acute lymphoblastic leukemia\t178 (42.6)\t274 (26.5)\t< 0.01\t\n Acute myeloid leukemia\t23 (5.5)\t61 (5.9)\t\t\n Acute biphenotypic leukemia\t9 (2.2)\t8 (0.8)\t\t\n Ewing/Primitive neuroectodermal tumor\t7 (1.7)\t44 (4.3)\t\t\n Extracranial germ cell tumor\t5 (1.2)\t26 (2.5)\t\t\n Hepatic tumor\t18 (4.3)\t39 (3.8)\t\t\n Hodgkin lymphoma\t12 (2.9)\t34 (3.3)\t\t\n Leukemia other\t2 (0.5)\t4 (0.4)\t\t\n Neuroblastoma\t27 (6.5)\t78 (7.5)\t\t\n Non-Hodgkin's lymphoma\t78 (18.7)\t166 (16.0)\t\t\n Non-rhabdomyosarcoma soft-tissue sarcomas\t8 (1.9)\t34 (3.3)\t\t\n Osteosarcoma\t20 (4.8)\t126 (12.2)\t\t\n Other solid tumor\t5 (1.2)\t14 (1.4)\t\t\n Renal tumor\t17 (4.1)\t30 (2.9)\t\t\n Retinoblastoma\t5 (1.2)\t75 (7.2)\t\t\n Rhabdomyosarcoma\t4 (1.0)\t22 (2.1)\t\t\nHereditary syndrome or genetic disease\t\t\t\t\n No\t416 (99.5)\t1,025 (99.0)\t0.53\t\n Yes\t2 (0.5)\t10 (1.0)\t\t\n 13q deletion syndrome\t0\t2 (20.0)\t\t\n Beckwith-Wiedemann syndrome\t0\t1 (10.0)\t\t\n Marfans syndrome\t1 (50.0)\t0\t\t\n Neurofibromatosis\t0\t2 (20.0)\t\t\n Noonan syndrome\t0\t2 (20.0)\t\t\n Rothmund Thompson syndrome\t0\t1 (10.0)\t\t\n Tuberous sclerosis\t1 (50.0)\t0\t\t\n WAGR 11P13 deletion syndrome\t0\t1 (10.0)\t\t\n Williams syndrome\t0\t1 (10.0)\t\t\nValues are presented as median (range) or number (%).\n\nTable 2. Cumulative doses of chemotherapeutics and details of treatment\n\n\tNon-dexrazoxane (n=418)\tDexrazoxane (n=1,035)\tp-value\t\nNo. (%)\tMedian (range)\tNo. (%)\tMedian (range)\t\nCumulative doses of chemotherapeutics (mg/m2)\t\t\t\t\t\t\n Etoposide\t122\t1,830 (120-6,340)\t447\t1,820 (40-15,430)\t0.52\t\n Cyclophosphmide\t297\t2,570 (310-35,370)\t718\t4,030 (4-74,110)\t< 0.01\t\n Total anthracyclinesa)\t411b)\t150 (15.4-665.1)\t1,032c)\t210 (17-753.9)\t< 0.01\t\n Daunomycin (daunorubicin)\t164\t75 (18-347)\t304\t80 (18.4-392)\t0.20\t\n Doxorubicin (adriamycin)\t364\t120 (15-691)\t909\t180 (17.3-665)\t< 0.01\t\n Idarubicin\t27\t50 (6-113)\t80\t60 (10.7-248)\t0.03\t\n Epirubicin\t1\t208\t13\t100 (31.1-1,091)\t1.00\t\n Mitoxantrone\t15\t40 (16-100)\t35\t40 (12-55)\t0.73\t\nTotal duration of chemotherapy (day)d)\t-\t652 (0-2,655)\t-\t366 (1-3,444)\t< 0.01\t\nTotal duration of anthracycline (day)d)\t-\t161 (0-1,889)\t-\t168 (0-2,974)\t0.90\t\nAge at first anthracycline (yr)\t-\t5 (0-26)\t-\t6 (0-21)\t0.73\t\nTotal dose of dexrazoxane (mg/m2)\t-\t-\t-\t2,390 (125-36,989)\t< 0.01\t\nTotal duration of dexrazoxane (day)d)\t-\t-\t-\t167 (1-2,974)\t< 0.01\t\nG-CSF administration during neutropenia\t297 (71.2)\t-\t890 (86.0)\t-\t< 0.01\t\nRadiotherapy\t134 (32.1)\t-\t201 (19.4)\t-\t< 0.01\t\nRadiotherapy on thorax\t9 (2.2)\t-\t29 (2.8)\t-\t0.48\t\nRadiation dose (Gy)\t-\t18 (2-63)\t-\t22.5 (0.45-147)\t0.01\t\nG-CSF, granulocyte colony-stimulating factor.\n\na) Cumulative dose of total anthracyclines (mg/m2)=daunorubicin (mg/m2)×0.833+doxorubicin (mg/m2)+idarubicin (mg/m2)×5+epirubicin (mg/m2)×0.67+mitoxantrone (mg/m2)×4,\n\nb) Dose data of 7 patients were not available,\n\nc) Dose data of 3 patients were not available,\n\nd) Total duration of the drug=date of last administration– date of first administration.\n\nTable 3. Characteristics of patients with secondary malignancies\n\nNo.\tSex\tAge at initial diagnosis (yr)\tPrimary diagnosis\tPrimary treatment\tTime to secondary malignancy from initial diagnosis (mo)\tSecondary malignancy\tSurvival status\t\nRT\tRT field\tG-CSF\tCumulative doses of chemotherapeutics\t\nEtoposide (g/m2)\tCyclophosphamide (g/m2)\t\nDexrazoxane group (n=880)\t\n1\tM\t1\tNeuroblastoma\tN\t-\tY\t6.5\t12.9\t59.2\tPapillary thyroid cancer\tAlive\t\n2\tM\t1\tAcute lymphoblastic leukemia\tY\tBrain/spine\tY\t0\t1.6\t77\tPapillary thyroid cancer\tAlive\t\n3\tF\t0\tRetinoblastoma\tY\tOrbit\tY\t4.5\t11.3\t77.4\tOsteosarcoma\tDeath d/t disease\t\n4\tF\t1\tRetinoblastoma\tY\tOrbit\tY\t3.7\t23.8\t96.6\tOsteosarcoma\tDeath d/t infection\t\n5\tF\t1\tRetinoblastoma\tY\tRight retina\tY\t4.7\t15.9\t99.9\tOsteosarcoma\tAlive\t\n6\tM\t6\tCNS PNET\tY\tBrain\tY\t2.7\t31.5\t29.5\tNon-Hodgkin's lymphoma\tAlive\t\n7\tF\t8\tExtracranial germ cell tumor\tN\t-\tY\t1.9\t0\t82.2\tChodrosarcoma\tAlive\t\n8\tF\t8\tOsteosarcoma\tN\t-\tY\t0\t0\t25.6\tAcute myeloid leukemia\tAlive\t\n9\tM\t10\tOsteosarcoma\tN\t-\tY\t0\t0\t28.6\tAcute myeloid leukemia\tAlive\t\n10\tM\t10\tHodgkin lymphoma\tY\tLeft neck/axillary\tY\t0\t3.6\t21.9\tAcute myeloid leukemia\tAlive\t\n11\tF\t13\tNeuroblastoma\tY\tAdrenal\tY\t6.7\t74.1\t74.5\tAcute myeloid leukemia\tDeath d/t infection\t\n12\tM\t15\tAcute lymphoblastic leukemia\tN\t-\tY\t0\t4.2\t114.6\tOptic glioma\tAlive\t\nNon-dexrazoxane group (n=344)\t\n13\tF\t0\tExtracranial germ cell tumor\tN\t-\tY\t2.2\t0\t15.9\tAcute myeloid leukemia\tDeath d/t hepatic failure\t\n14\tF\t2\tNon-Hodgkin's lymphoma\tN\t-\tY\t0\t7.4\t62.4\tLangerhan's histiocytosis (left occipital)\tAlive\t\n15\tF\t6\tAcute lymphoblastic leukemia\tY\tBrain\tN\t0\t0.6\t166.3\tExtranodal marginal zone lymphoma\tAlive\t\n16\tM\t12\tOsteosarcoma\tN\t-\tY\t0.5\t8.2\t52\tMyelodysplastic syndrome\tAlive\t\nRT, radiation; G-CSF, granulocyte colony-stimulating factor; M, male; N, no; Y, yes; F, female; d/t, due to; CNS PNET, central nervous system primitive neuroectodermal tumor.\n\nTable 4. Analysis of the risk factors for secondary malignancy\n\nFactor\tUnivariate analysis\tMultivariate analysis\t\nUnadjusted HR (95% CI)\tp-value\tAdjusted HR (95% CI)\tp-value\t\nDexrazoxane group vs. non-dexrazoxane group\t3.46 (0.92-13.07)\t0.07\t-\t-\t\nAge (yr)\t0.97 (0.85-1.09)\t0.55\t-\t-\t\nSex (female vs. male)\t2.30 (0.82-6.47)\t0.11\t-\t-\t\nSyndrome or genetic disease (yes vs. no)\t3.14 (0.03-23.39)\t0.50\t-\t-\t\nG-CSF (yes vs. no)\t5.05 (1.03-91.25)\t0.09\t-\t-\t\nPrevious radiation (yes vs. no)\t3.12 (1.15-8.45)\t0.03\t-\t-\t\nCumulative dose of etoposide (mg/m2)\t1.31 (1.16-1.47)\t< 0.01\t-\t-\t\nCumulative dose of cyclophosphamide (mg/m2)\t1.08 (1.06-1.10)\t< 0.01\t-\t-\t\nCumulative dose of total anthracyclines (mg/m2)\t2.88 (1.82-4.58)\t< 0.01\t-\t-\t\nTotal duration of anthracycline (mo)\t1.06 (1.05-1.07)\t< 0.01\t1.05 (1.03-1.06)\t< 0.01\t\nTime after last anthracycline (mo)\t0.98 (0.97-0.99)\t< 0.01\t0.99 (0.98-0.99)\t< 0.01\t\nTotal duration of chemotherapy (mo)\t1.05 (1.04-1.07)\t< 0.01\t-\t-\t\nHR, hazard ratio; CI, cumulative incidence.\n==== Refs\nReferences\n1 Harake D Franco VI Henkel JM Miller TL Lipshultz SE Cardiotoxicity in childhood cancer survivors: strategies for prevention and management Future Cardiol 2012 8 647 70 22871201 \n2 Brewster DH Clark D Hopkins L Bauer J Wild SH Edgar AB Subsequent hospitalisation experience of 5-year survivors of childhood, adolescent, and young adult cancer in Scotland: a population based, retrospective cohort study Br J Cancer 2014 110 1342 50 24366296 \n3 Choi HS Park ES Kang HJ Shin HY Noh CI Yun YS Dexrazoxane for preventing anthracycline cardiotoxicity in children with solid tumors J Korean Med Sci 2010 25 1336 42 20808678 \n4 Barry EV Vrooman LM Dahlberg SE Neuberg DS Asselin BL Athale UH Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane J Clin Oncol 2008 26 1106 11 18309945 \n5 Tebbi CK London WB Friedman D Villaluna D De Alarcon PA Constine LS Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease J Clin Oncol 2007 25 493 500 17290056 \n6 Walker DM Fisher BT Seif AE Huang YS Torp K Li Y Dexrazoxane use in pediatric patients with acute lymphoblastic or myeloid leukemia from 1999 and 2009: analysis of a national cohort of patients in the Pediatric Health Information Systems database Pediatr Blood Cancer 2013 60 616 20 22948886 \n7 Vrooman LM Neuberg DS Stevenson KE Asselin BL Athale UH Clavell L The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium Eur J Cancer 2011 47 1373 9 21514146 \n8 Seif AE Walker DM Li Y Huang YS Kavcic M Torp K Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients Pediatr Blood Cancer 2015 62 704 9 24668949 \n9 Blanco JG Sun CL Landier W Chen L Esparza-Duran D Leisenring W Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes: a report from the Children's Oncology Group J Clin Oncol 2012 30 1415 21 22124095 \n10 Florescu M Cinteza M Vinereanu D Chemotherapy-induced cardiotoxicity Maedica (Buchar) 2013 8 59 67 24023601 \n11 Kremer LC van Dalen EC Offringa M Ottenkamp J Voute PA Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study J Clin Oncol 2001 19 191 6 11134212 \n12 Lipshultz SE Adams MJ Cardiotoxicity after childhood cancer: beginning with the end in mind J Clin Oncol 2010 28 1276 81 20142585 \n13 Lipshultz SE Scully RE Lipsitz SR Sallan SE Silverman LB Miller TL Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial Lancet Oncol 2010 11 950 61 20850381 \n14 Mozdzanowska D Wozniewski M Radiotherapy and anthracyclines: cardiovascular toxicity Contemp Oncol (Pozn) 2015 19 93 7 26034385 \n15 Swain SM Whaley FS Ewer MS Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials Cancer 2003 97 2869 79 12767102 \n16 Vega-Stromberg T Chemotherapy-induced secondary malignancies J Infus Nurs 2003 26 353 61 14624175 \n17 Hawkins MM Wilson LM Stovall MA Marsden HB Potok MH Kingston JE Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer BMJ 1992 304 951 8 1581717 \n18 Haddy N Le Deley MC Samand A Diallo I Guerin S Guibout C Role of radiotherapy and chemotherapy in the risk of secondary leukaemia after a solid tumour in childhood Eur J Cancer 2006 42 2757 64 16965909 \n19 Friedman DL Whitton J Leisenring W Mertens AC Hammond S Stovall M Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study J Natl Cancer Inst 2010 102 1083 95 20634481 \n20 Choi DK Helenowski I Hijiya N Secondary malignancies in pediatric cancer survivors: perspectives and review of the literature Int J Cancer 2014 135 1764 73 24945137 \n21 Bhuller KS Zhang Y Li D Sehn LH Goddard K McBride ML Late mortality, secondary malignancy and hospitalisation in teenage and young adult survivors of Hodgkin lymphoma: report of the Childhood/Adolescent/Young Adult Cancer Survivors Research Program and the BC Cancer Agency Centre for Lymphoid Cancer Br J Haematol 2016 172 757 68 26727959\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "51(1)",
"journal": "Cancer research and treatment",
"keywords": "Anthracyclines; Cancer; Childhood; Dexrazoxane; Risk factors; Second neoplasm",
"medline_ta": "Cancer Res Treat",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018943:Anthracyclines; D002316:Cardiotonic Agents; D066126:Cardiotoxicity; D002648:Child; D002675:Child, Preschool; D064730:Dexrazoxane; D005163:Factor Analysis, Statistical; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015999:Multivariate Analysis; D009369:Neoplasms; D016609:Neoplasms, Second Primary; D056910:Republic of Korea; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "357-367",
"pmc": null,
"pmid": "29764117",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "11134212;12767102;14624175;1581717;16965909;17290056;18309945;20142585;20634481;20808678;20850381;21514146;22124095;22871201;22948886;24023601;24366296;24668949;24945137;26034385;26727959",
"title": "Risk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients.",
"title_normalized": "risk factor analysis for secondary malignancy in dexrazoxane treated pediatric cancer patients"
}
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"literaturereference_normalized": "risk factor analysis for secondary malignancy in dexrazoxane treated pediatric cancer patients",
"qualification": "3",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20190312",
"receivedate": "20190312",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16062083,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190418"
}
] |
{
"abstract": "Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice.\n\n\n\nTo conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies.\n\n\n\nSystematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018.\n\n\n\nNonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder.\n\n\n\nIndependent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data.\n\n\n\nCoprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies.\n\n\n\nOf 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90).\n\n\n\nIn cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs.",
"affiliations": "Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York.;Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York.;Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York.;Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York.;Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York.",
"authors": "Masuda|Takahiro|T|;Misawa|Fuminari|F|;Takase|Masayuki|M|;Kane|John M|JM|;Correll|Christoph U|CU|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1001/jamapsychiatry.2019.1702",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-622X",
"issue": "76(10)",
"journal": "JAMA psychiatry",
"keywords": null,
"medline_ta": "JAMA Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D012559:Schizophrenia",
"nlm_unique_id": "101589550",
"other_id": null,
"pages": "1052-1062",
"pmc": null,
"pmid": "31365048",
"pubdate": "2019-10-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review",
"references": "22009159;26841681;27404582;21596442;21185230;9310563;24435842;26043321;17891257;21369751;25422511;19595447;15651052;9818633;3802833;16863012;25321616;27106681;18363452;16825203;27774015;28155220;29274734;10877304;23842012;23477752;23810019;29868849;16360555;3616518;18262321;24229745;26842482;28655284;27297936;27919182;27388573;20345873;10789670;17592904;12839430;15000267;10360124;29697804;16173147;18461677;23256986;16542321;12845415;23849151;17137759;19601707;21052043;27265707;19920946;12505141;26541815;26407790",
"title": "Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics: A Systematic Review and Meta-analysis of Cohort Studies.",
"title_normalized": "association with hospitalization and all cause discontinuation among patients with schizophrenia on clozapine vs other oral second generation antipsychotics a systematic review and meta analysis of cohort studies"
}
|
[
{
"companynumb": "US-OTSUKA-2019_030994",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021436",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Tablet",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Product used for unknown indication",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ABILIFY"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "No adverse event",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Masuda T, Misawa F, Takase M, Kane JM, Correll CU. Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics: A Systematic Review and Meta-analysis of Cohort Studies. JAMA Psychiatry. 2019",
"literaturereference_normalized": "association with hospitalization and all cause discontinuation among patients with schizophrenia on clozapine vs other oral second generation antipsychotics a systematic review and meta analysis of cohort studies",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211004",
"receivedate": "20211004",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19916847,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Advances in cancer chemotherapy have increased the opportunities of treating patients with cancer with renal dysfunction. Here we report the case of a 64-year-old woman with recurrent colorectal cancer who was treated with bevacizumab (BEV) combination chemotherapy. Although proteinuria caused by BEV developed early during the treatment and her renal function gradually deteriorated, BEV combination chemotherapy could be continued for 48 cycles over 2.5 years for controlling disease progression without other adverse events such as hypertension, decreased serum albumin level, or edema. After BEV discontinuation, proteinuria gradually improved and further renal function deterioration was not observed. Because the therapeutic options available for metastatic colorectal cancer are limited, balancing the risks and benefits of continuing chemotherapy is important in cases of adverse events.",
"affiliations": "Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. [email protected].;Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.",
"authors": "Kataoka|Shigeki|S|http://orcid.org/0000-0002-1072-8367;Nishikawa|Yoshitaka|Y|;Funakoshi|Taro|T|;Horimatsu|Takahiro|T|;Kondo|Naoya|N|;Matsubara|Takeshi|T|;Yanagita|Motoko|M|;Matsumoto|Shigemi|S|;Muto|Manabu|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-01060-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(3)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Bevacizumab; Colorectal neoplasms; Proteinuria; Renal insufficiency; Risk assessment",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077150:Oxaliplatin; D011507:Proteinuria",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "316-319",
"pmc": null,
"pmid": "31707696",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-term survival and renal dysfunction in a patient with recurrent colorectal cancer treated with Bevacizumab.",
"title_normalized": "long term survival and renal dysfunction in a patient with recurrent colorectal cancer treated with bevacizumab"
}
|
[
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-251195",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugdosagetext": "UNK",
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"drugindication": "PROPHYLAXIS",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "OXALIPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"medicinalproduct": "5-FUOROURACIL"
},
{
"actiondrug": "1",
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"activesubstancename": "BEVACIZUMAB"
},
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"drugdosagetext": "7.5 MG/KG",
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"medicinalproduct": "BEVACIZUMAB."
},
{
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},
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"drugdosagetext": "130 MG/M2",
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"medicinalproduct": "OXALIPLATIN."
},
{
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"activesubstancename": "CAPECITABINE"
},
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"drugadministrationroute": "065",
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"drugdosagetext": "2000 MG/M2/DAY",
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"drugindication": "CHEMOTHERAPY",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CAPECITABINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CALCIUM FOLINAT"
}
],
"patientagegroup": null,
"patientonsetage": "64",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Proteinuria",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypersplenism",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood creatinine increased",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KATAOKA S, NISHIKAWA Y, FUNAKOSHI T, HORIMATSU T, KONDO N, MATSUBARA T, ET AL. LONG-TERM SURVIVAL AND RENAL DYSFUNCTION IN A PATIENT WITH RECURRENT COLORECTAL CANCER TREATED WITH BEVACIZUMAB. CLIN J GASTROENTEROL. 2020?13(3):316-319",
"literaturereference_normalized": "long term survival and renal dysfunction in a patient with recurrent colorectal cancer treated with bevacizumab",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200625",
"receivedate": "20200625",
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},
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"sendertype": "2"
},
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"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
},
{
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"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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"activesubstance": {
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},
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"medicinalproduct": "ELPLAT"
},
{
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},
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"drugdosagetext": "900 MG, Q3W",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CAPECITABINE."
},
{
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"activesubstancename": "CAPECITABINE"
},
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"drugdosagetext": "1200 MG, Q3W",
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"medicinalproduct": "CAPECITABINE."
},
{
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},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DEXAMETHASONE SODIUM PHOSPHATE."
},
{
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"activesubstancename": "BEVACIZUMAB"
},
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"drugdosageform": "INJECTION",
"drugdosagetext": "7.5 MG/KG",
"drugenddate": "20120915",
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{
"abstract": "We report a case of a 56-year-old woman admitted to our hospital for status epilepticus. Three months before hospitalization, the patient underwent gross total removal of a glioblastoma with BCNU wafer implantation in the left parietal lobe. The cavity was subsequently lined with five BCNU wafers. After admission, magnetic resonance imaging(MRI)showed cyst formation accompanied by strong edema, with no recurrence of glioblastoma. She was initially administered antiepileptic drugs and glycerol with betamethasone, after which her seizures stopped but recurred one month later due to a decrease in betamethasone. The BCNU wafers were removed four months after the initial surgery, after which the seizures completely stopped. Histopathological examination of the cavity indicated the presence of inflamed tissue and no recurrence of glioblastoma. Neurosurgeons should be aware of the possibility of cyst formation after BCNU wafer implantation for malignant gliomas. In this manuscript, we provide a case presentation and a review of the literature.",
"affiliations": "Department of Neurosurgery, Nara Medical University.",
"authors": "Nakase|Kenta|K|;Matsuda|Ryosuke|R|;Nishimura|Fumihiko|F|;Nakamura|Mitsutoshi|M|;Motoyama|Yasushi|Y|;Park|Young-Su|YS|;Nakase|Hiroyuki|H|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D002330:Carmustine",
"country": "Japan",
"delete": false,
"doi": "10.11477/mf.1436203113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2603",
"issue": "43(8)",
"journal": "No shinkei geka. Neurological surgery",
"keywords": null,
"medline_ta": "No Shinkei Geka",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D001932:Brain Neoplasms; D002330:Carmustine; D003131:Combined Modality Therapy; D003560:Cysts; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016896:Treatment Outcome",
"nlm_unique_id": "0377015",
"other_id": null,
"pages": "747-52",
"pmc": null,
"pmid": "26224470",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Symptomatic Cyst Formation after BCNU Wafer Implantation for Glioblastoma.",
"title_normalized": "a case of symptomatic cyst formation after bcnu wafer implantation for glioblastoma"
}
|
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{
"abstract": "Adverse effects of linezolid are typically limited to diarrhea, nausea, and headache when shorter durations are used; however, as extended durations of linezolid therapy are increasingly more common, additional monitoring parameters should be considered in these patients. We describe a unique case of hypoglycemia, lactic acidosis, and pancreatitis related to an extended duration of linezolid therapy. A 52-year-old woman presented with altered mental status, abdominal pain, and hypotension following six weeks of linezolid and ertapenem therapy. Laboratory data revealed an initial blood glucose of 40 mg/dL and metabolic acidosis secondary to lactic acidosis. Finally, her abdominal pain on admission was likely related to an enlarged pancreas noted on computed tomography of her abdomen. Due to suspected linezolid toxicity, the patient received two intermittent hemodialysis sessions to remove linezolid and correct the metabolic acidosis. Given limited data on long-term monitoring of patients receiving extended durations of linezolid therapy, we suggest periodic monitoring of lactate, arterial blood gas, and blood glucose. If patients present with this triad of symptoms secondary to linezolid therapy, adverse effects should be treated with dextrose and intravenous thiamine while reserving hemodialysis for those with metabolic acidosis refractory to thiamine.",
"affiliations": "Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.;Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.;Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.;Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.",
"authors": "Tobias|Philip E|PE|https://orcid.org/0000-0001-9904-3999;Varughese|Christy A|CA|;Hanson|Amy P|AP|;Gurnani|Payal K|PK|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid; D005947:Glucose; D013831:Thiamine",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190018782787",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "33(2)",
"journal": "Journal of pharmacy practice",
"keywords": "critical care; drug information; infectious disease; medication safety; pharmacy education",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000140:Acidosis, Lactic; D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents; D005260:Female; D005947:Glucose; D006801:Humans; D007003:Hypoglycemia; D007239:Infections; D000069349:Linezolid; D008875:Middle Aged; D010195:Pancreatitis; D006435:Renal Dialysis; D013831:Thiamine",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "222-225",
"pmc": null,
"pmid": "29911459",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Linezolid Induced Toxicity.",
"title_normalized": "a case of linezolid induced toxicity"
}
|
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{
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{
"abstract": "Mycobacterium kansasii, a nontuberculous mycobacterium, can lead to lung disease similar to tuberculosis. Immunotherapeutic biologic agents predispose to infections with mycobacteria, including M kansasii. T-cell-mediated interferon gamma release assays like QuantiFERON-TB Gold Test (QFT) are widely used by clinicians for the diagnosis of infections with Mycobacterium tuberculosis; however, QFT may also show positive result with certain nontuberculous mycobacterial infections. We report a case of M kansasii pulmonary infection, with a positive QFT, in an immunocompromised patient receiving prednisone, leflunomide and tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody. This case highlights the risk of mycobacterial infections with the use of various biologic agents and the need for caution when interpreting the results of interferon gamma release assays.",
"affiliations": "Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, Chicago, Illinois. Electronic address: [email protected].;Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, Chicago, Illinois.;Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, Chicago, Illinois.;Infectious Diseases Section, Department of Internal Medicine, Presence Saint Joseph Hospital, Chicago, Illinois.",
"authors": "Saleem|Nasir|N|;Saba|Raya|R|;Maddika|Srikanth|S|;Weinstein|Mitchell|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2016.03.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "353(4)",
"journal": "The American journal of the medical sciences",
"keywords": "Biologic therapy; Mycobacterium kansasii; QuantiFERON-TB; Tocilizumab",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D019909:Mycobacterium kansasii",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "394-397",
"pmc": null,
"pmid": "28317629",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mycobacterium kansasii Infection in a Patient Receiving Biologic Therapy-Not All Reactive Interferon Gamma Release Assays Are Tuberculosis.",
"title_normalized": "mycobacterium kansasii infection in a patient receiving biologic therapy not all reactive interferon gamma release assays are tuberculosis"
}
|
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"literaturereference": "SALEEM N, SABA R, MADDIKA S, WEINSTEIN M.. MYCOBACTERIUM KANSASII INFECTION IN A PATIENT RECEIVING BIOLOGIC THERAPY-NOT ALL REACTIVE INTERFERON GAMMA RELEASE ASSAYS ARE TUBERCULOSIS.. AM-J-MED-SCI (THE AMERICAN JOURNAL OFTHE MEDICAL SCIENCES). 2017;353(4):394-397",
"literaturereference_normalized": "mycobacterium kansasii infection in a patient receiving biologic therapy not all reactive interferon gamma release assays are tuberculosis",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170720",
"receivedate": "20170712",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13746401,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
}
] |
{
"abstract": "BACKGROUND\nVenous thromboembolism is a well-known complication of Cushing syndrome. Deep vein thrombosis and pulmonary embolic events have been widely reported in patients with Cushing syndrome, but cerebral venous sinus thrombosis remains a much less common finding in these patients.\n\n\nMETHODS\nWe report one of the first cases of cerebral venous sinus thrombosis in a patient with Cushing disease. An 18-year-old man presented to our clinic with accelerated weight gain despite an active lifestyle and unchanged diet. Workup revealed adrenocorticotrophic hormone-dependent hypercortisolism, and magnetic resonance imaging demonstrated a 6-mm pituitary microadenoma, consistent with Cushing disease. He underwent endoscopic transsphenoidal resection and achieved the desired postoperative adrenal insufficiency. The patient was discharged home, but presented again in a delayed fashion with profound cerebral venous sinus thrombosis requiring a prolonged hospitalization.\n\n\nCONCLUSIONS\nPrevious studies have suggested that the coagulation profile of patients with Cushing syndrome normalizes when measured 12 months after correction of hypercortisolism, but these patients may remain hypercoagulable for an undefined period postoperatively, despite becoming adrenally insufficient. Although there have been scarce reports of cerebral venous sinus thrombosis in non-adrenocorticotrophic hormone-dependent Cushing syndrome, we report the first case of cerebral venous sinus thrombosis postoperatively in a patient with Cushing disease in remission.",
"affiliations": "Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA; Minimally Invasive Cranial Base and Pituitary Surgery, Rosa Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Neurosurgery, Lenox Hill Hospital, Northwell Health, New York, New York, USA.;Department of Neurosurgery, UChicago Medicine, Chicago, Illinois, USA.;Minimally Invasive Cranial Base and Pituitary Surgery, Rosa Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA; Section of Rhinology, Sinus, and Skull Base Surgery, Head and Neck Institute, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Neurosurgery and Division of Endocrinology, Diabetes and Metabolism in the Department of Medicine, Weill Cornell Medicine, New York, New York, USA.;Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA; Minimally Invasive Cranial Base and Pituitary Surgery, Rosa Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA; Section of Rhinology, Sinus, and Skull Base Surgery, Head and Neck Institute, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address: [email protected].",
"authors": "Soni|Pranay|P|;Koech|Hilary|H|;Silva|Danilo|D|;Das|Paramita|P|;Sindwani|Raj|R|;Dobri|Georgiana|G|;Recinos|Pablo F|PF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.10.077",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "134()",
"journal": "World neurosurgery",
"keywords": "Cerebral venous sinus thrombosis; Cushing disease; Cushing syndrome; Hypercoagulable; Venous thromboembolism",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000236:Adenoma; D000293:Adolescent; D006801:Humans; D008297:Male; D019635:Neurosurgical Procedures; D047748:Pituitary ACTH Hypersecretion; D010911:Pituitary Neoplasms; D011183:Postoperative Complications; D012851:Sinus Thrombosis, Intracranial; D019851:Thrombophilia",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "86-89",
"pmc": null,
"pmid": "31639504",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cerebral Venous Sinus Thrombosis After Transsphenoidal Resection: A Rare Complication of Cushing Disease-Associated Hypercoagulability.",
"title_normalized": "cerebral venous sinus thrombosis after transsphenoidal resection a rare complication of cushing disease associated hypercoagulability"
}
|
[
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-049035",
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{
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},
{
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},
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},
{
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"activesubstancename": "HEPARIN SODIUM"
},
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}
],
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{
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}
],
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},
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"literaturereference": "SONI P, KOECH H, SILVA D, DAS P, SINDWANI R, DOBRI G, ET AL.. CEREBRAL VENOUS SINUS THROMBOSIS AFTER TRANSSPHENOIDAL RESECTION: A RARE COMPLICATION OF CUSHING DISEASE-ASSOCIATED HYPERCOAGULABILITY.. WORLD-NEUROSURG. 2020?13486-89",
"literaturereference_normalized": "cerebral venous sinus thrombosis after transsphenoidal resection a rare complication of cushing disease associated hypercoagulability",
"qualification": "1",
"reportercountry": "US"
},
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},
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},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200713"
},
{
"companynumb": "US-TEVA-2020-US-1218202",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "DESMOPRESSIN"
},
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"drugdosagetext": ".3 MILLIGRAM DAILY; 0.1 MG THREE TIMES A DAY",
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"drugintervaldosagedefinition": "804",
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"medicinalproduct": "DESMOPRESSIN"
},
{
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},
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"drugdosagetext": "STARTED AT UNKNOWN DOSAGE",
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"drugindication": "DIABETES INSIPIDUS",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "DESMOPRESSIN"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"drugadministrationroute": "042",
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CEREBRAL VENOUS SINUS THROMBOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"medicinalproduct": "HEPARIN"
}
],
"patientagegroup": null,
"patientonsetage": "18",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypoxia",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cerebral venous sinus thrombosis",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SONI P, KOECH H, SILVA D, DAS P, SINDWANI R, DOBRI G, ET AL. CEREBRAL VENOUS SINUS THROMBOSIS AFTER TRANSSPHENOIDAL RESECTION: A RARE COMPLICATION OF CUSHING DISEASE-ASSOCIATED HYPERCOAGULABILITY. WORLD-NEUROSURG 2020?134:86-89.",
"literaturereference_normalized": "cerebral venous sinus thrombosis after transsphenoidal resection a rare complication of cushing disease associated hypercoagulability",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200420",
"receivedate": "20200407",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17635937,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20200713"
}
] |
{
"abstract": "OBJECTIVE\nIn contrast with other opioids, there are few cases of tramadol-related respiratory depression described in the literature, and renal impairment is a proposed risk factor. The aim of this study is to determine the prevalence of and predisposing factors for tramadol-related apnea in patients referred to our center.\n\n\nMETHODS\nAll patients referred to Loghman-Hakim Hospital between February 2009 and April 2010 with pure tramadol intoxication were identified retrospectively. Data collected included the patient's age, sex, ingested dose, route of exposure, reason for poisoning (acute overdose or supratherapeutic use), previous history of suicidal attempts, previous history of drug or substance abuse (including tramadol), and clinical features on admission including seizures and apnea.\n\n\nRESULTS\nWe identified 525 patients with deliberate self-poisoning (359; 68.4%) or abuse (146; 27.8%), and in 114 (21.7%) of these, there was a history of tramadol abuse. Four hundred twenty-nine (81.7%) of patients had acute poisoning and were referred to hospital within 6 hours of ingestion. Nineteen patients (3.6%) experienced apnea and received respiratory support (16; 84.2%) or naloxone administration (3; 15.8%) within 24 hours of ingestion (mean, 7.7 ± 7 hours; range, 1-24 hours). The mean dose ingested by patients experiencing apnea was 2125 ± 1360 mg (range, 200-4600 mg), which was significantly higher than those who did not experience apnea, 1383 ± 1088 mg (range, 100-6000 mg), P < .001. One death occurred in each group, which was significant (P < .001). Renal impairment was not observed in any of the patients who experienced apnea.",
"affiliations": "Department of Clinical Toxicology, Shahid Beheshti University of Medical Scienses, Tehran 13336, Iran. [email protected]",
"authors": "Hassanian-Moghaddam|Hossein|H|;Farajidana|Hoorvash|H|;Sarjami|Saeedeh|S|;Owliaey|Hamid|H|",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "31(1)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D001049:Apnea; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007492:Iran; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D014147:Tramadol",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "26-31",
"pmc": null,
"pmid": "22809771",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tramadol-induced apnea.",
"title_normalized": "tramadol induced apnea"
}
|
[
{
"companynumb": "IR-JNJFOC-20190708292",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "020281",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "200 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugstructuredosagenumb": "200",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRAMADOL HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": "40",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional product misuse",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HASSANIAN-MOGHADDAM H, FARAJIDANA H, SARJAMI S, OWLIAEY H. TRAMADOL-INDUCED APNEA. AM J EMERG MED. 2013?31:26-31",
"literaturereference_normalized": "tramadol induced apnea",
"qualification": "1",
"reportercountry": "IR"
},
"primarysourcecountry": "IR",
"receiptdate": "20190715",
"receivedate": "20190715",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 16569994,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
},
{
"companynumb": "IR-JNJFOC-20190712878",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "1000 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRAMADOL HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": "20",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Poisoning deliberate",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional product misuse",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HASSANIAN-MOGHADDAM H, FARAJIDANA H, SARJAMI S, OWLIAEY H. TRAMADOL-INDUCED APNEA. AM J EMERG MED. 2013?31:26-31",
"literaturereference_normalized": "tramadol induced apnea",
"qualification": "1",
"reportercountry": "IR"
},
"primarysourcecountry": "IR",
"receiptdate": "20190712",
"receivedate": "20190712",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 16566574,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
},
{
"companynumb": "IR-JNJFOC-20190712563",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "020281",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "1000 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRAMADOL HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": "21",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Poisoning deliberate",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HASSANIAN-MOGHADDAM H, FARAJIDANA H, SARJAMI S, OWLIAEY H. TRAMADOL-INDUCED APNEA. AM J EMERG MED. 2013?31:26-31",
"literaturereference_normalized": "tramadol induced apnea",
"qualification": "1",
"reportercountry": "IR"
},
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{
"abstract": "In this review, we first present a case of chronic myeloid leukemia with acute psychosis, and then we will discuss the incidence of cancer in patients with psychotic disorders, the manifestations of new-onset psychosis, and the prevalence of preexisting psychosis in cancer patients, coupled with their impact on the treatment, diagnosis, and prognosis of cancer. This was a case that presented with acute psychosis and was found to have an elevated white blood cell count upon admission to an inpatient psychiatric unit. He was diagnosed with chronic myeloid leukemia and successfully managed with imatinib/dasatinib therapy. Psychiatrically, he was stabilized on two long-acting injectable medications to help maintain adherence. We were able to eliminate his active psychotic symptoms and return him to normal functioning in affect and thinking, achieving sustained compliance with treatment. We identified multiple inconsistencies in screening for cancer of all types in these patients, masking of signs and symptoms that would typically clue physicians to the presence of cancers, underreporting of symptoms, and disparate access to healthcare resources in patients with mental disorders when compared to the general population. Treatment of cancer in these patients as compared to the general population has also been shown to be incongruent, which will be elaborated upon. Psychiatric interventions, as well as supportive measures, for treating patients who are facing challenges during active cancer treatment will be discussed.",
"affiliations": "Department of Psychiatry, University of Missouri Kansas City School of Medicine, 1000 E. 24th Street, Kansas City, MO 64108, USA.;University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.;University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.;University of Missouri-Kansas City, Kansas City, MO, USA.;Department of Psychiatry, Brookdale University Hospital Medical Center, Brooklyn, NY, USA.;Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Government Medical College, Surat, GJ, India.;A.J. Institute of Medical Sciences and Research Centre, NH66, Kuntikan, Mangalore, Karnataka, India.",
"authors": "Bellman|Val|V|;Russell|Nina|N|;Depala|Kartik|K|;Dellenbaugh|Alexandra|A|;Desai|Saral|S|;Vadukapuram|Ramu|R|;Patel|Shweta|S|;Srinivas|Sushma|S|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.14740/wjon1402",
"fulltext": "\n==== Front\nWorld J Oncol\nWorld J Oncol\nElmer Press\nWorld Journal of Oncology\n1920-4531\n1920-454X\nElmer Press\n\n10.14740/wjon1402\nReview\nChallenges in Treating Cancer Patients With Unstable Psychiatric Disorder\nCancer Patients With Psychiatric Disorders\nBellman Val ah\nRussell Nina b\nDepala Kartik b\nDellenbaugh Alexandra c\nDesai Saral d\nVadukapuram Ramu e\nPatel Shweta f\nSrinivas Sushma g\na Department of Psychiatry, University of Missouri Kansas City School of Medicine, 1000 E. 24th Street, Kansas City, MO 64108, USA\nb University of Missouri Kansas City School of Medicine, Kansas City, MO, USA\nc University of Missouri-Kansas City, Kansas City, MO, USA\nd Department of Psychiatry, Brookdale University Hospital Medical Center, Brooklyn, NY, USA\ne Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA\nf Government Medical College, Surat, GJ, India\ng A.J. Institute of Medical Sciences and Research Centre, NH66, Kuntikan, Mangalore, Karnataka, India\nh Corresponding Author: Val Bellman, Department of Psychiatry, University of Missouri Kansas City School of Medicine, 1000 E. 24th Street, Kansas City, MO 64108, USA. Email: [email protected]\n10 2021\n5 10 2021\n12 5 137148\n28 7 2021\n17 8 2021\nCopyright 2021, Bellman et al.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIn this review, we first present a case of chronic myeloid leukemia with acute psychosis, and then we will discuss the incidence of cancer in patients with psychotic disorders, the manifestations of new-onset psychosis, and the prevalence of preexisting psychosis in cancer patients, coupled with their impact on the treatment, diagnosis, and prognosis of cancer. This was a case that presented with acute psychosis and was found to have an elevated white blood cell count upon admission to an inpatient psychiatric unit. He was diagnosed with chronic myeloid leukemia and successfully managed with imatinib/dasatinib therapy. Psychiatrically, he was stabilized on two long-acting injectable medications to help maintain adherence. We were able to eliminate his active psychotic symptoms and return him to normal functioning in affect and thinking, achieving sustained compliance with treatment. We identified multiple inconsistencies in screening for cancer of all types in these patients, masking of signs and symptoms that would typically clue physicians to the presence of cancers, underreporting of symptoms, and disparate access to healthcare resources in patients with mental disorders when compared to the general population. Treatment of cancer in these patients as compared to the general population has also been shown to be incongruent, which will be elaborated upon. Psychiatric interventions, as well as supportive measures, for treating patients who are facing challenges during active cancer treatment will be discussed.\n\nLeukemia\nPsychosis\nMania\nCancer screening\nAntipsychotics\nCompliance\n==== Body\npmcIntroduction\n\nPsychosis is broadly defined as impaired reality testing. Psychotic symptoms, such as hallucinations, delusions, paranoia, and agitation, may increase the risk of self-harm or risky behavior in patients, and can contribute to an inability to meet one’s basic needs. Psychosis can be a symptom or complication of a multitude of psychiatric disorders, including thought disorders and mood disorders, and it can also be an acute manifestation of substance use or underlying medical conditions, such as cancer. This case report raises questions about whether patients burdened with serious mental illness are receiving appropriate cancer screenings and preventive care related to risk factors for cancer. It is equally important to continuously monitor, confront, and problem-solve patient actions that threaten to interfere with the continuation of chemotherapy, such as missing appointments, noncompliance, or abruptly leaving therapy.\n\nCase Presentation\n\nClinical manifestations\n\nThe patient is a 39-year-old African American male, single, and unemployed, with a past medical history of psychotic disorders and recurrent manic episodes starting in 2018. This patient presented to the emergency department after making homicidal threats towards family members. Upon admission, the patient continued to act “erratically” with pressured speech and flight of ideas. He appeared to be disorganized, illogical, and constantly agitated. The patient was found to have an elevated white blood cell (WBC) count ranging between 41,000 to 92,000, lactate dehydrogenase (LDH) of 767, and uric acid of 5.6 on admission to the behavioral health unit. Reportedly, he had been treated for psychosis four times in 2018 and 2019 before being admitted to our unit in September 2020. Each time, his WBC was elevated but considered to be reactive and not clinically significant.\n\nCourse of treatment\n\nUpon admission to inpatient psychiatric unit in September 2020, the patient was diagnosed with chronic myeloid leukemia based on a detected P210 BCR-ABL1 fusion transcript and elevated multiple myeloid cell lines. Psychiatrically, the patient’s presentation appeared to be consistent with schizoaffective disorder, bipolar type. He refused to have bone marrow biopsy done due to extreme and persistent distrust of others without a sufficient logical basis. Despite significant therapy to help understand his paranoid thinking, the patient did not display any insight into the problematic nature of his behavior and symptoms. Initially he was extremely resistant to treatment due to irrational persecutory beliefs (e.g., medication is poison, the physician is an enemy). He also could not initiate the proposed course of chemotherapy due to being violent as a defensive reaction to delusional or hallucinatory content.\n\nChemotherapy and psychopharmacological management\n\nHe was started on imatinib 400 mg daily (September, 2020) but was lost to follow-up and had not been on treatment for 3 months due to psychiatric decompensation. He was restarted on imatinib and hydroxyurea in December, 2020 but developed prolonged pancytopenia in January, 2021. Subsequent discontinuation of hydroxyurea and transition to dasatinib were effective for improving thrombocytopenia as well as neutropenia.\n\nPsychiatrically, he was stabilized on long-acting injectables (LAIs) paliperidone palmitate (234 mg) and loxapine (100 mg) orally (PO) twice a day (BID) in September, 2020. He was readmitted to the psychiatric hospital in December 2020, restarted on home medications, but was noted to be irritable and easily agitated, and thus mood stabilizer was considered. Patient was initially resistant to mood stabilizers and continued to demonstrate behaviors uncontrolled with gabapentin; thus, this was discontinued, and he was started on lithium. Patient was noted with increased sedation and slurring speech on lithium, and it was ultimately discontinued. By this point, the patient was overall showing improvement in his behaviors, so the psychiatry team opted not to trial a new antipsychotic. Given his non-compliance with oral medications, it was prudent to have him on two LAI medications as opposed to one LAI and oral agent. Patient’s loxapine was discontinued, and he was started on 5 mg of haloperidol PO BID with subsequent transition to haloperidol decanoate.\n\nFollow-up and outcomes\n\nUpon initial discharge in September 2020, he continued unhealthy behaviors (e.g., smoking, poor diet, use of mood-altering substances) despite a diagnosis of cancer and a physician’s recommendation to alter these habits. Although he attended his oncology appointments, he would leave within 1 - 2 minutes of arriving. Three months later, he was readmitted to psychiatry, and a petition for a 21-day hold was granted. He was psychiatrically stabilized on two LAI medications. Psychiatry initially sought a petition for a 90-day hold, given difficulties in placement of the patient, but as he had shown significant improvement on the unit, the petition was dropped, and the patient was allowed to sign in voluntarily; he was later safely discharged to the community. The patient demonstrated meaningful improvement in health status and continued compliance with his outpatient treatment plan and visits to the oncology clinic within the next 90 days after discharge.\n\nEpidemiology of Psychotic Disorders Among Cancer Patients\n\nNumerous epidemiological studies have explored the prevalence of psychotic disorders and affective conditions in cancer patients. The findings of most of these studies appear to be paradoxical. Extensive population-based studies performed regarding the prevalence rate of schizophrenia and bipolar disorder have shown that prevalence has not changed drastically over the years. The prevalence rate for schizophrenia is between 0.3% and 1% of the general population [1]. Life expectancy is about 20% (15 - 20 years) shorter than those without the condition, especially in developed nations [1]. There has been a gradual rise in the prevalence rate over the past few decades, from 13.1 million cases in 1990 to 20.9 million cases in 2016 [2]. There is a 0.3-1.5% global prevalence rate for bipolar disorder, while in the past year, the US prevalence rate was about 2.9% among men and 2.8% among females [3].\n\nThe earliest hypothesis regarding the prevalence of cancer in schizophrenia developed in 1909 [1]. Since then, researchers have worked on the idea that patients with schizophrenia have a lower risk of developing cancer compared to the population without the condition. When reviewing historical studies exploring the prevalence of psychotic disorders in cancer patients, the results appear to be conflicting. A cross-sectional study of patients’ electronic records by the Clalit Research Institute in Israel showed that women with schizophrenia spectrum disorders have higher prevalence rates of cancer than men with the same condition. A meta-analysis of standardized incidence ratios of cancer in patients with schizophrenia and their first-degree relatives was performed and compared with general population samples from the University of Queensland, Australia in 2008. It was found that the overall cancer incidence in patients with schizophrenia was not significantly increased (standardized incidence ratio (SIR) = 1.05, confidence interval (CI): 0.95 - 1.15). Lung cancer incidence was slightly increased (SIR = 1.31, CI: 1.01 - 1.71), but was reduced after adjusting for smoking prevalence. Breast cancer rates in female patients have significantly increased [4]. The higher incidence of breast cancer found in women with schizophrenia may likely, in part, be due to low parity, which is typical of women with psychiatric disorders. Some researchers have suggested that hyperprolactinemia, a side effect associated with neuroleptic drug therapy, might lead to an increased incidence of breast cancer [5].\n\nData from the Clalit Institute study also revealed that the prevalence rate of cancer of all types, and prostate cancer specifically, was lower in men with schizophrenia than in healthy controls [6]. The conclusion drawn by the Clalit Institute was that men with schizophrenia having apparently reduced cancer rates likely reflect under-diagnosis of certain cancer types, perhaps due to disparities in healthcare access [6].\n\nFrom an epidemiological perspective, the relationship between severe mental illness (SMI) and cancer prevalence may be skewed due to the generally shorter life expectancy associated with SMI. With the increased prevalence of tobacco use in this population coupled with the metabolic side effects of long-term antipsychotic use, death from cardiovascular causes often precludes potential cancers that they may have developed if they were to have longer life spans [7]. Although some cancers have a lower incidence in schizophrenia, as described below, it is important to note that patients with schizophrenia are still at an increased risk of metabolic and cardiovascular disease, and many of the risk factors for these disorders overlap with those for cancer.\n\nIn terms of biological links between SMI and cancer, multiple studies have shown an increased activity of natural killer cells in patients with schizophrenia, which may explain the lower rate of malignancy in patients with SMI, even with an increased rate of smoking [8]. However, the mortality rates of these patients due to cardiovascular causes remain high, and this can be a confounder, as these patients may die from these issues prior to cancer development.\n\nThere have also been six published incidence studies completed thus far that have analyzed the relative risk of cancer in patients with schizophrenia compared to the general population. These papers suggested that the tumor suppressor gene p53 may play a role in the relatively decreased incidence of malignancy in patients with schizophrenia: p53 may be overly active in these patients, thereby increasing levels of apoptosis at baseline and killing cells prior to becoming cancerous [9]. Recent evidence suggests that chemotherapy-induced changes may be associated with excessive neuroinflammatory response and subsequent behavioral decompensation [10]. Activated microglia may be involved in metabolism of inflammatory cytokines and neurotransmitters in patients with severe manic [11] or psychotic reactions [12]. Those changes may lead to long-term alteration of synaptic transmission, dopamine metabolism [12] and psychosis development [13]. Neuroinflammatory hypothesis may explain the therapeutic potential of various psychopharmacological agents in modulation of behavioral disturbances among cancer patients. For example, lithium can modulate adenylate cyclase-related GPCR signaling pathway and glycogen synthase kinase 3 beta (GSK-3β) activity [14]. Figure 1 summarizes other potential molecular and cellular mechanisms underlying mood disturbances and psychosis in cancer patients.\n\nFigure 1 Molecular and cellular mechanisms underlying mood disturbances and psychosis in cancer patients (adapted from Watkins et al, 2014 [11]). 5-HT: serotonin; BDNF: brain-derived neurotrophic factor; CNS: central nervous system; C-RP, C-reactive protein; GSK3-β: glycogen synthase kinase 3 beta; IDO: indoindoleamine 2,3-dioxygenase; IL-1β: interleukin-1 beta; iNOS: inducible nitric oxide synthase; Map38: p38 mitogen-activated protein kinase; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; RNS: reactive nitrogen species; ROS: reactive oxygen species; TNFα: tumor necrosis factor alpha.\n\nThere have also been multiple studies that noted increases in prolactin levels in patients with schizophrenia, likely due to the effects of prolonged antipsychotic use on the tuberoinfundibular system, and a concurrent increase in breast cancer risk in patients with SMI [15]. Overall, the data on the association between SMI and malignancy are limited, and at times, conflicting, as detailed above. This study provides an opportunity to elucidate the relationship between SMI and the prevalence of cancer going forward, and can serve as a basis to examine the discrepancies in data, as it provides a clear case of hematological malignancy developing in the setting of SMI.\n\nManifestation of Psychosis and Mania in Cancer Patients\n\nPsychosis is a symptom complex characterized by hallucinations, delusions, cognitive problems, and disorganized speech or behavior [16]. Medical disorders may present with psychosis first, necessitating a methodical approach to diagnosis to determine the reason. Thus, an oncologic origin, such as a steroid-producing tumor, a space-occupying brain lesion, or a paraneoplastic etiology, should be suspected if psychosis develops slowly [17]. SMI is described as schizophrenia or bipolar disorder that requires long-term therapy and results in disability or dysfunction [18]. Patients with SMI, such as schizophrenia, major depressive disorder, schizoaffective disorder, and bipolar disorder, have been shown to have shortened life expectancy by at least 13 - 30 years [19].\n\nCardiovascular disease and cancer are the primary causes of death in this population, implying that prompt and adequate preventive measurements could help reduce premature death [20]. Patients with SMI, particularly schizophrenia, are less likely to receive adequate cancer treatment, such as chemotherapy, radiation therapy, or surgery [21, 22]. Weinstein et al (2016) stated the key recommendations for cancer screening in this vulnerable population, such as providing a community health professional or peer counselor to assist the patient in navigating the screening process and making informed decisions and increasing mental health service providers’ awareness of cancer screening [23]. By communicating effectively, providing routine emotional support, screening for psychiatric disorders, prescribing anxiolytic and antidepressant medications appropriately, referring patients to support groups, collaborating with mental health professionals, and dealing with end-of-life issues, oncologists can help patients with advanced cancer experience less psychological distress [24]. Discrepancies in cancer screening among patients with psychotic disorders surely contribute to the higher mortality rates mentioned previously.\n\nWhen looking into the difficulties in diagnosing and treating cancer patients with psychotic or mood disorders, contrasting new onset psychosis and/or mania in cancer patients with exacerbation of psychosis or mood disorder is warranted. The most commonly reported new-onset psychiatric illnesses in cancer patients are adjustment disorders, anxiety, and depression related to developing the disease. Moreover, affective conditions have been proven to precipitate acute psychotic episodes in cancer patients. Difficulty arises in diagnosing new-onset psychosis or mania in cancer patients because cancer, depending on type and location, is known to cause delirium. Delirium may present with psychosis but is typically precipitated by non-psychological stressors, and does not imply underlying mental illness. Delirium may be precipitated by dehydration, polypharmacy, infection, immobility (including restraint use), malnutrition, and the use of bladder catheters [25]. It is a typically reversible condition. However, in two separate studies, delirium was associated with increased mortality in cancer patients [25, 26]. This adds further difficulty to the diagnosis of new-onset mental illness versus psychosis in cancer patients. Excluding delirium-induced psychosis, there is limited information available discussing new-onset psychotic disorders in cancer patients.\n\nNew-onset psychiatric illnesses have been associated with increased mortality in patients with cancer. A Swedish cohort of 1,615 patients who underwent surgery for esophageal cancer and had no prior psychiatric history were followed. It was found that the mortality rate of all causes was greater among patients who developed psychiatric disorders during or after treatment for their cancer [27]. A case report published by Bernad et al in 2013 examined the case of a 62-year-old man who developed anhedonia, paranoid delusions, insomnia, and irritability after treatment of prostate adenocarcinoma with external beam radiation and triptorelin (gonadotropin-releasing hormone agonist) therapy [28]. After his treatment ended and his psychosis resolved, it was concluded that his psychosis was likely due to androgen deprivation therapy used in the treatment of cancer, and he remained stable on aripiprazole 2 mg at the 2-year follow-up [28]. Another case report published in the Journal of Pediatric Hematology-Oncology in 2011 analyzed a 16-year-old male patient who developed delusions, insomnia, and grandiosity following the diagnosis and initial treatment of a non-seminomatous germ cell tumor. He was initially treated with bleomycin, etoposide, and cisplatin (BEP) chemotherapy, along with dexamethasone, for the first 7 days of treatment. His psychiatric symptoms developed on day 14 of treatment, and dexamethasone was discontinued. The patient did not worsen following this, but he was stabilized on risperidone. It was concluded that his psychosis was most likely secondary to stress related to cancer diagnosis and treatment, history of traumatic brain injury (TBI) at age 5, and corticosteroid administration [29]. The patients examined in both of these case reports recovered from their respective cancers as expected and maintained psychiatric stability on antipsychotics.\n\nPre-existing psychotic disorders have been known to be exacerbated in patients with cancer. A cancer diagnosis can cause or exacerbate anxiety and depression in patients who are already afflicted with mental illness [30]. Patients with mental illness have higher mortality rates from cancer.\n\nScreening for Cancer in Psychiatric Patients\n\nOur patient had at least two episodes of elevated WBC count associated with exacerbation of affective and psychotic symptoms. The complete relationship between the immune system, psychosis, and mood symptom severity is not fully known; however, clinical studies have found a correlation between WBC, mood symptoms and psychosis. Two studies measured WBC with bipolar mood symptom severity and depression symptoms to assess whether cell count had any effect. For one trial, among the 482 participants, for each 1.0 × 109/L WBC deviation, the overall bipolar mood symptoms increased greatly for men but not for women. The other trial showed that a higher deviation in median WBC showed an increasing trend in the Montgomery-Aasberg Depression Rating Scale scores among men but not women [31]. Another study analyzed 68 patients with schizophrenia during psychomotor excitation and then followed up about 1 month later during a medicated recovery phase. During psychomotor excitation, abnormal lab values were prevalent. Of these lab values, the most frequent ones seen in ≥ 35% of patients were low serum potassium, high levels of uric acid, fasting blood glucose, lactate dehydrogenase, and WBC count [32]. It is believed that there is an inflammatory mechanism that triggers increases in WBC in patients with mood and psychotic symptoms. Leukocyte counts in the serum samples of 28 children with new-onset psychosis showed a significant increase in absolute monocytes and lymphocytes in comparison to children without psychosis. Although these trials have shown statistically significant correlations between the WBC count and mood/psychotic symptoms there are several challenges. Only a small number of individuals are studied, as it is not only difficult to enroll patients with mood disorders; it is also challenging to follow up with them [33]. Screening patients with these symptoms can also be very challenging.\n\nIn reviewing previous studies on cancer screening in patients with mental disorders, a few in particular stand out. In a meta-analysis of Howard et al, multiple studies found no difference in screening rates when the rates of cancer screening of patients with mental disorders (including schizophrenia and manic-depressive psychosis) were compared with those of the general population [5]. Others, however, found that there were lower rates of cancer screening in patients with mental disorders when compared to a control group. The reason for the clear conflict in these findings is difficult to pinpoint. Within the meta-analysis, it was noted that most of the studies that found no difference in screening rates employed fewer participants with psychotic disorders compared to other mental illnesses [5]. Druss et al found that screening uptake was lower for patients with psychosis than for the general population, and that a coexisting substance abuse disorder reduced uptake even further [34]. Possible reasons suggested for this phenomenon are low income, lack of transportation, lack of familiar healthcare providers, and lack of communication with healthcare providers.\n\nPatients with schizophrenia spectrum disorders often lack access to effective cancer screening or medical attention [6]. Patients with psychotic disorders tend to resist cancer screening. Moreover, patients lost to follow-up or shifting away from treatment could also be responsible for variations in the prevalence result, especially among men. A further explanation for this diverse prevalence, especially relating to the finding that women have an increased rate of cancer, has been linked to different studies identifying breast, cervical, or uterine cancer as high-risk cancer types [35]. Another study focused on identifying mental disorders before the diagnosis of breast cancer showed an increase in the prevalence of mental disorders in one-fourth of Medicare-enrolled women [36]. However, Kahan et al (2018) showed no statistically significant association between breast cancer and bipolar disorder in women [37]. In another study, most of the excess cancer risk was found in males with bipolar disorder compared to those with schizophrenia [38]. The overall trend of a generally lower incidence of cancer in schizophrenic men might be accurate, especially when we consider some forms of cancer that occur in men but usually remain undetectable for years, such as prostate cancer. Lastly, patients with psychotic disorders tend to smoke twice as often as the normal population. As a result, they are expected to have an increased risk of lung cancer. However, most epidemiological studies have not found a direct link to explain the relationship between the current prevalence rate of schizophrenic individuals and the risk of lung cancer [39]. The presence of mental illness prior to the diagnosis of cancer creates both diagnostic and treatment challenges. Overall, the literature discussed suggests that individuals with SMIs are less likely than other groups to receive screening for cancers of all types.\n\nManagement of Cancer in Patients With Severe Psychotic and Bipolar Disorders\n\nIn patients with severe psychotic and bipolar disorders, the management of cancer presents difficulties of its own. Chronic somatic comorbidities in schizophrenia or bipolar disorder result in excessive mortality, as stated above. These somatic comorbidities are often under-treated and under-detected [40]. Higher mortality rates from cancer in patients with mental disorders could be multifactorial, including the initial presentation of their cancer not receiving appropriate attention to challenges in the treatment of psychiatric patients [41].\n\nIt has been posited that psychiatric patients are less likely to report or seek treatment for telltale symptoms of cancer. One such factor underlying this phenomenon could be a difference in pain threshold. Atik et al (2007) proposed that patients with schizophrenia have a higher pain threshold when compared to the general population, which may make them resistant to seeking treatment for pain due to underlying cancer [42]. However, this is likely inaccurate for patients with bipolar disorder, as it has been associated with increased pain sensitivity [42]. People with medical conditions and co-existing mental illnesses are less likely to be treated for general medical conditions than people with medical conditions and no existing mental illnesses [43].\n\nDiscussion of nonmedical barriers to the management of cancer in patients with psychotic disorders is warranted. Patients presenting with acute psychosis may be difficult to assess physically or mentally. This may be due in part to largely inadequate follow-up found in this population, or due to the behavior typical of acutely psychotic patients. Patients in a psychotic state may be non-communicative, interruptive, paranoid, or even combative, especially with unfamiliar caregivers. Even after diagnosis, psychiatric patients, particularly those with schizophrenia, may still have difficulty understanding their diagnoses or the necessary treatments [30]. Inagaki et al also pointed to the distinct possibility of exacerbating a patient’s symptoms of schizophrenia when informing them of their cancer diagnosis [30]. This is a unique barrier to treatment specific to cancer patients with SMI, and there has been little research on the methods of overcoming this barrier. These patients have also been shown to have lower adherence to treatment plans and are more likely to miss follow-up appointments. Kisely et al studied the reason that psychiatric patients had a 30% higher cancer mortality rate than the general population [41]. After performing a population-based record linkage analysis, they concluded that although cancer incidence is not higher in psychiatric patients than in the general population, these patients are more likely to have metastases at diagnosis. It was hypothesized that cancer is more likely to be unrecognized in psychiatric patients than in the general population, and that they were less likely to receive equitable primary care. This is supported by the finding that psychiatric patients were less likely to receive weight measurements, blood pressure measurements, and treatment for hyperlipidemia, particularly in the USA, Canada, UK, and Australia in 2000 [44]. They also found that psychiatric patients are less likely to receive specialized interventions, receive less chemotherapy, and are less likely to receive surgery after cancer diagnosis. Psychiatric patients are typically excluded from drug trials [41].\n\nCompetency to consent to treatment and decision-making capacity is also a consideration when it comes to incongruence in the treatment of cancer patients with psychotic disorders. Patients with psychotic disorders, such as schizophrenia, typically have a shorter lifespan when compared to the general population. This reveals a disparity regarding access to quality end-of-life care for these patients. Another barrier to treatment for patients with psychotic disorders is the phenomenon of diagnostic overshadowing by their treating physician. It is not uncommon for physicians to discount or pay less attention to the symptoms reported by their patients with psychotic disorders, and oftentimes, the physician will simply attribute these symptoms to the patient’s mental illness. Symptoms of mental illness may therefore obscure the physician to the symptoms of cancer (or other illnesses) [45]. With this background, a clearer picture begins to form about inequality in care for psychiatric patients with a diagnosis of cancer.\n\nRole of Antipsychotic Medications\n\nAntipsychotic medications may have a role in cancer incidence in patients with mental disorders on the psychotic spectrum. For instance, as discussed earlier, women with schizophrenia have a higher incidence of breast cancer. It is believed that hyperprolactinemia-inducing antipsychotic medications can further progress pre-existing precancerous breast lesions [46]. However, many studies have shown that these medications do not increase the risk of breast cancer [47]. Some studies have even shown the anti-cancer properties of some drugs, such as aripiprazole [48]. Many antipsychotic drugs can inhibit cellular proliferation, induce apoptosis, inhibit migration or metastasis, cause cell cycle arrest, or alter the viability of cancer cells in vivo and in vitro. Thus, they may be used to treat various cancers at higher dosages [49, 50]. Some data also show that these drugs can be used to augment chemotherapy and treat the side effects of chemotherapy [50]. Table 1 [51-69] summarizes the most commonly used antipsychotics in oncology settings.\n\nTable 1 Commonly Used Antipsychotics in Oncology Settings\n\nAntipsychotic agent\tStarting dose (mg)\tScheduling\tMaximum daily dose (mg)\tReferences\t\nQuetiapine\t25 - 50 mg PO\tQ12 - 24h\t800 mg\tSakamoto et al, 2020 [51]; Shinno et al, 2007 [52]; Verwimp-Hoeks et al, 2012 [53]\t\nOlanzapine (Zydis)\t2.5 - 10 mg PO\tQ12 - 24h\t20 mg\tSanomachi et al, 2017 [54]; Bitter et al, 2004 [55]; Breibart et al, 2002 [56]\t\nRisperidone (M-Tab)\t0.25 - 2 mg PO\tQ12h\t6 mg\tKishi et al, 2012 [57]; Reutfors et al, 2017 [58]\t\nChlorpromazine\t12.5 - 50 mg PO/IM/IV\tQ4 - 12h\t300 mg\tMcIver et al, 1994 [59]; Kamgar-Dayhoff et al, 2021 [60]; Csatary, 1972 [61]\t\nHaloperidol\t0.25 - 1 mg PO or IV\tQ2 - 12h PO/IV/SQ\t20 mg\tRadha Krishna et al, 2012 [62]; Hui et al, 2017 [63]; Wang et al, 2012 [64]\t\nLoxapine\t10 - 50 mg PO. The usual therapeutic range is 60 - 100 mg daily.\tQ12h\t250 mg\tRiddle et al, 2017 [65]; Schmiedl et al, 2019 [66]; Rahman et al, 2014 [67]\t\nClozapine\t12.5 - 25 mg PO\tQ12h (varies)\tUp to 300 - 400 mg/day\tDeodhar et al, 2014 [68]; Pakhre et al, 2016 [69]\t\nPO: orally; IM: intramuscularly; IV: intravenous; q12h: every 12 hours.\n\nPsychosis can be a pre-existing condition due to underlying mental illness or can be brought on by cancer or its treatment, and psychotic symptoms, including delusions, hallucinations, and disorganized behaviors/thoughts can be addressed by antipsychotic medications [70]. The selection of drugs depends on the patient’s symptoms and the properties of the drug in question [71]. Haloperidol is the first-line drug for psychosis in cancer patients, followed by risperidone and low-dose quetiapine in general hospital settings [72].\n\nAntipsychotic medications are known to have high rates of adverse effects. Both typical and atypical antipsychotics can cause electrocardiogram (ECG) abnormalities, which put them at a higher arrhythmia risk, and they increase the risk of coronary events, both of which lead to chances of sudden cardiac death [73, 74]. Clozapine is specifically known to cause cardiotoxicity and myocarditis, which should be taken into consideration in patients on chemotherapy [75]. Second-generation antipsychotics cause metabolic side effects, such as weight gain, dyslipidemia, hyperglycemia, and insulin resistance, all of which can cause mortality and are risk factors for cardiovascular disease [76]. Antipsychotic use can cause bleeding, venous thromboembolism, and platelet function impairment, which increases the chances of stroke, thromboembolism, and cardiovascular events [77]. These side effects may increase the morbidity and mortality of cancer patients being treated for psychiatric illnesses. First, these symptoms could further mask the signs and symptoms of cancer and become barriers to diagnosis and screening. Second, these side effects may contribute to mortality when combined with certain types of cancer afflicting a patient.\n\nAtypical antipsychotics can be utilized for various types of chronic pain, but an intriguing opportunity for use in treating cancer pain is being researched. Oftentimes, cancer pain is chronic, as most people battle cancer for longer than 3 months at a time. One study showed that around 59% of patients experienced pain during cancer treatment. About 64% of these patients reported advanced cancer pain. Even for patients with curative treatment, 33% still claim to experience pain [78]. Regarding already established guidelines, the World Health Organization (WHO) cancer pain management guidelines suggest using non-opioid analgesics when initiating therapy for a patient. This is due to multiple factors: opioids are not only highly addictive but also have many side effects. A small study that assessed the benefit of atypical antipsychotics for the pain of eight cancer patients who were already titrated on opioids found that the drugs, unfortunately, did not control the pain. Using olanzapine as the drug of choice, the patients reported a significant reduction in their daily pain scores, and it was also noted that their daily opioid use decreased a great amount as well. The patients also had cognitive disorders and showed positive improvements in cognitive impairment and anxiety [79]. Further, when studied on mouse models, quetiapine showed analgesic effects on cancer-induced bone pain [80]. There is still much more to learn regarding the treatment of cancer pain with atypical antipsychotics. Currently, the theory is mainly supported through animal models and small cases studies. Nonetheless, antipsychotics have generally shown efficacy in pain management across the board and are an innovative approach to treating chronic pain in cancer patients with concomitant psychosis. Figure 2 summarizes analgetic properties of certain antipsychotics.\n\nFigure 2 Potential analgetic properties of certain antipsychotic agents.\n\nChemotherapy-Induced Mania: Should We Use Mood Stabilizers?\n\nSeveral chemotherapy regimens have been linked to secondary mania and agitation in patients without a previous psychiatric history. Specifically, it was suggested that our patient partially relapsed after the cycle of imatinib, as this coincided with the onset of psychomotor agitation and several episodes of behavioral dysregulation. After readjustment of antipsychotic therapy, symptoms subsided within 15 days. Table 2 [17, 81-89] summarizes chemotherapeutic agents associated with similar presentations.\n\nTable 2 Chemotherapy-Induced Affective and Behavioral Disturbances\n\nAgent\tMalignancy\tPresentation\tReferences\t\n5-fluorouracil\tColorectal cancer\tAcute manic episode\tHa et al, 2011 [81]\t\nMethotrexate\tAcute lymphocytic leukemia (ALL)\tAcute manic episode\tHariram et al, 2013 [82]\t\nCisplatin\tTonsillar cancer\tMania and poor impulse control\tBarlinn et al, 2015 [83]\t\nDocetaxel and cisplatin\tNon-small cell lung cancer\tLate-onset bipolar disorder\tDeKay et al, 2011 [84]\t\nCisplatin\tGastric cancer\tHypomania\tMatsunaga et al, 2012 [85]\t\nCapecitabine and oxaliplatin\tColorectal cancer\tAcute manic episode\tGarg et al, 2018 [17]\t\nDexamethasone\tNon-small cell lung cancer\tSteroid-induced mania\tWarren et al, 2019 [86]\t\nLenalidomide, bortezomib, dexamethasone\tMultiple myeloma\tMania and hyperactive delirium\tPavlova et al, 2020 [87]\t\nDasatinib\tChronic myeloid leukemia\tDepression with agitation\tSami et al, 2014 [88]\t\nImatinib and dasatinib\tChronic myeloid leukemia\tDepression with agitation\tQuek et al, 2009 [89]\t\n\nLithium, a commonly used mood stabilizer, has shown many antineoplastic properties that may contribute to reducing cancer incidence in psychiatric patients [90]. Lithium can inhibit the growth of cancer cells and inhibit cancer cell invasion and metastasis [91, 92]. Valproate, another mood stabilizer, is a histone deacetylase inhibitor that exhibits antineoplastic activities both in vivo and in vitro [93]. Although the exact mechanism of action is not understood, both lithium and valproic acid may be used to augment the effect of chemotherapy agents in cancer patients [93, 94]. However, cancer patients on mood stabilizers are at a higher risk of developing serious adverse effects. For example, lithium levels can fluctuate greatly in cancer patients taking nephrotoxic chemotherapeutic agents. Similarly, carbamazepine may cause serious bone marrow suppression when administered alongside chemotherapeutic agents, causing bone marrow suppression [95].\n\nPsychotherapeutic Treatment Modalities\n\nCancer is a stressful life event that may cause psychological stress and new-onset depression or anxiety, but cancer or its treatment can also exacerbate symptoms of preexisting schizophrenia and bipolar disorder [70]. Psychotherapy has been proven to help reduce negative thoughts, help patients develop adaptive defenses, and help family members enhance support for the patient at home [95, 96]. Psychotherapy may not cure the symptoms of schizophrenia or bipolar disorder in cancer patients, but it can be moderately helpful in treating some depressive symptoms [97, 98]. Acceptance and commitment therapy, a type of therapy involving meaning and mindfulness developed by Steven Hayes, can be used for pre-existing psychiatric conditions in cancer patients [99]. Cancer support groups or group therapies can be used to keep patients motivated, help them relieve anxiety, and educate them [100].\n\nA qualitative study performed in Australia examined the self-reported consequences of attending cancer support groups and surveyed what these groups provided to cancer patients that other supportive relationships did not. The most common benefit noted by the support group attendees was a feeling of increased empowerment and agency. Patients felt that support group attendance and connecting with other patients with a cancer diagnosis gave them a stronger sense of control, a better understanding of living with cancer, and positive interactions with others (especially concerning the medical profession). The support groups relieved the family and friends of the patients of the burden of care and provided a safe space for expression for those connected to the patients in question. In doing so, this strengthened these relationships and reduced interpersonal stress, as reported by the participants in this study [100].\n\nFuture Recommendations\n\nCancer treatment in patients with psychotic mental disorders is very complex and needs more attention. Dispelling the stigma attached to mental illnesses and enrolling more mentally ill patients in clinical trials is the first step to improve their prognosis. In their study of cancer in the SMI, Irwin et al (2019) recommended a bridge intervention, which is a more person-centered approach of collaborative efforts of patients, psychiatrists, social workers, oncologists, and family members to help them better navigate the multiple facets of cancer care [101]. Evidence-based practice with newer and better psychotherapeutic and psychopharmacological interventions with fewer side effects is needed to provide these patients with a better quality of life. In order to ensure equity in cancer care, we encourage large-scale, well-designed studies to identify the risk factors and associations between mental illness and cancer.\n\nConclusions\n\nTo summarize, the diagnosis and treatment of cancer in patients with pre-existing SMIs, such as bipolar disorder and schizophrenia, can be challenging. Although the incidence of cancer is the same as in the general population, mortality rates have been shown to be higher. There are many risk factors potentiating cancer in patients with SMI, including cigarette smoking, use of antipsychotic medication, poor self-care, lack of timely screening, and poor access to medical care. There are significant barriers that play a role in treating these patients. Due to the apparent stigma associated with mental health and acuity related to cancer symptoms, physicians may not give them the same attention as other patients, which can negatively impact timely cancer screening and diagnosis and may even undermine the cancer symptoms, causing them to go undetected until the cancer metastasizes. Patients with schizophrenia and bipolar disorder may exhibit poor cognitive functioning, and difficulty with comprehension of the seriousness of their cancer diagnosis. These patients may have financial and social constraints and may be unable to adhere to treatment and follow-up care. Oncologists may be hesitant in enrolling these patients in clinical trials or recommend intensive treatment due to their noncompliance. Cancer diagnosis and treatment are stressors that may cause new-onset depression or anxiety and exacerbate pre-existing mental illnesses. All these barriers discussed can cause disparity in the diagnosis and treatment of cancer in patients with SMI; therefore, a more targeted approach to cancer care is needed in this challenging population.\n\nThe project was approved by the Institutional Review Board (IRB) of the University of Missouri Kansas City. This work would not have been possible without the academic support of UMKC, Department of Psychiatry and Center for Behavioral Medicine. We are grateful to all of those with whom we have had the pleasure to work during this and other related projects. We thank our colleagues who provided insight and expertise that greatly assisted the research, although they may not agree with all of the interpretations/conclusions of this paper. We thank our colleagues and attendings for comments that greatly improved the manuscript.\n\nFinancial Disclosure\n\nNo funding to declare. We have no financial activities to disclose. We have no financial relationships associated with the submitting author and all co-authors.\n\nConflict of Interest\n\nAll authors have no conflict of interest to report. We did not receive any payment or services from a third party for any aspect of the submitted work. We do not have any patents, whether planned, pending or issued, that could be considered broadly relevant to this work.\n\nAuthor Contributions\n\nAll authors of this research paper have directly participated in the acquisition, analysis, or interpretation of data for the work. NR, KD assisted with data analysis and interpretation of clinical data from the EMR. NR, KD, AD, SD, RV, SP, and SS supplied the acquisition and interpretation of data from the literature, drafting of manuscript. VB provided the conception and design of the review, revised the manuscript critically for important intellectual content prior and gave final approval of the version to be submitted.\n\nData Availability\n\nData are available within the article and in a public repository that issues datasets with DOIs.\n==== Refs\nReferences\n\n1 Chou FH Tsai KY Wu HC Shen SP Cancer in patients with schizophrenia: What is the next step? Psychiatry Clin Neurosci 2016 70 11 473 488 10.1111/pcn.12420 27392126\n2 Charlson FJ Ferrari AJ Santomauro DF Diminic S Stockings E Scott JG McGrath JJ et al Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016 Schizophr Bull 2018 44 6 1195 1203 10.1093/schbul/sby058 29762765\n3 NIMH. Bipolar disorder. 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"fulltext_license": "CC BY-NC",
"issn_linking": "1920-4531",
"issue": "12(5)",
"journal": "World journal of oncology",
"keywords": "Antipsychotics; Cancer screening; Compliance; Leukemia; Mania; Psychosis",
"medline_ta": "World J Oncol",
"mesh_terms": null,
"nlm_unique_id": "101564097",
"other_id": null,
"pages": "137-148",
"pmc": null,
"pmid": "34804276",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "31402867;24716500;26131945;24185382;31390582;16732749;28197007;31685559;10728718;30806345;10970677;31618686;24880509;21379357;24167698;25687772;26051358;22038577;12223244;22252186;14687871;7963786;31622875;29946207;11802085;29778097;15655426;27392126;24891711;20599423;17847017;31108054;10964345;28975307;26012508;28453966;29599381;27112326;25115782;22834659;26952940;24677189;10584719;30696722;21519541;32746451;24074357;31671770;16303220;23491967;18216074;31439658;12075032;22872746;21383636;23595787;27823949;29762765;33668518;16870963;23930615;26130586;17353530;10084570;19064960;11386985;27377891;32626629;23022930;10737278;26663383;31722645;28103434;25547500;22219014;31632882;4115079;29061799;25651838;18331573;27126391;31750236;21935426;20634880;30828767;28844558;24151022;31908647;34262651;27668891;28938233;22045828;11997204;24448212",
"title": "Challenges in Treating Cancer Patients With Unstable Psychiatric Disorder.",
"title_normalized": "challenges in treating cancer patients with unstable psychiatric disorder"
}
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"literaturereference": "Bellman V, Russell N, Depala K, Dellenbaugh A, Desai S, Vadukapuram R et al. Challenges in treating cancer patients with unstable psychiatric disorder. World Journal of Oncology. 2021;12(5):137-148",
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{
"abstract": "The overlap syndrome of primary biliary cholangitis (formerly called primary biliary cirrhosis) and primary sclerosing cholangitis is an extremely rare condition that has never been described in association with other immune-mediated diseases, including psoriatic arthritis. While treatment with anti-Tumour Necrosis Factor-alpha (TNF-α) agents has proved to be effective in inflammatory arthropathies such as psoriatic arthritis, they have been employed in only a limited number of patients with autoimmune hepatitis, and their effectiveness is unclear.\n\n\n\nWe report the case of a 51-year-old female affected with psoriatic arthritis concomitant to overlapping primary biliary cholangitis and primary sclerosing cholangitis in whom 28 months of adalimumab treatment improved the symptoms of the inflammatory arthropathy as well as those of both cholangiopathies.\n\n\n\nOur results suggest that further studies examining the therapeutic role of this particular TNF-α blocker are warranted in cholestatic autoimmune hepatitis patients, and in particular in those individuals in whom the disease is associated with inflammatory arthropathies.",
"affiliations": "Rheumatology Unit, Department of Medicine, University Hospital of Padua, Padua, Italy. [email protected].;Rheumatology Unit, Department of Medicine, University Hospital of Padua, Padua, Italy.;Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua, Italy.;Rheumatology Unit, Department of Medicine, University Hospital of Padua, Padua, Italy.;Rheumatology Unit, Department of Medicine, University Hospital of Padua, Padua, Italy.",
"authors": "Del Ross|Teresa|T|;Ruffatti|Amelia|A|;Floreani|Annarosa|A|;Hoxha|Ariela|A|;Punzi|Leonardo|L|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1186/s12891-016-1335-x",
"fulltext": "\n==== Front\nBMC Musculoskelet DisordBMC Musculoskelet DisordBMC Musculoskeletal Disorders1471-2474BioMed Central London 133510.1186/s12891-016-1335-xCase ReportThe efficacy of adalimumab in psoriatic arthritis concomitant to overlapping primary biliary cholangitis and primary sclerosing cholangitis: a case report Del Ross Teresa +039 049 [email protected] 1Ruffatti Amelia [email protected] 1Floreani Annarosa [email protected] 2Hoxha Ariela [email protected] 1Punzi Leonardo [email protected] 11 Rheumatology Unit, Department of Medicine, University Hospital of Padua, Padua, Italy 2 Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padua, Italy 22 11 2016 22 11 2016 2016 17 48520 7 2016 9 11 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe overlap syndrome of primary biliary cholangitis (formerly called primary biliary cirrhosis) and primary sclerosing cholangitis is an extremely rare condition that has never been described in association with other immune-mediated diseases, including psoriatic arthritis. While treatment with anti-Tumour Necrosis Factor-alpha (TNF-α) agents has proved to be effective in inflammatory arthropathies such as psoriatic arthritis, they have been employed in only a limited number of patients with autoimmune hepatitis, and their effectiveness is unclear.\n\nCase presentation\nWe report the case of a 51-year-old female affected with psoriatic arthritis concomitant to overlapping primary biliary cholangitis and primary sclerosing cholangitis in whom 28 months of adalimumab treatment improved the symptoms of the inflammatory arthropathy as well as those of both cholangiopathies.\n\nConclusion\nOur results suggest that further studies examining the therapeutic role of this particular TNF-α blocker are warranted in cholestatic autoimmune hepatitis patients, and in particular in those individuals in whom the disease is associated with inflammatory arthropathies.\n\nKeywords\nPsoriatic arthritisPrimary biliary cirrhosisPrimary sclerosing cholangitisAnti-TNF-alpha drugsissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nWhile a variety of immunological diseases, including rheumatoid arthritis (RA), have been reported in patients affected by primary biliary cholangitis (formerly called primary biliary cirrhosis) (PBC) [1], primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel disease (IBD), and particularly with ulcerative colitis (UC) [2]. Until now only one case of a psoriatic arthritis (PsA)-PBC association has been reported [3], and, to the best of our knowledge, no cases of PsA associated to PSC have ever been described in the literature. The PBC-PSC overlap syndrome is, moreover, an extremely rare condition that has been described in only eight cases [4].\n\nThe development of Tumour Necrosis Factor-α (TNF-α) blockers has represented a milestone in the treatment of inflammatory joint diseases. Adalimumab, which is a fully human anti-TNF-α monoclonal antibody, has been shown to be effective in achieving remission and in preventing radiographic progression of joint damage in patients with RA and other inflammatory arthropathies, including PsA. It has also been found to be efficacious in treating skin and nail lesions in PsA patients [5]. Although a pathogenic hypothesis [6, 7] would justify the use of anti-TNF-α drugs for both PBC and PSC, treatment outcome is nevertheless uncertain. A double-blind, placebo-controlled, randomized study examining Infliximab treatment in PSC patients concluded that it was inefficacious in the small group studied [8]. It was likewise ineffective in a case of PBC associated with RA [9], although it did prove to be efficacious in a case of PSC that was complicated by ankylosing spondylitis and UC [10]. Etanercept led to an improvement in both liver enzymes and arthritis in two cases of RA associated with PBC [9, 11]. Prescribed to treat IBD in a patient who was also suffering from PBC, Adalimumab treatment led to a favourable clinical and laboratory response with regard to both disorders [12]. To date, no cases of PBC, PSC, or overlapping PBC-PSC associated with inflammatory arthropathies have been treated with Adalimumab. The current report describes a case in which Adalimumab treatment led to clinical improvement in arthritis symptoms and in nail lesions and also lowered cholestasis indices in a PsA patient with overlapping PBC-PSC syndrome.\n\nCase presentation\nIn September 2011 a 51-year-old Caucasian woman with a history of psoriasis and type-2 diabetes mellitus developed a mild psoriasis together with dactylitis affecting the right fourth finger and arthritis of the fourth metacarpophalangeal (MCP) joint of the right hand. In November 2011 she was referred our outpatient clinic. Dactylitis of the fourth finger of the right hand and swelling, redness and pain of the distal interphalangeal (DIP) joint of the second digit of the right hand were noted during the physical examination. Laboratory results at that time included: Erythrocyte sedimentation rate (ESR) = 100 mm/h (normal range 0–39 mm/h), C-reactive protein (CRP) = 3.99 mg/l (normal range 0–6 mg/l), gamma-glutamyltransferase (γGT) = 237 IU/l (normal range 3–45 IU/ml), and alkaline phosphatase (ALP) = 201 IU/l (normal range 53–141 IU/ml). The patient was treated with methylprednisolone for 6 months; treatment was started with doses of 16 mg/die that were tapered to 4 mg/die. She also received 15 mg weekly oral Methotrexate (MTX) for 6 months beginning in May 2012 with poor results. In March 2012, hand X-rays uncovered periostitis of the proximal phalanx of the right fourth digit; ultrasound (US) and powerdoppler evaluation revealed flexor tenosynovitis of the fourth finger of the right hand and a small erosion in the head of the fourth MCF of the right hand. An US-guided corticosteroid injection of the tendon sheath was adminstered.\n\nIn April 2012 the patient presented to the Gastroenterology Unit of the University of Padova Medical Centre. Biochemical testing confirmed abnormal cholestatic patterns that had been persisting since 2009 (γGT 229 IU/ml and ALP 201 IU/ml). At that time the patient showed: antimitochondrial antibody (AMA) positivity in immunofluorescence with a 1:160 titre, immunoblotting positivity for M2, 3E and anti pg 210, total serum cholesterol = 240 mg/dl (range ≤ 200 mg/dl), serum IgM = 7.31 g/L (range 0.4–2.38 g/L), normal transaminases, negative hepatitis B and C serum markers. The patient showed no symptom of cholestasis; the liver and spleen were not palpable. A liver biopsy, which was performed in May 2012, showed marked fibrosis of the portal tracts extending to the parenchyma, interface hepatitis, and a vanishing bile duct picture with the remaining ducts showing regressive alterations of cholangiocytes together with biliary metaplasia. The histological picture was compatible with stage III PBC. Ursodeoxycholic acid (UDCA), which was begun in April 2012 at 10 mg/Kg/day, was later increased to 15 mg/Kg/day; a partial reduction in γGT and ALP was recorded. In July 2012, the patient underwent Magnetic Resonance Imaging (MRI) cholangiography of the upper abdomen which revealed a marked reduction of the right segmental duct extended for 2.5 cm, with upstream dilatation, and pronounced stenosis of the biliary tree in the 5th and 6th hepatic segment considered characteristic of PSC. MRI typically shows multiple strictures and dilatations of the intrahepatic biliary tree in PSC patients. In our case, the coexistence of a liver biopsy compatible with PBC and MRI results typical of PSC permitted us to formulate a diagnosis of PBC-PSC overlap syndrome.\n\nGiven the absence of both the histopathological features of IgG4-related disease and abundant IgG4+ plasma cells in the liver biopsy material, the hypothesis of IgG4-associated cholangitis was excluded. Furthermore, there were no signs of synchronous involvement of other organs.\n\nIn October 2012, arthritis of the fourth right DIP joint and severe nail psoriasis were two new symptoms that were added to the clinical picture (Fig. 1a). Hand X-rays showed new erosions in the fourth right MCF and DIP (Fig. 1b). Adalimumab treatment (40 mg fortnightly), which was begun at that time, led to notable relief of the pain and stiffness. Three months later the painful swellings of the second and fourth right DIP joints showed marked improvement, and the nail of the fourth right finger appeared normal (Fig. 2a). The patient’s Health Assessment Questionnaire (HAQ) disability index score fell from 0.750 to 0.375, the Disease Activity Score 28 (DAS28) fell from 4.25 to 3.18 and the Disease Activity in Psoriatic Arthritis (DAPSA) score fell from 17.37 to 4.29. Liver function tests improved, the ALP normalized, and the γGT and IgM improved (respectively falling to 124 IU/L and 5.35 g/L). Twelve months later, the HAQ continued to fall reaching 0.25, the DAS 28 fell to 1.80, and the DAPSA to 2.69. Hand X-rays showed that the bone erosion infourth right DIP joint seemed to have disappeared while the erosion at the base of the first phalanx persisted (Fig. 2b). Unfortunately, we do not have Computerized Tomography (CT) or MRI confirmation of these findings. Twenty-eight months later, the patient’s HAQ and DAS 28 values were stable, the DAPSA was 5.29 (low disease activity), the γGT and serum IgM had fallen even further (respectively reaching 98 IU/ml, and 4.93 g/L), and the ALP remained at normal levels (107 IU/ml) (Fig. 3). At present, the patient continues to receive Adalimumab and enjoys good health.Fig. 1 Right hand: arthritis of the fourth distal interphalangeal joint with severe nail psoriasis (a). Radiograph of the right hand: erosions in the fourth metacarpophalangeal and distal interphalangeal joints (b)\n\n\nFig. 2 Right hand:swelling of the fourth distal interphalangeal joint was markedly improved, and nail appeared normal (a). Radiograph of the right hand: the bone erosion in the fourth distal interphalangeal joint seemed to have disappeared (b)\n\n\nFig. 3 The cholestatic enzyme pattern during Adalimumab treatment. UDCA: ursodeoxycholic acid\n\n\n\n\nDiscussion\nThe current report describes for the first time a patient affected with PsA as well as with an overlapping PBC-PSC syndrome who was treated with Adalimumab which led to a clinical improvement in arthritis symptoms and lowered the indexes of cholestasis.\n\nA recent study demonstrated a strong positive correlation of 44 non-human leukocyte antigen (HLA) loci for PSC that were also identified in seven immunological disorders including psoriasis [13]. In addition, susceptibility to PSC may be determined by polymorphisms of TNF genes [14]. The existence of TNF-α gene promoter variants that act as markers of both disease severity and response to treatment has been hypothesized for inflammatory arthropathies. The main TNF-α and TNF-α receptor polymorphisms also seem to be able to predict response to TNF-α blockers in PsA patients [15, 16]. As genetic factors play an important role in anti-TNF-α response in inflammatory arthropathies, it could be argued that they influence the effect of anti-TNF-α treatment in autoimmune colangiopathies or at least in some clinical phenotypes. It is also possible that different genetic combinations predispose patients to a particular clinical phenotype influencing response to treatment.\n\nIn the case outlined here in which PsA was associated with an overlapping PBC-PSC syndrome, the patient’s good response to TNF-α blockers seems to confirm the important role of TNF-α in the pathogenesis of these diseases. In addition, the fact that some TNF-α blockers are effective in different cholestatic autoimmune liver diseases in the presence of an inflammatory arthropathy is a particularly interesting, thought-provoking finding [9–12].\n\nAdalimumab also proved to be effective in the case studied, even in connection to the radiographic alterations (bone erosions in the fourth right DIP) which seemed to disappear (Fig. 2b). It is nevertheless possible that the marked improvement in the patient’s bone condition was linked to the precocious therapeutic intervention that was implemented.\n\nConclusion\nConcomitant autoimmune diseases and/or immune-mediated disorders, which share genetic basis and possibly similar molecular pathways, have frequently been found in the same patient. As genetic factors play a vital role in the susceptibility to inflammatory arthropathies and in determining a drug’s effect, they may also be involved in the development of autoimmune colangiopathies and/or of some clinical phenotypes. A TNF-α polymorphism may explain both TNF-α’s pathogenic role in clinical subsets as well as the response to TNF-α blockers. In the case described here, the concomitant presence of PsA and the PBC-PSC overlap syndrome as well as the patient’s good response to TNF-α blockers all seem to confirm a common pathogenesis and point to the hypothesis that the use of anti-TNF-α drugs could be effective in one or more subsets of autoimmune colangiopathies. Notably, the clinical phenotype of the autoimmune colangiopathies that respond favorably to anti-TNF-α drugs seems to be the one in which inflammatory arthropathy is also present, as has been reported by our as well as other research groups.\n\nFuture studies will be able to verify the efficacy of TNF-α blockers in autoimmune cholangiopathies associated to inflammatory arthropathies and to identify the clinical subsets that are responsive to different anti-TNF-α agents.\n\nAbbreviations\nALPAlkaline phosphatase\n\nAMAAntimitochondrial antibody\n\nCRPC-reactive protein\n\nCTComputerized tomography\n\nDAPSADisease activity in psoriatic arthritis\n\nDAS28Disease activity score\n\nDIPDistal interphalangeal\n\nESRErythrocyte sedimentation rate\n\nHAQHealth Assessment Questionnaire\n\nHLAHuman leukocyte antigen\n\nIBDInflammatory bowel disease\n\nMCPMetacarpophalangeal\n\nMRIMagnetic resonance imaging\n\nMTXMethotrexate\n\nPBCPrimary biliary cholangitis (formerly called primary biliary cirrhosis)\n\nPsAPsoriatic arthritis\n\nPSCPrimary sclerosing cholangitis\n\nRARheumatoid arthritis\n\nTNF-αTumour necrosis factor-α\n\nUCUlcerative colitis\n\nUDCAUrsodeoxycholic acid\n\nγGTGamma-glutamyltransferase\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll of the data appear within the manuscript.\n\nAuthors’ contributions\nTDR and AH provided the clinical data included in the text and approved the final version of the manuscript. TDR and AF participated in the treatment decisions. TDR and AF wrote the manuscript draft. AR and LP revised it critically and approved the modified text. All the authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no conflicts of interest concerning this article.\n\nConsent for publication\nA written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Floreani A Franceschet I Cagazzon N Primary biliary cirrhosis: overlaps with other autoimmune disorders Semin liver dis 2014 34 352 360 10.1055/s-0034-1383734 25057958 \n2. Yimam KK Bowlus CL Diagnosis and classification of primary sclerosing cholangitis Autoimmun rev 2014 13 445 450 10.1016/j.autrev.2014.01.040 24424180 \n3. D’Amico E Palazzi C Capani F Remission of psoriatic arthritis after porto-caval anastomosis in a patient with primary biliary cirrhosis J rheumatol 1999 26 236 9918274 \n4. Floreani A Motta R Cagazzon N Franceschet I Roncalli M Del Ross T The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis Dig liver dis 2015 47 432 435 10.1016/j.dld.2015.02.002 25747115 \n5. Van den Bosch F Manger B Goupille P Mchugh N Rodevand E Holk P Effectiveness of adalimumab in treating patients with active psoriatic arthritis and predictors of good clinical responses for arthritis, skin and nail lesions Ann rheum dis 2010 69 394 399 10.1136/ard.2009.111856 19815494 \n6. Barak V Selmi C Schlesinger M Blank M Agmon-Levin N Kalickman I Serum inflammatory cytokines, complement components, and soluble interleukin 2 receptor in primary biliary cirrhosis J autoimm 2009 33 178 182 10.1016/j.jaut.2009.09.010 \n7. Aoki CA Bowlus CL Gershwin ME The immunobiology of primary sclerosing cholangitis Autoimm rev 2005 4 137 143 10.1016/j.autrev.2004.09.003 \n8. Hommes DW Erkelens W Ponsioen C Stokkers P Rauws E van der Spek M A double-blind placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis J clin gastroenterol 2008 42 522 526 10.1097/MCG.0b013e3181662426 18344886 \n9. Spadaro A Scrivo R Riccieri V Valesini G Effect of tumor necrosis factor alpha antagonists in a patient with rheumatoid arthritis and primary biliary cirrhosis Joint bone spine 2008 75 87 89 10.1016/j.jbspin.2007.03.003 17890133 \n10. Duca I Ramírez De La Piscina P Estrada S Calderòn R Spicakova K Urtasun L Steroid-refractory ulcerative colitis and associated primary sclerosing cholangitis treated with infliximab World j gastroenterol 2013 19 590 593 10.3748/wjg.v19.i4.590 23382642 \n11. Kubo S Iwata S Saito K Tanaka Y Successful treatment of primary biliary cirrhosis with etanercept in a patient with rheumatoid arthritis Joint bone spine 2011 78 535 536 10.1016/j.jbspin.2011.04.014 21703904 \n12. Triantafillidis JK Durakis S Merikas E Crohn’s disease of the small bowel, complicated by primary biliary cirrhosis, Hashimoto thyroiditis, and Raynaud’s phenomenon: favorable response of all disorders to adalimumab treatment Gastroenterol hepatol bed bench 2013 6 101 105 24834253 \n13. Liu JZ Hov JR Folseraas T Ellinghaus E Rushbrook SM Doncheva NT Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis Nat genet 2013 45 670 675 10.1038/ng.2616 23603763 \n14. Lu S Huang X Zhong H Chen Z Peng Q Deng Y Tumor necrosis factor alpha (TNF-alpha) genetic polymorphisms and the risk of autoimmune liver disease: a meta-analysis J genet 2013 92 617 628 10.1007/s12041-013-0272-9 24371186 \n15. Morales-Lara MJ Canete JD Torres-Moreno D Hernández MV Pedrero F Celis R Effects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in patients with rheumatoid and psoriatic arthritis Joint bone spine 2012 79 591 596 10.1016/j.jbspin.2012.02.003 22480748 \n16. De Simone C Farina M Maiorino A Fanali C Perino F Flamin A TNF-alpha gene polymorphisms can help to predict response to etanercept in psoriatic patients J eur acad dermatol venereol 2015 29 1786 1790 10.1111/jdv.13024 25726968\n\n",
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"medline_ta": "BMC Musculoskelet Disord",
"mesh_terms": "D000068879:Adalimumab; D000893:Anti-Inflammatory Agents; D015535:Arthritis, Psoriatic; D015209:Cholangitis, Sclerosing; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary; D008875:Middle Aged",
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"title": "The efficacy of adalimumab in psoriatic arthritis concomitant to overlapping primary biliary cholangitis and primary sclerosing cholangitis: a case report.",
"title_normalized": "the efficacy of adalimumab in psoriatic arthritis concomitant to overlapping primary biliary cholangitis and primary sclerosing cholangitis a case report"
}
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"abstract": "Presentations of drug-induced liver injury (DILI) are highly variable. Although biochemical evidence of cholestasis is common, the extent of aminotransferase elevations and patterns of liver injury vary. Patients may be asymptomatic, and many cases may never be diagnosed. We describe a case of memantine-induced hepatotoxicity in an elderly patient with Alzheimer's dementia, with probable causality for drug-induced liver injury, as assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) score.",
"affiliations": "Internal Medicine, Walter Reed National Military Medical Center, Bethesda, MD.;Gastroenterology, Walter Reed National Military Medical Center, Bethesda, MD.;Gastroenterology, Walter Reed National Military Medical Center, Bethesda, MD.;Gastroenterology, Walter Reed National Military Medical Center, Bethesda, MD.;Gastroenterology, Walter Reed National Military Medical Center, Bethesda, MD.",
"authors": "Shumar|John|J|;Ordway|Sarah|S|;Junga|Zachary|Z|;Sadowski|Brett|B|;Torres|Dawn|D|",
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"title": "Memantine-Induced Liver Injury With Probable Causality as Assessed Using the Roussel Uclaf Causality Assessment Method (RUCAM).",
"title_normalized": "memantine induced liver injury with probable causality as assessed using the roussel uclaf causality assessment method rucam"
}
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"literaturereference_normalized": "memantine induced liver injury with probable causality as assessed using the roussel uclaf causality assessment method rucam",
"qualification": "1",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20200122"
},
{
"companynumb": "US-ALEMBIC PHARMACUETICALS LIMITED-2019SCAL000998",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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},
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"literaturereference": "SHUMAR J, ORDWAY S, JUNGA Z, SADOWSKI B, TORRES D. MEMANTINE-INDUCED LIVER INJURY WITH PROBABLE CAUSALITY AS ASSESSED USING THE ROUSSEL UCLAF CAUSALITY ASSESSMENT METHOD (RUCAM). ACG CASE REPORTS JOURNAL. 2019?6 (8):E00184",
"literaturereference_normalized": "memantine induced liver injury with probable causality as assessed using the roussel uclaf causality assessment method rucam",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
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}
] |
{
"abstract": "Nonbacterial thrombotic endocarditis (NBTE) is a potential complication of antiphospholipid syndrome (APS) manifesting as noninfectious lesions on one or more cardiac valves. There are limited tools to inform clinicians regarding which APS patients would benefit most from echocardiographic screening for this complication.\n\n\n\nWe tested the hypothesis that the risk of both prevalent and incident NBTE is directly related to the number of positive laboratory assays for APS.\n\n\n\nIn this single-center, retrospective, cohort study design, consecutive patients with confirmed APS seen at Mayo Clinic Rochester, MN (1/1/1993-6/26/2016), were identified by searching a centralized electronic database. Demographic data, clinical presentation, echocardiographic features, laboratory findings, and survival data were scrutinized.\n\n\n\nDuring the study period, 611 patients met the diagnostic criteria for APS and 386 (63%) underwent echocardiography. Of these, 58 (15%) were found to have NBTE. NBTE was more common in those with double (19.4%) and triple-positive laboratory criteria (27.0%) compared with single-positive disease (5.7%, P < .001). Survival free of NBTE diagnosis was significantly shorter in those patients with >1 positive laboratory assay (P < .01). Cox proportional hazard analysis suggests that patients with APS are more likely to be diagnosed with NBTE if they have >1 positive laboratory assay (relative risk 20.1; 95% confidence interval 1.3-316.6; P < .03).\n\n\n\nAntiphospholipid syndrome carries a high prevalence of NBTE (15%). This prevalence is particularly high for patients with either double- or triple-positive laboratory criteria.",
"affiliations": "Gonda Vascular Center, Mayo Clinic, Rochester, MN.;Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.;Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.;Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.;Gonda Vascular Center, Mayo Clinic, Rochester, MN.",
"authors": "Lenz|Charles J|CJ|;Mankad|Rekha|R|;Klarich|Kyle|K|;Kurmann|Reto|R|;McBane|Robert D|RD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jth.14798",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "18(6)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "Libman-Sacks endocarditis; Marantic endocarditis; antiphospholipid antibody syndrome; lupus anticoagulant; nonbacterial endocarditis",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D016736:Antiphospholipid Syndrome; D015331:Cohort Studies; D004696:Endocarditis; D059905:Endocarditis, Non-Infective; D006801:Humans; D007753:Laboratories; D015995:Prevalence; D012189:Retrospective Studies",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "1408-1414",
"pmc": null,
"pmid": "32180317",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Antiphospholipid syndrome and the relationship between laboratory assay positivity and prevalence of non-bacterial thrombotic endocarditis: A retrospective cohort study.",
"title_normalized": "antiphospholipid syndrome and the relationship between laboratory assay positivity and prevalence of non bacterial thrombotic endocarditis a retrospective cohort study"
}
|
[
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-031808",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": "022512",
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"medicinalproduct": "PRADAXA"
}
],
"patientagegroup": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cerebrovascular accident",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MCBANE R, LENZ C, MANKAD R, KLARICH K, KURMANN R. ANTIPHOSPHOLIPID SYNDROME AND THE RELATIONSHIP BETWEEN LABORATORY ASSAY POSITIVITY AND PREVALENCE OF NON?BACTERIAL THROMBOTIC ENDOCARDITIS: A RETROSPECTIVE COHORT STUDY. JOURNAL OF THROMBOSIS AND HAEMOSTASIS. 2020?18(6):1408?1414.",
"literaturereference_normalized": "antiphospholipid syndrome and the relationship between laboratory assay positivity and prevalence of non bacterial thrombotic endocarditis a retrospective cohort study",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200702",
"receivedate": "20200702",
"receiver": {
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},
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"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessother": 1,
"transmissiondate": "20201103"
}
] |
{
"abstract": "Diabetes mellitus-related cardiomyopathy (DMCMP), defined as left ventricular (LV) dysfunction caused by hyperglycemia in the absence of coronary artery disease, leads to heart failure (HF). Previous studies have shown that treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of HF. The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also on direct actions on the myocardium, leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP.\n\n\n\nThirty-five symptomatic non-ischemic HF patients with LV ejection fraction > 40% and type 2 diabetes mellitus (T2DM) treated with empagliflozin (EMPA group) and 20 controls treated without SGLT2i were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the EMPA group was further divided into early DMCMP (n = 16, ECV ≤ 30%) and advanced DMCMP (n = 19, ECV > 30%) groups and followed up prospectively. Echocardiography was performed at baseline and after 12 months. LV function assessed as LV global longitudinal strain (LVGLS) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e') were compared.\n\n\n\nECV was strongly correlated with T2DM duration (r2 = 0.65, p < 0.001). At baseline, each group had a similar background. After 12 months, the EMPA group, especially the early DMCMP group, showed remarkable improvements in LVGLS (ΔLVGLS: 2.9 ± 3.0% (EMPA) vs. 0.6 ± 2.2% (controls), p = 0.005, and 4.6 ± 1.5% (early DMCMP) vs. 1.6 ± 3.3% (advanced DMCMP), p = 0.003) and E/e' (ΔE/e': - 1.5 ± 4.7 vs. - 0.3 ± 3.0, p = 0.253, and - 3.4 ± 5.5 vs. - 0.1 ± 3.5, p = 0.043).\n\n\n\nThe positive effects of empagliflozin on LV dysfunction were more remarkable in early than in advanced DMCMP. Early intervention of SGLT2i for DMCMP may be preferable.",
"affiliations": "Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan. [email protected].;Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan.;Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan.;Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan.;Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan.;Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan.;Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan.",
"authors": "Oka|Satoshi|S|0000-0001-6257-1421;Kai|Takahiko|T|;Hoshino|Katsuomi|K|;Watanabe|Kazunori|K|;Nakamura|Jun|J|;Abe|Makoto|M|;Watanabe|Akinori|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12872-021-02024-3",
"fulltext": "\n==== Front\nBMC Cardiovasc Disord\nBMC Cardiovasc Disord\nBMC Cardiovascular Disorders\n1471-2261\nBioMed Central London\n\n2024\n10.1186/s12872-021-02024-3\nResearch Article\nEffects of empagliflozin in different phases of diabetes mellitus-related cardiomyopathy: a prospective observational study\nhttp://orcid.org/0000-0001-6257-1421\nOka Satoshi [email protected]\n\nKai Takahiko\nHoshino Katsuomi\nWatanabe Kazunori\nNakamura Jun\nAbe Makoto\nWatanabe Akinori\ngrid.415119.9 0000 0004 1772 6270 Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka 426-8677 Japan\n29 4 2021\n29 4 2021\n2021\n21 2178 12 2020\n19 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nDiabetes mellitus-related cardiomyopathy (DMCMP), defined as left ventricular (LV) dysfunction caused by hyperglycemia in the absence of coronary artery disease, leads to heart failure (HF). Previous studies have shown that treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of HF. The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also on direct actions on the myocardium, leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP.\n\nMethods\n\nThirty-five symptomatic non-ischemic HF patients with LV ejection fraction > 40% and type 2 diabetes mellitus (T2DM) treated with empagliflozin (EMPA group) and 20 controls treated without SGLT2i were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the EMPA group was further divided into early DMCMP (n = 16, ECV ≤ 30%) and advanced DMCMP (n = 19, ECV > 30%) groups and followed up prospectively. Echocardiography was performed at baseline and after 12 months. LV function assessed as LV global longitudinal strain (LVGLS) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e′) were compared.\n\nResults\n\nECV was strongly correlated with T2DM duration (r2 = 0.65, p < 0.001). At baseline, each group had a similar background. After 12 months, the EMPA group, especially the early DMCMP group, showed remarkable improvements in LVGLS (ΔLVGLS: 2.9 ± 3.0% (EMPA) vs. 0.6 ± 2.2% (controls), p = 0.005, and 4.6 ± 1.5% (early DMCMP) vs. 1.6 ± 3.3% (advanced DMCMP), p = 0.003) and E/e′ (ΔE/e′: − 1.5 ± 4.7 vs. − 0.3 ± 3.0, p = 0.253, and − 3.4 ± 5.5 vs. − 0.1 ± 3.5, p = 0.043).\n\nConclusions\n\nThe positive effects of empagliflozin on LV dysfunction were more remarkable in early than in advanced DMCMP. Early intervention of SGLT2i for DMCMP may be preferable.\n\nKeywords\n\nDiabetes mellitus-related cardiomyopathy\nHeart failure\nSodium–glucose co-transporter 2 inhibitor\nLeft ventricular dysfunction\nLeft ventricular global longitudinal strain\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nType 2 diabetes mellitus (T2DM) is an important risk factor for the development of cardiovascular disease and heart failure (HF) [1]. Diabetes mellitus-related cardiomyopathy (DMCMP), which manifests as left ventricular (LV) dysfunction that occurs independently of coronary artery disease and hypertension [2], has been attracting attention as a cause of HF. Hyperglycemia drives LV dysfunction and remodeling through the progression of microvascular endothelial dysfunction, myocardial injury, and interstitial fibrosis, which lead to DMCMP [3]. Decreased LV global longitudinal strain (LVGLS) and the increased ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e′) are observed as signs of LV dysfunction from the early phase of DMCMP [4, 5]. If LV remodeling progresses, DMCMP develops to symptomatic HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF) [3].\n\nSeveral mega-trials have shown that treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of major adverse cardiovascular events, including exacerbation of HF [6–8]. Furthermore, it was recently shown that SGLT2i treatment was associated with lowering the risk of cardiovascular death and hospitalization for HFrEF consistently from the early to late periods after the start of administration, regardless of the presence or absence of T2DM [9, 10]. Thus, the beneficial effects of SGLT2i treatment on HF are explained not only by their indirect actions, such as glycemic control or osmotic diuresis, but also by their direct actions on the myocardium, which lead to improvements in LV function [11, 12]. One example of direct action is inhibition of the sodium-hydrogen exchanger (NHE), which may in turn lead to a reduction in myocardial injury, fibrosis, and LV dysfunction [13].\n\nHowever, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this study was to compare the efficacy of SGLT2i treatment on LV dysfunction between the early and advanced phases of DMCMP.\n\nMethods\n\nPatients\n\nThis was a prospective observational study conducted at a single center. Consecutive symptomatic HF patients with T2DM who were hospitalized in Fujieda Municipal General Hospital (Japan) were screened for eligibility. The diagnosis of T2DM was based on the World Health Organization criteria [14]. After a cardiac assessment, patients diagnosed with DMCMP with LV ejection fraction (EF) > 40%, and treated with starting the administration of empagliflozin (at a dose of 10 mg daily) were enrolled as the EMPA group. Contrast-enhanced cardiac magnetic resonance (CMR) was performed in all patients in the EMPA group, and their myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis, was evaluated. According to previous reports [15, 16], global ECV > 30% was considered elevated with advanced replacement myocardial fibrosis. Therefore, the EMPA group was further divided into the early DMCMP group (global ECV ≤ 30%) and advanced DMCMP group (global ECV > 30%). Meanwhile, to confirm the efficacy of empagliflozin on LV dysfunction, DMCMP patients with LVEF > 40% who had never used SGLT2i were also included as a control group after a cardiac assessment with plain CMR. All participants were prospectively followed up.\n\nExclusion criteria were as follows: (1) age < 20 or > 80 years; (2) in-hospital death; (3) New York Heart Association (NYHA) class I or brain natriuretic peptide (BNP) < 100 pg/mL; (4) LVEF ≤ 40%; (5) coronary artery disease, hypertensive heart disease, or other cardiomyopathy; (6) valvular or congenital heart disease; (7) LVGLS within normal range (absolute value ≥ 18%) [4]; (8) type 1 diabetes mellitus or insulin-dependent T2DM with a C-peptide immunoreactivity index < 0.8 [17] or use of insulin; (9) newly diagnosed T2DM (< 1 year) or no antidiabetic medications before the start of administration of empagliflozin; (10) previous use of SGLT2i; (11) persistent arrhythmia; (12) pacemaker implantation; (13) contraindication for CMR (implanted metallic objects, allergy to contrast media, or bronchial asthma); (14) estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2; (15) malignant tumor or inflammatory disease; (16) pregnancy; (17) refusal to provide informed consent, and (18) history of myocardial infarction, cerebral infarction, pancreatitis, or hospitalization for HF. To exclude patients with coronary artery disease, coronary angiography was performed in all participants. Patients with ≥ 90% coronary artery stenosis were excluded. Patients with 75% stenosis were also excluded if a > 10% ischemic area matched with angiography results was proven by myocardial perfusion scintigraphy. Regarding hypertensive heart disease, patients with diastolic blood pressure ≥ 90 mmHg were excluded [3]. Regarding other cardiomyopathies, patients with regional LV wall motion abnormalities, late gadolinium enhancement (LGE), excessive LV dilatation (LV end-diastolic volume index > 97 mL/m2 [3]), and excessive LV hypertrophy (LV myocardial mass index > 69 g/m2 for women or > 91 g/m2 for men [18]) as evaluated by CMR were not included. Because contrast-enhanced CMR was not performed in the control group patients, they were exempted from LGE assessment.\n\nOutcomes\n\nThe primary outcome was improvement in LV function, defined as changes in LV systolic function assessed as LVGLS and diastolic function assessed as E/eʹ between baseline and 12 months after starting the administration of empagliflozin. The secondary outcomes were the NYHA class after 12 months and the changes in glycated hemoglobin (HbA1c) and BNP levels between baseline and after 12 months.\n\nAnthropometrics and blood tests\n\nAt the time of enrollment, age, sex, height, body weight, blood pressure, and heart rate of all participants were recorded. NYHA class and serum hemoglobin, HbA1c, sodium, eGFR, and BNP levels at admission were used as baseline data. Fasting C-peptide and plasma glucose levels were measured along with a hematocrit measurement at the time of CMR, and the C-peptide immunoreactivity index was calculated using the following formula: fasting C-peptide/fasting plasma glucose × 100. Serum HbA1c and BNP levels were also measured routinely at 12 months.\n\nUltrasonic echocardiography\n\nUltrasonic echocardiography was performed at baseline and after 12 months using an Aplio 400® (Canon Medical Systems Corporation, Tochigi, Japan) by two cardiac ultrasonographers who were blinded to the patients’ backgrounds. Two-dimensional gray-scale cine loops from three consecutive heartbeats were obtained at end-expiratory apnea from standard parasternal and apical views. According to the guidelines of the American Society of Echocardiography/European Association of Cardiovascular Imaging [19], standard echocardiographic measurements were performed. LVEF was measured using the modified Simpson method. The E-wave velocity was measured using pulsed-wave Doppler recording from the apical four-chamber view. Spectral pulsed-wave Doppler-derived e′ was obtained by averaging the septal and lateral mitral annulus, and the E/e′ was calculated to obtain an estimate of LV filling pressure. LVGLS was measured using two-dimensional speckle-tracking echocardiography. Speckle-tracking strain was analyzed using the 2D Wall Motion Tracking Application® software (Canon Medical Systems Corporation, Tochigi, Japan). While maximizing the frame rate, the LV endocardial border was traced manually at the end-diastolic frame. The software automatically tracked the myocardium throughout the cardiac cycle. The peak values of six segmental longitudinal strains were obtained from the apical four-, three-, and two-chamber views, and the LVGLS was calculated by averaging the values (Fig. 1).Fig. 1 Example of assessment of left ventricular global longitudinal strain (LVGLS) and extracellular volume fraction (ECV). Apical four- (a), three- (b), and two-chamber (c) views of two-dimensional speckle-tracking echocardiography imaging are shown. LVGLS was calculated by averaging the values from these results. Maps of the LV basal short-axis segment with a modified Look-Locker inversion recovery sequence, native T1 mapping (d), post-contrast T1 mapping (e), and calculated ECV mapping (f) are shown. Global ECV value was calculated by averaging the values of the American Heart Association 16-segment model (g)\n\nCMR scanning protocol\n\nAll CMR exams were performed using a 3.0-T scanner (Ingenia®; Philips, Eindhoven, Netherlands) with a 32-element cardiac receiver coil. Vector-electrocardiogram-gated standard steady-state free precession cine sequences were acquired in short axes covering the whole LV and long-axis (four-, three-, and two-chamber) views. LGE images were acquired 10 min post-contrast (Gadovist® 0.1 mmol/kg) injection. T1 maps were generated before and 15 min after gadolinium contrast injection using a modified Look-Locker inversion recovery sequence [20] during breath-holding in end-expiration to produce 11 raw images with increasing inversion times (TI, 100–5000 ms) in an LV short-axis view (TR/TE, 2.20/1.02 ms; flip angle, 20°). Blood samples were taken for hematocrit determination within 24 h before the scan. All maps were analyzed using Ziostation2® version 2.9 2–2 (Ziosoft, Tokyo, Japan). Myocardial T1 values and ECV were determined by drawing regions of interest in each segment of the LV slice according to the American Heart Association 16-segment model (Fig. 1). ECV values were calculated according to the following formula: ECV = (1 − HCT) × (1/T1 valuemyocardium post − 1/T1 valuemyocardium pre)/(1/T1 valueblood post − 1/T1 valueblood pre). The global ECV was calculated by averaging the values of the 16 segments.\n\nStatistical analysis\n\nWe included data from all patients in the analysis of baseline characteristics and outcomes according to the intention-to-treat principle. Normally distributed continuous variables are expressed as mean and standard deviation. Levene’s test showed that T2DM duration, eGFR, BNP, left atrial dimension, and LV end-diastolic dimension were not distributed normally. These variables are expressed as median and interquartile range. Student’s t-test or Mann–Whitney U test was used to compare differences between the two groups, where appropriate. The differences between two matched samples were compared using a paired t-test. A simple linear regression analysis was performed to evaluate the correlations. All statistical tests were two-tailed, and values of p < 0.05 were considered to indicate statistical significance. IBM SPSS Statistics® version 19.0 (SPSS, Chicago, IL, USA) was used for statistical analyses.\n\nResults\n\nBaseline characteristics\n\nA total of 984 HF patients were hospitalized between April 1, 2017, and June 1, 2019, and 215 of these patients with T2DM were screened for eligibility. A flow diagram of patient recruitment for this study is illustrated in Fig. 2. A total of 35 DMCMP patients treated with empagliflozin were enrolled as the EMPA group. Meanwhile, 20 control patients treated without SGLT2i also participated. At baseline, both groups had similar backgrounds (Table 1).Fig. 2 Enrollment and follow-up. Flow diagram shows the recruitment and follow-up process of this study. Abbreviations: CAG, coronary angiography; CMR, cardiac magnetic resonance; DMCMP, diabetes mellitus-related cardiomyopathy; ECV, extracellular volume fraction; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; SGLT2i, sodium-glucose co-transporter 2 inhibitor; T2DM, type 2 diabetes mellitus; UCG, ultrasonic echocardiography\n\nTable 1 Baseline characteristics of all participants\n\n\tEMPA group (n = 35)\tControl group (n = 20)\tp value\t\nBackgrounds\t\nAge (years old)\t66.4 ± 10.0\t65.7 ± 10.5\t0.794\t\nMale gender (%)\t26 (74.3)\t15 (75.0)\t0.954\t\nBody mass index (kg/m2)\t24.2 ± 4.4\t24.5 ± 4.5\t0.755\t\nNYHA class\t3.1 ± 0.8\t2.8 ± 0.8\t0.208\t\nSystolic blood pressure (mmHg)\t122.8 ± 16.1\t121.8 ± 19.0\t0.828\t\nDiastolic blood pressure (mmHg)\t77.6 ± 8.6\t74.7 ± 6.4\t0.195\t\nHeart rate (bpm)\t79.2 ± 10.4\t80.9 ± 11.1\t0.583\t\nHypertension (%)\t29 (82.9)\t16 (80.0)\t0.796\t\nDyslipidemia (%)\t29 (82.9)\t15 (75.0)\t0.493\t\nT2DM duration (months)\t48 (24–103)\t44 (31–47)\t0.895\t\nHemoglobin (g/dl)\t14.1 ± 2.4\t13.4 ± 3.2\t0.381\t\nHbA1c (%)\t8.2 ± 1.5\t7.9 ± 0.7\t0.339\t\nSodium (mEq/l)\t139.1 ± 3.2\t139.8 ± 2.0\t0.375\t\neGFR (ml/min/1.73m2)\t73.7 (64.7–77.8)\t70.2 (57.9–77.9)\t0.489\t\nBNP (pg/ml)\t498 (304–709)\t525 (314–811)\t0.766\t\nUCG characteristics\t\nLAD (mm)\t44 (39–46)\t44 (40–45)\t0.916\t\nLVDd (mm)\t51 (48–54)\t50 (48–55)\t0.435\t\nLVEF (%)\t51.8 ± 10.5\t52.5 ± 10.7\t0.827\t\nLVGLS (absolute value) (%)\t7.2 ± 2.8\t7.6 ± 3.0\t0.642\t\nE/e′\t12.9 ± 5.0\t12.9 ± 5.1\t0.962\t\nCMR characteristics\t\nLVEDV index (ml/m2)\t61.5 ± 17.1\t60.5 ± 19.7\t0.836\t\nLVM index (g/m2)\t49.6 ± 11.7\t51.6 ± 14.3\t0.570\t\nMedications\t\nβ blocker (%)\t18 (51.4)\t11 (55.0)\t0.803\t\nACEi (%)\t4 (11.4)\t4 (20.0)\t0.395\t\nARB (%)\t26 (74.3)\t14 (70.0)\t0.737\t\nARNI (%)\t0 (0.0)\t0 (0.0)\t–\t\nLoop diuretics (%)\t28 (80.0)\t18 (90.0)\t0.479\t\nMRA (%)\t5 (14.3)\t4 (20.0)\t0.590\t\nTolvaptan (%)\t0 (0.0)\t2 (10.0)\t0.163\t\nSGLT2i (%)\t35 (100)\t0 (0.0)\t–\t\nMetformin (%)\t12 (34.3)\t4 (20.0)\t0.250\t\nDPP4i (%)\t28 (80.0)\t17 (85.0)\t0.493\t\nGLP-1 agonist (%)\t2 (5.7)\t0 (0.0)\t0.160\t\nThiazolidine (%)\t2 (5.7)\t0 (0.0)\t0.160\t\nSulfonylurea (%)\t2 (5.7)\t1 (5.0)\t0.913\t\nGrinide (%)\t0 (0.0)\t0 (0.0)\t–\t\nα-GI (%)\t6 (17.1)\t4 (20.0)\t0.796\t\nData are means ± SD for normally distributed data and medians and interquartile ranges for non-normally distributed data, or n (%). All statistical tests were 2-tailed, and p < 0.05 was considered significant (*)\n\nNYHA, New York Heart Association; T2DM, type 2 diabetes mellitus; HbA1c, glycated hemoglobin; eGFR, estimated glomerular filtration rate; BNP, brain natriuretic peptide; UCG, ultrasonic echocardiography; LAD, left atrial dimension; LVDd, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVGLS, left ventricular global longitudinal strain; E/e', ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity; CMR, cardiac magnetic resonance; LVEDV, left ventricular end-diastolic volume; LVM, left ventricular mass; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; MRA, mineralocorticoid receptorantagonist; SGLT2i, sodium-glucose co-transporter 2 inhibitor; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon like peptide-1; α-GI, alpha-glucosidase inhibitor\n\nThe EMPA group patients were further divided into early DMCMP (n = 16, global ECV: 27.5 ± 1.9%) and advanced DMCMP (n = 19, global ECV: 38.7 ± 5.3%) groups. The baseline characteristics of the two groups are summarized in Table 2. There were no significant differences in age, sex, NYHA class, HbA1c, BNP, LVGLS, and E/e′. However, LVEF was significantly lower in the advanced DMCMP group than in the early DMCMP group (55.9 ± 10.0% vs. 48.4 ± 9.8%, p = 0.032). The T2DM duration of the advanced DMCMP group was significantly longer than that of the early DMCMP group (22 [19–28] vs. 99 [72–118] months, p < 0.001). Interestingly, the global ECV value was strongly correlated with T2DM duration (r2 = 0.65, p < 0.001, Fig. 3).Table 2 Baseline characteristics of EMPA group\n\n\tEarly DMCMP group (n = 16)\tAdvanced DMCMP group (n = 19)\tp value\t\nBackgrounds\t\nAge (years old)\t63.1 ± 10.4\t69.2 ± 9.0\t0.070\t\nMale gender (%)\t14 (87.5)\t12 (63.2)\t0.097\t\nBody mass index (kg/m2)\t25.3 ± 5.0\t23.1 ± 3.8\t0.147\t\nNYHA class\t2.9 ± 0.7\t3.3 ± 0.8\t0.146\t\nSystolic blood pressure (mmHg)\t127.0 ± 18.6\t119.3 ± 13.0\t0.159\t\nDiastolic blood pressure (mmHg)\t76.9 ± 7.8\t78.1 ± 9.1\t0.698\t\nHeart rate (bpm)\t80.4 ± 9.1\t78.2 ± 11.6\t0.519\t\nHypertension (%)\t13 (81.3)\t16 (84.2)\t0.823\t\nDyslipidemia (%)\t13 (81.3)\t16 (84.2)\t0.823\t\nT2DM duration (months)*\t22 (19–28)\t99 (72–118)\t < 0.001\t\nHemoglobin (g/dl)\t14.7 ± 1.8\t13.7 ± 2.7\t0.241\t\nHbA1c (%)\t8.4 ± 1.7\t8.1 ± 1.3\t0.586\t\nSodium (mEq/l)\t139.4 ± 2.3\t138.8 ± 3.9\t0.560\t\neGFR (ml/min/1.73m2)\t73.7 (73.0–77.8)\t64.7 (58.4–77.2)\t0.185\t\nBNP (pg/ml)\t459 (383–709)\t498 (285–807)\t0.894\t\nC-peptide immunoreactivity index\t1.3 ± 0.2\t1.1 ± 0.3\t0.062\t\nHematocrit (%)\t42.1 ± 3.8\t40.8 ± 5.7\t0.432\t\nUCG characteristics\t\nLAD (mm)\t43 (41–46)\t44 (39–46)\t0.987\t\nLVDd (mm)\t50 (48–53)\t52 (49–58)\t0.280\t\nLVEF (%) *\t55.9 ± 10.0\t48.4 ± 9.8\t0.032\t\nLVGLS (absolute value) (%)\t7.9 ± 2.4\t6.7 ± 3.0\t0.207\t\nE/e′\t13.2 ± 6.1\t12.6 ± 3.8\t0.694\t\nCMR characteristics\t\nLVEDV index (ml/m2)\t56.7 ± 14.4\t65.6 ± 18.4\t0.125\t\nLVM index (g/m2)\t55.9 ± 10.0\t48.4 ± 9.8\t0.698\t\nNative T1 value (ms)*\t1224.6 ± 47.4\t1365.8 ± 52.7\t < 0.001\t\nECV (%)\t27.5 ± 1.9\t38.7 ± 5.3\t–\t\nMedications\t\nβ blocker (%)\t7 (43.8)\t11 (57.9)\t0.419\t\nACEi (%)\t2 (12.5)\t2 (10.5)\t0.860\t\nARB (%)\t12 (75.0)\t14 (73.7)\t0.932\t\nLoop diuretics (%)\t13 (81.3)\t15 (78.9)\t0.823\t\nMRA (%)\t3 (18.8)\t2 (10.5)\t0.503\t\nEmpagliflozin (%)\t16 (100)\t19 (100)\t–\t\nMetformin (%)\t4 (25.0)\t8 (42.1)\t0.297\t\nDPP4i (%)\t13 (81.3)\t15 (78.9)\t0.870\t\nGLP-1 agonist (%)\t0 (0.0)\t2 (10.5)\t0.163\t\nThiazolidine (%)\t0 (0.0)\t2 (10.5)\t0.163\t\nSulfonylurea (%)\t1 (6.3)\t1 (5.3)\t0.904\t\nα-GI (%)\t1 (6.3)\t5 (26.3)\t0.109\t\nData are means ± SD for normally distributed data and medians and interquartile ranges for non-normally distributed data, or n (%). All statistical tests were 2-tailed, and p < 0.05 was considered significant (*). ECV denotes extra-cellular volume fraction. Other abbreviations as in Table 1\n\nFig. 3 Scatter plot of extracellular volume fraction (ECV) value and type 2 diabetes mellitus (T2DM) duration. The basic linear regression line shows a strong correlation between the global ECV value (y-axis) and T2DM duration (x-axis)\n\nFinally, A total of 52 patients had 12 months of complete follow-up (Fig. 2).\n\nPrimary outcomes\n\nAfter 12 months, the EMPA group showed greater improvements in LVGLS than the control group (ΔLVGLS: 2.9 ± 3.0% vs. 0.6 ± 2.2%, p = 0.005, Fig. 4). Although not significant, a positive effect of empagliflozin on E/e′ was also observed (ΔE/e′: − 1.5 ± 4.7 vs. − 0.3 ± 3.0, p = 0.253, Fig. 4).Fig. 4 Results of primary outcomes: a comparison between EMPA and control groups. Left ventricular global longitudinal strain (LVGLS; absolute value) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e′) at baseline and 12 months after enrollment are shown in (a) and (c). The primary outcomes, changes in LVGLS and E/e′ between 12 months (ΔLVGLS and ΔE/e′) are shown in (b) and (d)\n\nFurthermore, the early DMCMP group showed more remarkable improvements in both LVGLS (ΔLVGLS: 4.6 ± 1.5% vs. 1.6 ± 3.3%, p = 0.003) and E/e′ (ΔE/e′: − 3.4 ± 5.5 vs. − 0.1 ± 3.5, p = 0.043) than the advanced DMCMP group (Fig. 5).Fig. 5 Results of primary outcomes of EMPA group: a comparison between early and advanced DMCMP groups. Left ventricular global longitudinal strain (LVGLS; absolute value) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e′) at baseline and 12 months after administration of empagliflozin are shown in (a) and (c). The primary outcomes, changes in LVGLS and E/e′ between 12 months (ΔLVGLS and ΔE/e′) are shown in (b) and (d). Improvements in LVGLS and E/eʹ are more remarkable in the early DMCMP group than in the advanced DMCMP group\n\nSecondary outcomes\n\nThere were no significant differences between the EMPA and control groups, and between the early and advanced DMCMP groups in NYHA class after 12 months (1.3 ± 0.4 vs. 1.3 ± 0.5, p = 0.699, and 1.2 ± 0.4 vs. 1.3 ± 0.5, p = 0.755, Table 3) and the changes in HbA1c and BNP between baseline and after 12 months (ΔHbA1c: − 1.3 ± 1.5% vs. − 0.9 ± 0.5%, p = 0.214, and − 1.6 ± 1.5% vs. − 1.0 ± 1.4%, p = 0.249, ΔBNP: − 305 [197–504] pg/mL vs. − 302 [188–574] pg/mL, p = 0.910, and − 305 [201–400] pg/mL vs. − 398 [143–537] pg/mL, p = 0.594, Table 3).Table 3 Secondary outcomes\n\n\tEMPA group\tControl group\tp value\tEarly DMCMP group\tAdvanced DMCMP group\tp value\t\nNYHA class\t\n12 months\t1.3 ± 0.4\t1.3 ± 0.5\t0.699\t1.2 ± 0.4\t1.3 ± 0.5\t0.755\t\nHbA1c (%)\t\n12 months\t7.1 ± 0.7\t7.0 ± 0.6\t0.473\t7.0 ± 0.6\t7.2 ± 0.7\t0.527\t\nΔHbA1c\t − 1.3 ± 1.5\t − 0.9 ± 0.5\t0.214\t − 1.6 ± 1.5\t − 1.0 ± 1.4\t0.249\t\nBNP (pg/ml)\t\n12 months\t122 (106–165)\t168 (127–240)\t0.087\t113 (106–160)\t143 (106–163)\t0.605\t\nΔBNP\t − 305 (197–504)\t − 302 (188–574)\t0.910\t − 305 (201–400)\t − 398 (143–537)\t0.594\t\nData are means ± SD for normally distributed data and medians and interquartile ranges for non-normally distributed data, or n (%)\n\nAll statistical tests were 2-tailed, and p < 0.05 was considered significant (*). Abbreviations as in Table 1\n\nDiscussion\n\nThe present study showed positive effects of empagliflozin on LV functional parameters. Furthermore, the improvements were more remarkable in the early DMCMP group than in the advanced DMCMP group. HF parameters, such as NYHA class and BNP, were equally improved in both the early and advanced DMCMP groups.\n\nCharacteristics of DMCMP\n\nHyperglycemia causes LV dysfunction, which leads to the development of DMCMP [3]. LV diastolic dysfunction is a classical LV functional abnormality observed in the preclinical phase of DMCMP [5]. LV longitudinal myocardial dysfunction has also been reported as one of the earliest markers of LV dysfunction in DMCMP [4]. If LV remodeling progresses, DMCMP develops into symptomatic HF showing restrictive HFpEF or dilated HFrEF phenotypes. Phenotype-specific pathophysiological mechanisms have recently been proposed for LV dysfunction and remodeling consisting of coronary microvascular endothelial dysfunction, interstitial fibrosis, and myocardial hypertrophy in HFpEF and cardiomyocyte cell death and extensive replacement fibrosis in HFrEF [3].\n\nIn this study, symptomatic HF patients with T2DM were enrolled. Thus, although we named the group of patients with ECV ≤ 30% as the early DMCMP group, they were not strictly in the early phase. Their ECV values were as high as those reported in a previous report of patients with T2DM and normal LV function [21], but their LVGLS and E/eʹ were relatively worse than those reported in other studies targeting patients with T2DM and stable HF [11, 12]. The baseline LVEF was lower in the advanced DMCMP group than in the early DMCMP group; thus, the advanced DMCMP group patients might have a nearly dilated HFrEF phenotype. Their ECV values were very high and suggested extensive replacement fibrosis.\n\nImpact of SGLT2i on LV functional parameters\n\nIn line with previous reports using dapagliflozin [11, 12], the administration of empagliflozin also improved LV functional parameters such as LVGLS and E/e′. A previous study showed that dapagliflozin was more effective in improving LVGLS in T2DM patients with HFpEF than HFrEF [12]. Furthermore, our research targeting DMCMP with the non-HFrEF phenotype revealed that empagliflozin treatment showed greater improvements in LVGLS and E/e′ in the early phase than in the advanced phase. The potential advantage of starting the administration of SGLT2i before the progression of LV remodeling among T2DM patients is suggested.\n\nMechanisms of direct cardiac effects\n\nIt is hypothesized that the direct cardiac effects of SGLT2i depend on a reduction in intracellular sodium by inhibiting NHE-1, which is expressed in the heart and vasculature [13]. In patients with T2DM and HF, the activity of NHE-1 is markedly enhanced. This increase facilitates the accumulation of intracellular sodium, which stimulates the reverse activity of the sodium-calcium exchanger, leading to an increase in intracellular calcium and myocardial injury [22]. The inhibition of NHE-1 reduces intracellular sodium and calcium concentrations, increases mitochondrial calcium, which restores mitochondrial function and a redox state, activates ATP production in the failing heart, and thus improves LV function [13]. In animal models, SGLT2i treatment, via the inhibition of NHE-1, reduces myocardial injury and fibrosis, slows the progression of DMCMP, and improves systolic and diastolic function [23–25]. These findings suggest that empagliflozin promotes reverse LV remodeling; thus, the lesser the degree of myocardial injury and fibrosis, the greater is the extent to which LV function could be restored by SGLT2i treatment.\n\nConsidering that there were no significant intergroup differences in ΔHbA1c, the reverse LV remodeling through the inhibition of NHE-1 was independent of the main effect of SGLT2i: glycemic control by blocking glucose reabsorption through SGLT2. Side effects, such as osmotic diuresis and inhibition of NHE, may be the reason why SGLT2i treatment is associated with lowering the risk of HF exacerbation regardless of the presence or absence of T2DM. The composite of direct and indirect cardiac actions of SGLT2i could improve HF parameters even in patients with advanced DMCMP.\n\nClinical implications\n\nLV longitudinal myocardial dysfunction and diastolic dysfunction are clinically important markers observed from the preclinical phase of DMCMP [4, 5], leading to HF. In the present study, symptomatic HF patients with LVEF > 40% and T2DM were enrolled and evaluated. As a result, treatment with empagliflozin improved LV functional parameters assessed as LVGLS and E/e′, which were more remarkable in the earlier phase of DMCMP. The phase progression was correlated with T2DM duration. These are clinically important findings indicating a potential benefit of early intervention with SGLT2i in HF patients with T2DM.\n\nStudy limitations\n\nThis study has some limitations. First, this was a small observational study conducted at a single center. Therefore, several biases were possible. For instance, the advanced DMCMP group characteristics, including lower baseline LVEF, could have affected various outcomes. Although the EMPA group tended to have more remarkable improvements in E/eʹ than the control group, the difference was not significant, in contrast to a previous report [11]. We consider that the small study number and population differences, having more advanced DMCMP patients with higher baseline E/eʹ and treatment-resistance, might have affected the result. Given the study limitations, empagliflozin may have a strong positive effect on LVGLS because it was shown even in the population. In addition, there were no significant intergroup differences in the use of other medications, but the medication such as β-blocker could also have affected the result. Although a multivariate analysis adjusted for baseline characteristics should be performed to evaluate the effective factors for improving LV function, it was not possible because of the limited number of cases. Second, contrast-enhanced CMR was not carried out in the control group patients. Due to a lack of ECV evaluation in the control group, assessments with an interaction test were not possible. Furthermore, a myocardial biopsy was not performed in this study. Although we performed coronary angiography and CMR to increase the diagnostic accuracy of DMCMP, the possibility that patients with other cardiomyopathies were still included cannot be denied, especially in the control group assessed without LGE. Third, we performed only a short-term assessment of LV function. If the follow-up period was longer, LV functional parameters might have improved further in the advanced DMCMP group.\n\nConclusions\n\nEmpagliflozin had positive effects on LV function that were more remarkable in the early DMCMP group with normal ECV values than in the advanced DMCMP group with elevated ECV values. The ECV increase was strongly correlated with T2DM duration. Thus, early SGLT2i administration for patients with HF and T2DM may be preferable.\n\nAbbreviations\n\nBNP Brain natriuretic peptide\n\nCMR Cardiac magnetic resonance\n\nDMCMP Diabetes mellitus-related cardiomyopathy\n\nECV Extracellular volume fraction\n\nEF Ejection fraction\n\neGFR Estimated glomerular filtration rate\n\nE/e′ Ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity\n\nGLS Global longitudinal strain\n\nHbA1c Glycated hemoglobin\n\nHF Heart failure\n\nHFpEF Heart failure with preserved ejection fraction\n\nHFrEF Heart failure with reduced ejection fraction\n\nLGE Late gadolinium enhancement\n\nLV Left ventricular\n\nNHE Sodium-hydrogen exchanger\n\nNYHA New York Heart Association\n\nSGLT2i Sodium-glucose co-transporter 2 inhibitor\n\nT2DM Type 2 diabetes mellitus\n\nAcknowledgements\n\nNot applicable.\n\nAuthors' contributions\n\nSO designed the study, carried out participant recruitment, performed coronary angiography, analyzed the data, and wrote the manuscript. TK, KH, KW, JN, MA, and AW assisted recruitment and coronary angiography. JN and AW assisted in manuscript revision. All authors have read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was approved by the ethics committee of the Fujieda Municipal General Hospital. All participants provided written informed consent before enrollment.\n\nConsent for publication\n\nThe consent to publish was obtained from all participants.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Kannel WB McGee DL Diabetes and cardiovascular disease. The Framingham study JAMA 1979 241 19 2035 2038 10.1001/jama.1979.03290450033020 430798\n2. Boudina S Abel ED Diabetic cardiomyopathy revisited Circulation 2007 115 25 3213 3223 10.1161/CIRCULATIONAHA.106.679597 17592090\n3. Petar MS Walter JP Clinical diabetic cardiomyopathy: a two-faced disease with restrictive or dilated phenolypes Eur Heart J 2015 36 1718 1727 10.1093/eurheartj/ehv134 25888006\n4. Ernande L Bergerot C Girerd N Thibault H Davidsen ES Pignon-Blanc PG Longitudinal myocardial strain alteration is associated with left ventricular remodeling in asymptomatic patients with type 2 diabetes mellitus J Am Soc Echocardiogr 2014 27 5 479 488 10.1016/j.echo.2014.01.001 24508363\n5. Chavali V Tyagi SC Mishra PK Predictors and prevention of diabetic cardiomyopathy Diabetes Metab Syndr Obes 2013 6 151 160 23610527\n6. Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes N Engl J Med 2015 373 22 2117 2128 10.1056/NEJMoa1504720 26378978\n7. Neal B Perkovic V Mahaffey KW de Zeeuw D Fulcher G Erondu N CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes N Engl J Med 2017 377 7 644 657 10.1056/NEJMoa1611925 28605608\n8. Wiviott SD Raz I Bonaca MP Mosenzon O Kato ET Cahn A Dapagliflozin and cardiovascular outcomes in type 2 diabetes. DECLARE-TIMI 58 Investigators N Engl J Med 2019 380 4 347 357 10.1056/NEJMoa1812389 30415602\n9. McMurray JJV Solomon SD Inzucchi SE Kober L Kosiborod MN Martinez FA DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction N Engl J Med 2019 381 21 1995 2008 10.1056/NEJMoa1911303 31535829\n10. Packer M Anker SD Butler J Filippatos G Pocock SJ Carson P EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure N Engl J Med. 2020 383 15 141324 10.1056/NEJMoa2022190\n11. Soga F Tanaka H Tatsumi K Mochizuki Y Sano H Toki H Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure Cardiovasc Diabetol 2018 17 132 139 10.1186/s12933-018-0775-z 30296931\n12. Tanaka H Soga F Tatsumi K Mochizuki Y Sano H Toki H Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure Cardiovasc Diabetol 2020 19 6 14 10.1186/s12933-019-0985-z 31910853\n13. Packer M Anker SD Butler J Fillippatos G Zannad F Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action JAMA Cardiol 2017 2 9 1025 1029 10.1001/jamacardio.2017.2275 28768320\n14. Alberti KG Zimmet PZ Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation Diabet Med 1998 15 7 539 553 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S 9686693\n15. Yang EY Ghosn MG Khan MA Gramze NL Brunner G Nabi F Myocardial extracellular volume fraction adds prognostic information beyond myocardial replacement fibrosis Circ Cardiovasc Imaging 2019 12 12 e009535 10.1161/CIRCIMAGING.119.009535 31838882\n16. Wong TC Piehler KM Kang IA Kadakkal A Kellman P Schwartzman DS Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission Euro Heart J 2014 35 10 657 664 10.1093/eurheartj/eht193\n17. Iwata M Matsushita Y Fukuda K Wakura T Okabe K Koshimizu Y Secretory units of islets in transplantation index is a useful predictor of insulin requirement in Japanese type 2 diabetic patients J Diabetes Investig 2014 5 5 570 580 10.1111/jdi.12181\n18. Olivotto I Maron MS Autore C Lesser JR Rega L Casolo G Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy J Am Coll Cardiol 2008 52 7 559 566 10.1016/j.jacc.2008.04.047 18687251\n19. Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging Eur Heart J Cardiovasc Imaging 2015 16 3 233 270 10.1093/ehjci/jev014 25712077\n20. Messroghli DR Radjenovic A Kozerke S Higgins DM Sivananthan MU Ridgway JP Modified look-locker inversion recovery (MOLLI) for high-resolution T1 mapping of the heart Magn Reson Med 2004 52 141 146 10.1002/mrm.20110 15236377\n21. Cao Y Zeng W Cui Y Kong X Wang M Yu J Increased myocardial extracellular volume assessed by cardiovascular magnetic resonance T1 mapping and its determinants in type 2 diabetes mellitus patients with normal myocardial systolic strain Cardiovasc Diabetol 2018 17 1 7 18 10.1186/s12933-017-0651-2 29301529\n22. Kohlhaas M Maack C Adverse bioenergetic consequences of Na+-Ca2+ exchanger-mediated Ca2+ influx in cardiac myocytes Circulation 2010 122 22 2273 2280 10.1161/CIRCULATIONAHA.110.968057 21098439\n23. Baartscheer A Schumacher CA Wust RC Fiolet Jan WT Stienen Ger JM Coronel R Empagliflozin decreases myocardial cytoplasmic Na + through inhibition of the cardiac Na +/H + exchanger in rats and rabbits Diabetologia 2017 60 3 568 573 10.1007/s00125-016-4134-x 27752710\n24. Lin B Koibuchi N Hasegawa Y Sueta D Toyama K Uekawa K Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice Cardiovasc Diabetol 2014 13 148 162 10.1186/s12933-014-0148-1 25344694\n25. Habibi J Aroor AR Sowers JR Jia G Hayden MR Garro M Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes Cardiovasc Diabetol 2017 16 1 9 23 10.1186/s12933-016-0489-z 28086951\n\n",
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"abstract": "A 47-year-old man with ulcerative colitis was transferred to our hospital due to progressive dyspnea. Electrocardiography on admission showed ST elevation in leads II, III, aVF, and V5-V6. Coronary angiography revealed no remarkable coronary stenosis, and left ventriculography showed a depressed left ventricular ejection fraction (EF) of 23%. Although the patient received percutaneous cardiopulmonary support, his EF progressively decreased (7-15%), and both ventricular tachycardia (VT) and high-degree atrial-ventricular block occurred. An endomyocardial biopsy showed eosinophilic infiltration in the myocardium. Steroid therapy improved the patient's EF. However, his severe inferior wall hypokinesis and non-sustained VT remained after the abovementioned treatment.",
"affiliations": "Department of Cardiology, Nagaoka Chuo General Hospital, Japan.;Department of Cardiology, Nagaoka Chuo General Hospital, Japan.;Department of Cardiology, Niigata Cancer Center Hospital, Japan.;Department of Cardiology, Nagaoka Chuo General Hospital, Japan.;Department of Hematology, Nagaoka Chuo General Hospital, Japan.;Department of Cardiology, Nagaoka Chuo General Hospital, Japan.;Department of Cardiology, Nagaoka Chuo General Hospital, Japan.;Yuzawa Community Medical Center, Japan.;Graduate School of Health Science, Niigata University School of Medicine, Japan.",
"authors": "Tagawa|Minoru|M|;Nakamura|Yuichi|Y|;Okura|Yuji|Y|;Nanba|Hitomi|H|;Kishi|Kenji|K|;Akashi|Erina|E|;Ochiai|Yukie|Y|;Asai|Yasuhiro|Y|;Chinushi|Masaomi|M|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3056813010.2169/internalmedicine.1528-18Case ReportSuccessful Treatment of Acute Fulminant Eosinophilic Myocarditis in a Patient with Ulcerative Colitis Using Steroid Therapy and Percutaneous Cardiopulmonary Support Tagawa Minoru 1Nakamura Yuichi 1Okura Yuji 2Nanba Hitomi 1Kishi Kenji 3Akashi Erina 1Ochiai Yukie 1Asai Yasuhiro 4Chinushi Masaomi 5\n1 Department of Cardiology, Nagaoka Chuo General Hospital, Japan\n2 Department of Cardiology, Niigata Cancer Center Hospital, Japan\n3 Department of Hematology, Nagaoka Chuo General Hospital, Japan\n4 Yuzawa Community Medical Center, Japan\n5 Graduate School of Health Science, Niigata University School of Medicine, JapanCorrespondence to Dr. Minoru Tagawa, [email protected]\n\n18 12 2018 15 4 2019 58 8 1111 1118 12 5 2018 4 9 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 47-year-old man with ulcerative colitis was transferred to our hospital due to progressive dyspnea. Electrocardiography on admission showed ST elevation in leads II, III, aVF, and V5-V6. Coronary angiography revealed no remarkable coronary stenosis, and left ventriculography showed a depressed left ventricular ejection fraction (EF) of 23%. Although the patient received percutaneous cardiopulmonary support, his EF progressively decreased (7-15%), and both ventricular tachycardia (VT) and high-degree atrial-ventricular block occurred. An endomyocardial biopsy showed eosinophilic infiltration in the myocardium. Steroid therapy improved the patient's EF. However, his severe inferior wall hypokinesis and non-sustained VT remained after the abovementioned treatment. \n\nfulminant myocarditiseosinophilic myocarditisventricular tachycardiaatrial-ventricular blockpercutaneous cardiopulmonary supportsteroid therapy\n==== Body\nIntroduction\nEosinophilic myocarditis (EM) is a relatively rare disorder, characterized by eosinophilic infiltration. EM can be caused by infections or allergic diseases (1, 2). The disease is often fatal, and a particularly high in-hospital mortality rate has been reported when EM presents in the fulminant form (also known as acute necrotizing EM) (3, 4). Myocarditis associated with ulcerative colitis (UC) is also a rare disorder with a serious risk of mortality (5, 6). An endomyocardial biopsy facilitates the definite diagnosis of EM (7, 8), and steroid therapy has been used for the treatment of EM (9). In this report, we describe the case of a 47-year-old man who had fulminant EM complicated with UC. He also experienced ventricular tachycardia (VT) and high-degree atrial-ventricular (A-V) block. He was ultimately treated with steroid therapy which improved the patient's left ventricular function.\n\nCase Report\nA 47-year-old man was referred to our hospital from another medical clinic with progressive dyspnea and left ventricular dysfunction on echocardiography (UCG). He had been treated for UC with 5-aminosalicylic acid (5-ASA) (Asacol, 2,400 mg/day) for 15 years at the hospital. He complained of a common cold two days before he was transported to our hospital due to worsening of his dyspnea at rest.\n\nUpon arrival at the emergency room, he was alert with a blood pressure of 127/88 mmHg and body temperature of 37.3℃. An electrocardiogram (ECG) showed sinus rhythm with a heart rate of 103 beats per minute, ST elevation in leads I, II, III, aVF, and V5-V6, and ST depression in leads V1-V2 (Fig. 1A). The hematological and serological examination results demonstrated positive troponin T and elevated levels of alanine transaminase (ALT) and lactate dehydrogenase (LDH). The patient's creatine kinase (CK), creatine kinase-muscle/brain (CPK-MB), and brain natriuretic peptide (BNP) levels were elevated (CK: 2,255 IU/L, CPK-MB: 178 IU/L, and BNP: 1,342.04 pg/mL). His C-creative protein (CRP) level was also elevated (9.90 mg/dL). In contrast, count of both leukocytes [white blood cells (WBCs)] and eosinophils were within the normal ranges (WBC: 5,290/μL, eosinophils: 30/μL). Chest radiography revealed cardiomegaly [Cardio-Thoracic ratio (CTR)=56.2%] without lung congestion. UCG showed a normal-sized left ventricle (LV), diffuse hypokinesis of the LV with an ejection fraction (EF) of 30%, particularly severe hypokinesis lateral to the posterior wall, and mild hypertrophy of the LV wall.\n\nFigure 1. Electrocardiogram (ECG) changes during admission. (A) ECG obtained on admission shows a sinus rhythm with a heart rate of 103 beats per minute, ST elevation in leads I, II, III, aVF, and V5-V6, and ST depression in leads V1-V2. (B) ECG performed on day 4 after admission shows complete left bundle branch brock (CLBBB) and intermittent I-III-degree atrioventricular (A-V) block intermittently. (C) ECG performed after recovery shows improvement in the poor R voltages and wide QRS. Abnormal Q waves in leads III, and aVF and inverted T wave in leads in II, III, aVF, and V6 remain.\n\nAfter obtaining informed consent, we performed cardiac catheterization. The right ventricular pressure and LV end diastolic pressure (EDP) were evaluated [pulmonary artery=34/21 (26) mmHg; LV=112/EDP 34 mmHg]. The cardiac index (CI) was 1.58 L/min/m2. Coronary angiography revealed no remarkable coronary stenosis. Left ventriculography showed a depressed LVEF of 23.0% with diffuse hypokinesis and particularly severe hypokinesis with inferior to the posterior wall (Fig. 2A). We suspected fulminant myocarditis and performed an endomyocardial biopsy. Intra-aortic balloon pump (IABP) support was then initiated. Immunoglobulin therapy (60 g/day) and continuous intravenous heparin infusion (15,000 μ/day) were started to prevent LV thrombosis.\n\nFigure 2. Left ventriculography (LVG) performed on admission and echocardiography (UCG) performed on day 3 after admission. (A) Left ventricle angiography showing a depressed left ventricular ejection fraction (LVEF) of 23.0% with diffuse hypokinesis, with paticulary severe inferior-to-posterior wall hypokinesis. (B) UCG on day 3 after admission showing that the left ventricular (LV) function was decreased, with an ejection fraction of 15%. Thickening of the LV wall can be seen.\n\nOn the day after admission, the patient's dyspnea had progressed, and his systolic blood pressure had decreased to 80 mmHg. His CI decreased from 3.0 to 0.7-1.2 L/min/m2 with IABP support. An ECG revealed abnormal Q waves in leads II, III, and aVF. Percutaneous cardiopulmonary support (PCPS) and temporary pacing were initiated under ventilator support. Administration of 5-ASA (Pentasa 3,000 mg/day) was continued with a nasotracheal tube to prevent worsening of UC.\n\nOn days 3-5 after admission, the patient's systolic blood pressure was decreased to 60 mmHg, and his cardiac function deteriorated (CI=0.5-0.7 L/min/m2) despite PCPS, IABP (Fig. 3), and intravenous administration of dopamine and dobutamine. An ECG revealed complete left bundle branch brock (CLBBB) and intermittent I-III-degree A-V block (Fig. 1B). Chest radiography revealed cardiomegaly and progressive lung congestion (Fig. 4A). UCG showed that the patient's LV function had decreased (EF=8-11%), and the LV wall had become thick (13.6-15.2 mm) (Fig. 2B). Furthermore, non-sustained to sustained monomorphic VT occurred frequently, necessitating electrical cardioversion to sinus rhythm (Fig. 5). The CK and CPK-MB levels were consistently evaluated (CK: 786-2,262 IU/L, CPK-MB: 33-178 IU/L). The patient's eosinophil count remained within the normal ranges (10-30/μL) (Fig. 3).\n\nFigure 3. The clinical course of the acute phase. The CI and EF via two-dimensional echocardiography decreased after admission despite PCPS, IABP, and intravenous catecholamine infusion. The CI and EF improved with steroid treatment. LV dysfunction lasted until day 11 after admission; PCPS support was used for 15 days. The peripheral eosinophilia count is within the normal range. CI: cardiac index, EF: ejection fraction, WBC: leukocyte, Eosino: eosinophil, CK: creatine kinase, CPK-MB: creatine kinase-muscle/brain, PCPS: percutaneous cardiopulmonary support, IABP: intra-aortic balloon pumping, mPSL: methylprednisolone, PSL: prednisolone\n\nFigure 4. Chest radiography performed during admission. (A) Chest radiography performed on day 4 after admission showing cardiomegaly and progression of lung congestion. (B) Chest radiography performed after recovery showing a decrease in the cardiothoracic rate and the disappearance of lung congestion.\n\nFigure 5. Electrocardiography results. ECG showing monomorphic sustained ventricular tachycardia (VT) with a rate of 150 beats per minute on day 4 after admission. The patient’s blood pressure decreased to 40-50 mmHg with sustained VT. Electrical cardioversion (which was allowed in the present case) was needed to recover to sinus rhythm.\n\nOn day 5 after admission, the histological results of the endomyocardial biopsy revealed inflammation caused by eosinophilia, degranulation of eosinophil granules and damage to the myocardial muscles (Fig. 6). These findings were compatible with fulminant EM (acute necrotizing EM). Steroid pulse therapy (methylprednisolone 1,000 mg/day×3 days) was initiated, followed by intravenous administration of methylprednisolone at 125 mg/day. Administration of 5-ASA acid was discontinued.\n\nFigure 6. Histological images of an endocardial biopsy. (A, B) Eosinophilia and lymphocyte infiltration and damage to the myocardial muscles (Hematoxylin and Eosin (H&E) staining) (A: ×100, B: ×400). (C, D) Infiltration of eosinophils and degranulation of eosinophil granules (C: H&E staining, ×600, D: direct fast scarlet stain, ×600).\n\nAfter starting the patient on steroid therapy, his blood pressure improved to 90 mmHg. On day 7 after admission, his ST-T elevation in leads II, IIII, aVF, and V5-V6, CLBBB, and A-V block improved. In contrast, non-sustained and sustained VT reproducibly occurred but were suppressed by intravenous administration of amiodarone.\n\nThe patient's LV dysfunction remained consistently decreased (EF=21-23%, CI=0.7-0.8 L/min/m2) until day 11 after admission. PCPS support was needed for 15 days in total (Fig. 3). To discontinue PCPS support, intravenous administration of milrinone (0.125 μg/kg/min) was started for 2 days. IABP was also discontinued on day 18 after admission.\n\nThe patient's cardiac function improved from this point. An ECG showed that the patient's poor R voltages and wide QRS had improved. However, abnormal Q waves in leads III and aVF and inverted T wave in leads in II, III, aVF, and V6 remained (Fig. 1C). The patient's cardiomegaly and lung congestion had improved on chest radiography (Fig. 4B). UCG revealed improvement in the LV function but severe hypokinesis with inferior-to-posterior thinning of the LV wall (Fig. 7B). We started the patient on anticoagulant treatment. We switched him from intravenous methylprednisolone to oral prednisolone (60 mg/day), which was tapered carefully to 17.5 mg/day at discharge, and the outpatient maintenance dose was tapered to 10 mg/day. Although a low dose of beta-blocker (carvedilol at 1.25 to 2.5 mg/day) was also started to prevent heart failure and VT, the beta-blocker was discontinued because of the patient's decreased blood pressure and heart rate. Therefore, oral amiodarone (200 mg/day) was started to prevent VT recurrence.\n\nFigure 7. Left ventriculography (LVG) and echocardiography (UCG) performed after recovery. (A) LVG showing a left ventricular ejection fraction (LVEF) of 40.5% with severe inferior-to-posterior wall hypokinesis associated with aneurysmal changes. (B) UCG showing improvement in the LV function. Inferior to posterior wall hypokinesis remains associated with the thinning of the LV wall.\n\nAfter the patient provided his informed consent, we performed cardiac catheterization on day 82 after admission. The right ventricular pressure and LV EDP were normalized (pulmonary artery=24/9 mmHg (12); LV=101/EDP 7 mmHg). His CI was 3.59 L/min/m2. Left ventriculography revealed an LVEF of 40.5% with severe hypokinesis and aneurysmal changes to the inferior-to-posterior wall (Fig. 7A). The histological results of the endomyocardial biopsy revealed no infiltration of eosinophils. The patient did not agree to the treatment of an implantable cardioverter defibrillator (ICD). Myocarditis, congestive heart failure, and ventricular arrhythmic attack did not occur as a result of treatment during a follow-up period of 61 months.\n\nDiscussion\nIn the present case, severe LV dysfunction in addition to episode of VT and high-degree A-V block continued for several days despite IABP and PCPS support due to acute fulminant EM. Steroid therapy after the histological diagnosis of EM improved the LV function. However, severe hypokinesis with thinning of the inferior-to-posterior wall of the LV and non-sustained VT remained in the long term.\n\nAs mentioned previously, EM is a rare form of myocardial inflammation characterized by eosinophilic infiltration that is often accompanied by peripheral eosinophilia (1, 2, 10, 11). The disease is often fatal, with high in-hospital mortality rates, particularly when it presents in the fulminant form (1, 3, 4, 12). Patients with fulminant myocarditis have an increased risk of mortality compared to patients with non-fulminant myocarditis and often require mechanical circulatory support, including PCPS and ventricular assist devices, as well as heart transplantation (13). The present patient had a decreased blood pressure and cardiac function despite receiving IABP and PCPS. Furthermore, both VT and A-V block occurred frequently. Although we had treated him under the diagnosis of fulminant myocarditis, his clinical course was very serious.\n\nDespite this serious clinical course, the patient's peripheral eosinophil count was within the normal range (14, 15). This meant that we were unable to arrive at a diagnosis of EM until a histological analysis of his myocardial biopsy sample revealed eosinophilc infiltration into the myocardium. Brambatti et al. reported that peripheral eosinophilia is absent in up to 25% of the patients with EM and that this fact probably contributes to the underdiagnosis of EM without an endomyocardial biopsy and the high rate of a diagnosis only after sudden death (1). In that report, only 5 of 39 (12.8%) patients without eosinophilia at admission developed peripheral eosinophilia between the second and sixth days of hospitalization (1). Morimoto et al. also reported that the initial eosinophil count was <500/mm3 in 50% of the patients with EM, and the reason why eosinophilia is not present in the peripheral blood in some patients with EM may be that peripheral blood eosinophils migrate into the tissues, with the bone marrow unable to respond immediately with increased production (14). In addition, the steroid therapy administered after days 5 might have reduced the percentage of peripheral eosinophils and thereby masked the elevation of the eosinophil count in the present case (4, 16).\n\nAn endomyocardial biopsy is the gold standard for diagnostic testing (7, 8, 17). Indeed, an endomyocardial biopsy revealed EM in the present case, leading to steroid therapy that ultimately improved the patient's LV dysfunction. In the long term, a histological analysis of an endomyocardial biopsy sample revealed no eosinophilia.\n\nUC is a severe disease with many extra-colonic manifestations, such as skin involvement, rheumatic problems, and ocular complications. The frequency of myocarditis associated with UC has been studied only rarely, but there appears to be a high risk of mortality in these patients (5, 6). The mechanisms of myocarditis associated with UC have not been fully elucidated. Controversy surrounds whether steroid therapy is always necessary for the treatment of EM (1). In contrast, some reports have shown that the treatment of myocarditis with and without eosinophilia associated with UC is focused and effective for the management of UC, often using steroid therapy and/or immunosuppression therapy along with heart failure therapy (6, 18). Previous reports have also demonstrated that steroid therapy is a frequently used and effective treatment for EM patients with UC (6). In the present case, steroid therapy may have been effective for the treatment of both EM and UC. A prompt diagnosis and treatment can lead to the resolution of cardiac dysfunction in these cases.\n\nEosinophilic infiltration to the myocardium has been described as a hypersensitivity response induced by a variety of causes, including drugs, parasitic infections, and neoplasia (1). EM is frequently encountered in autoimmune disorders, such as Churg-Strauss syndrome and Löffler's disease (19). 5-ASA, also known as mesalamine or mesalazine, and its derivatives remain key in the treatment of UC and provide disease-free maintenance therapy (20). However, some reports have revealed that the use of medications containing 5-ASA may cause a rare but potentially lethal side effect involving inflammation in the form of myocarditis or pericarditis (21, 22). In the present case, the patient had previously been treated with 5-ASA, and we were unable to completely rule out the possibility of 5-ASA-associated EM. However, before admission, the patient had been treated with 5-ASA for 15 years without experiencing any 5-ASA-induced complications. The key distinguishing feature of 5-ASA-induced inflammation is the appearance of symptoms and signs shortly after the initiation of 5-ASA therapy (21). It should also be noted that the discontinuation of treatment for UC can induce severe complications, such as the bleeding from the colon seen in the present case. Furthermore, the UC had not worsened under treatment with 5-ASA and steroid therapy. The patient had cold-like symptoms 2 days before the onset of the remaining symptoms, and his symptoms had failed to resolve by 11 days after admission despite the discontinuation of 5-ASA administration. These facts suggested the possibility that the EM was triggered by an infection and associated with UC rather than hypersensitivity to 5-ASA.\n\nIntravenous immunoglobulin has been used to treat several autoimmune or inflammatory diseases. Some reports have demonstrated the effectiveness of intravenous immunoglobulin therapy against fulminant myocarditis (23). Although intravenous immunoglobulin was also used in some cases with EM, its effectiveness in this respect is still unclear (16, 17). The present patient was diagnosed with fulminant myocarditis, and intravenous immunoglobulin was started on the admission day. However, there was no obvious improvement of the LV dysfunction. Therefore, whether or not intravenous immunoglobulin is effective for EM should be investigated in the future.\n\nEM often present in the fulminant form, with abrupt impairment of the LV function and a high risk of malignant arrhythmia (1). Many of these patients experience complete recovery of their cardiac function before discharge (1, 24). In the present case, the patient's myocardial damage persisted, and non-sustained VT occurred. The patient's LV dysfunction lasted for 15 days after admission, resulting in potentially severe myocardial damage due to inflammation. In patients complicated with LV dysfunction due to myocarditis, it is important to determine whether or not chronic myocarditis remains.\n\nIn conclusion, the details of this case report suggest that patients with EM should be carefully treated and followed-up to ensure that the long-term outcomes are satisfactory.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Brambatti M , Matassini MV , Adler ED , Klingel K , Camici PG , Ammirati E \nEosinophilic myocarditis: characteristics, treatment, and outcomes . J Am Coll Cardiol \n70 : 2363 -2375 , 2017 .29096807 \n2. Kindermann I , Barth C , Mahfound F , et al \nUpdate on myocarditis . J Am Coll Cardiol \n59 : 779 -792 , 2012 .22361396 \n3. Herzog CA , Snover DC , Staley NA \nAcute necrotizing eosinophilic myocarditis . Br Heart J \n52 : 343 -348 , 1984 .6466521 \n4. Watanabe N , Nakagawa S , Fukunaga T , Fukunaga S , Hatakeyama K , Hayashi T \nAcute necrotizing eosinophilic myocarditis successfully treated by high dose methylprednisolone . Jpn Circ J \n65 : 923 -926 , 2001 .11665801 \n5. Mowat NAG , Bennett N , Finlayson JK , Brunt PW , Lancaster WM \nMyocarditis complicating ulcerative colitis . Br Heart J \n36 : 724 -727 , 1974 .4414769 \n6. Murphy K , Waldo O , Lohrmann GM , Tazelaar HD , Jokerst CE , Mookadam F \nEosinophilia and ulcerative colitis associated with eosinophilic myocarditis . Tex Heart Inst J \n44 : 219 -222 , 2017 .28761405 \n7. Maisch B , Pankuweit S \nCurrent treatment options in (peri)myocarditis and inflammatory cardiomyopathy . Herz \n37 : 644 -656 , 2012 .22996288 \n8. Callan PD , Baltabaeva A , Kamal M , et al \nAcute fulminant necrotizing eosinophilic myocarditis: early diagnosis and treatment . ESC Heart Failure \n4 : 660 -664 , 2017 .29154424 \n9. Kawano S , Kato J , Kawano N , et al \nClinical features and outcomes of eosinophilic myocarditis patients treated with prednisolone ant a single institution over a 27-year period . Intern Med \n50 : 975 -981 , 2011 .21532219 \n10. Ginsberg F , Parrillo JE \nEosinophilic myocarditis . Heart Failure Clin \n1 : 419 -429 , 2005 .\n11. French AJ , Weller CV \nInterstitial myocarditis following the clinical and experimental use of sulfonamide drugs . Am J Pathl \n18 : 109 -121 , 1942 .\n12. Sabatine MS , Poh KK , Mega JL , Shepard JA , Stone JR , Frosch MP \nCase records of the Massachusetts general hospital. Case 36-2007. A 31-year-old woman with rash, fever, and hypotension . N Engl J Med \n21 : 2167 -2178 , 2007 .\n13. Saito S , Toda K , Myagawa S , et al \nDiagnosis, medical treatment, and stepwise mechanical circulatory support for fulminant myocarditis . J Artif Organs \n21 : 172 -179 , 2018 .29236180 \n14. Morimoto S , Kubo N , Hiramitsu S , et al \nChanges in the peripheral eosinophil count in patients with acute eosinophilic myocarditis . Heart Vessels \n18 : 193 -196 , 2003 .14520487 \n15. Fozing T , Zouri N , Tost A , Breit R , Seeck G , Koch C , Oezbek C \nManagement of a patient with eosinophilic myocarditis and normal peripheral eosinophil count: case report and literature review . Cir Heart Fail \n7 : 692 -694 , 2014 .\n16. Yonenaga A , Hasumi E , Fujiu K , et al \nPrognostic improvement of acute necrotizing eosinophilic myocarditis (ANEM) through a rapid pathological diagnosis and appropriate therapy . Int Heart J \n59 : 641 -646 , 2018 .29628475 \n17. Howell E , Paivanas N , Stern J , Vidula H \nTreatment of acute necrotizing eosinophilic myocarditis with immunosuppression and mechanical circulatory support . Cir Heart Fail \n9 : e003665 , 2016 .\n18. Varnavas V , Reisch N , Perrey M , et al \nRecurrent lymphocyte myocarditis in a young male with ulcerative colitis . Eur J Med Res \n19 : 11 , 2014 .24576324 \n19. Setoguchi M , Okishige K , Sugiyama K , et al \nSudden cardiac death associated with Churg-Strauss syndrome . Cir J \n73 : 2355 -2359 , 2009 .\n20. Dignass A , Lindsay JO , Sturm A , et al \nSecond European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management . J Crohns Colitis \n6 : 991 -1030 , 2012 .23040451 \n21. Brown G \n5-aminosalicylic acid-associated myocarditis and pericarditis: a narrative review . Can J Hosp Pharm \n69 : 466 -472 , 2016 .28123193 \n22. Ishikawa N , Imamura T , Nakajima K , et al \nAcute pericarditis associated with 5-aminosalicylic acid (5-ASA) treatment for severe active ulcerative colitis . Intern Med \n40 : 901 -904 , 2001 .11579953 \n23. Kishimoto C , Shioji K , Hashimoto T , et al \nTherapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy: analysis of leukocyte balance . Heart Vessels \n29 : 336 -342 , 2014 .23702697 \n24. Al Ali AM , Straatman LP , Allard MF , Ignaszewski AP \nEosinophilic myocarditis: case series and review of literature . Can J Cardiol \n22 : 1233 -1237 , 2006 .17151774\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(8)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "atrial-ventricular block; eosinophilic myocarditis; fulminant myocarditis; percutaneous cardiopulmonary support; steroid therapy; ventricular tachycardia",
"medline_ta": "Intern Med",
"mesh_terms": "D003093:Colitis, Ulcerative; D004802:Eosinophilia; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis; D062645:Percutaneous Coronary Intervention; D013256:Steroids; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome; D016277:Ventricular Function, Left",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1111-1118",
"pmc": null,
"pmid": "30568130",
"pubdate": "2019-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11579953;11665801;14520487;17151774;17386864;18032767;19491508;19970609;21532219;22361396;22996288;23040451;23702697;24576324;25028351;27940496;28123193;28761405;29096807;29154424;29236180;29628475;4414769;6466521",
"title": "Successful Treatment of Acute Fulminant Eosinophilic Myocarditis in a Patient with Ulcerative Colitis Using Steroid Therapy and Percutaneous Cardiopulmonary Support.",
"title_normalized": "successful treatment of acute fulminant eosinophilic myocarditis in a patient with ulcerative colitis using steroid therapy and percutaneous cardiopulmonary support"
}
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"primarysource": {
"literaturereference": "Tagawa M, Nakamura Y, Okura Y, Nanba H, Kishi K, Akashi E et al.. Successful treatment of acute fulminant eosinophilic myocarditis in a patient with ulcerative colitis using steroid therapy and percutaneous cardiopulmonary support. INTERNAL MEDICINE. 2019;58 (8):1111-8",
"literaturereference_normalized": "successful treatment of acute fulminant eosinophilic myocarditis in a patient with ulcerative colitis using steroid therapy and percutaneous cardiopulmonary support",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20211202",
"receivedate": "20190618",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16446684,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220304"
},
{
"companynumb": "JP-ALLERGAN-1924168US",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021252",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "2400 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COLITIS ULCERATIVE",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
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"drugstructuredosagenumb": "2400",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MESALAZINE UNK"
}
],
"patientagegroup": null,
"patientonsetage": "47",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Product use issue",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Left ventricular dysfunction",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Eosinophilic myocarditis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Atrioventricular block",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TAGAWA M, NAKAMURA Y, OKURA Y, NANBA H, KISHI K, AKASHI E, ET AL. SUCCESSFUL TREATMENT OF ACUTE FULMINANT EOSINOPHILIC MYOCARDITIS IN A PATIENT WITH ULCERATIVE COLITIS USING STEROID THERAPY AND PERCUTANEOUS CARDIOPULMONARY SUPPORT. INTERNAL MEDICINE. 2019?58(8):1111-1118",
"literaturereference_normalized": "successful treatment of acute fulminant eosinophilic myocarditis in a patient with ulcerative colitis using steroid therapy and percutaneous cardiopulmonary support",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190611",
"receivedate": "20190611",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16414899,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190711"
}
] |
{
"abstract": "A 50-year-old man developed acute sub-massive pulmonary thromboembolism and proximal deep venous thrombosis. A continuous intravenous infusion of unfractionated heparin (UFH) was started, and an inferior vena cava (IVC) filter was implanted. He developed symptomatic complete obstruction of the filter 6 days after the initiation of UFH, and he was transferred to our hospital. We started pulse-spray catheter-directed thrombolysis (CDT) with urokinase. However, thrombocytopenia occurred 11 days after the initiation of heparin. We suspected heparin-induced thrombocytopenia (HIT) with thrombosis (HITT), and switched from UFH to argatroban. In addition, we continued pulse-spray CDT. As a result, thrombocytopenia improved and thrombolysis was successful without complications of recurrent thromboembolism or bleeding, leading to retrieval of the IVC filter. The antigen assay for HIT was strongly positive, supporting our diagnosis. In patients with suspected HIT it is important to switch from heparin to an alternative anticoagulant as soon as possible, and pulse-spray CDT with urokinase and argatroban as anticoagulant therapy may be effective treatment for thrombo-occlusions of IVC filters in patients with HITT. <Learning objective: Thrombo-occlusion is a serious complication of inferior vena cava filters. Anticoagulant therapy alone is not effective for dissolving thrombo-occlusions of inferior vena cava filters. In patients with heparin-induced thrombocytopenia with thrombosis, pulse-spray catheter-directed thrombolysis with urokinase and argatroban as anticoagulant therapy may be effective treatment for venous thrombo-occlusion.>.",
"affiliations": "Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.",
"authors": "Ogihara|Yoshito|Y|;Yamada|Norikazu|N|;Matsuda|Akimasa|A|;Ota|Satoshi|S|;Ito|Masaaki|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2015.12.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "13(4)",
"journal": "Journal of cardiology cases",
"keywords": "Heparin-induced thrombocytopenia; Pulse-spray catheter-directed thrombolysis; Thrombo-occlusion of inferior vena filter",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "112-116",
"pmc": null,
"pmid": "30546621",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": "23932558;9840035;12752095;23403505;22172244;17721634;16169262;21701111;22315270;16113796",
"title": "Pulse-spray catheter-directed thrombolysis with urokinase and argatroban for thrombo-occlusion of an inferior vena cava filter due to heparin-induced thrombocytopenia with thrombosis.",
"title_normalized": "pulse spray catheter directed thrombolysis with urokinase and argatroban for thrombo occlusion of an inferior vena cava filter due to heparin induced thrombocytopenia with thrombosis"
}
|
[
{
"companynumb": "JP-WATSON-2016-03978",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "017064",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "CONTINUOUS INTRAVENOUS INFUSION",
"drugenddate": null,
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"medicinalproduct": "HEPARIN"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "017064",
"drugbatchnumb": "UNCONFIRMED",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "CONTINUOUS INTRAVENOUS INFUSION",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PULMONARY EMBOLISM",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"medicinalproduct": "HEPARIN"
}
],
"patientagegroup": null,
"patientonsetage": "50",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Inferior vena caval occlusion",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Thrombosis",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Heparin-induced thrombocytopenia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OGIHARA Y, YAMADA N, MATSUDA A, OTA S, ITO M. PULSE-SPRAY CATHETER-DIRECTED THROMBOLYSIS WITH UROKINASE AND ARGATROBAN FOR THROMBO-OCCLUSION OF AN INFERIOR VENA CAVA FILTER DUE TO HEPARIN-INDUCED THROMBOCYTOPENIA WITH THROMBOSIS. J CARDIOL CASES. 2016?-:-",
"literaturereference_normalized": "pulse spray catheter directed thrombolysis with urokinase and argatroban for thrombo occlusion of an inferior vena cava filter due to heparin induced thrombocytopenia with thrombosis",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20160226",
"receivedate": "20160226",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12118578,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160526"
},
{
"companynumb": "JP-SHENZHEN TECHDOW PHARMACEUTICAL CO. LTD-JP-2016TEC0000021",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
"drugadministrationroute": "042",
"drugauthorizationnumb": "202732",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "DF, CONTINUOUS INFUSION [UNFRACTIONATED]",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PULMONARY EMBOLISM",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HEPARIN SODIUM INJECTION USP, PRESERVATIVE FREE"
},
{
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"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": "202732",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DEEP VEIN THROMBOSIS",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "HEPARIN SODIUM INJECTION USP, PRESERVATIVE FREE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": "202732",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTICOAGULANT THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HEPARIN SODIUM INJECTION USP, PRESERVATIVE FREE"
}
],
"patientagegroup": null,
"patientonsetage": "50",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": "65.2",
"reaction": [
{
"reactionmeddrapt": "Inferior vena caval occlusion",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Antithrombin III deficiency",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Thrombosis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Heparin-induced thrombocytopenia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Oedema peripheral",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OGIHARA Y, YAMADA N, MATSUDA A, OTA S, ITO M.. PULSE-SPRAY CATHETER-DIRECTED THROMBOLYSIS WITH UROKINASE AND ARGATROBAN FOR THROMBO-OCCLUSION OF AN INFERIOR VENA CAVA FILTER DUE TO HEPARIN-INDUCED THROMBOCYTOPENIA WITH THROMBOSIS.. J CARDIOL CASES. 2016;13(4):112-116",
"literaturereference_normalized": "pulse spray catheter directed thrombolysis with urokinase and argatroban for thrombo occlusion of an inferior vena cava filter due to heparin induced thrombocytopenia with thrombosis",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20160707",
"receivedate": "20160707",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12537660,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
}
] |
{
"abstract": "Loeys-Dietz syndrome is a recently described condition which causes cardiovascular, craniofacial, neurocognitive and skeletal abnormalities due to mutations in components of the transforming growth factor-β signalling pathway. Associated vascular abnormalities include vessel tortuosity and an increased incidence of vascular dissection. Pregnancy increases the risk of aortic dissection compared to non-pregnant individuals and an underlying condition such as Loeys-Dietz syndrome increases this further. While aortic dissection is well described in pregnancy in Loeys-Dietz syndrome, some women can have uncomplicated deliveries, particularly when the risks of the condition are actively managed. Such pregnancies should be considered high-risk, and women should be counselled and managed accordingly. Here we describe two pregnancies in one woman, both with successful outcomes, followed by a summary of the key management principles.",
"affiliations": "Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Coombe Women and Infants University Hospital, Dublin, Ireland.;Department of Cardiology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Oxford University Hospitals NHS Foundation Trust, Oxford, UK.",
"authors": "Thomas|Katharine E|KE|https://orcid.org/0000-0002-7788-4663;Hogan|Jennifer|J|;Pitcher|Alex|A|;Mackillop|Lucy|L|;Blair|Edward|E|;Frise|Charlotte J|CJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X19852819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "14(1)",
"journal": "Obstetric medicine",
"keywords": "Loeys–Dietz syndrome; aortic dissection",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "42-45",
"pmc": null,
"pmid": "33995573",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "16928994;20838339;29270370;15731757;31043570;27780078;28082385;24086486;16601194;30165544;27708702;24577266;10489951",
"title": "Loeys-Dietz syndrome in pregnancy.",
"title_normalized": "loeys dietz syndrome in pregnancy"
}
|
[
{
"companynumb": "NVSC2021GB156323",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": "75527",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK(MATERNAL DOSE: INCREASED TO TWICE DAILY)",
"drugenddate": null,
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"drugindication": null,
"drugintervaldosagedefinition": null,
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"medicinalproduct": "BISOPROLOL"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": null,
"drugadministrationroute": "064",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK (MATERNAL DOSE: 1.25 MG)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BISOPROLOL"
}
],
"patientagegroup": "1",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Premature baby",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "THOMAS KE, HOGAN J, PITCHER A, MACKILLOP L, BLAIR E, FRISE CJ. LOEYS?DIETZ SYNDROME IN PREGNANCY. OBSTETRIC MEDICINE. 2021?14(1):42?5",
"literaturereference_normalized": "loeys dietz syndrome in pregnancy",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20210921",
"receivedate": "20210714",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19566418,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20211014"
},
{
"companynumb": "US-BAYER-2015-431023",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "999999",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS OF ABORTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACETYLSALICYLIC ACID({=100 MG)"
}
],
"patientagegroup": "5",
"patientonsetage": "22",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Premature labour",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Pyelonephritis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Nephrolithiasis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Premature delivery",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Flank pain",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZOZZARO-SMITH P; BACAK S; SELIGMAN N. LOEYS-DIETZ SYNDROME IN PREGNANCY. CASE REPORTS IN PERINATAL MEDICINE. 2015;4 (2):113-115",
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"qualification": "3",
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},
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"receivedate": "20150930",
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},
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"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
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"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20151125"
},
{
"companynumb": "NVSC2021GB156317",
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{
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},
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"medicinalproduct": "LEVOTHYROXINE."
}
],
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"reaction": [
{
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "THOMAS KE, HOGAN J, PITCHER A, MACKILLOP L, BLAIR E, FRISE CJ. LOEYS?DIETZ SYNDROME IN PREGNANCY. OBSTETRIC MEDICINE. 2021?14(1):42?5",
"literaturereference_normalized": "loeys dietz syndrome in pregnancy",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20210921",
"receivedate": "20210715",
"receiver": {
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},
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"sender": {
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},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a significant adverse cutaneous reaction most often induced by drugs and by acute infections. Its clinical hallmark is the sudden onset of multiple, disseminated, non-follicular, sterile pustules on an erythematous background usually arising in intertriginous folds, associated with fever, massive neutrophilia and sometimes eosinophilia. Antitubercular therapy is described as an uncommon cause of AGEP. We report the onset of disseminated non-follicular sterile pustules on an erythematous background in a 68-year-old man receiving a combination of isoniazid, pyrazinamide and rifampicin that may have been the etiologic agents. A thorough history, including a medication history, with clinicopathologic correlation is crucial in patients presenting with acute diffuse pustular lesions.",
"affiliations": "Department of Dermatology, University of Rome Sapienza, Rome, Italy. [email protected]",
"authors": "Cantisani|C|C|;Paradisi|A|A|;Richetta|A G|AG|;Mattozzi|C|C|;Calvieri|S|S|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "Italy",
"delete": false,
"doi": "10.7417/CT.2013.1546",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9074",
"issue": "164(2)",
"journal": "La Clinica terapeutica",
"keywords": null,
"medline_ta": "Clin Ter",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000368:Aged; D000995:Antitubercular Agents; D006801:Humans; D008297:Male",
"nlm_unique_id": "0372604",
"other_id": null,
"pages": "e137-8",
"pmc": null,
"pmid": "23698216",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute generalized exanthematous pustulosis during antituberculosis therapy.",
"title_normalized": "acute generalized exanthematous pustulosis during antituberculosis therapy"
}
|
[
{
"companynumb": "IT-SA-2015SA039654",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISONIAZID\\PYRAZINAMIDE\\RIFAMPIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "050705",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": "6 TABLTS, ALL TAKEN TOGETHER ONCE",
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"drugindication": "TUBERCULOSIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"medicinalproduct": "PYRAZINAMIDE/RIFAMPICIN/ISONIAZID"
},
{
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"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
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"drugcharacterization": "2",
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"drugindication": "CROHN^S DISEASE",
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"medicinalproduct": "INFLIXIMAB"
}
],
"patientagegroup": "6",
"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Red blood cell sedimentation rate increased",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Rash pruritic",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Rash erythematous",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Leukocytosis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Erythema",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Skin oedema",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Skin exfoliation",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Rash pustular",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Skin lesion",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Acute generalised exanthematous pustulosis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CANTISANI C, PARADISI A, RICHETTA AG, MATTOZZI C, CALVIERI S. ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS DURING ANTITUBERCULOSIS THERAPY. CLIN TER. 2013 JAN 01;164(2):E137-8. DOI: 10.7417/CT.2013.1546",
"literaturereference_normalized": "acute generalized exanthematous pustulosis during antituberculosis therapy",
"qualification": "1",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20150508",
"receivedate": "20150401",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10974247,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Omalizumab is a monoclonal anti-immunoglobulin E antibody used for the treatment of severe perennial allergic asthma. Previous reports have suggested that omalizumab treatment can be associated with the development of eosinophilic granulomatosis with poliangiitis (EGPA) (formerly known as Churg-Strauss syndrome) and an increased risk of malignancy. Long-term risks of omalizumab treatment are not very well defined. Here, we report the case of a 75-year-old woman with concurrent occurrence of EGPA and brain tumor after more than 7 years of omalizumab treatment. The possibility of EGPA should be borne in mind during long-term treatment with omalizumab. Despite the absence of definitive data, an association may also exist between the development of malignancy and omalizumab use.",
"affiliations": "Pulmonology Department, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey [email protected].;Pathology Department, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey.;Rheumatology Department, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey.;Pulmonology Department, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey.",
"authors": "Borekci|S|S|;Aydin|O|O|;Hatemi|G|G|;Gemicioglu|B|B|",
"chemical_list": "D000069444:Omalizumab",
"country": "England",
"delete": false,
"doi": "10.1177/0394632015572567",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0394-6320",
"issue": "28(1)",
"journal": "International journal of immunopathology and pharmacology",
"keywords": "Churg-Strauss syndrome; anti-IgE; asthma; eosinophilic granulomatosis with poliangiitis; malignancy; omalizumab",
"medline_ta": "Int J Immunopathol Pharmacol",
"mesh_terms": "D000368:Aged; D001932:Brain Neoplasms; D015267:Churg-Strauss Syndrome; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D000069444:Omalizumab",
"nlm_unique_id": "8911335",
"other_id": null,
"pages": "134-7",
"pmc": null,
"pmid": "25816417",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Development of eosinophilic granulomatosis with poliangiitis (Churg-Strauss syndrome) and brain tumor in a patient after more than 7 years of omalizumab use: A case report.",
"title_normalized": "development of eosinophilic granulomatosis with poliangiitis churg strauss syndrome and brain tumor in a patient after more than 7 years of omalizumab use a case report"
}
|
[
{
"companynumb": "PHHY2015TR057751",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUTICASONE\\FLUTICASONE PROPIONATE"
},
"drugadditional": null,
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"drugauthorizationnumb": "019957",
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"drugcharacterization": "1",
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"drugdosagetext": "1000 UG, QD",
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"drugindication": "ASTHMA",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "FLUTICASONE"
},
{
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"activesubstancename": "FLUTICASONE\\FLUTICASONE PROPIONATE"
},
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"drugdosagetext": "1000 UG, QD",
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"medicinalproduct": "FLUTICASONE"
},
{
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"activesubstance": {
"activesubstancename": "OMALIZUMAB"
},
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"drugcharacterization": "1",
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"drugdosagetext": "300 MG, QMO",
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"medicinalproduct": "XOLAIR"
},
{
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"activesubstancename": "FLUTICASONE\\FLUTICASONE PROPIONATE"
},
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"drugdosagetext": "500 UG, QD",
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosagenumb": "500",
"drugstructuredosageunit": "004",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUTICASONE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SALMETEROL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "100 UG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ASTHMA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstartdateformat": null,
"drugstructuredosagenumb": "100",
"drugstructuredosageunit": "004",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SALMETEROL"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MONTELUKAST SODIUM"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ASTHMA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MONTELUKAST SODIUM."
}
],
"patientagegroup": null,
"patientonsetage": "75",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Allergic granulomatous angiitis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Asthma",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Purpura",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypersensitivity vasculitis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Syncope",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Brain neoplasm",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BOREKCI S, AYDIN O, HATEMI G, GEMICIOGLU B.. DEVELOPMENT OF EOSINOPHILIC GRANULOMATOSIS WITH POLIANGIITIS (CHURG-STRAUSS SYNDROME) AND BRAIN TUMOR IN A PATIENT AFTER MORE THAN 7 YEARS OF OMALIZUMAB USE: A CASE REPORT. INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY. 2015;28(1):134-137",
"literaturereference_normalized": "development of eosinophilic granulomatosis with poliangiitis churg strauss syndrome and brain tumor in a patient after more than 7 years of omalizumab use a case report",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20150515",
"receivedate": "20150515",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11116253,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation.",
"affiliations": "Department of Nephrology, Charité Universitätsmedizin, Berlin, Germany.",
"authors": "Budde|K|K|;Bunnapradist|S|S|;Grinyo|J M|JM|;Ciechanowski|K|K|;Denny|J E|JE|;Silva|H T|HT|;Rostaing|L|L|;|||",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.12955",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "14(12)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "calcineurin inhibitor: tacrolimus; clinical research/practice; clinical trial; immunosuppressant; immunosuppression/immune modulation; kidney transplantation/nephrology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D016559:Tacrolimus; D013997:Time Factors",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2796-806",
"pmc": null,
"pmid": "25278376",
"pubdate": "2014-12",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial.",
"title_normalized": "novel once daily extended release tacrolimus lcpt versus twice daily tacrolimus in de novo kidney transplants one year results of phase iii double blind randomized trial"
}
|
[
{
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{
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},
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] |
{
"abstract": "We report the sixth case of osseous metaplasia that has occurred in the last 5 years, after a deceased-donor renal transplant was performed on a young man. While its clinical significance is unclear and probably irrelevant, osseous metaplasia is one of the most relevant principles of regenerative medicine, where every bodily district contains progenitor cells that can generate cells specific to the germ layer from which they come. After the Case Report, we review the literature and speculate on the underlying pathophysiology of osseous metaplasia. Available data seem to support the hypothesis that osteogenic precursor cells, inducing factors, and a suitable environment are key for osseous metaplasia.",
"affiliations": "From the Wake Forest University School of Medicine, Winston-Salem, NC, USA.",
"authors": "Sanders|Brian P|BP|;Orlando|Giuseppe|G|;Peloso|Andrea|A|;Katari|Ravi S|RS|;Iskandar|Samy S|SS|;Farney|Alan C|AC|;Rogers|Jeffrey|J|;Soker|Shay|S|;Stratta|Robert J|RJ|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1304-0855",
"issue": "12(4)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D001706:Biopsy; D005260:Female; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008679:Metaplasia; D009999:Ossification, Heterotopic; D012038:Regeneration; D044968:Regenerative Medicine; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "371-3",
"pmc": null,
"pmid": "25095714",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Osseus metaplasia in kidney allografts as a paradigm of regenerative medicine principles.",
"title_normalized": "osseus metaplasia in kidney allografts as a paradigm of regenerative medicine principles"
}
|
[
{
"companynumb": "US-SA-2014SA117923",
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],
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"reactionmeddraversionpt": "17.1",
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},
{
"reactionmeddrapt": "Diabetes mellitus",
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},
{
"reactionmeddrapt": "Hypertension",
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}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2006"
}
},
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"literaturereference": "SANDERS BP, ORLANDO G, PELOSO A, KATARI RS, ISKANDAR SS, FARNEY AC ET AL. OSSEUS METAPLASIA IN KIDNEY ALLOGRAFTS AS A PARADIGM OF REGENERATIVE MEDICINE PRINCIPLES. EXP CLIN TRANSPLANT. 2014;4:371-73. DOI: 10.6002/ECT.2013.0149.",
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{
"abstract": "Eosinophilic fasciitis (EF) is characterized by symmetrical thickening of subcutaneous muscular fascia, causing skin induration with wrinkles and prominent hair follicles: the classic peau d'orange. Eosinophilia is a characteristic-albeit not universal-finding. We present the case of a 43-year-old pregnant woman diagnosed with EF during pregnancy who had extensive cutaneous involvement and severe functional repercussions, including worsening of lung function and intrauterine growth restriction as a possible complication. Treatment with prednisone was initiated during gestation and it was necessary to increase the dose. After delivery, methotrexate treatment was initiated and the corticosteroid dose progressively decreased, with progressive worsening in the torso and abdomen and secondary dyspnea due to thoracic pressure. Treatment with infliximab was then initiated, with favorable progress, though residual ankle and tarsal joint stiffness and significant muscular atrophy in the limbs continued. The triggering factor of EF was not identified. In a systematic search of the medical literature, three cases of EF in pregnant woman without clear triggers were found. Interestingly, all three cases progressed favorably with steroid treatment. Apart from this case, there are only seven published cases of infliximab use in the literature, all with moderate or complete response. Infliximab could be an option for corticosteroid-dependent EF with no response to other options.",
"affiliations": "Internal Medicine Department, Hospital Costa del Sol, Marbella, Spain. [email protected].;Internal Medicine Department, Hospital Costa del Sol, Marbella, Spain.;Dermatology Department, Hospital Costa del Sol, Marbella, Spain.;Dermatology Department, Hospital Costa del Sol, Marbella, Spain.;Pathology Department, Hospital Costa del Sol, Marbella, Spain.;Internal Medicine Department, Hospital Regional Universitario de Málaga, Málaga, Spain.",
"authors": "Jiménez-García|Nicolás|N|http://orcid.org/0000-0002-6839-0303;Aguilar-García|Josefa|J|;Fernández-Canedo|Inés|I|;Blázquez-Sánchez|Nuria|N|;Fúnez-Liébana|Rafael|R|http://orcid.org/0000-0002-3012-3947;Romero-Gómez|Carlos|C|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-021-04787-6",
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"issn_linking": "0172-8172",
"issue": "41(8)",
"journal": "Rheumatology international",
"keywords": "Corticosteroid dependence; Eosinophilic fasciitis; Infliximab; Intrauterine growth restriction; Methotrexate; Pregnancy",
"medline_ta": "Rheumatol Int",
"mesh_terms": null,
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1531-1539",
"pmc": null,
"pmid": "33484332",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "1224441;1191357;24424187;30910631;2704516;430815;29247348;28734566;3232080;534317;10622780;12814048;10499315;25876839;24152641;24048117;29235676;23040360;25245261;26550776;22235043;31474594;26559760;29101481;17345001;27541801;30302114;20375823;31974818;31130746;16539821;29446454;29984277;31820721;10792237;18173597;31870916;9973169;7134742;8098769;26934036;26525956;21989991;9222928;9718158;14973643;21530881;32860239",
"title": "Eosinophilic fasciitis in a pregnant woman with corticosteroid dependence and good response to infliximab.",
"title_normalized": "eosinophilic fasciitis in a pregnant woman with corticosteroid dependence and good response to infliximab"
}
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{
"abstract": "Case presentation: A 72-year-old man with non-small-cell lung cancer received four cycles of pembrolizumab-containing chemotherapy. He developed multiple immune-related adverse events (irAEs) and discontinued immune checkpoint inhibitors (ICIs); however, he developed immune-related hepatitis and grade 4 neutropenia at 92 days and 118 days, respectively, from discontinuation. He received G-CSF and methylprednisolone pulse therapy and recovered from neutropenia 12 days later. Discussion & conclusion: ICI-induced neutropenia is a life-threatening condition. The longest recorded onset in one study cohort is 26 days after the final administration of ICIs. This case developed strikingly delayed immune-related neutropenia manifesting as a delayed irAE. Clinicians should pay close attention to delayed immune-related neutropenia as a possible life-threatening irAE after ICI treatment.",
"affiliations": "Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.;Hematology, Graduate School of Medicine, Osaka City University, Osaka, 545-8585, Japan.",
"authors": "Nakako|Soichiro|S|;Nakashima|Yasuhiro|Y|;Okamura|Hiroshi|H|;Tani|Yoko|Y|;Ueda|Takahiro|T|;Makuuchi|Yosuke|Y|;Kuno|Masatomo|M|;Takakuwa|Teruhito|T|;Nishimoto|Mitsutaka|M|;Koh|Hideo|H|;Nakamae|Hirohisa|H|;Hino|Masayuki|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/imt-2021-0131",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": null,
"journal": "Immunotherapy",
"keywords": "checkpoint inhibitor; delayed immune-related events (DIREs); hematological toxicity; immune-related adverse events; immune-related hepatitis; immunotherapy; neutropenia; pembrolizumab",
"medline_ta": "Immunotherapy",
"mesh_terms": null,
"nlm_unique_id": "101485158",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34758635",
"pubdate": "2021-11-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Delayed immune-related neutropenia with hepatitis by pembrolizumab.",
"title_normalized": "delayed immune related neutropenia with hepatitis by pembrolizumab"
}
|
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}
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},
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},
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"medicinalproduct": "PEMETREXED"
}
],
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"patientonsetage": "72",
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"reaction": [
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatic function abnormal",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "Nakako S, Nakashima Y, Okamura H, Tani Y, Ueda T, Makuuchi Y, et al. Delayed immune-related neutropenia with hepatitis by pembrolizumab. Immunotherapy. 2022;14(2)",
"literaturereference_normalized": "delayed immune related neutropenia with hepatitis by pembrolizumab",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20220407",
"receivedate": "20220407",
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},
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"senderorganization": "FDA-Public Use",
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},
"serious": 1,
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}
] |
{
"abstract": "Since polymerase and surface genes overlap in hepatitis B virus (HBV), an antiviral-induced mutation in the polymerase gene may alter the surface antigenicity in patients with chronic hepatitis B (CHB), but this possibility has not been clearly confirmed. This study aimed to determine the drug susceptibility and surface antigenicity of the patient-derived mutants.\n\n\n\nFull-length HBV genomes isolated from four entecavir-resistant CHB patients were cloned and sequenced. Around 10 clones of full-length HBV obtained from each patient were analysed and registered in the NCBI GenBank. Representative clones were further characterized by in vitro drug susceptibility and surface antigenicity assays.\n\n\n\nThe rtL180M + rtM204V mutations were common among all the clones analysed. Additionally, the ETV resistance mutations rtT184A/L, rtS202G and rtM250V were found among three patients. Most of the ETV-resistant mutants had amino acid alterations within the known epitopes recognized by T- and B-cells in the HBV surface and core antigens. The in vitro drug susceptibility assay showed that all tested clones were resistant to ETV treatment. However, they were all susceptible to ADV and TDF. More importantly, the rtI169T mutation in the RT domain, led to the sF161L mutation in the overlapping S gene, which decreased in surface antigenicity.\n\n\n\nThe ETV resistance mutations can affect the antigenicity of the HBsAg proteins due to changes in the overlapping sequence of this surface antigen. Thus, the apparent decline or disappearance of HBsAg needs to be interpreted cautiously in patients with previous or current antiviral resistance mutations.",
"affiliations": "Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.;Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.;Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.",
"authors": "Park|Soree|S|0000-0003-0500-2227;Park|Eun-Sook|ES|;Koo|Ja Eun|JE|;Park|Yong Kwang|YK|;Lee|Ah Ram|AR|;Dezhbord|Mehrangiz|M|;Cho|Eun Sook|ES|;Ahn|Sung Hyun|SH|;Kim|Doo Hyun|DH|;Lee|Jeong-Hoon|JH|;Lee|Han Chu|HC|0000-0002-7631-4124;Kim|Kyun-Hwan|KH|0000-0001-5266-072X",
"chemical_list": "D000954:Antigens, Surface; D000998:Antiviral Agents; D019259:Lamivudine; C413685:entecavir; D006147:Guanine",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.14446",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "40(7)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "antivirals; drug resistance; entecavir; hepatitis B virus; surface antigenicity",
"medline_ta": "Liver Int",
"mesh_terms": "D000954:Antigens, Surface; D000998:Antiviral Agents; D024882:Drug Resistance, Viral; D006147:Guanine; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D019259:Lamivudine; D009154:Mutation",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "1564-1577",
"pmc": null,
"pmid": "32216026",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Entecavir-resistant hepatitis B virus decreases surface antigenicity: A full genome and functional characterization.",
"title_normalized": "entecavir resistant hepatitis b virus decreases surface antigenicity a full genome and functional characterization"
}
|
[
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},
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},
{
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},
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},
{
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},
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}
],
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},
{
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},
{
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},
{
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}
],
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},
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"literaturereference": "PARK S, PARK E, KOO JE, PARK YK, LEE AR, DEZHBORD M ET AL.. ENTECAVIR-RESISTANT HEPATITIS B VIRUS DECREASES SURFACE ANTIGENICITY: A FULL GENOME AND FUNCTIONAL CHARACTERIZATION. LIVER INTERNATIONAL : OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION FOR THE. 2020?DOI.ORG/10.1111/LIV.14446",
"literaturereference_normalized": "entecavir resistant hepatitis b virus decreases surface antigenicity a full genome and functional characterization",
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},
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},
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"sendertype": "2"
},
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"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200713"
},
{
"companynumb": "KR-VIIV HEALTHCARE LIMITED-KR2020GSK061575",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "5",
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"activesubstancename": "ENTECAVIR"
},
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"medicinalproduct": "ENTECAVIR."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
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"drugauthorizationnumb": "021003",
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"drugcharacterization": "1",
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"drugdosagetext": "100 MG, QD",
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"drugindication": "HEPATITIS B",
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"drugstructuredosagenumb": "100",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LAMIVUDINE."
}
],
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"patientonsetage": "54",
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"reaction": [
{
"reactionmeddrapt": "Viral mutation identified",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatitis B DNA increased",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PARK S, PARK E, KOO JE, PARK YK, LEE AR, DEZHBORD M ET AL.. ENTECAVIR-RESISTANT HEPATITIS B VIRUS DECREASES SURFACE ANTIGENICITY: A FULL GENOME AND FUNCTIONAL CHARACTERIZATION. LIVER INTERNATIONAL : OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION FOR THE. 2020?DOI.ORG/10.1111/LIV.14446",
"literaturereference_normalized": "entecavir resistant hepatitis b virus decreases surface antigenicity a full genome and functional characterization",
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},
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200713"
},
{
"companynumb": "KR-GLAXOSMITHKLINE-KR2020GSK061575",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
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"drugstartdate": null,
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"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ENTECAVIR."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "021003",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "100 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HEPATITIS B",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "100",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LAMIVUDINE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADEFOVIR"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HEPATITIS B",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ADEFOVIR"
}
],
"patientagegroup": null,
"patientonsetage": "69",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Viral mutation identified",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatitis B DNA increased",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PARK S, PARK E, KOO JE, PARK YK, LEE AR, DEZHBORD M ET AL.. ENTECAVIR-RESISTANT HEPATITIS B VIRUS DECREASES SURFACE ANTIGENICITY: A FULL GENOME AND FUNCTIONAL CHARACTERIZATION. LIVER INTERNATIONAL : OFFICIAL JOURNAL OF THE INTERNATIONAL ASSOCIATION FOR THE. 2020?DOI.ORG/10.1111/LIV.14446",
"literaturereference_normalized": "entecavir resistant hepatitis b virus decreases surface antigenicity a full genome and functional characterization",
"qualification": "3",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20200410",
"receivedate": "20200410",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 17657033,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200713"
}
] |
{
"abstract": "Voided urine is routinely collected from renal transplant patients to screen for polyomavirus. In rare cases, atypical lymphoid cells can be detected in voided urine and raise the suspicion of post-transplant lymphoproliferative disorder (PTLD). However, further immunohistochemistry of the cell block and flow cytometry is frequently limited by the low cellularity and poor preservation of voided urine. Therefore, PTLD of the renal allograft is usually diagnosed from tissue biopsy or nephrectomy specimens. Herein, we report a rare case of atypical cells in a voided urine cytology specimen from a kidney transplant recipient. Needle core biopsy of the renal allograft showed monomorphic PTLD. Diagn. Cytopathol. 2017;45:69-72. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.;Department of Internal Medicine, Section of Nephrology & Biomedical Proteomics, University of Manitoba, Winnipeg, Manitoba, Canada.;Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.;Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.;Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.;Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.",
"authors": "Lu|Miao|M|;Ho|Julie|J|;Azordegan|Nazila|N|;Perry|Anamarija M|AM|;Gibson|Ian W|IW|;Baker|Patricia|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/dc.23602",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1097-0339",
"issue": "45(1)",
"journal": "Diagnostic cytopathology",
"keywords": "cytology; flow cytometry; post-transplant lymphoproliferative disorders; voided urine",
"medline_ta": "Diagn Cytopathol",
"mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D008875:Middle Aged; D014556:Urine",
"nlm_unique_id": "8506895",
"other_id": null,
"pages": "69-72",
"pmc": null,
"pmid": "27633876",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical cells in a voided urine cytology specimen in a renal transplant recipient.",
"title_normalized": "atypical cells in a voided urine cytology specimen in a renal transplant recipient"
}
|
[
{
"companynumb": "CA-ASTELLAS-2017US003053",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "FORMULATION UNKNOWN",
"drugdosagetext": "UNK UNK, UNKNOWN FREQ.",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RENAL TRANSPLANT",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "THYMOGLOBULIN"
},
{
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},
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"drugdosageform": "FORMULATION UNKNOWN",
"drugdosagetext": "UNK UNK, UNKNOWN FREQ.",
"drugenddate": null,
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"drugindication": "RENAL TRANSPLANT",
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"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "5",
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"activesubstancename": "PREDNISONE"
},
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"drugcumulativedosagenumb": null,
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"drugdosageform": "FORMULATION UNKNOWN",
"drugdosagetext": "UNK UNK, UNKNOWN FREQ.",
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"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "FORMULATION UNKNOWN",
"drugdosagetext": "UNK UNK, UNKNOWN FREQ.",
"drugenddate": null,
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"drugindication": "RENAL TRANSPLANT",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": null,
"patientonsetage": "47",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Abnormal loss of weight",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Epstein-Barr virus infection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Transplant dysfunction",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haematuria",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hydronephrosis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diffuse large B-cell lymphoma",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Kidney enlargement",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MIAO L, HO J, AZORDEGAN N, PERRY AM, GIBSON IW, BAKER P. ATYPICAL CELLS IN A VOIDED URINE CYTOLOGY SPECIMEN IN A RENAL TRANSPLANT RECIPIENT. DIAGNOSTIC CYTOPATHOLOGY. 2016;45(1):69-72",
"literaturereference_normalized": "atypical cells in a voided urine cytology specimen in a renal transplant recipient",
"qualification": "1",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20170127",
"receivedate": "20170127",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13157945,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170428"
}
] |
{
"abstract": "Anthracyclines have proved to be one of the most effective chemotherapeutic agents in the treatment of numerous solid tumors and hematologic malignancies in both adult and pediatric patients. Their clinical benefit, however, is sometimes hampered by the development of cardiotoxicity, a process that still remains elusive despite decades of investigation. It has been postulated that anthracycline-induced cardiotoxicity is mediated in part by reactive oxygen species and redox cycling. This article reviews anthracycline cardiotoxicity in terms of historical significance, epidemiology, current detection strategies, prevention strategies, and patient care after anthracycline-based chemotherapy.",
"affiliations": "Division of Cardiovascular Medicine, Cardio-Oncology Center of Excellence, Washington University in St Louis, 660 South Euclid Avenue, Campus Box 8086, St Louis, MO 63110-1093, USA.;Division of Cardiovascular Medicine, Cardio-Oncology Center of Excellence, Washington University in St Louis, 660 South Euclid Avenue, Campus Box 8086, St Louis, MO 63110-1093, USA. Electronic address: [email protected].",
"authors": "Alvarez-Cardona|Jose|J|;Lenihan|Daniel J|DJ|",
"chemical_list": "D018943:Anthracyclines",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ccl.2019.08.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-8651",
"issue": "37(4)",
"journal": "Cardiology clinics",
"keywords": "Anthracycline cardiotoxicity; Cardioprotection; Chemotherapeutic agents; Left ventricular ejection fraction (LVEF)",
"medline_ta": "Cardiol Clin",
"mesh_terms": "D018943:Anthracyclines; D066126:Cardiotoxicity; D014943:Global Health; D006801:Humans; D015994:Incidence; D012307:Risk Factors; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "8300331",
"other_id": null,
"pages": "355-363",
"pmc": null,
"pmid": "31587778",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Anthracycline Cardiotoxicity: It Is Possible to Teach an Old Dog Some New Tricks.",
"title_normalized": "anthracycline cardiotoxicity it is possible to teach an old dog some new tricks"
}
|
[
{
"companynumb": "US-DRREDDYS-USA/USA/19/0115448",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HODGKIN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "BLEOMYCIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DACARBAZINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HODGKIN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DACARBAZINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HODGKIN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "VINCRISTINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "208657",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
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"drugindication": "HODGKIN^S DISEASE",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXORUBICIN HYDROCHLORIDE LIPOSOME INJECTION 20 MG/10 ML (2 MG/ML) AND"
}
],
"patientagegroup": null,
"patientonsetage": "24",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cardiotoxicity",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ALVAREZ-CARDONA J, LENIHAN D. ANTHRACYCLINE CARDIOTOXICITY: IT IS POSSIBLE TO TEACH AN OLD DOG SOME NEW TRICKS. CARDIOLOGY CLINICS. 2019?37(04):355-63. DOI:10.1016/J.CCL.2019.08.001",
"literaturereference_normalized": "anthracycline cardiotoxicity it is possible to teach an old dog some new tricks",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20191104",
"receivedate": "20191022",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16945204,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
},
{
"companynumb": "US-TEVA-2019-US-1132055",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "63097",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "FOR 6 CYCLES",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INVASIVE LOBULAR BREAST CARCINOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"medicinalproduct": "DOXORUBICIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADO-TRASTUZUMAB EMTANSINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "INVASIVE LOBULAR BREAST CARCINOMA",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRASTUZUMAB-EMTANSINE (T-DM1)"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PERTUZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"drugcharacterization": "1",
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"drugdosageform": null,
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"drugindication": "INVASIVE LOBULAR BREAST CARCINOMA",
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"medicinalproduct": "PERTUZUMAB."
},
{
"actiondrug": "5",
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"activesubstancename": "DENOSUMAB"
},
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"drugdosageform": null,
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"drugenddateformat": null,
"drugindication": "INVASIVE LOBULAR BREAST CARCINOMA",
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"medicinalproduct": "DENOSUMAB"
},
{
"actiondrug": "5",
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"activesubstancename": "FLUOROURACIL"
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"abstract": "Chlorhexidine-based skin preparations are frequently used in orthopaedic surgery. We report 2 recent cases of patients suffering significant allergic reactions to ChloraPrepTM complicating routine foot and ankle surgery. We advise vigilance for this possible issue and recommend thorough removal of all preparation at the end of the procedure.",
"affiliations": "Specialist Registrar, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Foot and Ankle Fellow, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Consultant Orthopaedic Surgeon, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Electronic address: [email protected].;Specialist Registrar, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Foot and Ankle Fellow, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Consultant Orthopaedic Surgeon, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.;Specialist Registrar, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Foot and Ankle Fellow, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Consultant Orthopaedic Surgeon, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.;Specialist Registrar, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Foot and Ankle Fellow, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom; Consultant Orthopaedic Surgeon, Department of Orthopaedics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.",
"authors": "Dick|Alastair G|AG|;Dhinsa|Baljinder|B|;Walker|Roland P|RP|;Singh|Samrendu|S|",
"chemical_list": "D000891:Anti-Infective Agents, Local; D002710:Chlorhexidine",
"country": "United States",
"delete": false,
"doi": "10.1053/j.jfas.2018.08.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1067-2516",
"issue": "58(1)",
"journal": "The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons",
"keywords": "allergy; chlorhexidine; rash; surgical preparation; surgical safety",
"medline_ta": "J Foot Ankle Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000891:Anti-Infective Agents, Local; D002710:Chlorhexidine; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D008297:Male; D019637:Orthopedic Procedures; D011300:Preoperative Care",
"nlm_unique_id": "9308427",
"other_id": null,
"pages": "192-194",
"pmc": null,
"pmid": "30448375",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed Allergic Reaction to ChloraPrepTM in Foot and Ankle Surgery.",
"title_normalized": "delayed allergic reaction to chlorapreptm in foot and ankle surgery"
}
|
[
{
"companynumb": "GB-DEXPHARM-20180945",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHLORHEXIDINE GLUCONATE\\ISOPROPYL ALCOHOL"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "201708",
"drugstartdateformat": "610",
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CHLORAPREP"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "2017",
"drugstartdateformat": "602",
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SALINE"
}
],
"patientagegroup": "5",
"patientonsetage": "40",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypersensitivity",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Bacterial infection",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201708"
}
},
"primarysource": {
"literaturereference": "DICK AG, DHINSA B, WALKER RP, SINGH S. DELAYED ALLERGIC REACTION TO CHLORAPREPTM IN FOOT AND ANKLE SURGERY. JOURNAL OF FOOT AND ANKLE SURGERY. 2018. DOI: 10.1053/J.JFAS.2018.08.019",
"literaturereference_normalized": "delayed allergic reaction to chlorapreptm in foot and ankle surgery",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20181223",
"receivedate": "20181223",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 15754093,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
}
] |
{
"abstract": "The most important and unique adverse effect of abacavir (ABC) is fatal hypersensitivity reaction (HSR). The objective of this report is to describe a case of ABC induced HSR that occurred in an Indian HIV patient during treatment. Although this adverse effect is not uncommon, it is perhaps underreported or has never been reported so far in an Indian case scenario. A 44-year-old known case of HIV-1 was admitted in view of his worsening condition and very low CD4 cell counts 3 cells/μL. He was on anti-retroviral therapy since three years but not regular. On the basis of treatment failure, non-compliance and progressive low CD4 counts, the anti HIV regime was switched over to abacavir 600 mg+ atazanavir/ ritonavir 300mg/100mg Two weeks after ABC therapy he presented with maculopapular rash, headache and signs of hepatic damage (serum AST, ALP and ALT increased to 3-4 fold) suggestive of hypersensitivity reaction. As we know discontinuation of the drug is the ultimate litmus test to confirm diagnosis of drug induced adverse reaction. We did confirm ABC induced HSR by de-challenge wherein, rash disappeared within 2-3 days and LFT came back to normal within 5 days. However, no rechallenge was done. HSR was more in favour of ABC because atazanavir failed to produce any similar reaction after re-challenge.",
"affiliations": "Postgraduate, Department of Pharmacology, Kasturba Medical College, Manipal University , Manipal, Karnataka, India .;Associate Professor, Department of Pharmacology, Kasturba Medical College , Manipal University, Manipal, Karnataka, India .;Professor and HOD, Department of Medicine, Kasturba Medical College and Hospital , Manipal University,Manipal, Karnataka, India .;Associate Professor, Department of Pharmacology, Kasturba Medical College , Manipal University, Manipal, Karnataka, India .;Postgraduate, Department of Pharmacology, Kasturba Medical College , Manipal University, Manipal, Karnataka, India .",
"authors": "Janardhanan|Manju|M|;Amberkar V|Mohan Babu|MB|;Vidyasagar|Sudha|S|;Kumari K|Meena|M|;Holla|Sadhana N|SN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2014/10063.4820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "8(9)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "De-challenge; Hepatic damage; Maculopapular rash; Underreported",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "HD01-2",
"pmc": null,
"pmid": "25386460",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports",
"references": "20190882;12017401;21480946;18256392;21592453;23393027;15024131",
"title": "Hypersensitivity Reaction Associated with Abacavir Therapy in an Indian HIV Patient - A Case Report.",
"title_normalized": "hypersensitivity reaction associated with abacavir therapy in an indian hiv patient a case report"
}
|
[
{
"companynumb": "IN-VIIV HEALTHCARE LIMITED-IN2014GSK028624",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
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"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "COTRIMOXAZOLE"
},
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "EFAVIRENZ + LAMIVUDINE + TENOFOVIR DISOPROXIL FUMARATE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABACAVIR"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "020977",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "300 MG, BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HIV INFECTION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "300",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ABACAVIR."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATAZANAVIR\\RITONAVIR"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
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"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ATAZANAVIR + RITONAVIR"
}
],
"patientagegroup": null,
"patientonsetage": "44",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pruritus",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood test abnormal",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypersensitivity",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatic function abnormal",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pancytopenia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin lesion",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JANARDHANAN M, AMBERKAR MB, VIDYSAGAR S, KUMARI M AND HOLLA SN. HYPERSENSITIVITY REACTION ASSOCIATED WITH ABACAVIR THERAPY IN AN INDIAN HIV PATIENT- A CASE REPORT. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 2014;8 (9):1-2",
"literaturereference_normalized": "hypersensitivity reaction associated with abacavir therapy in an indian hiv patient a case report",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20150730",
"receivedate": "20150730",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11323551,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20151125"
}
] |
{
"abstract": "Non-small cell lung cancer (NSCLC) patients with HER2 mutations and amplification may benefit from HER2-targeted therapy, including afatinib. However, the data regarding the clinical activity of afatinib in Chinese patients with NSCLC harboring HER2 alterations are limited.\nWe retrospectively included metastatic NSCLC patients harboring HER2 alterations who treated with afatinib. The clinical outcomes included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). The genomic profiling data after progression on afatinib were analyzed.\nWe included 54 patients harboring HER2 mutations and 12 patients harboring HER2 amplification. The ORR was 24% (95% CI, 16-36%), the median PFS was 3.3 months (95% CI, 2.2-4.4), and the median OS was 13.9 months (95% CI, 11.4-16.5). Patients with HER2 exon 20 mutations had numerically worse ORR (17% vs 42%), shorter PFS (2.6 vs 5.8 months, HR, 2.5; 95% CI, 1.2-5.5; P = 0.015) and OS (12.9 vs 33.3 months, HR, 4.4; 95% CI, 1.3-14.8; P = 0.009) than patients with other mutations. For HER2-amplified patients, the ORR was 33% (95% CI, 14-61%), the median PFS was 3.3 months (95% CI, 2.6-4.0), and the median OS was 13.4 months (95% CI, 0-27.6). The most frequently mutated genes in afatinib-resistant patients were TP53 (44%) and EGFR (33%). Three afatinib-resistant patients harbored secondary HER2 alterations.\nOur results suggest that afatinib has a promising anti-tumor activity in patients with NSCLC harboring HER2 alterations. To our knowledge, this is the largest retrospective study about the clinical activity of afatinib in NSCLC patients with HER2 alterations.",
"affiliations": "Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.;Department of Respiratory Disease, Taizhou Hospital, Taizhou, China.;The Medical Department, 3D Medicines Inc, Shanghai, China.;Department of Medical Oncology, Lishui Center Hospital, Lishui, China.;Department of Medical Oncology, Baotou Cancer Hospital, Baotou, China.;Department of Respiratory Disease, Ningbo Medical Center, Lihuili Eastern Hospital, Ningbo, China.;Department of Thoracic Disease Center, Rongjun Hospital, Jiaxing, China.;The Medical Department, 3D Medicines Inc, Shanghai, China.;Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.",
"authors": "Song|Zhengbo|Z|;Lv|Dongqing|D|;Chen|Shiqing|S|;Huang|Jianhui|J|;Wang|Liping|L|;Xu|Shuguang|S|;Chen|Huafei|H|;Wang|Guoqiang|G|;Lin|Quan|Q|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.657283",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.657283\nOncology\nOriginal Research\nEfficacy and Resistance of Afatinib in Chinese Non-Small Cell Lung Cancer Patients With HER2 Alterations: A Multicenter Retrospective Study\nSong Zhengbo 1 2 * †\n\nLv Dongqing 3 †\nChen Shiqing 4 †\n\nHuang Jianhui 5\nWang Liping 6\nXu Shuguang 7\nChen Huafei 8\nWang Guoqiang 4\nLin Quan 9 *\n\n1 Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China\n2 Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China\n3 Department of Respiratory Disease, Taizhou Hospital, Taizhou, China\n4 The Medical Department, 3D Medicines Inc, Shanghai, China\n5 Department of Medical Oncology, Lishui Center Hospital, Lishui, China\n6 Department of Medical Oncology, Baotou Cancer Hospital, Baotou, China\n7 Department of Respiratory Disease, Ningbo Medical Center, Lihuili Eastern Hospital, Ningbo, China\n8 Department of Thoracic Disease Center, Rongjun Hospital, Jiaxing, China\n9 Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China\nEdited by: Hideharu Kimura, Kanazawa University, Japan\n\nReviewed by: Sagun Parakh, University of Melbourne, Australia; Valerio Gristina, University of Palermo, Italy\n\n*Correspondence: Quan Lin, [email protected]; Zhengbo Song, [email protected]\nThis article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work\n\n07 5 2021\n2021\n11 65728322 1 2021\n06 4 2021\nCopyright © 2021 Song, Lv, Chen, Huang, Wang, Xu, Chen, Wang and Lin\n2021\nSong, Lv, Chen, Huang, Wang, Xu, Chen, Wang and Lin\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground\n\nNon-small cell lung cancer (NSCLC) patients with HER2 mutations and amplification may benefit from HER2-targeted therapy, including afatinib. However, the data regarding the clinical activity of afatinib in Chinese patients with NSCLC harboring HER2 alterations are limited.\n\nPatients and methods\n\nWe retrospectively included metastatic NSCLC patients harboring HER2 alterations who treated with afatinib. The clinical outcomes included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). The genomic profiling data after progression on afatinib were analyzed.\n\nResults\n\nWe included 54 patients harboring HER2 mutations and 12 patients harboring HER2 amplification. The ORR was 24% (95% CI, 16–36%), the median PFS was 3.3 months (95% CI, 2.2–4.4), and the median OS was 13.9 months (95% CI, 11.4–16.5). Patients with HER2 exon 20 mutations had numerically worse ORR (17% vs 42%), shorter PFS (2.6 vs 5.8 months, HR, 2.5; 95% CI, 1.2–5.5; P = 0.015) and OS (12.9 vs 33.3 months, HR, 4.4; 95% CI, 1.3–14.8; P = 0.009) than patients with other mutations. For HER2-amplified patients, the ORR was 33% (95% CI, 14–61%), the median PFS was 3.3 months (95% CI, 2.6–4.0), and the median OS was 13.4 months (95% CI, 0–27.6). The most frequently mutated genes in afatinib-resistant patients were TP53 (44%) and EGFR (33%). Three afatinib-resistant patients harbored secondary HER2 alterations.\n\nConclusions\n\nOur results suggest that afatinib has a promising anti-tumor activity in patients with NSCLC harboring HER2 alterations. To our knowledge, this is the largest retrospective study about the clinical activity of afatinib in NSCLC patients with HER2 alterations.\n\nnon-small cell lung cancer (NSCLC)\nHER2\nafatinib\nefficacy\nresistance\n==== Body\nIntroduction\n\nLung cancer is one of the most common malignant tumors, causing approximate 25% of the total cancer-related deaths (1). About 85% of patients with lung cancer are histologically diagnosed as non-small cell lung cancer (NSCLC) (2). Several driver genes alterations, including EGFR (epidermal growth factor receptor) activating mutations, ALK (anaplastic lymphoma kinase) rearrangement, ROS1 (repressor of silencing 1) fusions, BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations, MET (MET proto-oncogene, receptor tyrosine kinase) alterations, and RET (ret proto-oncogene) fusions, are frequently detected in the patients with NSCLC (3). Targeted therapies based on these genes have been approved by the Food and Drug Administration (FDA), changing the treatment of NSCLC (4).\n\nHuman epidermal growth factor receptor 2 (HER2, also known as ERBB2) is a cancer driver gene, and 1.7–3% of NSCLC patients harbor HER2 mutations (5–7). Most HER2 mutations in NSCLC are present in exon 20, such as Y772_A775dup and G778_P780dup. In addition, HER2 gene amplification occurs in 3 to 14.3% of lung adenocarcinomas (7–9). HER2 activating mutations and amplification may activate tyrosine kinase and downstream signaling pathways, therefore conferring sensitivity to HER2-targeted therapy, such as trastuzumab, ado-trastuzumab (T-DM1) and tyrosine kinase inhibitors (TKIs). At present, T-DM1 is the only recommended HER2-targeted inhibitor for HER2-mutated NSCLC patients by National Comprehensive Cancer Network (NCCN) Guidelines, with an overall response rate (ORR) of 44% (10). However, no HER2-targeted therapy has been approved for patients with NSCLC harboring HER2 mutations or amplification.\n\nAfatinib is an irreversible ERBB family inhibitor, which has been approved for EGFR-mutated lung cancer and become one of the most common therapy in NSCLC patients. In a phase II trial with 13 advanced NSCLC with HER2 exon 20 mutations, the overall response rate (ORR) of afatinib as second-line treatment was 7.7% and the median progression-free survival (PFS) was 15.9 weeks (11). Several retrospective trials revealed better activity of afatinib in patients with HER2 exon 20 mutations, with an ORR from 13 to 33% (5, 12–15). However, the interpretation of the results from all these studies were limited by the small sample sizes. In addition, the efficacy of HER2-TKI in patients with HER mutations besides HER2 exon 20 mutations and HER2 amplification has been rarely studied. Seven patients with other HER2 mutations except exon 20 mutations were enrolled into the phase II trial of T-DM1, and two of these patients had a partial response, with a S310F (exon 8) mutation and a V659E (exon 17) mutation, respectively (10). Another research showed that three of four NSCLC patients with V659E or G660R (exon 17, located in transmembrane domain) achieved responses from afatinib treatment (16).\n\nHerein, we conducted a multicenter, retrospective study to analyze the anti-tumor activity of afatinib in patients with NSCLC harboring HER2 alterations including mutations and amplification. Furthermore, we tried to explore the potential secondary resistant mechanisms of afatinib by next generation sequencing (NGS). We present the following article/case in accordance with the STROBE reporting checklist.\n\nMethods\n\nPatients and Study Design\n\nThis multicenter, retrospective study included patients with non-small cell lung cancer (NSCLC) harboring HER2 alteration treated with afatinib between May 2015 and July 2019, from Zhejiang Cancer Hospital, Taizhou Hospital, Baotou Cancer Hospital, Lihuili Eastern Hospital and Rongjun Hospital. Eligible patients were 18 years or older, and had a diagnosis of stage IV NSCLC, a HER2 alteration, measurable disease as per investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST), v1.1. Patients received afatinib at a dose of 40 mg daily until disease progression or intolerable adverse events. This retrospective study was approved by the Institutional Review Board Committee of Zhejiang Cancer Hospital. Research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. The informed consent was waived because of the retrospective nature of this study.\n\nData Collection and Response Assessment\n\nBaseline clinical information were collected from electronic medical records, including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, tumor histology, smoking status, HER2 alteration subtype, and afatinib treatment line. These clinical data were verified independently by two oncologist physicians. Tumor size measurement according to radiologic imaging was conducted by radiologists. Best response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST, v1.1). The outcomes were ORR, PFS, and overall survival (OS). ORR was defined as the proportion of patients who have a partial response (PR) or complete response (CR). PFS was defined as the time interval from initial afatinib treatment to progression or death from any cause. OS was defined as the duration from the beginning of afatinib treatment to death from any cause.\n\nMolecular Testing\n\nThe baseline HER2 gene alterations were tested by NGS in an accredited local laboratory (for example as shown in Figure S1 ). Genomic profiling when progression on afatinib treatment was tested in a CLIA-accredited/CAP-certified laboratory (3D Medicines Inc., Shanghai, China). The NGS panel targeted cancer-related genes was performed on the NextSeq500 platform (Illumina, CA, USA) (17). DNA extracts (30–200 ng) were sheared to 250 bp fragments using an S220 focused-ultrasonicator (Covaris). Libraries were prepared using the KAPA Hyper Prep Kit (KAPA Biosystems) following the manufacturer’s protocol. The captured libraries were loaded onto a NextSeq500 platform for 100 bp paired-end sequencing with a mean sequencing depth of 500×.\n\nRaw data of paired samples (an FFPE sample and its normal tissue control) were mapped to the reference human genome hg19 using the Burrows–Wheeler Aligner (v0.7.12). PCR duplicate reads were removed and sequence metrics were collected using Picard (v1.130) and SAMtools (v1.1.19), respectively. Variant calling was performed only in the targeted regions. Somatic single nucleotide variants (SNVs) were detected using an in-house developed R package to execute a variant detection model based on binomial test. Local realignment was performed to detect indels. Variants were then filtered by their unique supporting read depth, strand bias, base quality as previously described. All variants were then filtered using an automated false positive filtering pipeline to ensure sensitivity and specificity at an allele frequency (AF) of ≥1%. Single-nucleotide polymorphism (SNPs) and indels were annotated by ANNOVAR against the following databases: dbSNP (v138), 1000Genome and ESP6500 (population frequency >0.015). Only missense, stopgain, frameshift and non-frameshift indel mutations were kept. Copy number variations (CNVs) and gene rearrangements were detected. The interpretation of variants were based on American College of Medical Genetics and Genomics (ACMG) standards and guidelines.\n\nStatistical Analyses\n\nAll statistical analyses were conducted using the SPSS statistical package, version 20.0 (SPSS Inc®, Chicago, Illinois, USA) and GraphPad prism v6 (GraphPad, La Jolla, CA, USA). The PFS and OS were estimated by Kaplan–Meier curves, with P value determined by a log-rank test. And we calculated hazard ratio (HR) and its 95% confidence intervals (CIs) by Cox regression. Univariate and multivariate analyses were performed by Cox proportional hazard model. A two-sided P <.05 was considered statistically significant.\n\nResults\n\nBaseline Characteristics\n\nA total of 66 patients with lung cancer were included in this retrospective study. The baseline characteristics are shown in Table 1 . The median age was 59 years (range, 30–81), and 65% (43/66) were female. Eight patients (12%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 and the rest were ECOG 0–1. Most patients were adenocarcinoma (92%, 61/66) and non-smokers (67%, 44/66). Ten (15%) patients had brain metastases. All the patients received afatinib as a single agent. The median line of afatinib treatment was 2 (range, 1–7). Twenty-four patients (36%, 24/66) received afatinib as first-line therapy, and 42 patients (64%, 42/66) as second-line or beyond therapy ( Table 1 ). The median follow-up period was 13.9 months (range: 2.1–39.5).\n\nTable 1 Baseline characteristics.\n\nSex, n (%)\t\t\n Male\t23 (35%)\t\n Female\t43 (65%)\t\nAge, years\t\t\n Median (range)\t59 (30–81)\t\nECOG performance status, n (%)\t\t\n 0\t12 (18%)\t\n 1\t46 (70%)\t\n 2\t8 (12%)\t\nHistology, n (%)\t\t\n Adenocarcinoma\t61 (92%)\t\n Squamous carcinoma\t4 (6%)\t\n Adenosquamous carcinoma\t1 (2%)\t\nSmoking status, n (%)\t\t\n Yes\t21 (32%)\t\n No\t44 (67%)\t\n Unknown\t1 (2%)\t\nNumber of metastases\t\t\n Median (range)\t2 (1–7)\t\nPrevious treatments\t\t\n Chemotherapy\t39 (59%)\t\n Bevacizumab\t4 (6%)\t\n TKI\t3 (5%)\t\nAnti-PD-1/L1 inhibitors\t2 (3%)\t\nAfatinib treatment line, n (%)\t\t\n First\t24 (36%)\t\n Second or beyond\t42 (64%)\t\nHER2 alterations, n (%)\t\t\n HER2 mutations\t54 (82%)\t\n exon 20 mutations\t42\t\n other mutations\t12\t\n HER2 amplification\t12 (18%)\t\nECOG, Eastern Cooperative Oncology Group; HER2, Human epidermal growth factor receptor 2; TKI, tyrosine kinase inhibitor.\n\nFifty-four patients (82%) harbored mutations in HER2 gene ( Figure 1 ), most of which were identified in exon 20 (78%, 42/54). In addition, twelve patients carried HER2 amplification. Among the patients with HER2-mutated lung cancer, the most common mutation was Y772_A775dup (33%, 18/54), followed by G778_P780dup (19%, 10/54) and G776delinsVC/LC (15%, 8/54).\n\nFigure 1 HER2 mutational map.\n\nClinical Activity of Afatinib in NSCLC Patients With HER2 Alterations\n\nThe responses to afatinib were evaluated according to RECIST 1.1 ( Figure 2 ), and the best response to afatinib was partial response (PR) in 16 patients (24%), stable disease (SD) in 24 patients (36%), and progressive disease (PD) in 26 patients (39%, Table 2 ). The ORR was 24% (95% CI, 16–36%), and disease control rate (DCR) was 61% (95% CI, 49–72%).\n\nFigure 2 Maximum percentage change from baseline in target lesions.\n\nTable 2 Clinical activity of afatinib in NSCLC patients with HER2 alterations.\n\nVariable\t\nBest response, n (%)\t\n Partial response\t16 (24%)\t\n Stable disease\t24 (36%)\t\n Progressive disease\t26 (39%)\t\nOverall response rate, %\t24%\t\nDisease control rate, %\t61%\t\nProgression-free survival\t\t\n Events, n (%)\t62 (94%)\t\n Median, months (95% CI)\t3.3 (2.2–4.4)\t\nOverall survival\t\t\n Events, n (%)\t40 (61%)\t\n Median, months (95% CI)\t13.9 (11.4–16.5)\t\nCI, confidence interval.\n\nAs data cutoff, 62 (94%) out of 66 patients had died or had disease progression and 40 (61%) patients had died. The median PFS was 3.3 months (95% CI, 2.2–4.4), and the median OS was 13.9 months (95% CI, 11.4–16.5) ( Table 2 and Figure 3 ). The median duration of response was 7.1 months (95%CI, 6.4–7.7 months). Furthermore, we deeply analyzed the efficacy of afatinib in patients with different HER2 alterations. Among the patients with a HER2 mutation, the ORR, mPFS and mOS were 22%, 3.4 months (95% CI, 1.4–4.7) and 14.6 months (95% CI, 11.6–17.6), similar with the whole cohort ( Table 3 ). In addition, four of the patients with HER2 amplification (33%, 4/12) achieved a PR ( Figure 2 ). The mPFS and mOS of these patients were respectively 3.3 months (95% CI, 2.6–4.0) and 13.4 months (95% CI, 0–27.6), comparable to those of the patients with a HER2 mutation ( Figures 3C, D ).\n\nFigure 3 Kaplan–Meier estimates of progression-free survival and overall survival of NSCLC Patients with HER2 alterations. (A, B) progression-free survival and overall survival of the whole cohort; (C, D) progression-free survival and overall survival according to HER2 mutations or amplification.\n\nTable 3 Clinical Activity of Afatinib according to HER2 alterations.\n\nHER2 alterations\tORR, %\tmPFS, month (95%CI)\tmOS, month (95%CI)\t\nMutations\t22%\t3.4 (1.4–4.7)\t14.6 (11.6–17.6)\t\n exon 20 mutations\t17%\t2.6 (0.9–4.1)\t12.9 (8.8–17.0)\t\n Y772_A775dup\t33%\t\t\t\n G778_P780dup\t10%\t\t\t\n G776delinsVC/LC\t0\t\t\t\n 775_G776insSVMA\t0\t\t\t\n A775_G776insVVMA\t0\t\t\t\n V777L\t0\t\t\t\n other mutations\t42%\t5.8 (0–10.1)\t33.3 (1.2–65.5)\t\nAmplification\t33%\t3.3 (2.6–4.0)\t13.4 (0–27.6)\t\nCI, confidence interval; HER2, Human epidermal growth factor receptor 2; mOS, median overall survival; mPFS, median progression-free survival; ORR, overall response rate.\n\nSince HER2 exon 20 mutation is the most common mutation for HER2 in patients with NSCLC, we further compared the outcomes of patients with exon 20 mutation and other mutations. As for HER2 exon 20 mutations, the total ORR was 17%, and the ORRs of the patients with Y772_A775dup mutation and G778_P780dup were 33 and 10%, respectively, while the ORR was 0% in patients with other exon 20 mutations including G776delinsVC/LC, A775_G776insSVMA, A775_G776insVVMA, and V777L ( Table 3 ). In patients with other HER2 mutations, five (42%) out of 12 patients achieved a PR (L655V [exon 17], H878Y [exon 21], R896G [exon 22], M960V [exon 24] and L1173V [exon 27]). Patients with HER2 exon 20 mutations had worse PFS (2.6 vs 5.8 months, HR, 2.5; 95% CI, 1.2–5.5; P = 0.015) and OS (12.9 vs 33.3 months, HR, 4.4; 95% CI, 1.3–14.8; P = 0.009) than patients with other HER2 mutations ( Figure S2 ).\n\nWe also performed subgroup analysis according afatinib treatment lines. The ORR was 42% in patients who received afatinib as first-line treatment compared with 14% in those who received afatinib as secondary-line or beyond treatment. Patients who received afatinib as secondary-line or beyond treatment had shorter PFS and OS compared with patients who received afatinib as first-line treatment (mPFS = 2.7 vs 4.7 months; OS = 11.2 vs 15.6 months; Figure S3 ). Multivariate analysis showed that afatinib treatment line and brain metastasis were associated with PFS (P = 0.026 and 0.017, respectively), and ECOG performance status was associated with OS (P = 0.046) ( Tables S1 and S2 ).\n\nPotential Biomarkers for Resistance to Afatinib\n\nTo reveal potential biomarkers of resistance to afatinib, NGS was performed from blood or tissue samples of nine patients after progression on afatinib treatment. Pathogenic and likely pathogenic mutations were analyzed. We observed most patients (78%, 7/9) still harbored HER2 alterations after afatinib treatment ( Table S3 ). Among these patients, three patients harbored secondary HER2 alterations (p.G776delinsLC [patient 3], Y772_A775dup [patient 4], and amplification [patient 6], Table S3 ). The most frequently mutated genes in afatinib-resistant patients were TP53 (44%) and EGFR (33%). Besides, one patient carried a NRAS mutation and another patient had no HER2 alteration nor other pathogenic mutation when progression on afatinib ( Table S3 ).\n\nDiscussion\n\nIn the present study, afatinib showed promising anti-tumor activity in patients with NSCLC harboring HER2 alterations including HER2 exon 20 mutations, other mutations and HER2 amplification. To our knowledge, this is the largest retrospective study on clinical activity of afatinib in NSCLC patients with HER2 alterations.\n\nMost previous studies focused on HER2 exon 20 insertions. Recent studies reported that NSCLC patients with HER2 exon 20 insertions had an ORR of 13–19% from afatinib treatment (14, 15, 18). The sole to date prospective study (11) on afatinib in NSCLC patients with HER2 exon 20 insertions only enrolled 13 patients, with a modest clinical outcomes (ORR = 7.7%). In the largest cohort of NSCLC patients with HER2 exon 20 insertions, Mazières et al. (12) reported clinical activity of chemotherapy and HER2-targeted drugs. The ORR of the patients (N = 29) treated with TKIs (neratinib, afatinib, and lapatinib) was 7.4%. Among the patients (N = 11) who were treated with afatinib, the ORR was 18.2%. In the present study, most HER2 mutations were exon 20 insertions (61%), which was similar with previous studies. We observed an ORR of 17% in these patients, which was comparable with previous retrospective studies. Of the patents with most common Y772_A775dup mutation, ORR was 33%, which suggests that these patients might have better clinical outcome from afatinib.\n\nMoreover, we found HER2 other mutations except exon 20 mutations were also sensitive to afatinib. Five (42%) of these patients achieved response from afatinib treatment. Among these patients who were response to afatinib, one patient with a L655V (exon 17) mutation had a PFS of 8.1 months. L655V (exon 17) is located in transmembrane domain (TMD) that is important to stabilize the active HER2 homodimer (19). And L655V is close to V659/G660, which were demonstrated to be sensitive to afatinib (16). One lung squamous cell carcinoma patient with a HER2 R896G (exon 22) mutation had a long PFS of 14.5 months, which was recently reported as a case report (20). Another patient with a M960V (exon 24) mutation received afatinib as third-line therapy, and achieved a PR and a PFS of 7.1 months. The other two patients respectively harbored H878Y (exon 21) and L1173V (exon 27), and the PFS were 22.7 and 25.0 months, respectively. These results suggest that the patients with HER2 other mutations except exon 20 mutations could also benefit from HER2-targeted inhibitors.\n\nSo far, the standard care for NSCLC patients with HER2 amplification is chemotherapy. Although T-DM1 is recommended by NCCN Guidelines for HER2-mutated NSCLC patients, no HER2-targerd inhibitors are approved for NSCLC patients with HER2 mutations or amplification. In a phase II trial of dacomitinib in lung cancer patients with HER2 alterations, none of four patients with HER2-amplified tumors responded (21). Recently, two studies on HER-mutated NSCLC patients treated with pyrotinib, a pan-HER inhibitor, showed that ORRs were 53.3 and 30%, and mPFSs were 6.4 months and 6.9 months, respectively (22, 23). An in vitro study and phase II trial demonstrated another pan-HER inhibitor poziotinib had potent clinical activity against HER2 mutations (24, 25). In breast cancer, gastric Cancer, and colorectal cancer, HER2 amplification was demonstrated to be associated with the clinical outcomes of HER2-targeted treatment (26, 27). In this study, we presented an ORR of 33% in the NSCLC patients with HER2 amplification, and this is the first time that clinical activity of afatinib in HER2-amplified NSCLC patients has been reported. These results indicate HER2-targeted treatment might be one of the choices for these patients.\n\nPrimary and acquired resistance is the main reason for progression disease when patients received TKIs treatment. Currently, we know much about the mechanisms for resistance of EGFR-targeted treatment, but researches about resistance to HER2-targerted inhibitors in NSCLC patients are lacking. Chuang et al. (13) suggested PIK3CA mutation and HER2 gene amplification may be the potential mechanisms for resistance during HER2-targeted treatment. However, the results were analyzed from four cases, which is hard to reach statistical significance. Herein, we performed NGS for nine patients when progression on afatinib treatment. Of three patients harbored secondary HER2 alterations, two carried a HER2 exon 20 insertion and another carried HER2 amplification as secondary alteration. Previous studies demonstrated that secondary ALK mutations could induce resistance of ALK inhibitors (28, 29). Whether HER2 secondary alterations resistance mechanism to afatinib need to be determined in further studies. In addition, we found TP53 was recurrently mutated (44%) in afatinib-resistant patients. Several studies reported that TP53 mutations were associated with inferior clinical effect of EGFR-targeted inhibitors (30–32). One patient harbored TP53 and RB1 co-mutations, which were associated with an increasing risk for small cell transformation and resistance to TKIs treatment (33–36).\n\nThis study still has several limitations. Firstly, we cannot completely avoid the reporting bias because of this work’s retrospective nature. Secondly, due to a lack of control arm, comparison with other therapies was not feasible. Thirdly, only nine patients were performed NGS when progression, so these data cannot fully reflect the whole cohort and no statistical significance can be reached about resistance of afatinib. Despite these limitations, this study provides deep insights into clinical activity of afatinib in NSCLC with HER2 alterations.\n\nConclusion\n\nOur results suggest that afatinib has a potential efficacy in these patients, especially in the patients with HER2 amplification or other pathologic mutations in exons except exon 20. Further studies, especially prospective studies, are warranted to investigate the clinical activity of afatinib and the mechanism of resistance to HER2-targeted therapy.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Zhejiang Cancer Hospital. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nAll authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication. ZS and QL contributed to the study design. All authors were responsible for interpretation of the results. ZS and SC contributed to statistical analysis. ZS and SC prepared the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nAuthors SC and GW were employed by company 3D Medicines Inc.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.657283/full#supplementary-material\n\nSupplementary Figure 1 Next-generation sequencing result showed a HER2 Y772_A775dup mutation. The BAM file was viewed using integrative genomics viewer.\n\nClick here for additional data file.\n\nSupplementary Figure 2 Kaplan-Meier estimates of progression-free survival and overall survival according to according to HER2 mutations. 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J Thorac Oncol (2019) 14 (10 ):1784–93. 10.1016/j.jtho.2019.06.002\n36 Marcoux N Gettinger SN O’Kane G Arbour KC Neal JW Husain H . Egfr-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. J Clin Oncol (2019) 37 (4 ):278–85. 10.1200/JCO.18.01585\n\n",
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"abstract": "The report a rare case of oxytocin-induced severe maternal bradyarrhythmia of a young healthy term primigravida with a singleton pregnancy in spontaneous labour. Augmentation of labour was initiated immediately following the diagnosis of poor progression of labour at four centimetres dilatation. An oxytocin infusion was administered as per standard hospital titration protocol. The patient developed ongoing, persistent episodes of severe bradycardia within six hours of commencement of the oxytocin infusion, as detected by routine pulse oximeter for maternal heart rate monitoring and confirmed manually. Oxytocin was ceased as soon this was recognised, and delivery was expedited by emergency caesarean section both for inadequate progress in labour and the inability to continue oxytocin infusion. Despite being theoretically known to cause cardiac arrhythmias, as a side effect, to our knowledge this is the first reported case in published literature of oxytocin-induced maternal bradycardia.",
"affiliations": "Gold Coast University Hospital, Department of Obstetrics and Gynecology, QLD, Australia.;Gold Coast University Hospital, Department of Obstetrics and Gynecology, QLD, Australia.;Gold Coast University Hospital, Department of Obstetrics and Gynecology, QLD, Australia.;Gold Coast University Hospital, Department of Obstetrics and Gynecology, QLD, Australia.",
"authors": "Abuladze|N|N|;Gould|N|N|;Williams|S|S|;Wong|A|A|",
"chemical_list": "D010120:Oxytocics; D010121:Oxytocin",
"country": "Georgia (Republic)",
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"journal": "Georgian medical news",
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"medline_ta": "Georgian Med News",
"mesh_terms": "D000328:Adult; D015360:Analgesia, Epidural; D001919:Bradycardia; D002585:Cesarean Section; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007751:Labor, Induced; D050498:Live Birth; D010120:Oxytocics; D010121:Oxytocin; D011247:Pregnancy",
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"pmid": "30702065",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "A RARE CASE OF OXYTOCIN-INDUCED MATERNAL CARDIAC BRADYARRHYTHMIA DURING LABOUR.",
"title_normalized": "a rare case of oxytocin induced maternal cardiac bradyarrhythmia during labour"
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"abstract": "Melioidosis, an infectious disease caused by Burkholderia pseudomallei, is endemic in the Northern Australia and South-East Asia. It is an emerging disease in the Indian subcontinent. Melioidosis tends to run a potentially lethal course in immunocompromised individuals and data in renal transplantation are scarce. The clinical presentation of melioidosis is diverse, mimicking several other infectious diseases. Diagnosis could be delayed in transplant recipients. Choice and duration of antimicrobial therapy, management of immunosuppression, and patient and graft outcomes are other issues to be addressed. We report septicemic melioidosis with pulmonary involvement in a 32-year old renal transplant recipient that caused acute allograft dysfunction.",
"affiliations": "Department of Medicine, Nephrology Division, Dhanalakshmi Srinivasan Medical College, Perambalur, India; Department of Nephrology, Sundaram Hospital, Tiruchirappalli, Tamil Nadu, India.",
"authors": "Sathiavageesan|S|S|",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-26-37910.4103/0971-4065.168142Case ReportSepticemic melioidosis in a transplant recipient causing graft dysfunction Sathiavageesan S. 121 Department of Medicine, Nephrology Division, Dhanalakshmi Srinivasan Medical College, Perambalur, India2 Department of Nephrology, Sundaram Hospital, Tiruchirappalli, Tamil Nadu, IndiaAddress for correspondence: Dr. S. Sathiavageesan, Department of Nephrology, Sundaram Hospital, 17, EVR Road, Puthur, Tiruchirappalli - 620 017, Tamil Nadu, India. E-mail: [email protected] 2016 26 5 379 382 Copyright: © Indian Journal of Nephrology2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Melioidosis, an infectious disease caused by Burkholderia pseudomallei, is endemic in the Northern Australia and South-East Asia. It is an emerging disease in the Indian subcontinent. Melioidosis tends to run a potentially lethal course in immunocompromised individuals and data in renal transplantation are scarce. The clinical presentation of melioidosis is diverse, mimicking several other infectious diseases. Diagnosis could be delayed in transplant recipients. Choice and duration of antimicrobial therapy, management of immunosuppression, and patient and graft outcomes are other issues to be addressed. We report septicemic melioidosis with pulmonary involvement in a 32-year old renal transplant recipient that caused acute allograft dysfunction.\n\nKey words\nAllograft dysfunctionmelioidosisrenal transplantationsepticemia\n==== Body\nIntroduction\nMelioidosis, an infectious disease caused by Burkholderia pseudomallei, has been reported sporadically from various parts of India.[123] Data in renal transplant recipients are scarce.[456] We report a case of septicemic melioidosis in a renal transplant recipient presenting with pneumonia, mediastinal lymphadenopathy, and graft dysfunction.\n\nCase Report\nA 32-year-old man underwent preemptive kidney transplantation for diabetic nephropathy. He received a kidney from his mother. He had 4/6 human leukocyte antigen match, negative cross match and received no induction. He received triple-drug immunosuppression with tacrolimus (trough level 9.1 ng/ml at the fifth posttransplant month), azathioprine 2 mg/kg/day, and prednisolone 10 mg/day. He manifested gastrointestinal intolerance to both mycophenolate and enteric coated mycophenolic acid, and hence azathioprine was chosen. He had completed vaccination against hepatitis B, pneumococcus, and varicella-zoster prior to transplant. Cotrimoxazole prophylaxis was excluded due to the previous hypersensitivity. His allograft functioned normally (serum creatinine 1.2 mg/dl) until the fifth posttransplant month when he presented with continuous high-grade fever with chills and rigor and dry cough of 6 days duration. His vitals initially remained stable. Apart from pyrexia, clinical examination was unremarkable.\n\nInvestigations were notable for neutrophilic leukocytosis with leftward shift and allograft dysfunction. Serum creatinine was 1.5 mg/dl at the presentation. Blood and urine culture grew no organisms. Blood film was negative for malarial parasite. Ultrasonogram and Doppler study of allograft were unremarkable. Chest radiograph [Figure 1] revealed superior mediastinal widening. Computerized tomography of chest [Figures 2 and 3] revealed subpleural nodules in the right upper lobe, some of them showing cavitation and extensive mediastinal lymphadenopathy involving para- and pre-tracheal, carinal, and bilateral hilar nodes [Figure 4]. Endobronchial ultrasound guided needle aspiration of mediastinal nodes yielded purulent material rich in neutrophils. The lymph node aspirate and bronchoalveolar lavage sample did not yield any specific organism upon staining and culture.\n\nFigure 1 Chest radiograph revealing superior mediastinal widening\n\nFigure 2 Computed tomography thorax axial section – arrows point to subpleural nodules\n\nFigure 3 Computed tomography thorax axial section – arrow points to a cavitating nodule\n\nFigure 4 Computed tomography thorax revealing extensive mediastinal lymphadenopathy\n\nHe was given empiric antimicrobial coverage for community-acquired pneumonia with intravenous ceftriaxone and oral levofloxacin. He continued to have fever and was prescribed new regimens which included piperacillin tazobactam, meropenem, and vancomycin. He continued to have fever and progressed to sepsis with hypotension. Serum creatinine increased to 1.9 mg/dl in the 4th week of illness. Immunosuppression was reduced – azathioprine was stopped, and tacrolimus dose reduced to maintain a trough level of 7.2 ng/ml. He was resuscitated, and allograft biopsy was performed which revealed acute tubular injury. By the 4th week of illness, he began to expectorate sputum the culture of which grew B. pseudomallei. Melioidosis was diagnosed and intravenous ceftazidime was initiated. Fever remitted on the 5th day after starting treatment. Since he was allergic to cotrimoxazole, he was treated with oral doxycycline for eradication therapy. He remained afebrile at the end of three months of eradication therapy with good allograft function (serum creatinine 1.3 mg/dl).\n\nDiscussion\nFever and allograft dysfunction have a wide range of differentials in transplant recipients. This patient presented with high-grade continuous fever with chills and rigor, pneumonia with cavitating nodules, and extensive mediastinal lymphadenopathy. He failed to respond to empiric antibiotic therapy for community-acquired pneumonia. He progressed to sepsis syndrome with hypotension and graft dysfunction. Initial considerations included reactivation tuberculosis (in lieu of past tuberculous pleural effusion) with dissemination, fungal infections such as aspergillosis, cryptococcosis, and bacterial infections such as staphylococcal pneumonia which could cavitate. Although posttransplant lymphoproliferative disorder (PTLD) was a diagnostic possibility based on the findings of imaging studies,[7] acute presentation with high grade continuous fever and progression to sepsis made PTLD unlikely. Staphylococcal pneumonia presents with thin-walled cavities distended with air (pneumatoceles)[8] while the patient had thick walled cavities. Blood culture grew none and sputum culture done in the 4th week of illness isolated B. pseudomallei.\n\nMelioidosis is endemic in the Northern Australia and South-East Asia.[9] It is being increasingly recognized in India.[123] There is a paucity of information regarding the magnitude of this infection in the different regions of India. The causative agent B. pseudomallei, a Gram-negative aerobic bacillus, is a saprophyte found in the soil and surface water. It is a facultative intracellular organism transmitted by inhalation, ingestion, and cutaneous inoculation.[10] The infection can result in the clinical disease or a latent infection.[10] Melioidosis in transplant recipients could be due to primary infection or reactivation of latent infection. The clinical presentation could be acute, subacute, or chronic.\n\nPneumonia is the most common clinical presentation of patients with melioidosis.[10] Acute melioidosis pneumonia has a spectrum ranging from fulminant septic shock with high mortality to mild pneumonia with little mortality. On chest radiographs, diffuse nodular infiltrates often develop throughout both lungs with predilection for upper lobes. The nodules may coalesce and cavitate due to caseous necrosis.[10] Mediastinal adenopathy could occur.[11]\n\nDiabetes mellitus, alcoholism, renal failure, and steroid therapy predispose to severe forms of melioidosis such as septicemic and pneumonic forms.[10] Predisposition in these situations reflects impairment of neutrophil and other phagocytic cell functions.[12]\n\nDiagnosis is based on isolation in culture[13] or by serological investigations[141516] such as indirect hemagglutination, or enzyme-linked immunosorbent assay. B. pseudomallei readily grows in commercial culture media but could be mistaken for Pseudomonas species.[13] Polymerase Chain Reaction assay of buffy coat could be used to detect this organism in febrile patients.[17] Treatment recommendation[10] for adults consists of initial intensive therapy for at least 14 days with any one of intravenous ceftazidime, meropenem, or imipenem followed by eradication therapy for minimum of three months with cotrimoxazole or doxycycline. It may take a prolonged period of fever defervescence (mean 12 days in a South Indian study),[18] and hence antibiotics need not be transitioned prematurely.\n\nThe patient in this report had documented hypersensitivity to cotrimoxazole which precluded routine prophylaxis with the drug. Whether cotrimoxazole prophylaxis could prevent melioidosis in transplant recipients needs to be answered. Even though empiric regimen included Meropenem, to which he might have responded, he was prematurely transitioned to another antibiotic. After a diagnosis of melioidosis, he was treated with intravenous ceftazidime for 15 days. Diabetes mellitus and immunosuppressive therapy predisposed him to life threatening melioidosis.\n\nConclusion\nTransplant recipients are prone to develop life-threatening forms of melioidosis such as pneumonic and septicemic forms. Allograft dysfunction could result from sepsis and hypotension. Prompt consideration of this infection in transplant recipients in endemic regions in the setting of fever, pneumonia, lymphadenopathy, visceral abscess, and sepsis could facilitate early diagnosis, institution of specific antimicrobial therapy, and fasten recovery. Since it may take a long time for defervescence of fever even with appropriate antimicrobial therapy, establishing a diagnosis of melioidosis will help to avoid premature withdrawal of effective antimicrobial drugs.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 John TJ Jesudason MV Lalitha MK Ganesh A Mohandas V Cherian T Melioidosis in India: The tip of the iceberg? Indian J Med Res 1996 103 62 5 8926030 \n2 Gopalakrishnan R Sureshkumar D Thirunarayan MA Ramasubramanian V Melioidosis: An emerging infection in India J Assoc Physicians India 2013 61 612 4 24772696 \n3 Saravu K Mukhopadhyay C Vishwanath S Valsalan R Docherla M Vandana KE Melioidosis in southern India: Epidemiological and clinical profile Southeast Asian J Trop Med Public Health 2010 41 401 9 20578524 \n4 John GT Ahmed I Jacob CK Jesudason MV Lalitha MK Melioidosis in a renal transplant recipient Transplant 2003 76 262 \n5 Jabbar Z Han TM Gagan F Expect the unexpected: Pleuro-pulmonary melioidosis in a renal transplant recipient Transpl Infect Dis 2013 15 E40 3 23278969 \n6 Franco-Paredes C Jacob JT Hidron A Rodriguez-Morales AJ Kuhar D Caliendo AM Transplantation and tropical infectious diseases Int J Infect Dis 2010 14 e189 96 19647464 \n7 Vrachliotis TG Vaswani KK Davies EA Elkahammas EA Bennett WF Bova JG CT findings in posttransplantation lymphoproliferative disorder of renal transplants AJR Am J Roentgenol 2000 175 183 8 10882272 \n8 Macfarlane J Rose D Radiographic features of staphylococcal pneumonia in adults and children Thorax 1996 51 539 40 8711686 \n9 Cheng AC Currie BJ Melioidosis: Epidemiology, pathophysiology, and management Clin Microbiol Rev 2005 18 383 416 15831829 \n10 Currie BJ Burkholderia pseudomallei and Burkholderia mallei : Melioidosis and Glanders Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases 2010 7th ed Philadelphia Churchil Livingstone Elsevier 2869 80 \n11 Dhiensiri T Puapairoj S Susaengrat W Pulmonary melioidosis: Clinical-radiologic correlation in 183 cases in northeastern Thailand Radiology 1988 166 711 5 3340766 \n12 Easton A Haque A Chu K Lukaszewski R Bancroft GJ A critical role for neutrophils in resistance to experimental infection with Burkholderia pseudomallei J Infect Dis 2007 195 99 107 17152013 \n13 Dance DA Wuthiekanun V Naigowit P White NJ Identification of Pseudomonas pseudomallei in clinical practice: Use of simple screening tests and API 20NE J Clin Pathol 1989 42 645 8 2472432 \n14 Sirisinha S Anuntagool N Dharakul T Ekpo P Wongratanacheewin S Naigowit P Recent developments in laboratory diagnosis of melioidosis Acta Trop 2000 74 235 45 10674655 \n15 Cheng AC O’brien M Freeman K Lum G Currie BJ Indirect hemagglutination assay in patients with melioidosis in northern Australia Am J Trop Med Hyg 2006 74 330 4 16474092 \n16 Chantratita N Wuthiekanun V Thanwisai A Limmathurotsakul D Cheng AC Chierakul W Accuracy of enzyme-linked immunosorbent assay using crude and purified antigens for serodiagnosis of melioidosis Clin Vaccine Immunol 2007 14 110 3 17093104 \n17 Sankar S Vadivel K Nandagopal B Jesudason MV Sridharan G A multiplex nested PCR for the simultaneous detection of Salmonella typhi, Mycobacterium tuberculosis, and Burkholderia pseudomallei in Patients with Pyrexia of Unknown Origin (PUO) in Vellore, South India Mol Diagn Ther 2014 18 315 21 24385404 \n18 Jesudason MV Anbarasu A John TJ Septicaemic melioidosis in a tertiary care hospital in south India Indian J Med Res 2003 117 119 21 14575177\n\n",
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"journal": "Indian journal of nephrology",
"keywords": "Allograft dysfunction; melioidosis; renal transplantation; septicemia",
"medline_ta": "Indian J Nephrol",
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"abstract": "Despite the risk of bleeding is a well-known adverse effect of oral anticoagulants, there is scarce evidence on the preventability of oral anticoagulant-induced bleedings. Therefore, we investigated the potential risk factors related to preventable cases of oral anticoagulant-induced bleedings.\nWe performed a study using Individual Case Safety Reports (ICSRs) with an oral anticoagulant as suspected drug among those reported through the spontaneous reporting system of Campania Region from 1 July 2012 to 31 December 2017. The P-method was used for the preventability assessment of all cases of bleeding.\nIn total, 58 cases out of 253 (22.9%) were preventable, and the most reported suspected drug was an indirect oral anticoagulant (warfarin). Sixty-eight critical criteria for preventability were identified, all related to healthcare professionals' practices. The most detected risk factor related to healthcare professionals' practices was the labeled drug-drug interaction for both direct and indirect oral anticoagulants.\nOur findings describe the most reported risk factors for preventability of oral anticoagulant-induced bleedings. These factors may be useful for targeting interventions to improve pharmacovigilance activities in our regional territory and to reduce the burden of medication errors and inappropriate prescription.",
"affiliations": "Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Section of Pharmacology \"L. Donatelli\", Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania \"Luigi Vanvitelli\", Naples, Italy.",
"authors": "Mascolo|Annamaria|A|;Ruggiero|Rosanna|R|;Sessa|Maurizio|M|;Scavone|Cristina|C|;Sportiello|Liberata|L|;Rafaniello|Concetta|C|;Rossi|Francesco|F|;Capuano|Annalisa|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2019.00425",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2019.00425PharmacologyOriginal ResearchPreventable Cases of Oral Anticoagulant-Induced Bleeding: Data From the Spontaneous Reporting System Mascolo Annamaria 1*†Ruggiero Rosanna 1†Sessa Maurizio 12Scavone Cristina 1Sportiello Liberata 1Rafaniello Concetta 1Rossi Francesco 1‡Capuano Annalisa 1‡1Section of Pharmacology “L. Donatelli”, Department of Experimental Medicine, Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, University of Campania “Luigi Vanvitelli”, Naples, Italy2Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, DenmarkEdited by: Ali H. Eid, American University of Beirut, Lebanon\n\nReviewed by: Alessandro Di Minno, University of Naples Federico II, Italy; Jun Xiao Feng, University of Science and Technology of China, China; Leonardo Augusto Moraes, National University of Singapore, Singapore\n\n*Correspondence: Annamaria Mascolo, [email protected]†These authors have contributed equally to this work\n\n‡These authors are both lead authors\n\nThis article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology\n\n30 4 2019 2019 10 42509 1 2019 03 4 2019 Copyright © 2019 Mascolo, Ruggiero, Sessa, Scavone, Sportiello, Rafaniello, Rossi and Capuano.2019Mascolo, Ruggiero, Sessa, Scavone, Sportiello, Rafaniello, Rossi and CapuanoThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background\nDespite the risk of bleeding is a well-known adverse effect of oral anticoagulants, there is scarce evidence on the preventability of oral anticoagulant-induced bleedings. Therefore, we investigated the potential risk factors related to preventable cases of oral anticoagulant-induced bleedings.\n\nMethods\nWe performed a study using Individual Case Safety Reports (ICSRs) with an oral anticoagulant as suspected drug among those reported through the spontaneous reporting system of Campania Region from 1 July 2012 to 31 December 2017. The P-method was used for the preventability assessment of all cases of bleeding.\n\nResults\nIn total, 58 cases out of 253 (22.9%) were preventable, and the most reported suspected drug was an indirect oral anticoagulant (warfarin). Sixty-eight critical criteria for preventability were identified, all related to healthcare professionals’ practices. The most detected risk factor related to healthcare professionals’ practices was the labeled drug–drug interaction for both direct and indirect oral anticoagulants.\n\nConclusion\nOur findings describe the most reported risk factors for preventability of oral anticoagulant-induced bleedings. These factors may be useful for targeting interventions to improve pharmacovigilance activities in our regional territory and to reduce the burden of medication errors and inappropriate prescription.\n\noral anticoagulantbleedingpreventability assessmentspontaneous reporting systemadverse effect\n==== Body\nIntroduction\nOral anticoagulant therapy is widely used for the prevention of stroke and systemic embolism in patients with atrial fibrillation, or for the prevention and treatment of deep vein thrombosis and pulmonary embolism (Raj et al., 1994; Monaco et al., 2017). Oral anticoagulants can be divided into “indirect oral anticoagulants,” like vitamin K antagonists (VKAs; warfarin, or acenocoumarol), which have been the cornerstone of the anticoagulation therapy for decades, and into the more recently approved “direct oral anticoagulants” (DOACs), which are selective inhibitors of single coagulation factors. Belongs to DOACs the reversible direct thrombin inhibitor (dabigatran), and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) (Sabir et al., 2014; Monaco et al., 2017). Since their introduction, these more recent drugs have added some advantages to the clinical practice, like the rapid onset of action, the more predictable pharmacokinetics and pharmacodynamics, the potentially reduced risk for drug-drug interactions, and the absence of routine coagulation monitoring (Mekaj et al., 2015; Eikelboom and Merli, 2016; Hicks et al., 2016; Monaco et al., 2017). Thanks to these properties, DOACs represent an effective alternative to VKAs, offering also important safety advantages in terms of risk of bleeding (Eikelboom and Merli, 2016). Accordingly, a large phase III study has shown a consistent reduction of the risk of cerebral hemorrhagic events with DOACs compared to warfarin (Ruff et al., 2014), but DOACs may be associated with a higher risk of gastrointestinal bleedings (Holster et al., 2013; Ruff et al., 2014).\n\nDespite the risk of bleeding is a well-known adverse effect of oral anticoagulants that requires constant monitoring in a real-life context, the evidence on the preventability of oral anticoagulant-induced bleedings is meager. This can be even more interesting considering that among predisposing causes of anticoagulant-induced adverse drug reactions (ADRs), there are medication errors (Piazza et al., 2011; Sessa et al., 2018a) that represent in general an important cause of preventable ADRs (European Medicine Agency, 2013). Moreover, the importance of evaluating the preventability of ADRs is nowadays suggested by both European Medicine Agency and World Health Organization as part of pharmacovigilance-based activities to achieve an effective risk minimization (European Medicine Agency, 2013; Pal et al., 2015). In light of this consideration and taking into account that no study has been conducted in our country to directly evaluate the preventability of bleeding cases reporting an oral anticoagulant as a suspected drug, we decided to conduct a pharmacovigilance study on spontaneous reporting data to fill this gap in knowledge. Therefore, the primary aim of this study was to assess the preventability of bleeding cases reporting an oral anticoagulant as a suspected drug among those sent through the Campania spontaneous reporting system from July 2012 to December 2017.\n\nMaterials and Methods\nData Source\nIndividual Case Safety Reports (ICSRs) with an oral anticoagulant as a suspected drug were selected among those reported through the spontaneous reporting system from 1 July 2012 to 31 December 2017. ICSRs were retrieved from the Italian National database for Pharmacovigilance (Rete Nazionale di Farmacovigilanza, RNF). This database collects all ICSRs reported spontaneously or deriving from active pharmacovigilance projects or observational studies. In Italy, every healthcare institution has his own Responsible Person for Pharmacovigilance that provides to send to the RNF each ICSR received from a reporter. We collected for preventability assessment only ICSRs sent to the RNF by one Italian Region (Campania).\n\nDescriptive and Statistical Analyses\nFor descriptive purposes, information on age, gender, type of reporter, seriousness, outcome, action taken to solve the ADRs, causality assessment, and number of reported suspected drugs were provided separately for all cases, for all cases of bleeding, and for “preventable” cases of bleeding. Bleeding cases were defined as all cases that reported at least one hemorrhagic adverse event among those described in the ICSR. Cases without hemorrhagic events were classified as not bleeding cases and were analyzed separately. Moreover, ICSRs were classified based on the suspected drug in those reporting an indirect oral anticoagulant (warfarin or acenocoumarol), and those reporting a DOAC (dabigatran, edoxaban, rivaroxaban, or apixaban). All reported preferred terms (PTs) related to bleedings were tabled according to their system organ class (SOC) (Brown et al., 1999). For gastrointestinal bleedings, when their location in the gastrointestinal tract was available in the ICSRs, we classified them into “upper gastrointestinal bleedings” and “lower gastrointestinal bleedings” for each oral anticoagulant. We classified as belonging to the group “upper gastrointestinal bleedings” any hemorrhagic event that occurs between the oropharynx and the ligament of Treitz, or any event that could be highly associated with upper gastrointestinal bleedings (e.g., melena or hematemesis). We classified instead into the group “lower gastrointestinal bleedings” any hemorrhagic event that occurs from the ligament of Treitz to the anus. Reporting odds ratio (ROR), its’ 95% confidence interval (95%CI) and the chi-square test were computed to evaluate if the drugs undervaluation had a lower/higher probability of lower/upper gastrointestinal bleeding when compared to dabigatran. Dabigatran was used as a reference drug considering that clinical evidence has shown a higher risk of lower gastrointestinal bleeding for this drug compared to warfarin (Kolb et al., 2018). For each comparison, a post hoc power calculation was performed to assess the achieved statistical power as described by Wang and Chow (2007). For all cases of bleedings, therapeutic indications of oral anticoagulants were tabled. Additionally, the three most reported PTs for each SOC not related to bleeding were tabled. For each ICSR, the seriousness of ADRs was codified as described in the International Council on Harmonization E2D guidelines (European Medicines Agency, 2003), whereas the outcome was categorized into six categories (recovered, improvement, resolution with sequelae, unchanged clinical condition, death, and not available) according to national law. The causality assessment evaluation was performed using the Naranjo algorithm according to the Italian Medicine Agency (AIFA) (Naranjo et al., 1981). Finally, we showed our contribution to the national spontaneous reporting system in terms of pooled ICSRs using the online public report of ADRs (RAM system).\n\nPreventability Assessment\nThe P-method was used for the preventability assessment of all cases of bleeding. This method is an algorithm developed by World Health Organization to assess the preventability of ADRs reported in the spontaneous reporting system, and it was validated by pharmacovigilance centers during the WHO Program for International Drug Monitoring (Benkirane et al., 2015). Moreover, it has been validated in several projects of Campania Region that aimed to explore the use of P-method for the preventability assessment of adverse reactions induced by several drug classes (e.g., non-steroidal anti-inflammatory drugs, psychotropic drugs, contrast media, and statins) (Sessa et al., 2016b,c, 2017, 2018b). The P-method based on three steps of evaluation. The first step involved the causality assessment between the drug and the ADR, and we used the Naranjo algorithm. The second step based on the evaluation of the mechanism underlying the ADR in terms of dependency on dose, time, patient susceptibility, or an unknown mechanism. Finally, the last step involved the identification of critical criteria for preventability. The preventability criteria are classified into three sections: healthcare professionals’ practice, product/drug, and patient. There are 16 critical criteria related to the healthcare professionals’ practice, two critical criteria related to the product/drug, and two critical criteria related to the patient. The criteria related to healthcare professionals are incorrect drug dose, administration route, duration, storage, laboratory or clinical monitoring, expired drug, wrong indication, inappropriate prescription for patient’s underlying medical condition or according to the characteristics of the patient, documented hypersensitivity, labeled drug–drug interaction, therapeutic duplication, withdrawal syndrome, and necessary medication not given. The criteria related to the product/drug are poor drug quality and counterfeit drug, and the criteria related to the patient behavior are the non-compliance and self-medication (Benkirane et al., 2015; Sessa et al., 2016c). According to this methodology, a case can be classified as preventable if it is found at least one critical criterion for preventability. In this study, three clinical pharmacologists (one medical doctor and two pharmacists) with multiyear experience in pharmacovigilance and preventability assessment evaluated the preventability of oral anticoagulant-induced bleedings through a case-by-case approach. For the entire evaluation, when the consultation of the Summary of Product Characteristics (SmPC) was needed, those published by the AIFA were used. Details regarding the operative framework for preventability of ICSRs are provided elsewhere (Sessa et al., 2016b,c, 2017).\n\nFor all preventable cases of bleeding, the time to event was computed as the difference in days between the onset date of the adverse event and the start date of anticoagulant therapy. A boxplot of time to event was generated for direct and indirect oral anticoagulants. Finally, a cases series of preventable ICSRs was provided.\n\nResults\nIn the period from July 2012 to December 2017, 25,609 ICSRs were sent to Campania Pharmacovigilance Regional Centre, of which 453 reported an oral anticoagulant as suspected drug contributing to the 2.4% of national ICSRs (N = 18606). The mean age of patients was 72.5 years [standard deviation (SD): 11.2 years], with 52.3% of cases occurred in female patients. In most ICSRs (92.1%), one medical product was reported as a suspected drug. ICSRs were mainly classified by the reporter as not serious (264; 58.3%). Cases classified as serious were for 17.2% related to hospitalizations, for 11.9% registered as clinically significant conditions, for 2.4% defined as life-threatening, and for 1.5% related to the death of the patient. In 66.9% of cases, several actions were taken to solve the ADRs. The main reporter was the physician with 261 (57.6%) out of 453 ICSRs. Causality assessment was probable for 128 (28.3%) cases and possible for 325 (71.7%) cases. Characteristics of cases were presented in Table 1. Because in each ICSR more than one ADR could be reported, we observed a total of 676 ADRs for ICSRs (1.5 suspected ADRs per ICSR). A total of 399 out of 676 ADRs were not related to bleedings. Among them, the six most reported ADRs were abnormal coagulation profile (35/399; 8.8%), epigastric abdominal pain (28/399; 7.0%), dyspepsia (28/399; 7.0%), increased international normalized ratio (INR) (28/399; 7.0%), anemia (21/399; 5.3%), and fluctuating INR (16/399; 4.0%) (Table 2).\n\nTable 1 Demographic characteristics and distribution for the type of reporter, drug, documentation, seriousness, outcome, causality assessment, and action taken of cases involving oral anticoagulants recognized in Campania spontaneous reporting system from July 2012 – December 2017.\n\nVariable\tLevel\tCases of bleeding disorders (N = 253)\tPreventable cases of bleeding disorders (N = 58)\tTotal (N = 453)\t\nGender\tFemale\t134 (53.0)\t36 (62.1)\t237 (52.3)\t\n\tMale\t117 (46.2)\t22 (37.9)\t212 (46.8)\t\n\tNot available\t2 (0.8)\t–\t4 (0.9)\t\nAge\tMean (standard deviation)\t72.9 (10.9)\t74.4 (10.9)\t72.5 (11.2)\t\nSeriousness\tSerious–other clinically significant condition\t29 (11.5)\t5 (8.6)\t54 (11.9)\t\n\tSerious–death\t6 (2.4)\t3 (5.2)\t7 (1.5)\t\n\tSerious–significant or permanent disability\t–\t–\t1 (0.2)\t\n\tSerious–hospitalization\t55 (21.7)\t17 (29.3)\t78 (17.2)\t\n\tSerious–life threatening\t9 (3.6)\t3 (5.2)\t11 (2.4)\t\n\tNot defined\t9 (3.6)\t–\t38 (8.4)\t\n\tNot serious\t145 (57.3)\t30 (51.7)\t264 (58.3)\t\nOutcome\tDeath\t6 (2.4)\t3 (5.2)\t7 (1.5)\t\n\tImprovement\t93 (36.8)\t20 (34.5)\t143 (31.6)\t\n\tUnchanged clinical condition\t18 (7.1)\t9 (15.5)\t23 (5.1)\t\n\tNot available\t52 (20.6)\t6 (10.3)\t129 (28.5)\t\n\tRecovered\t71 (28.1)\t20 (34.5)\t134 (29.6)\t\n\tResolution with sequelae\t13 (5.1)\t–\t17 (3.8)\t\nReporter\tPhysicians\t142 (56.1)\t16 (27.6)\t261 (57.6)\t\n\tPharmacist\t95 (37.5)\t40 (69.0)\t124 (27.4)\t\n\tOther health care professional\t8 (3.2)\t1 (1.7)\t27 (6.0)\t\n\tPatient/Citizen or other non-healthcare professional figure\t8 (3.2)\t1 (1.7)\t41 (9.1)\t\nCausality\tPossible\t152 (60.1)\t43 (74.1)\t325 (71.7)\t\n\tProbable\t101 (39.9)\t15 (25.9)\t128 (28.3)\t\nAction taken\tYes\t176 (69.6)\t44 (75.9)\t303 (66.9)\t\n\tNo\t77 (30.4)\t14 (24.1)\t150 (33.1)\t\nOral anticoagulant\tIndirect oral anticoagulant\t179 (70.8)\t53 (91.4)\t248 (54.7)\t\n\tWarfarin\t161 (63.6)\t44 (83.0)\t223 (49.2)\t\n\tAcenocoumarol\t18 (7.1)\t9 (17.0)\t25 (5.5)\t\n\tDirect oral anticoagulant\t74 (29.2)\t5 (8.6)\t205 (45.3)\t\n\tDabigatran\t35 (13.8)\t3 (5.2)\t125 (27.6)\t\n\tRivaroxaban\t21 (8.3)\t1 (1.7)\t42 (9.3)\t\n\tApixaban\t16 (6.3)\t–\t35 (7.7)\t\n\tEdoxaban\t2 (0.8)\t1 (1.7)\t3 (0.7)\t\nNumber of reported suspected drugs\t>1\t24(9.5)\t17 (29.3)\t36 (7.9)\t\n\t1\t229 (90.5)\t41 (70.7)\t417 (92.1)\t\n\t\nTable 2 Adverse drug reactions (ADRs) not related to bleeding categorized by system organ class (SOC) and three most reported preferred terms in Individual Case Safety Reports (ICSRs) reporting anticoagulants as suspected drugs.\n\nSOC and ADRs\tNumber of cases (%)\t\nGastrointestinal disorders\t115 (28.8)\t\nEpigastric abdominal pain\t28 (7.0)\t\nDyspepsia\t28 (7.0)\t\nDiarrhea\t9 (2.3)\t\nInvestigations\t95 (23.8)\t\nAbnormal coagulation profile\t35 (8.8)\t\nIncreased INR\t28 (7.0)\t\nFluctuating INR\t16 (4.0)\t\nNervous system disorders\t33 (8.3)\t\nHeadache\t7 (1.7)\t\nCerebrovascular accident\t3 (0.8)\t\nStroke\t3 (0.8)\t\nBlood and lymphatic system disorders\t31 (7.8%)\t\nAnemia\t21 (5.3)\t\nThrombocytopenia\t3 (0.8)\t\nPancytopenia\t1 (0.3)\t\nGeneral disorders and administration site conditions\t26 (6.5)\t\nAsthenia\t7 (1.7)\t\nTherapeutic failure\t4 (1.0)\t\nFacial edema\t2 (0.5)\t\nSkin and subcutaneous tissue disorders\t24 (6.0)\t\nItch\t5 (1.2)\t\nSweating\t3 (0.8)\t\nErythema\t2 (0.5)\t\nRenal and urinary disorders\t13 (3.3)\t\nRenal failure\t6 (1.5)\t\nRenal lesion\t2 (0.5)\t\nDecreased renal function\t1 (0.3)\t\nRespiratory, thoracic, and mediastinal disorders\t12 (3.0)\t\nDyspnea\t8 (2.0)\t\nCough\t1 (0.3)\t\nRespiratory distress\t1 (0.3)\t\nVascular disorders\t12 (3.0)\t\nThrombosis\t2 (0.5)\t\nHypertension\t2 (0.5)\t\nVasculitis\t1 (0.3)\t\nCardiac disorders\t9 (2.3)\t\nAtrial fibrillation\t4 (1.0)\t\nPalpitation\t1 (0.3)\t\nPericardial effusion\t1 (0.3)\t\nEar and labyrinth disorders\t6 (1.5)\t\nVertigo\t4 (1.0)\t\nPeripheral vertigo\t2 (0.5)\t\nPsychiatric disorders\t6 (1.5)\t\nDrowsiness\t2 (0.5)\t\nHallucination\t1 (0.3)\t\nAgitation\t1 (0.3)\t\nHepatobiliary disorders\t5 (1.2)\t\nHypertransaminasemia\t1 (0.3)\t\nCholangitis\t1 (0.3)\t\nJaundice\t1 (0.3)\t\nInjury, poisoning, and procedural complications\t3 (0.8)\t\nOverdose\t2 (0.5)\t\nContusion\t1 (0.3)\t\nMusculoskeletal and connective tissue disorders\t3 (0.8)\t\nJoint effusion\t1 (0.3)\t\nHydrarthrosis\t1 (0.3)\t\nRhabdomyolysis\t1 (0.3)\t\nInfections and infestations\t3 (0.8)\t\nRhinopharyngitis\t1 (0.3)\t\nInfections\t1 (0.3)\t\nUrinary infection\t1 (0.3)\t\nEye disorders\t1 (0.3)\t\nDiplopia\t1 (0.3)\t\nImmune system disorders\t1 (0.3)\t\nAllergy\t1 (0.3)\t\nMetabolism and nutrition disorders\t1 (0.3)\t\nInappetence\t1 (0.3)\t\nTotal\t399 (100.0)\t\n\t\nINR: international normalized ratio.Cases of Bleeding\nA total of 253 cases (55.8%) out of 453 ICSRs reported at least one adverse event related to bleeding. Characteristics of cases associated with bleeding events are presented in Table 1. Specifically, a total of 161 cases related to warfarin, 35 cases to dabigatran, 21 cases to rivaroxaban, 18 cases to acenocoumarol, 16 cases to apixaban, and two cases to edoxaban. The most reported therapeutic indications for direct or indirect oral anticoagulants were atrial fibrillation and antithrombotic prophylaxis (Supplementary Table S1). A total of 277 suspected ADRs were related to bleedings, of which 193 were related to indirect oral anticoagulants. For indirect oral anticoagulant, most adverse events belong to the SOC “respiratory, thoracic, and mediastinal disorders” (87/193; 45.1%), followed by “gastrointestinal disorders” (56/193; 29.0%), “renal and urinary disorders” (20/193; 10.4%), “vascular disorders” (11/193; 5.7%), “nervous system disorders” (11/193; 5.7%), “skin and subcutaneous tissue disorders” (4/193; 2.1%), “injury, poisoning and procedural complications” (2/193; 1.0%), “musculoskeletal and connective tissue disorders” (1/193; 0.5%), and “eye disorders” (1/193; 0.5%). For DOAC, most adverse events belong to the SOC “gastrointestinal disorders” (37/84; 44.0%), followed by “respiratory, thoracic, and mediastinal disorders” (14/84; 16.7%), “renal and urinary disorders” (8/84; 9.5%), “vascular disorders” (8/84; 9.5%), “nervous system disorders” (5/84; 6.0%), “injury, poisoning, and procedural complications” (4/84; 4.8%), “skin and subcutaneous tissue disorders” (3/84; 3.6%), “reproductive system and breast disorders” (3/84; 3.6%), “musculoskeletal and connective tissue disorders” (1/84; 1.2%), and “eye disorders” (1/84; 1.2%) (Table 3). In the evaluation of upper and lower gastrointestinal bleedings for different oral anticoagulants, we found that only 64 of 93 (68.8%) gastrointestinal bleedings met the criteria for classification, of this 35 were related to warfarin, five to acenocoumarol, 14 to dabigatran, five to rivaroxaban, and five to apixaban (Table 4). These bleeding events were mostly distributed into the group “upper gastrointestinal bleeding” for warfarin, acenocoumarol, and apixaban, and into the group “lower gastrointestinal bleeding” for dabigatran and rivaroxaban (Table 4). All cases had both narrative and documental information required for the case evaluation.\n\nTable 3 Adverse drug reactions related to bleeding categorized by system organ class (SOC) in Individual Case Safety Reports (ICSRs) reporting oral anticoagulants as suspected drugs.\n\nSOC Reported adverse events\tCases with indirect oral anticoagulants N (%)\tCases with direct oral anticoagulants N (%)\t\nGastrointestinal disorders\t56(29.0)\t37(44.0)\t\nRectal bleeding\t15(7.8)\t11(13.1)\t\nBleeding gums\t9 (4.7)\t3 (3.6)\t\nMelena\t14(7.3)\t7 (8.3)\t\nHematemesis\t7 (3.6)\t1 (1.2)\t\nBleeding in the digestive tract\t4 (2.1)\t1 (1.2)\t\nErosive gastritis\t2 (1.0)\t–\t\nAbdominal hematoma\t1 (0.5)\t–\t\nBleeding in the tongue\t1 (0.5)\t–\t\nGastric bleeding\t1 (0.5)\t2 (2.4)\t\nGastric ulcer\t1 (0.5)\t–\t\nGastrointestinal bleeding\t–\t3 (3.6)\t\nIntestinal bleeding\t–\t4 (4.8)\t\nDuodenal ulcer bleeding\t1 (0.5)\t–\t\nBleeding of hemorroids\t–\t1 (1.2)\t\nHemorrhagic intestinal diverticulitis\t–\t1 (1.2)\t\nBleeding in the mouth\t–\t1 (1.2)\t\nBleeding from polyps\t–\t1 (1.2)\t\nEsophageal ulcer\t–\t1 (1.2)\t\n\t\nRespiratory, thoracic, and mediastinal disorders\t87(45.1)\t14(16.7)\t\nEpistaxis\t78(40.4)\t10(11.9)\t\nHemoptysis\t6 (3.1)\t2 (2.4)\t\nBlood-tinged sputum\t2 (1.0)\t–\t\nCoughing up blood\t1 (0.5)\t1 (1.2)\t\nHemothorax\t–\t1 (1.2)\t\n\t\nRenal and urinary disorders\t20(10.4)\t8 (9.5)\t\nHematuria\t19(9.8)\t7 (8.3)\t\nHemorrhagic cystitis\t1 (0.5)\t–\t\nChromaturia\t–\t1 (1.2)\t\n\t\nVascular disorders\t11(5.7)\t8 (9.5)\t\nHematoma\t4 (2.1)\t2 (2.4)\t\nHemorrhage\t7 (3.6)\t5 (6.0)\t\nHemorrhagic shock\t–\t1 (1.2)\t\n\t\nSkin and subcutaneous tissue disorders\t4 (2.1)\t3 (3.6)\t\nEcchymosis\t3 (1.6)\t–\t\nBleeding of skin ulcer\t1 (0.5)\t–\t\nPetechia\t–\t2 (2.4)\t\nLower extremity ulcer\t–\t1 (1.2)\t\n\t\nNervous system disorders\t11(5.7)\t5 (6.0)\t\nCerebral hemorrhage\t9 (4.7)\t4 (4.8)\t\nCerebrovascular accident\t1 (0.5)\t–\t\nHemorrhagic stroke\t1 (0.5)\t–\t\nIntracerebral hemorrhage\t–\t1 (1.2)\t\n\t\nMusculoskeletal and connective tissue disorders\t1 (0.5)\t1 (1.2)\t\nMuscle hematoma\t1 (0.5)\t–\t\nHemarthrosis\t–\t1 (1.2)\t\n\t\nEye disorders\t1 (0.5)\t1 (1.2)\t\nConjunctival hemorrhage\t1 (0.5)\t1 (1.2)\t\n\t\nInjury, poisoning, and procedural complications\t2 (1.0)\t4 (4.8)\t\nSubdural hemorrhage\t1 (0.5)\t–\t\nSubdural hematoma\t1 (0.5)\t3 (3.6)\t\nEpidural hematoma\t–\t1 (1.2)\t\n\t\nReproductive system and breast disorders\t–\t3 (3.6)\t\nMenorrhagia\t–\t1 (1.2)\t\nVaginal bleeding\t–\t1 (1.2)\t\nIntermenstrual bleeding\t–\t1 (1.2)\t\n\t\nTable 4 Distribution of upper and lower gastrointestinal bleedings for each oral anticoagulant.\n\nOral anticoagulant\tUpper gastrointestinal bleeding N (%)\tLower gastrointestinal bleeding N (%)\t\nWarfarin\t22 (62.9)\t13 (37.1)\t\nAcenocoumarol\t4 (80)\t1 (20)\t\nDabigatran\t5 (35.7)\t9 (64.3)\t\nRivaroxaban\t2 (40)\t3 (60)\t\nApixaban\t4 (80)\t1 (20)\t\n\t\nPreventability of Cases of Bleeding\nIn total, 58 cases out of 253 (22.9%) were preventable. Preventable cases were mostly reported by healthcare structures located in the province of Avellino (N = 39; 67.2%), followed by Napoli (N = 8; 13.8%), Caserta (N = 7; 12.1%), and Benevento (N = 4; 6.9%). A full agreement was reached for all cases by clinical pharmacologists involved in preventability assessment. Considering the hemorrhagic nature of these events, the underlying mechanism of ADRs was classified as dose-related in all cases (Figure 1). Sixty-eight critical criteria related to healthcare professionals’ practices were detected in 58 preventable cases (Supplementary Table S2). Specifically, we observed five different categorizations of the criteria related to health professionals’ practice. In 75.9% of preventable cases, pharmacological and/or non-pharmacological treatments (as action taken) were required to treat the ADRs, of which 23 cases also required drug withdrawal. Characteristics of preventable cases are reported in Table 1 and the clinical description of each case is reported in Supplementary Table S2. The median times to event were 8 days [interquartile range (IQR): 5–31], and 1533 days (IQR: 328–4805) for DOAC and indirect oral anticoagulants, respectively (Figure 2).\n\nFIGURE 1 Characteristics of bleeding cases involving oral anticoagulants recognized in Campania spontaneous reporting system from July 2012 to December 2017.\n\nFIGURE 2 Time to event of preventable cases. ICSRs were screened among those reported in Campania spontaneous reporting system from July 2012 to December 2017.\n\nPreventable Cases Related to the Use of Indirect Oral Anticoagulants\nIn 53 out of 58 (91.4%) preventable cases, the reported suspected drug was an indirect oral anticoagulant. Specifically, 44 (83.0%) cases reported as suspected drug warfarin and 9 (17.0%) cases reported as suspected drug acenocoumarol. A total of 59 critical criteria related to healthcare professionals’ practices were identified. The most detected critical criteria were labeled drug–drug interactions (50/59; 84.7%), followed by the inappropriate prescription for patient’s underlying medical condition (6/59; 10.2%), and the wrong indication (3/59; 5.1%). A total of 94 drugs were involved in labeled drug–drug interactions. The most reported drug–drug interactions were with proton pump inhibitors (26/50; 52.0%), or statins (15/50; 30.0%). Accordingly, the active ingredients most involved in drug-drug interactions were pantoprazole (9/94; 9.6%), lansoprazole (9/94; 9.6%), allopurinol (7/94; 7.4%), omeprazole (6/94; 6.4%), acetylsalicylic acid (5/94; 5.3%), atorvastatin (5/94; 5.3%), amiodarone (5/94; 5.3%), and simvastatin (4/94; 4.2%) (Supplementary Table S2). The most reported inappropriate prescription for patient’s underlying medical condition was the prescription of an indirect oral anticoagulant in a patient with ulcer (4/6; 66.6%), erosive gastroduodenitis (1/6; 16.7%), or history of cerebral hemorrhage (1/6; 16.7%). The three preventable cases related to a wrong indication were the use of an indirect oral anticoagulant for peripheral obliterating arteriopathy, acute heart failure, or hypertension. Details for each preventable case are provided in Supplementary Table S2.\n\nPreventable Cases Related to the Use of Direct Oral Anticoagulants\nIn five out of 58 (8.6%) preventable cases, the reported suspected drug was a DOAC. Specifically, three (60.0%) cases reported as suspected drug dabigatran, one case rivaroxaban, and one case edoxaban. A total of nine critical criteria were identified. All criteria were related to healthcare professionals’ practices. The most detected critical criteria were labeled drug–drug interactions (3/9; 33.3%), followed by the incorrect dose (3/9; 33.3%), and the inappropriate prescription according to the characteristics of the patient (3/9; 33.3%). The three cases of labeled drug–drug interaction reported as suspected drugs rivaroxaban, dabigatran, and edoxaban. In one case, the labeled drug–drug interaction was the concomitant prescription of rivaroxaban and methimazole in accordance with the SmPC of methimazole. Another case was related to the concominant administration of dabigatran and amiodarone. The last case is the concomitant intake of edoxaban and acetylsalicylic acid in an elderly patient. The critical criteria incorrect dose and inappropriate prescription according to the characteristics of the patient were reported in the same three cases and were all related to the suspected drug dabigatran. In these cases, the patient was treated with 220 mg/day of dabigatran, but according to the SmPC, the recommended dose in elders (>75 years) is 150 mg/day. Details for each preventable case are provided in Supplementary Table S2.\n\nComparison of the Reporting Probability of Lower/Upper Gastrointestinal Bleeding Among Oral Anticoagulants\nDabigatran was associated with an increased reporting probability of lower gastrointestinal bleedings rather than upper gastrointestinal bleedings if compared to warfarin (ROR 0.33, 95%CI 0.09–1.19; reference group: dabigatran), acenocoumarol (ROR 0.14, 95%CI 0.01–1.61; reference group: dabigatran), rivaroxaban (ROR 0.83, 95%CI 0.10–6.78; reference group: dabigatran), and apixaban (ROR 0.14, 95%CI 0.01–1.61; reference group: dabigatran). Abovementioned computations were not statistically significant; however, we had no statistical power to detect statistically significant associations as described in Table 5.\n\nTable 5 Reporting odds ratio of lower/upper gastrointestinal bleeding with oral anticoagulant with dabigatran as reference drug.\n\nOral anticoagulant\tControl group\tReporting odds ratio (95% confidence interval)\tP-value\tPower (1 - beta error probability)\t\nWarfarin\tDabigatran\t0.33 (0.09–1.19)\t0.08\t0.4\t\nAcenocoumarol\tDabigatran\t0.14 (0.01–1.61)\t0.08\t0.38\t\nRivaroxaban\tDabigatran\t0.83 (0.10–6.78)\t0.86\t0.05\t\nApixaban\tDabigatran\t0.14 (0.01–1.61)\t0.09\t0.38\t\n\t\nDiscussion\nThis is the first study conducted in our national territory to assess the preventability of oral anticoagulant-induced bleedings among ICSRs sent through the Campania region (Italy) spontaneous reporting system from 1 July 2012 to 31 December 2017.\n\nConsidering the few information available on the preventability of anticoagulant-induced bleedings, especially in Italy, our results may be of great novelty because we were able to provide “real-world evidence” on the quota of preventable ICSRs of bleeding in our Regional territory. Moreover, we provide detailed information on the most reported risk factors for oral anticoagulant-induced bleedings.\n\nIn our ICSRs, the mean age was 72.5 years (SD: 11.2 years) in accordance with data showing that in elders anticoagulants are one of main causes responsible for 60% of ADRs leading to hospitalization and 70% of ADRs occurring in hospital (Routledge et al., 2004). In addition, anticoagulants are more likely than other drugs to cause ADRs that result or prolong hospitalization (Davidsen et al., 1988; Bordet et al., 2001), accordingly most of our cases classified as serious reported the criteria “serious – hospitalization.”\n\nDespite in our Region, according to the last national report on drug usage, DOACs are most frequently used than indirect oral anticoagulants (7.2 DDD/1000/inhabitants/day vs. 2.2 DDD/1000/inhabitants/day) (AIFA, 2017), we observed a total of 248 (54.7%) ICSRs that reported an indirect oral anticoagulant as suspected drug. This may be related to the narrow therapeutic window of VKAs compared with DOACs (Fuster et al., 2006).\n\nOverall, from our findings it emerged that abnormalities in the INR, and gastrointestinal abdominal pain were among non-bleeding cases most frequently associated with oral anticoagulants, suggesting that these are the main concerns today by both patients and doctors during anticoagulant therapy. Accordingly, in the literature, the most frequent anticoagulant-associated ADRs are abnormal coagulation test, bleedings, and thrombocytopenia (Piazza et al., 2011). In particular, the occurrence of an excessive anticoagulant effect, such as an increase of INR or of activated partial thromboplastin time (aPTT), has been estimated approximately of 72% (Piazza et al., 2011).\n\nIn the analysis of bleedings cases (N = 253), the most reported suspected drug was an indirect oral anticoagulant (70.8%). Moreover, we observed that most bleeding events induced by indirect oral anticoagulant belonged to the SOC “respiratory, thoracic, and mediastinal disorders” (45.1%), while for DOACs most adverse events belonged to the SOC “gastrointestinal disorders” (44%). This is in accordance with the higher risk found in scientific literature for the association DOACs and gastrointestinal bleedings (Ruff et al., 2014; Monaco et al., 2017). In the evaluation of upper and lower gastrointestinal bleedings, we were able to classify just 64 ADRs, of which a high number was reported with warfarin and dabigatran. Hemorrhagic events reported with warfarin were more frequently classified as upper gastrointestinal bleedings, while those reported with dabigatran were mostly classified as lower gastrointestinal bleedings. This is in accordance with data of a post hoc analysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial that has shown a rate of upper gastrointestinal bleedings similar between dabigatran and warfarin, whereas for lower gastrointestinal bleeding, the rate was higher with dabigatran than warfarin (Kolb et al., 2018). A hypothesis that could explain this finding considers the pharmacokinetic profile of dabigatran etexilate, which is absorbed principally in the stomach and proximal small bowel as an inactive prodrug and then converted to the active form by serum and hepatic esterases. However, the bioavailability of dabigatran is low (3–7%) with an unabsorbed quota being converted to active dabigatran in the distal bowel and then excreted in the feces. This active quota in the distal bowel may be responsible for the onset of lower gastrointestinal bleeding, with a rate even higher than warfarin, which is not activated in the bowel (Feagins and Weideman, 2018).\n\nDifferent factors are able to influence the risk of gastrointestinal bleeding in patients treated with oral anticoagulants, including the advancing age, concomitant use of acetylsalicylic acid, history of gastrointestinal bleedings, prior/current smokers, atrial fibrillation, and other comorbidities (e.g., renal failure, anemia, diabetes mellitus) (Di Minno et al., 2015). Accordingly, we found that the most reported therapeutic indication for oral anticoagulants was atrial fibrillation and that among concomitant drugs there was the use of acetylsalicylic acid.\n\nFor bleedings cases belonging to the SOC “nervous system disorders,” according to literature, we found a lower number of cases related to a DOAC than a VKA (Eikelboom and Merli, 2016).\n\nBy applying the P-method, 58 (22.9%) cases of bleedings were preventable, with a total of 68 critical criteria identified. Considering the characteristics of patients in preventable cases, it should be noted that the advanced age was the most reported risk factor for bleedings. In addition, other frequent reported bleeding risk factors were the concomitant clinical conditions like hypertension, diabetes, hepatic or renal damage, and cerebrovascular diseases. Other reported risk factors, although rarely reported, were the prolonged use of warfarin (more than 30 years), the presence of malignancy (multiple myeloma), and hypochromic anemia (AIFA, 2010; Di Minno et al., 2015). All critical criteria were related to healthcare professionals’ practices, and the most reported risk factor was the inappropriate prescription of a drug able to induce drug–drug interactions with oral anticoagulants. In this regard, the potential harm of the so-called “polypharmacy” has been known for some time (Hudson, 1968) being considered as a major medical problem in some countries, and a challenge for the World Health Organization in organizing action programs on multiple therapy (Hogerzeil, 1995). For oral anticoagulants, the potential harm caused by pharmacodynamics and pharmacokinetics interactions with drugs, foods, herbs, and over-the-counter medications was already described in an Italian critical review (Di Minno et al., 2017). Unfortunately, we were able to focus only on drug–drug interaction based on our data source and the preventability tool used. In our results, the most reported drugs involved in drug–drug interactions with an indirect oral anticoagulant were proton pump inhibitors, statins, allopurinol, acetylsalicylic acid, and amiodarone. Accordingly, the evidence suggests a role of the aforementioned drugs as potential risk factors for the development of clinically relevant drug–drug interaction leading to VKA-induced ADRs (Nutescu et al., 2011; Forbes and Polasek, 2017). In accordance with the scientific literature, drugs more involved in drug–drug interaction with DOACs were amiodarone, methimazole, and acetylsalicylic acid (Rafaniello et al., 2016; Forbes and Polasek, 2017; Gelosa et al., 2018). While amiodarone is involved in pharmacokinetic drug–drug interaction as a moderate inhibitor of CYP3A4 and P-gp (Forbes and Polasek, 2017), methimazole may induce a pharmacodynamics interaction through its antivitamin K property (AIFA, 2005). The double effect of antiplatelet and anticoagulant therapy on the bleeding risk is well known, and sometimes well accepted considering the antithrombotic effect achieved by the combined treatment (Dale et al., 1980). In fact, in our preventable case, the co-treatment with apixaban and acetylsalicylic acid has only caused a minor bleeding (epistaxis) in an elderly patient. Moreover, six preventable cases of bleeding with indirect oral anticoagulants were related to the inappropriate prescription of warfarin in patients with hemorrhagic tendencies like an ulcer, erosive gastroduodenitis, or history of cerebral hemorrhage, which are all recognized as part of risk prediction tools for anticoagulant-associated hemorrhages (Shoeb and Fang, 2013).\n\nInteresting, more than half of preventable cases required a pharmacological and/or non-pharmacological treatment to resolve the ADR, presuming a high potential clinical and economic burden on the health care system (Sultana et al., 2013). In this perspective, it seems very important for Competent Authorities to promote the precocious detection of ADRs, and initiatives to quantify their preventable quota in order to reduce where possible the healthcare costs.\n\nWe found a different median time to event for direct and indirect oral anticoagulants that was higher for VKAs. One possible explanation for this finding may be the different monitoring of the therapy in patients treated with indirect oral anticoagulants, which are more strictly monitored in the first months of therapy than thereafter. On the contrary, patients in therapy with DOAC are in a fixed-dose regimen since the early start of treatment without any need of routine coagulation monitoring or therapeutic drug monitoring. This may predispose to some dosing error especially in elders. In fact, three of our preventable cases were related to the administration of a dabigatran dose exceeding the maximum recommended dosage in the SmPC for elderly patients.\n\nThis study has been promoted by the Campania Pharmacovigilance Regional Centre as part of initiatives to ensure drug safety during the last years (Sessa et al., 2015, 2016a,d; Auricchio et al., 2017; Mascolo et al., 2017; Scavone et al., 2017), and based on our results, other initiatives will be started to establish a proper diagnostic therapeutic plan for the management of anticoagulant therapy and their ADRs, especially in those provinces with the high amount of preventable cases. Moreover, the promotion of appropriate use of these drugs could implicate a massive benefit in terms of public health for our Regional territory, considering also the high morbidity and mortality associated with cardiovascular diseases. Therefore, the appropriate use of drugs like oral anticoagulants may highly affect and reduce cardiovascular risk, becoming highly beneficial for both patients and the National Health Service.\n\nStrengths and Limitations\nOur study has both strengths and limitations. An important strength of this study was the use of a validated tool to quantify preventable cases of ADRs potentially related to oral anticoagulants. However, an important limitation is the lack of generalizability due to the fact that the description of ICSRs characteristics associated with oral anticoagulant takes into account only a small population of an Italian region. Moreover, this study has all the limitations of the spontaneous reporting system, such as underreporting, differential reporting, irregular information quality, and lack of denominator data such as the user population and drug-exposure patterns. For this reason, the population in our study included only oral anticoagulant-induced ADRs patients rather than oral anticoagulant-exposed patients. Furthermore, another important limitation is the lack of information about possible drug–food or drug–herb interactions that cannot be detected for sure through the spontaneous reporting. In fact, this information is not an essential requirement for the spontaneous reporting of suspected ADRs but could represent an important risk factor for the detection of preventable ADRs whether it is added. Therefore, preventability tools that focus also on this aspect should be investigated.\n\nConclusion\nThis is the first study that described preventable cases of oral anticoagulants-related bleedings, of which all cases were related to healthcare professionals’ practices. The most detected critical criterion identified through the application of a validated tool for preventability assessment was the drug-drug interaction. Moreover, 48% of the preventable cases were classified as serious and 69% was associated with a positive outcome. We believe that an improvement of pharmacovigilance activities in our regional territory is needed to put into clinical practice the knowledge of the risk factors for oral anticoagulant-induced bleedings and to reduce the burden of medication errors and inappropriate prescription. Based on our results, several initiatives will be started in the Campania region to share the acquired experiences in routine clinical practice in order to promote the more appropriate use of oral anticoagulant therapy.\n\nAuthor Contributions\nAM, RR, MS, CS, LS, CR, FR, and AC drafted the work and revised it for important intellectual content, made substantial contributions to the acquisition, analysis, or interpretation of data for the work, approved the final version of the manuscript to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AM and RR developed the concept, designed the study, and wrote the manuscript.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2019.00425/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\nAIFA (2005 ). Summary pf the Product Characteristics (SmPC). \nAIFA (2010 ). Summary of the Product Characteristics (SmPC). \nAIFA (2017 ). L’uso dei Farmaci in Italia - Rapporto Nazionale 2017 - Regione Campania. \nAuricchio F. Scavone C. Cimmaruta D. Di Mauro G. Capuano A. Sportiello L. (2017 ). Drugs approved for the treatment of multiple sclerosis: review of their safety profile. \nExpert Opin. 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A method for estimating the probability of adverse drug reactions. \nClin. Pharmacol. Ther. \n30 \n239 –245 .7249508 \nNutescu E. Chuatrisorn I. Hellenbart E. (2011 ). Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. \nJ. Thromb. Thrombolysis \n31 \n326 –343 . 10.1007/s11239-011-0561-1 \n21359645 \nPal S. N. Olsson S. Brown E. G. (2015 ). The monitoring medicines project: a multinational pharmacovigilance and public health project. \nDrug Saf. \n38 \n319 –328 . 10.1007/s40264-015-0283-y \n25829215 \nPiazza G. Nguyen T. N. Cios D. Labreche M. Hohlfelder B. Fanikos J. (2011 ). Anticoagulation-associated adverse drug events. \nAm. J. Med. \n124 \n1136 –1142 . 10.1016/j.amjmed.2011.06.009 \n22114827 \nRafaniello C. Ferrajolo C. Sullo M. G. Sessa M. Sportiello L. Balzano A. (2016 ). Risk of gastrointestinal complications associated to NSAIDs, low-dose aspirin and their combinations: results of a pharmacovigilance reporting system. \nPharmacol. Res. \n104 \n108 –114 . 10.1016/j.phrs.2015.12.026 \n26739516 \nRaj G. Kumar R. McKinney W. P. (1994 ). Long-term oral anticoagulant therapy: update on indications, therapeutic ranges, and monitoring. \nAm. J. Med. Sci. \n307 \n128 –132 . 10.1097/00000441-199402000-00011 8141139 \nRoutledge P. A. O’Mahony M. S. Woodhouse K. W. (2004 ). Adverse drug reactions in elderly patients. \nBr. J. Clin. Pharmacol. \n57 \n121 –126 . 10.1046/j.1365-2125.2003.01875.x 14748810 \nRuff C. T. Giugliano R. P. Braunwald E. Hoffman E. B. Deenadayalu N. Ezekowitz M. D. (2014 ). Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. \nLancet \n383 \n955 –962 . 10.1016/S0140-6736(13)62343-0 \n24315724 \nSabir I. Khavandi K. Brownrigg J. Camm A. J. (2014 ). Oral anticoagulants for Asian patients with atrial fibrillation. \nNat. Rev. Cardiol. \n11 \n290 –303 . 10.1038/nrcardio.2014.22 \n24614113 \nScavone C. Sportiello L. Sullo M. G. Ferrajolo C. Ruggiero R. Sessa M. (2017 ). Safety profile of anticancer and immune-modulating biotech drugs used in a real world setting in campania region (Italy): BIO-cam observational study. \nFront. Pharmacol. \n8 :607 . 10.3389/fphar.2017.00607 \n28932193 \nSessa M. di Mauro G. Mascolo A. Rafaniello C. Sportiello L. Scavone C. (2018a ). Pillars and pitfalls of the new pharmacovigilance legislation: consequences for the identification of adverse drug reactions deriving from abuse, misuse, overdose, occupational exposure, and medication errors. \nFront. Pharmacol. \n9 :611 . 10.3389/fphar.2018.00611 \n29946258 \nSessa M. Rafaniello C. Scavone C. Mascolo A. di Mauro G. Fucile A. (2018b ). Preventable statin adverse reactions and therapy discontinuation. What can we learn from the spontaneous reporting system? \nExpert Opin. Drug Saf. \n17 \n457 –465 . 10.1080/14740338.2018.1458837 \n29619841 \nSessa M. Mascolo A. Andersen M. P. Rosano G. Rossi F. Capuano A. (2016a ). Effect of chronic kidney diseases on mortality among digoxin users treated for non-valvular atrial fibrillation: a nationwide register-based retrospective cohort study. \nPLoS One \n11 :e0160337 . 10.1371/journal.pone.0160337 \n27467520 \nSessa M. Rafaniello C. Sportiello L. Mascolo A. Scavone C. Maccariello A. (2016b ). Campania region (Italy) spontaneous reporting system and preventability assessment through a case-by-case approach: a pilot study on psychotropic drugs. \nExpert Opin. Drug Saf. \n15 \n9 –15 . 10.1080/14740338.2016.1221397 \n27875917 \nSessa M. Rossi C. Rafaniello C. Mascolo A. Cimmaruta D. Scavone C. (2016c ). Campania preventability assessment committee: a focus on the preventability of the contrast media adverse drug reactions. \nExpert Opin. Drug Saf. \n15 \n51 –59 . 10.1080/14740338.2016.1226280 \n27855534 \nSessa M. Sullo M. Mascolo A. Cimmaruta D. Romano F. Puca R. (2016d ). A case of figurate urticaria by etanercept. \nJ. Pharmacol. Pharmacother. \n7 \n106 –108 . 10.4103/0976-500X.184777 \n27440958 \nSessa M. Rossi C. Mascolo A. Grassi E. Fiorentino S. Scavone C. (2015 ). Suspected adverse reactions to contrast media in Campania region (Italy): results from 14 years of post-marketing surveillance. \nExpert Opin. Drug Saf. \n14 \n1341 –1351 . 10.1517/14740338.2015.1067301 \n26156557 \nSessa M. Sportiello L. Mascolo A. Scavone C. Gallipoli S. di Mauro G. (2017 ). Campania preventability assessment committee (Italy): a focus on the preventability of non-steroidal anti-inflammatory drugs’ adverse drug reactions. \nFront. Pharmacol. \n8 :305 . 10.3389/fphar.2017.00305 \n28603499 \nShoeb M. Fang M. C. (2013 ). Assessing bleeding risk in patients taking anticoagulants. \nJ. Thromb. Thrombolysis \n35 \n312 –319 . 10.1007/s11239-013-0899-7 \n23479259 \nSultana J. Cutroneo P. Trifirò G. (2013 ). Clinical and economic burden of adverse drug reactions. \nJ. Pharmacol. Pharmacother. \n4 \nS73 –S77 . 10.4103/0976-500X.120957 \n24347988 \nWang H. Chow S.-C. (2007 ). “Sample size calculation for comparing proportions,” in \nWiley Encyclopedia of Clinical Trials , eds\nD’Agostino R. B. Massaro J. (Hoboken, NJ : John Wiley & Sons, Inc. ).\n\n",
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},
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{
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}
],
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},
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"literaturereference_normalized": "preventable cases of oral anticoagulant induced bleeding data from the spontaneous reporting system",
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},
"primarysourcecountry": "IT",
"receiptdate": "20190805",
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},
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},
"serious": 1,
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}
] |
{
"abstract": "Lymphodepletion with non-myeloablative (NMA) chemotherapy is currently a prerequisite for adoptive cell therapy (ACT). ACT based on tumor-infiltrating lymphocytes has long been used in malignant melanoma (MM), but with the advance of ACT into new cancer diagnoses, the patient predisposition will change. The authors here evaluate the bone marrow (BM) toxicity of NMA in combination with checkpoint inhibition and a priori risk factors in a wide range of cancer diagnoses.\n\n\n\nThirty-one non-MM and MM patients were included from two different clinical trials with ACT. The treatment history was extracted from the medical records, together with the hematology data. Immune monitoring with flow cytometry was performed before and at several time points after therapy.\n\n\n\nNMA induced reversible myelosuppression in all patients. No significant differences in BM toxicity between MM and non-MM patients were found. The overall hematology counts were reconstituted within 3-6 months but with great individual heterogeneity, including eight patients who developed a second phase of neutropenia after hospital discharge. A performance status >0 was found, and shorter overall survival and sex were statistically associated with longer duration of anemia. By contrast, high expression of co-stimulatory markers CD28+ and CD27+ on T cells at baseline was significantly correlated with shorter duration of neutropenia (P = 0.010 and P = 0.009, respectively), anemia (P = 0.001 and P = 0.001, respectively) and thrombocytopenia (P = 0.017 and P = 0.030, respectively). In addition, following NMA, the authors saw a significant differentiation of T-cell phenotype associated with old age.\n\n\n\nACT with NMA and checkpoint inhibition is tolerable in patients with multiple cancer diagnoses and therapy backgrounds but comes with substantial transient BM toxicity that is comparable in both non-MM and MM patients. Baseline T-cell CD28/CD27 expression level is predictive of duration of BM toxicity. Furthermore, NMA conditioning induces changes in the immune system that may affect a patient's immunocompetence for many months following therapy.",
"affiliations": "National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.;National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.;National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.;Department of Hematology, Rigshospitalet, Copenhagen, Denmark.;National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.;National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. Electronic address: [email protected].",
"authors": "Kverneland|Anders H|AH|;Borch|Troels Holz|TH|;Granhøj|Joachim|J|;Sengeløv|Henrik|H|;Donia|Marco|M|;Svane|Inge Marie|IM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jcyt.2021.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1465-3249",
"issue": "23(8)",
"journal": "Cytotherapy",
"keywords": "adoptive cell therapy; conditioning chemotherapy; non-myeloablative conditioning; tumor-infiltrating lymphocytes",
"medline_ta": "Cytotherapy",
"mesh_terms": "D001853:Bone Marrow; D006801:Humans; D000074243:Immune Reconstitution; D008545:Melanoma; D012878:Skin Neoplasms; D019172:Transplantation Conditioning",
"nlm_unique_id": "100895309",
"other_id": null,
"pages": "724-729",
"pmc": null,
"pmid": "33933372",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bone marrow toxicity and immune reconstitution in melanoma and non-melanoma solid cancer patients after non-myeloablative conditioning with chemotherapy and checkpoint inhibition.",
"title_normalized": "bone marrow toxicity and immune reconstitution in melanoma and non melanoma solid cancer patients after non myeloablative conditioning with chemotherapy and checkpoint inhibition"
}
|
[
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"abstract": "We evaluated the clinical responses and radiographic outcomes of 90 patients with rheumatoid arthritis (RA) undergoing continuous or dose-adjusted infliximab treatment over 104 weeks.\nPatients received 3 mg/kg infliximab continuously (the contin group; n=50), or the dose escalation and de-escalation of infliximab (3, 6, and 10 mg/kg) from week 14 (the adjusted group; n=40) based on the patient's Disease Activity Score in 28 joints (DAS28). The retention rate, clinical response, and radiographic assessment were determined at week 104.\nThe contin and adjusted groups' retention rates at week 104 were 56.8 and 66.7%, and the groups' low disease activity in the DAS28 was 39.1 and 66.7%, respectively. Remission based on the DAS28 and the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) Boolean-based criteria was significantly increased in the adjusted group. In the radiographic assessment, there was also a significant reduction in the mean changes in total Sharp score. The cumulative rates of any adverse effects showed no significant difference between the groups.\nIn an assessment of adequate DAS28 results, the RA patients who did not respond to the initial dose of infliximab showed improved clinical responses and radiographic assessment after a dose adjustment of infliximab, without an increased risk of serious adverse events.",
"affiliations": "Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].;Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected].",
"authors": "Nozaki|Yuji|Y|;Nagare|Yasuaki|Y|;Ashida|Chisato|C|;Tomita|Daisuke|D|;Okada|Akinori|A|;Inoue|Asuka|A|;Kinoshita|Koji|K|;Funauchi|Masanori|M|;Matsumura|Itaru|I|",
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"doi": "10.2147/BTT.S187998",
"fulltext": "\n==== Front\nBiologicsBiologicsBiologics: Targets and TherapyBiologics : Targets & Therapy1177-54751177-5491Dove Medical Press 10.2147/BTT.S187998btt-12-171Original ResearchInfliximab dose adjustment can improve the clinical and radiographic outcomes of rheumatoid arthritis patients: REVIVE study results Nozaki Yuji Nagare Yasuaki Ashida Chisato Tomita Daisuke Okada Akinori Inoue Asuka Kinoshita Koji Funauchi Masanori Matsumura Itaru Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan, [email protected]: Yuji Nozaki, Department of Hematology and Rheumatology, Kindai University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan, Tel +81 72 366 0221, Fax +81 72 368 3732, Email [email protected] 27 11 2018 12 171 182 © 2018 Nozaki et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose\nWe evaluated the clinical responses and radiographic outcomes of 90 patients with rheumatoid arthritis (RA) undergoing continuous or dose-adjusted infliximab treatment over 104 weeks.\n\nPatients and methods\nPatients received 3 mg/kg infliximab continuously (the contin group; n=50), or the dose escalation and de-escalation of infliximab (3, 6, and 10 mg/kg) from week 14 (the adjusted group; n=40) based on the patient’s Disease Activity Score in 28 joints (DAS28). The retention rate, clinical response, and radiographic assessment were determined at week 104.\n\nResults\nThe contin and adjusted groups’ retention rates at week 104 were 56.8 and 66.7%, and the groups’ low disease activity in the DAS28 was 39.1 and 66.7%, respectively. Remission based on the DAS28 and the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) Boolean-based criteria was significantly increased in the adjusted group. In the radiographic assessment, there was also a significant reduction in the mean changes in total Sharp score. The cumulative rates of any adverse effects showed no significant difference between the groups.\n\nConclusion\nIn an assessment of adequate DAS28 results, the RA patients who did not respond to the initial dose of infliximab showed improved clinical responses and radiographic assessment after a dose adjustment of infliximab, without an increased risk of serious adverse events.\n\nKeywords\nrheumatoid arthritisDAS28infliximabmTSSdose adjustmentREVIVE\n==== Body\nIntroduction\nThe development of antitumor necrosis factor α (anti-TNFα) therapy provided a major advance in the treatment of patients with rheumatoid arthritis (RA).1 Infliximab is a monoclonal antibody specific for TNFα that, when administered in combination with methotrexate (MTX), has been shown to be effective in treating patients with active RA. The pivotal multinational clinical study, ie, the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT), showed that repeated treatment with 3 or 10 mg/kg infliximab was more effective than MTX alone in reducing the disease activity of RA, inhibiting the subjects’ joint damage, and improving their physical function.2,3\n\nIt is well known that some RA patients need a dose escalation from their initial dose of infliximab in order to maintain their level of physical activity. The ATTRACT trial and the Safety Trial for Rheumatoid Arthritis with Remicade Therapy (START) study also demonstrated a significant association between RA patients’ clinical responses and their trough serum infliximab levels.4,5 A dose-escalating study (RISING) that examined the impact of infliximab with MTX therapy on RA patients’ radiographic and clinical responses based on their trough serum levels demonstrated a significant correlation between the trough serum level and the European League against Rheumatism (EULAR) response or Disease Activity Score in 28 joints (DAS28) remission.6 However, there was no significant difference in the incidence of adverse events (AEs) regardless of the infliximab dose.6 The RISING study also demonstrated that infliximab inhibited the progression of joint damage in most of the patients.\n\nIn the present retrospective study (the REVIVE study; Remicade in validation and effectiveness of the clinical response and radiographic outcomes in the dose escalation and de-escalation strategy), we compared the clinical and radiographic outcomes in the following two groups: patients who were administered the combination therapy of MTX with 3 mg/kg infliximab continuously (the contin group) as the controls and patients who were administered the combination therapy of MTX with 3, 6, or 10 mg/kg infliximab based on the assessment of their DAS28 values as the dose escalation and de-escalation strategy (the adjusted group). The results of our analyses indicate that based on the assessment of the DAS28 at week 104 in this series of RA patients, compared to the patients who took the minimum infliximab dose (3 mg/kg) continuously, the patients whose infliximab dose was adjusted showed improved disease activity and an inhibition of the progression of joint damage.\n\nPatients and methods\nPatients\nThe REVIVE study enrolled 21–81-year-old Japanese patients who had suffered from RA for ≥6 months and showed active disease based on the American College of Rheumatology (ACR) criteria7 despite previous treatment with a conventional synthetic disease-modifying antirheumatic drug (csDMARD) and who had received a stable MTX dose (up to 16 mg/week). The patients’ RA was defined as ≥6 swollen joints and ≥6 tender joints and two or more of the following: C-reactive protein (CRP) ≥2.0 mg/dL; erythrocyte sedimentation rate (ESR) ≥28 mm/h; a global health score ≥20 mm on a 0–100 mm scale, ie, the patient’s global assessment of disease activity (PtGA), where 0= best and 100= worst; investigator-documented evidence of bone erosion on radiographs; and a positive finding of anticyclic citrullinated peptide antibodies (ACPA) or rheumatoid factor (RF). The patients were screened for latent and active tuberculosis. Concomitant oral corticosteroids (stable dose ≤10 mg of prednisolone/day or equivalent) were permitted.\n\nPatients were excluded if they had any other connective tissue disease with joint symptoms or therapy with other biological agents within 4 months before the initial infliximab infusion. Other exclusion criteria were as follows: a history of serious or opportunistic infection within 6 months before registration; active tuberculosis; hepatitis B virus, hepatitis C virus, or HIV carriers; and those with chronic infectious diseases.\n\nStudy design\nThis study was conducted from 2009 to 2017 at a single center, Kindai University Hospital (Osaka, Japan). Two patient groups were studied from week 0 (initiation of infliximab) to week 104. All of the patients received 3 mg/kg infliximab at weeks 0, 2, and 6. In one group, the patients received the combination therapy of MTX with 3 mg/kg infliximab continuously for the 104 weeks in accordance with their physician’s judgment (the contin group). In the other group, at week 14, the decision for infliximab dose escalation/de-escalation was made (with the patient’s agreement) based on the patient’s clinical response (the adjusted group).\n\nIn the adjusted group, the decision of whether to adjust the infliximab dose was then made every 8 weeks based on the patient’s DAS28–ESR,8 which was calculated by a physician who treated the allocated treatment group during the entire study period. If the patient did not reach a DAS28 of <3.2 for 4 months, the treating physician immediately adjusted the therapy by increasing the dose of infliximab. If the patient’s clinical response was consistently adequate (a DAS28 of <3.2 for ≥6 months), the dose of infliximab was decreased until it reached a stable dose. Following the starting dose of infliximab at 3 mg/kg, the dose of 3, 6, or 10 mg/kg infliximab was administered every 8 weeks from weeks 14 to 104 and the efficacy of the treatment was evaluated at weeks 26, 52, and 104.\n\nThe DAS28 calculations for dose adjustments were performed every 8 weeks, within 4 weeks before the next infusion of infliximab. If the patient’s DAS28 was ≥3.2, the dose of the next infusion was increased to 6 mg/kg every 8 weeks and finally to 10 mg/kg every 8 weeks. If a patient still had a DAS28 of ≥3.2 while receiving MTX along with 10 mg/kg infliximab, the infliximab was switched to another biological agent. In the case of a persistent good response (a DAS28 of <3.2 for ≥6 months), the dose of infliximab was reduced (from 10 to 6 and then to 3 mg/kg) at each next infusion.\n\nOver the entire 2-year study period, csDMARDs (other than tacrolimus, iguratimod, and salazosulfapyridine), nonsteroidal anti-inflammatory drugs (NSAIDs), oral glucocorticoids (prednisolone 10 mg/day), and folic acid preparations were permitted at the stable dose from ≥4 weeks before the initial infliximab infusion. All patients received concomitant MTX throughout the study. The patient’s dose of MTX had to be stable (ie, ≥6 mg/week; the approved maximum dose of MTX for RA in Japan is 16 mg/week) for >4 weeks just before the initial infliximab infusion and over the entire study period. Prednisolone could be tapered and discontinued. If a patient’s disease activity flared (ie, a DAS28 of ≥3.2 was observed) after the prednisone was tapered, the last effective dose was reintroduced. Prednisolone could be reintroduced only once: if, after a second discontinuation, the DAS28 increased again to ≥3.2, then, the next step in the protocol was taken. If side effects occurred, the responsible drug was reduced to the lowest tolerated dose. If a medication was not tolerated at all or was contraindicated, it was discontinued.\n\nThis study was conducted according to the principles expressed in the Declaration of Helsinki of 1983, and it was approved by the Research Ethics Committee of Kindai University of Medicine. In the guidelines for postmarketing observational studies in Japan, it is not necessary to obtain consent in all patients.9 However, we guaranteed the opportunity for refusal in an agreement with the patients and physicians because a written consent from all patients was not necessary.\n\nAEs were evaluated until week 104. In the patients in whom treatment was discontinued, AEs were assessed until 12 weeks after the final medication administration.\n\nRadiographic assessment\nPlain radiographs of each patient’s hands and feet were taken at baseline and at week 104 and evaluated and scored using the Steinbrocker class and the modified Sharp/van der Heijde scoring system.10,11 The baseline and week 104 radiographs were evaluated by two independent readers in accordance with reported methods.10,11 We calculated the mean changes from baseline in the modified total Sharp score (mTSS), the erosion score (ES), and the joint space narrowing score (JSN), with a range of 0–390. Radiographic nonprogression was defined as an mTSS score of ≤0.5. The smallest detectable change (SDC) is an estimate of the measurement error between readers of the films.12\n\nAssessment of clinical assessment\nThe RA patients’ demographic characteristics recorded at baseline included age, sex, disease duration, and current therapy. The endpoint for clinical response was the DAS28 at weeks 0, 26, 52, and 104. The EULAR response13 was evaluated at weeks 26, 52, and 104. At each visit, the following laboratory tests were performed. Efficacy endpoints included DAS28 values and the proportion of patients with DAS28 in EULAR responses, and the tender joint count (TJC), the swelling joint count (SJC) in 28 joints (both measured by the treating physician), and the PtGA. The laboratory parameters of CRP (mg/dL) and ESR (mm/h) were similarly assessed every 4 weeks from weeks 0 to 104. The RF (U/mL), ACPA (U/mL), and matrix metalloproteinase-3 (MMP-3; ng/mL) values were measured at baseline. The patient’s physical function at baseline was evaluated as the Health Assessment Questionnaire-Disability Index (HAQ-DI).14\n\nClinical remission was defined as achieving a DAS28 of <2.6 and one or none of the following criteria (ACR/EULAR Boolean-based criteria)15: the TJC, the SJC, the CRP, and the PtGA (a 100 mm VAS data converted to centimeter).\n\nSafety\nThe treating physician recorded all AEs and serious AEs and, if necessary, made treatment adjustments in accordance with the protocol described earlier. Serious AEs were defined as any adverse reaction resulting in any of the following outcomes: a life-threatening condition or death, a significant or permanent disability, a malignancy, hospitalization, or prolongation of hospitalization, a congenital abnormality, and a birth defect. Laboratory test results (hematological, blood chemistry, and urinalysis), chest radiographs, and electrocardiograms were also evaluated.\n\nStatistical analyses\nWe used the GraphPad Prism software (GraphPad Software, San Diego, CA, USA) and JMP Statistical Software (SAS Institute Inc., Cary, NC, USA) for the statistical analyses. Summary statistics of mean and SD or median and IQR, when appropriate, is presented for continuous variables. Categorical variables are presented as percentages. Comparisons between independent means were conducted with the Mann–Whitney U-test. Relationships between categorical variables were evaluated by the Chi-squared test. We assessed the survival rate for infliximab treatment using the Kaplan–Meier method, and the difference in retention curves was examined by means of a log-rank test. P-values <0.05 were considered statistically significant.\n\nResults\nBaseline characteristics and patient disposition\nWe retrospectively analyzed the cases of 90 patients with RA who received the combination therapy of MTX and infliximab. Of them, 50 patients were treated with infliximab 3 mg/kg continuously throughout the study (the contin group) and the other 40 patients underwent the dose escalation and de-escalation of infliximab (3, 6, and 10 mg/kg) on the basis of their DAS28 at week 14 (the adjusted group). Table 1 summarizes the baseline characteristics, laboratory findings, and treatment in the two groups.\n\nThere were no significant differences in the background between the two groups in age, sex, the disease duration, the percentage of bio-naive patients, the proportion of Steinbrocker class, the steroid and MTX dose, the positive percentage and titers of ACPA, RF, and MMP-3, clinical disease activity, HAQ-DI, or total Sharp score at baseline. Twenty-seven of the 50 patients (54.0%) in the contin group and 29 of the 40 patients (72.5%) in the adjusted group completed the study (Figure 1). In the contin group, the main reason for discontinuation was lack of efficacy (n=17) and there were AEs (n=6). In the adjusted group, the main reason for discontinuation was the lack of efficacy (n=6), economic problems (n=2) and the moving away (n=2) as the patient’s request, and maintaining remission (n=1). There were no AEs in the adjusted group.\n\nInfliximab treatment\nAt week 14, the decision to use the dose escalation and deescalation strategy with infliximab was performed based on the individual patient’s DAS28. Eighteen (45.0%) and nine (22.5%) of the 40 patients in the adjusted group received 3 mg/kg infliximab continuously at weeks 26 and 52, respectively (Figure S1). Eight (20.0%) patients were taking 3 mg/kg infliximab at week 104: two patients who underwent dose reduction from 6 mg/kg infliximab and nine patients whose treatment was discontinued (four patients due to the lack of efficacy and four patients at the patient’s request). After week 14, 17 (42.5%) and 18 (45.0%) patients underwent a dose escalation from 3 to 6 mg/kg at weeks 26 and 52, respectively. Fifteen (40.0%) patients were taking 6 mg/kg infliximab at week 104: two patients who underwent a dose reduction to 3 mg/kg and one patient who underwent a dose escalation to 10 mg/kg. Similarly, after week 14, three (7.5%) and five (12.5%) patients underwent a dose escalation from 6 to 10 mg/kg at weeks 26 and 52, respectively. Overall, six (15.0%) patients were taking 10 mg/kg at week 104 (including one patient who underwent a dose escalation from 6 mg/kg). The details of the dose escalation and de-escalation procedure are shown in Figure S1.\n\nRetention rate\nThe overall retention rate over the 104 weeks in the RA patients whose infliximab was withdrawn due to the lack of efficacy, the patient’s request, or sustained remission is illustrated in Figure 2A. In the contin and adjusted groups, the retention rates (95% CI) were 58.3% (52.3–66.1) and 80.0% (71.1–87.1) at week 52 and 54.0% (47.1–61.3) and 72.5% (65.3–78.0) at week 104, respectively. The overall retention rate in the adjusted group was thus significantly higher than that in the contin group at weeks 52 and 104. The retention rate among the patients who experienced a lack of efficacy is shown in Figure 2B. The retention rates (95% CI) were 61.2% (55.1–67.3) and 88.8% (79.2–91.1) at week 52 and 61.4% (52.3–68.2) and 83.3% (75.3–88.0) at week 104 in the contin and adjusted groups, respectively. The retention rate in the adjusted group was significantly and notably higher than that in the contin group at weeks 52 and 104.\n\nClinical efficacy\nFigure 3 shows the patients’ DAS28 scores and EULAR responses at weeks 0, 26, 52, and 104. At weeks 26 and 52, there were no significant differences between the two groups. At week 104, the DAS28 scores were significantly higher in the contin group compared to the adjusted group (4.0±1.9 and 2.5±1.3; Figure 3A). Figure 3B shows the changes from the baseline in DAS28 score at weeks 26, 52, and 104. In the adjusted group, the changes from the baseline in DAS28 were significant compared to the contin group (−2.5±−2.1 vs −1.1±−1.9, respectively).\n\nFigure 3C illustrates the EULAR responses at weeks 26, 52, and 104 in the two groups. The rate of responders (ie, those with a good or moderate response) at week 104 was 43.6% in the contin group and 87.5% in the adjusted group (*P<0.05). Conversely, the proportions of nonresponder patients at week 104 were 56.4% in the contin group and 12.5% in the adjusted group.\n\nThe proportions of disease activity based on DAS28 and ACR/EULAR Boolean-based criteria were evaluated at baseline and weeks 26, 52, and 104 (Figure 4A). In addition, the proportions of patients achieving low disease activity (LDA) at weeks 26, 52, and 104 – when LDA and remission based on the DAS28 (<3.2 and <2.6) and ACR/EULAR Boolean-based remission were evaluated – were significantly different between the contin and adjusted groups (Figure 4B). At week 104, LDA based on the DAS28 (<3.2) was achieved in 35% of the contin patients and in 68.5% of the adjusted patients. Remission based on DAS28 (<2.6) was also achieved in 25% of the contin patients and in 47.5% of the adjusted patients. The rates of ACR/EULAR Boolean-based remission were 2.2 vs 22.7, 15.4 vs 26.5, and 16.7 vs 39% at weeks 26, 52, and 104 in the contin and adjusted groups, respectively.\n\nWe also estimated the effect of steroid tapering in the contin and adjusted groups (Table 2). At baseline, the percentage of steroid users (52.3 vs 60.0%) and the steroid dose (3.8±5.1 vs 5.2±5.5 mg/day) were similar in the contin and adjusted groups. At week 104, the percentage of steroid users (36.4 vs 39.1%) and the steroid dose (1.7±2.5 vs 2.0±2.8 mg/day) in the contin and adjusted groups were decreased and the steroid dose had been tapered significantly compared to the values at baseline (*P<0.05,). In contrast, the cumulative steroid dose at week 104 was not significantly different between the contin and adjusted groups at 1,866.1±2,285.7 vs 2,118.5±2,629.9 mg, respectively. However, the reduction of steroid dose in the adjusted group tended to be smaller compared to that in the contin group (−3.2±2.7 vs −2.1±2.6 mg) at week 104.\n\nRadiographic progression\nAt baseline and at week 104, 57 radiographs were assessed (32 in the contin group and 25 in the adjusted group). The two groups were similar at baseline with respect to the number of erosions, joint space narrowing, and TSS (Tables 1 and 3). The comparison of the contin and adjusted groups’ baseline and week 104 radiographs showed a higher TSS with more erosions and joint narrowing spaces, but the difference was not significant at week 104 (Table 3).\n\nAt week 104, there were significant differences between the contin and adjusted groups in the mean changes in TSS at 5.7 (5.1–6.3) vs 1.9 (1.5–2.3) and in erosions at 1.6 (1.2–2.0) vs 0.3 (0.1–0.5), respectively. There was no significant difference in joint space narrowing: 4.1 (3.7–4.5) vs 1.6 (1.1–2.1) in the contin and adjusted groups, respectively (Figure 5A). The percentages of patients with no progression of joint damage (improved or no change; ΔmTSS ≤0.5) were 40.0 in the contin group and 64.3 in the adjusted group (a nonsignificant difference; Figure 5B).\n\nSafety assessments\nAt week 104, the cumulative rates of any AEs in the contin and adjusted groups were 34 and 30% and the cumulative rates of serious AEs were 18 and 12.5%, respectively (Table 4). Serious AEs occurred in 18% of the contin group: five patients developed a serious infection (one patient with herpes zoster, one patient with cellulitis, and three patients with pneumonia), one patient incurred interstitial pneumonia, and three patients experienced an injection site reaction. Serious AEs occurred in 15% of the adjusted group: five patients developed a serious infection (three patients with herpes zoster and two patients with pneumonia) and one patient developed a malignancy. Discontinuations due to AEs occurred in 10% of the patients in the contin group: one patient developed interstitial pneumonia, one patient showed a drug rash, and three patients had injection site reactions. No opportunistic infections, tuberculosis, and lymphomas were observed. Overall, 20% of the contin and adjusted groups had an infection through week 104, with nasopharyngitis and upper respiratory tract infections the most frequently reported. None of the serious infections in either group led to treatment discontinuation, although almost all of the serious infections led to hospitalization. Throughout the 104-week study period, there were no significant differences between the contin and adjusted groups in the number of cases of interstitial pneumonia (2 vs 0%), malignancies (breast cancer; 0 vs 2.5%), or injection site reaction (12 vs 7.5%), respectively.\n\nDiscussion\nIn a previous study, infliximab at 3 and 10 mg/kg given every 4–8 weeks for up to 2 years produced significant clinical, radiographic, and functional benefits in RA patients when added to background MTX therapy.2,3 However, some RA patients needed to be switched from infliximab treatment to other biological DMARDs due to an inadequate response. In general, switching these agents is a reasonable treatment strategy. In the SWITCH study, etanercept or adalimumab with an adequate or lower response in which RA patients were switched to infliximab.16 At week 10, approximately one-half of that study’s patients achieved a significantly improved DAS28–ESR, but approximately one-half of the responding patients required an infliximab dose escalation. The START trial17 assessed infliximab dose escalation in RA patients who showed an inadequate response to 3 mg/kg infliximab or whose disease flared following an initial response. Approximately 30% of the infliximab-treated patients in the START trial underwent dose escalation, and 80% of the patients who received up to three 1.5 mg/kg dose escalations achieved a 20% improvement in the total tender and swollen joint count after their last infliximab dose.\n\nIn contrast, an analysis of data from the Stockholm Bio-logics Registry revealed that the improvement in efficacy following infliximab dose escalation was small.18 In the ATTRACT study, the ACR response in patients treated with 3 mg/kg every 8 weeks tended to be lower than the responses obtained with a higher dose or a shorter perfusion interval.4\n\nThe pharmacokinetic analysis of serum samples from the ATTRACT patients showed that the serum level of infliximab was significantly more frequently undetectable in the patients treated with 3 mg/kg every 8 weeks compared to the patients treated with a higher dose (10 mg/kg) or a shorter treatment interval (every 4 weeks).4 More patients with detectable levels (>0.1 g/mL) of serum infliximab preinfusion showed ACR responses compared to the patients without detectable infliximab levels. The ATTRACT authors suggested that shortening of the dose interval would be preferable to increasing the dose at a constant interval.4 The RISING study investigated the efficacy and safety of RA treatment with infliximab, comparing 10 and 6 mg/kg with 3 mg/kg.6 The clinical response of mean percentage ACR improvement, the primary endpoint of that study, was 58.3% in the 10 mg/kg group and 51.3% in the 3 mg/kg group, presenting a significant difference. In addition, regarding the changes in the DAS28 and the EULAR response criteria, significantly higher responses were observed in the 10 mg/kg group compared to the 3 mg/kg group. In the radiographic assessment, the progression of joint damage was inhibited in most of the patients. The percentages of patients with no progression of joint damage (improved or no change) in the 3, 6, and 10 mg/kg groups were 93.0, 87.0, and 94.7%, respectively. However, these results were not significantly different.6 The START and RISING studies were also limited by their 1-year study duration. Some of the patients in these studies might have responded if the study had continued for longer than 1 year.\n\nAs an extended investigation, the REVIVE study was conducted to evaluate the clinical responses and radiographic outcomes of RA patients who were eligible to undergo an adjustment of infliximab in a dose escalation strategy and a de-escalation strategy based on their DAS28 scores for 2 years. About 20% of the patients in the adjusted group did not require any dose escalation or de-escalation and continued to receive 3 mg/kg infliximab throughout the 104 weeks. At weeks 26 and 52, there were no significant differences in DAS28 scores between the adjusted and contin groups. At week 104, remarkable changes in the DAS28 and the EULAR response criteria were observed; a significantly higher percentage of good responses was observed in the adjusted group compared to the contin group.\n\nIn addition, at week 104, nearly 50% of the patients achieved a significantly higher remission rate in the DAS28 (25 and 47.4% of the contin and adjusted groups, respectively) and in the ACR/EULAR Boolean-based criteria (16.7 and 39% of the contin and adjusted groups, respectively). Regarding the joint damage progression shown by the radio-graphic assessment, the changes in mTSS from baseline were significantly inhibited and radiographic nonprogression at week 104 was achieved at a higher rate in the adjusted group (64.3 and 40% in the adjusted and contin groups, respectively). These results indicate the importance of RA patients’ clinical responses and radiographic assessment, as highlighted by the difference between the two groups after week 52.\n\nInfliximab treatment has shown overall lower retention rates compared to adalimumab and etanercept.19 The retention rate for infliximab is in accordance with that in the Danish DANBIO registry, with a half-life of −2 years, and the authors of that study19 reported that the difference in the retention rate was most pronounced for withdrawal due to AEs but was also significant for infliximab compared to etanercept in the patients who withdrew due to the lack of efficacy. In contrast, a German registry showed that the short-term drug survival rates were similar for etanercept and infliximab.20 In the REVIVE study, the overall retention rate was higher than that in the DANBIO report at week 104.19 In addition, the retention rate in our adjusted group was increased compared to that in the contin group, but there was no significant difference in the retention rate between the two groups through week 104.\n\nIn contrast, the rate of adverse effects (including serious infections) in our patients who underwent the dose escalation and de-escalation strategies was not increased compared to the rate among the patients who underwent the continuous 3 mg/kg infliximab treatment. As observed in other investigations,5,6 patients with and without dose escalations did not show increased rates of AEs, serious AEs, infections, or serious infections.\n\nAs a retrospective study, the REVIVE study has some limitations. First, the lack of randomization and blinding may have resulted in bias by indication, channeling bias, and performance bias. Second, the disease duration in the adjusted group was shorter than that in the contin group, although no significant between-group differences in disease activity or radiographic findings were seen at baseline. Third, the study was also limited by the 2-year study duration. We cannot discuss the retention rate, clinical response, radiographic assessment, or safety profile at time points beyond 2 years.\n\nThe availability of biological agents has changed the treatment goals in patients with RA. Since treatments with biological agents are expensive, the increasing use of these agents represents a significant economic burden to society.21 In Japan, the mean total drug costs for 1 year of 3, 6, and 10 mg/kg infliximab therapies are 965,000 yen ($8,600 US dollars), 1,930,000 ($17,000), and 2,900,000 ($26,000), respectively – calculated using 60 kg (~132 lbs) as the average adult Japanese body weight. In Japan’s universal health care insurance system, the expenditures for the treatment of nonelderly and elderly patients differ. In general, the costs paid by patients <75 and ≥75 years are 30 and 10% of the total drug costs, respectively. In the present study, the infliximab therapy of two adjusted group patients who were <75 years had to be suspended due to the patients’ financial issues. The initial intensive therapy approach that used in the REVIVE study may be favorably economical for patients. Intensive therapy for the rapid achievement of stable LDA or remission has been associated with the maintenance of response upon tapering/withdrawal.22 The possibility of the tapering and the discontinuation of biological agents after LDA and remission are achieved must be considered, because of both the potential long-term safety issues and the economic burden associated with their expense.\n\nConclusion\nRA patients who did not respond to the initial dose of 3 mg/kg infliximab and those who initially responded but subsequently flared showed improved clinical responses and radiographic assessments after a dose escalation of infliximab treatment based on the assessment of the DAS28, without an increased risk of serious AEs, including serious infections.\n\nSupplementary material\nFigure S1 Patients’ disposition.\n\nNotes: The primary reasons for discontinuation are listed. In the adjusted group, the escalation and de-escalation of the infliximab dose were selected based on the individual patient’s DAS28 with the clinical response at week 14. The decision was reconsidered every 8 weeks. If the patient did not reach a DAS28 of ≥3.2 for 4 months, the infliximab dose was increased (6 or 10 mg/kg). If the clinical response was consistently adequate (DAS28<3.2 for ≥6 months), the infliximab dose was gradually de-escalated until the dose remained at a maintenance dose or the infliximab was discontinued (for patients in remission). The starting infliximab dose of 3 mg/kg (n=40) at week 14 was adjusted as 3, 6, or 10 mg/kg every 8 weeks. At week 26, the numbers of patients who were treated with infliximab at 3, 6, and 10 mg/kg were 18, 17, and 3, respectively. The treatment of two patients was discontinued at week 26 (lack of efficacy). At week 52, the numbers of patients treated with infliximab at 3, 6, and 10 mg/kg were 9, 18, and 5, respectively. Some patients were escalated from 3 to 6 mg/kg (n=2) and 10 mg/kg (n=1) via 6 mg/kg and from 6 to 10 mg/kg (n=1). As of week 52, the treatment of six patients was discontinued due to the lack of efficacy (n=2), the patient’s request (n=3), or remission (n=1). At week 104 as the endpoint, the numbers of patients treated at 3, 6, and 10 mg/kg infliximab were 6, 10, and 6, respectively. Some patients were de-escalated from infliximab 6 to 3 mg/kg (n=2) and escalated from infliximab 6 to 10 mg/kg (n=1). As of week 104, the treatment of four patients was discontinued due to the lack of efficacy (n=2) and the patient’s request (n=1).\n\nAbbreviation: DAS28, Disease Activity Score in 28 joints.\n\n Acknowledgments\nWe thank all of the investigators who participated in the REVIVE study: K Kishimoto, T Shiga, S Hino, K Sakai, and J Ri.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Patient flow chart.\n\nNotes: As controls, the contin group received 3 mg/kg infliximab continuously without DAS28 assessments from baseline (week 0) to week 104. The patients in adjusted group received 3, 6, or 10 mg/kg infliximab with DAS28 assessments as the strategy of dose escalation and de-escalation. If the patient did not reach a DAS28 of ≥3.2 for 4 months, the treating physician immediately adjusted the regimen by proceeding to the dose-escalation protocol. If the clinical response was consistently adequate (DAS28<3.2 for ≥6 months), the infliximab was gradually de-escalated until it remained at a maintenance dose. Starting from infliximab 3 mg/kg, infliximab at doses 3, 6, or 10 mg/kg was administered every 8 weeks from weeks 6 to 104, and the efficacy was evaluated at weeks 26, 52, and 104.\n\nAbbreviations: DAS28, Disease Activity Score in 28 joints; RA, rheumatoid arthritis.\n\nFigure 2 Retention rate.\n\nNote: Kaplan–Meier curves for the contin and adjusted groups regarding the time to withdrawal for any reason due to the lack of efficacy, adverse effects, or the patient’s request (A) and due to the lack of efficacy (B) from the start of infliximab to week 104. *P<0.05, contin group vs adjusted group.\n\nFigure 3 DAS28 and the EULAR response.\n\nNotes: (A) Time course of the DAS28 through week 104 following the initiation of infliximab treatment in the contin and adjusted groups (*P<0.05). (B) Time course of the changes in the DAS28 from the baseline at weeks 26, 52, and 104 as the clinical response to infliximab treatment (*P<0.05). (C) By comparing the DAS28 scores of a patient at different time points of baseline and the estimation at weeks 26, 52, and 104, it is possible to define an improved response. The rate of responders (ie, those with a good or moderate response) at week 104 was 43.6% in the contin group and 87.5% in the adjusted group (*P<0.05). The EULAR responses were categorized as follows. No response: DAS28 improvement ≤0.6 in present DAS28≤3.2, >3.2, ≤5.1, and >5.1 and DAS28 improvement >0.6 and ≤1.2 in present DAS28>5.1. Moderate response: DAS28 improvement >0.6 and ≤1.2 in present DAS28≤3.2, >3.2, and ≤5.1 and DAS28 improvement >1.2 in present DAS28>5.1, >3.2, and ≤5.1. Good response: DAS28 improvement >1.2 in present DAS28≤3.2. *P<0.05, contin group vs adjusted group.\n\nAbbreviations: DAS28, Disease Activity Score in 28 joints; EULAR, European League against Rheumatism.\n\nFigure 4 Remission rate in DAS28 and ACR/EULAR Boolean-based criteria.\n\nNotes: (A) Clinical response at baseline and weeks 26, 52, and 104 in the contin and adjusted groups according to DAS28 criteria. (B) DAS28-based low disease activity and remission and ACR/EULAR Boolean-based remission rates at weeks 26, 52, and 104 by the Chi-squared test (*P<0.05, **P<0.01, and ***P<0.001). The disease activity and criteria in the DAS28 and ACR/EULAR Boolean-based remission were categorized as follows. The DAS28 criteria: high: 5.1< DAS28, moderate: 3.2≤ DAS28≤5.1. Low: 2.6≤ DAS28<3.2. Remission: DAS28<2.6. ACR/EULAR Boolean-based remission: TJC, SJC, PtGA, and CRP all ≤1.\n\nAbbreviations: ACR, American College of Rheumatology; CRP, C-reactive protein; DAS28, Disease Activity Score in 28 joints; EULAR, European League against Rheumatism; PtGA, patient’s global assessment of disease activity; SJC, swelling joint count; TJC, tender joint count.\n\nFigure 5 Joint damage in radiographic assessment.\n\nNotes: The progression of joint damage in the contin and adjusted groups according to the mTSS at week 104. (A) The change in mTSS from baseline. (B) The rate of patients with progression, no change, or improvement in the mTSS (ΔmTSS ≤0.5), *P<0.05.\n\nAbbreviation: mTSS, modified total Sharp score.\n\nTable 1 Baseline demographic and disease characteristics\n\n\tContin group Infliximab 3 mg/kg, n=50\tAdjusted group Step-up and -down, n=40\t\nAge, years\t55.2±13.8\t53.7±12.6\t\nFemale, %\t62\t77.5\t\nRA duration, months\t80.4±103.6\t53.4±50.4\t\nBio naive, %\t86.7\t85.0\t\nMTX dose, mg/week\t7.7±2.6\t6.8±2.6\t\nSteroid use at baseline, %\t52.3\t60.0\t\nSteroid dose, mg/day\t3.8±5.1\t5.2±5.5\t\nACPA positive, %\t83.8\t84.4\t\nTiter, U/mL\t268.1±514.4\t182.3±230.7\t\nRF positive, %\t73.3\t71.4\t\nTiter, U/mL\t103.5±135.4\t99.1±115.7\t\nDAS28\t4.7±1.5\t5.1±1.1\t\nTJC, 28 joints\t6.2±6.2\t6.8±6.0\t\nSJC, 28 joints\t5.5±4.8\t7.2±5.7\t\nPtGA, mm\t52.7±26.6\t57.3±23.4\t\nESR, mm/h\t31.5±24.2\t33.2±24.2\t\nCRP, mg/dL\t1.9±2.3\t3.0±4.0\t\nMMP-3, ng/mL\t388.3±124.9\t398.5±132.5\t\nHAQDI\t0.9±0.8\t1.1±0.8\t\nSteinbrocker class, I/II/III/IV, %\t42.9/31.4/11.4/14.3\t36.7/30.0/13.3/20.0\t\nTotal Sharp score, 0–448, (IQR)\t22.2 (7.9–33.6)\t25.5 (7.3–42.6)\t\nNote: Values are median (25th to 75th percentiles) or mean±SD, unless otherwise indicated.\n\nAbbreviations: ACPA, anticitrullinated peptide antibody; CRP, C-reactive protein; DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; HAQDI, Health Assessment Questionnaire Disability Index; MMP-3, matrix metalloproteinase-3; MTX, methotrexate; PtGA, patient’s global assessment of disease activity; RA, rheumatoid arthritis; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count.\n\nTable 2 Steroid treatment at week 104\n\n\tContin group\tAdjusted group\t\nSteroid use, %\t36.4*\t39.1*\t\nSteroid dose, mg/day\t1.7±2.5*\t2.0±2.8*\t\nCumulative steroid dose, mg\t1,866.1±2,285.7\t2,118.5±2,629.9\t\nReduction of steroid dose, mg\t−2.1±2.6\t−3.2±2.7\t\nNotes: Values are mean±SD, unless otherwise indicated.\n\n* P<0.05, the percentage and dose at baseline vs those at week 104.\n\nTable 3 Radiographic progression\n\n\tContin group\t\tAdjusted group\t\nBaseline\tWeek 104\tBaseline\tWeek 104\t\nTotal Sharp score\t22.2 (7.9–33.6)\t27.9 (9.0–41.1)\t25.5 (7.3–42.6)\t27.4 (8.3–44.0)\t\nErosion score\t12.4 (1.0–23.4)\t13.8 (2.3–25.3)\t7.6 (0.6–14.5)\t7.9 (1.2–1.5)\t\nJoint space narrowing\t9.8 (1.4–18.1)\t14.1 (3.5–24.7)\t17.9 (3.4–52.3)\t19.5 (4.1–34.9)\t\nNote: Data are median and (IQR).\n\nTable 4 Safety assessment of the infliximab + methotrexate regimen\n\n\tContin group, n (%)\tAdjusted group, n (%)\t\nAny AE\t17 (34.0)\t12 (30.0)\t\nSerious AEs\t9 (18.0)\t6 (15.0)\t\nAEs leading to the discontinuation of infliximab\t5 (10.0)\t0 (0)\t\nInfections\t10 (20.0)\t8 (20.0)\t\nSerious infection\t5 (10.0)\t5 (12.5)\t\nInfections leading to study discontinuation\t0 (0)\t0 (0)\t\nInterstitial pneumonia\t1 (2.0)\t0 (0)\t\nMalignancy\t0 (0)\t1 (2.5)\t\nInjection site reaction\t6 (1)\t3 (7.5)\t\nNotes: Serious AEs as judged by the patients’ treating physicians. The patients who exhibited one or more AEs leading to the discontinuation of infliximab were only in the contin group. Discontinuations due to AEs occurred in five patients (one patient with interstitial pneumonia, one patient with cellulitis, and three patients with injection site reactions).\n\nAbbreviation: AEs, adverse events.\n==== Refs\nReferences\n1 Furst DE Breedveld FC Kalden JR Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003) Ann Rheum Dis 2003 62 Suppl 2 ii2 ii9 14532138 \n2 Lipsky PE van der Heijde DM St Clair EW Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group Infliximab and methotrexate in the treatment of rheumatoid arthritis N Engl J Med 2000 343 22 1594 1602 11096166 \n3 Maini RN Breedveld FC Kalden JR Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate Arthritis Rheum 2004 50 4 1051 1065 15077287 \n4 St Clair EW Wagner CL Fasanmade AA The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial Arthritis Rheum 2002 46 6 1451 1459 12115174 \n5 Rahman MU Strusberg I Geusens P Double-blinded infliximab dose escalation in patients with rheumatoid arthritis Ann Rheum Dis 2007 66 9 1233 1238 17392352 \n6 Takeuchi T Miyasaka N Inoue K Abe T Koike T RISING study Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study Mod Rheumatol 2009 19 5 478 487 19626391 \n7 Arnett FC Edworthy SM Bloch DA The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis Arthritis Rheum 1988 31 3 315 324 3358796 \n8 Prevoo ML van ’t Hof MA Kuper HH van Leeuwen MA van de Putte LB van Riel PL Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis Arthritis Rheum 1995 38 1 44 48 7818570 \n9 Takeuchi T Nakajima R Komatsu S Impact of adalimumab on work productivity and activity impairment in Japanese patients with rheumatoid arthritis: Large-scale, prospective, single-cohort ANOU-VEAU study Adv Ther 2017 34 3 686 702 28144917 \n10 Steinbrocker O Traeger CH Batterman RC Therapeutic criteria in rheumatoid arthritis J Am Med Assoc 1949 140 8 659 662 18150288 \n11 van der Heijde DM van Riel PL Nuver-Zwart IH Gribnau FW vad de Putte LB Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis Lancet 1989 1 8646 1036 1038 2565997 \n12 Bruynesteyn K Boers M Kostense P van der Linden S van der Heijde D Deciding on progression of joint damage in paired films of individual patients: smallest detectable difference or change Ann Rheum Dis 2005 64 2 179 182 15286006 \n13 Smolen JS Landewé R Breedveld FC EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs Ann Rheum Dis 2010 69 6 964 975 20444750 \n14 Fries JF Spitz P Kraines RG Holman HR Measurement of patient outcome in arthritis Arthritis Rheum 1980 23 2 137 145 7362664 \n15 Felson DT Smolen JS Wells G American college of rheumatology/European league against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials Ann Rheum Dis 2011 70 3 404 413 21292833 \n16 Fleischmann R Goldman JA Leirisalo-Repo M Infliximab efficacy in rheumatoid arthritis after an inadequate response to etanercept or adalimumab: results of a target-driven active switch study Curr Med Res Opin 2014 30 11 2139 2149 25050591 \n17 Westhovens R Yocum D Han J START Study Group The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial Arthritis Rheum 2006 54 4 1075 1086 16572442 \n18 van Vollenhoven RF Klareskog L Infliximab dosage and infusion frequency in clinical practice: experiences in the Stockholm biologics registry STURE Scand J Rheumatol 2007 36 6 418 423 18092261 \n19 Hetland ML Christensen IJ Tarp U All Departments of Rheumatology in Denmark Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry Arthritis Rheum 2010 62 1 22 32 20039405 \n20 Zink A Listing J Kary S Treatment continuation in patients receiving biological agents or conventional DMARD therapy Ann Rheum Dis 2005 64 9 1274 1279 15708884 \n21 Kobelt G Health economic issues in rheumatoid arthritis Scand J Rheumatol 2006 35 6 415 425 17343248 \n22 Tanaka Y Hirata S Is it possible to withdraw biologics from therapy in rheumatoid arthritis? Clin Ther 2013 35 12 2028 2035 24290736\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5475",
"issue": "12()",
"journal": "Biologics : targets & therapy",
"keywords": "DAS28; REVIVE; dose adjustment; infliximab; mTSS; rheumatoid arthritis",
"medline_ta": "Biologics",
"mesh_terms": null,
"nlm_unique_id": "101321511",
"other_id": null,
"pages": "171-182",
"pmc": null,
"pmid": "30568425",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "11096166;12115174;14532138;15077287;15286006;15708884;16572442;17343248;17392352;18092261;18150288;19626391;20039405;20444750;21292833;24290736;25050591;2565997;28144917;3358796;7362664;7818570",
"title": "Infliximab dose adjustment can improve the clinical and radiographic outcomes of rheumatoid arthritis patients: REVIVE study results.",
"title_normalized": "infliximab dose adjustment can improve the clinical and radiographic outcomes of rheumatoid arthritis patients revive study results"
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{
"abstract": "T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.",
"affiliations": "Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.;Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
"authors": "Wang|Ling|L|;Wang|Li-Ning|LN|;Zhou|Ji-Fang|JF|;Gao|Wen-Hui|WH|;Jiang|Chuan-He|CH|;Tang|Wei|W|;Zhao|Wei-Li|WL|;Hu|Jiong|J|;Jiang|Jie-Ling|JL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.627946",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.627946\nMedicine\nClinical Trial\nLow-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study\nWang Ling 1†\nWang Li-ning 1†\nZhou Ji-fang 2\n\nGao Wen-hui 1\nJiang Chuan-he 1\nTang Wei 1\nZhao Wei-li 1\nHu Jiong 1*\n\nJiang Jie-ling 1*\n1Department of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China\n2School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China\nEdited by: Raynier Devillier, Institut Paoli-Calmettes (IPC), France\n\nReviewed by: Ian James Martins, University of Western Australia, Australia; Thomas Pagliardini, Institut Paoli-Calmettes (IPC), France\n\n*Correspondence: Jie-ling Jiang [email protected]\nJiong Hu [email protected]\nThis article was submitted to Gene and Cell Therapy, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n23 2 2021\n2021\n8 62794610 11 2020\n14 1 2021\nCopyright © 2021 Wang, Wang, Zhou, Gao, Jiang, Tang, Zhao, Hu and Jiang.\n2021\nWang, Wang, Zhou, Gao, Jiang, Tang, Zhao, Hu and Jiang\nThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nT cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6–8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3–22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.\n\nallogeneic stem cell transplantation\nlow-dose decitabine\nmixed chimerism\npre-emptive therapy\nmyeloablative conditioning regimen\n==== Body\nIntroduction\n\nAllogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).\n\nSeveral studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).\n\nEpigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).\n\nMethods\n\nStudy Design\n\nThis was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.\n\nStudy Protocol\n\nThe inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.\n\nAll the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).\n\nFigure 1 Flow chart of the study design.\n\nDefinition of Response and Study Endpoints\n\nResponses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.\n\nThe primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.\n\nChimerism Analysis\n\nGenomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.\n\nSample Size Estimation and Statistical Analysis\n\nThis was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).\n\nConcerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.\n\nResults\n\nPatient Characteristics\n\nA total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.\n\nTable 1 Patient characteristics and outcomes.\n\nUPN\t#1\t#2\t#3\t#4\t#5\t#6\t#7\t#8\t#9\t#10\t#11\t#12\t#13\t#14\t\nAge\t45\t20\t45\t51\t20\t51\t16\t40\t29\t20\t60\t20\t20\t16\t\nSex\tM\tM\tF\tF\tM\tF\tM\tM\tM\tM\tM\tF\tM\tM\t\nDiagnosis\tCML\tALL\tAML\tMDS-EB2\tALL\tAML\tALL\tAML\tSezary\tT-NHL\tAML\tAML\tPh+ ALL\tALL\t\nDisease status at transplant\tCP3- T315I\tCR1\tCR1\tNR\tCR1\tCR1\tCR1\tCR2\tNR\tCR3\tMRD+ CR1\tMRD+ CR1\tCR1\tCR1\t\nDonor type\tHaplo\tMUD\tSib\tMUD\tSib\tSib\tHaplo\tSib\tMUD\tHaplo\tSib\tMUD\tHaplo\tSib\t\nGvHD status\tSkin cGvHD\t/\t/\t/\t/\t/\t/\t/\t/\t/\t/\t/\t/\t/\t\nIS prophylaxis\tFK506\tFK506\t/\tCsA\tFK506\t/\t/\t/\t/\tFK506\tFK506\tFK506\tFK506\tFK506\t\nTime of MC\t+90\t+60\t+100\t+60\t+76\t+120\t+101\t+157\t+180\t+92\t+35\t+75\t+30\t+30\t\nMRD level\t–\t–\t–\t–\t–\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nDC level\t89%\t97%\t82%\t76%\t89%\t93%\t91%\t89%\t93%\t92%\t81%\t91%\t59%\t85%\t\nDC after the first LD-DAC\t>99%\t95%\t89%\t94%\t81%\t>99%\t95%\t>99%\t96%\t95%\t93%\t97%\t2%\t98%\t\nDC after the second LD-DAC\t/\t>99%\t>99%\t86%\t90%\t/\t95%\t/\t>99%\t>99%\t>99%\t99%\t/\t/\t\nDC after the third LD-DAC\t/\t/\t/\t86%\t96%\t/\t2%\t/\t/\t/\t/\t/\t/\t/\t\nDC level at six-month\t>99%\t>99%\t>99%\t86%\t96%\t>99%\t2%\t>99%\t>99%\t>99%\t>99%\t99%\t0\t98%\t\nSix-month response\tCR\tCR\tCR\tPR\tMR\tCR\tNR\tCR\tCR\tCR\tCR\tCR\tNR\tMR\t\nGvHD*\t–\t–\t–\t+\t–\t–\t–\t–\t–\t–\t+\t–\t–\t–\t\nRelapse**\t–\t–\t–\t+\t–\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nGraft failure***\t–\t–\t–\t–\t–\t–\t+\t–\t–\t–\t–\t–\t+\t–\t\nNRM\t–\t–\t–\t–\t–\t–\t–\t–\t–\t–\t+\t–\t–\t–\t\nInremission\t+\t+\t+\t+\t+\t+\t+\t+\t+\t+\t–\t+\t+\t+\t\nOS (days)\t878+\t822+\t803+\t709+\t546+\t529+\t509+\t456+\t418+\t287+\t372\t321+\t257+\t130+\t\nUPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.\n\n* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.\n\n** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).\n\n*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.\n\nMC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.\n\nResponse to LD-DAC Treatment\n\nA total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).\n\nFigure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.\n\nThree patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).\n\nOverall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).\n\nToxicity and Complications\n\nEach adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.\n\nTable 2 Hematological toxicities after LD-DAC treatment (26 cycles).\n\n\tWBC (%)\tANC (%)\tHb (%)\tPLT (%)\t\nNone\t0\t2 (7.7)\t1 (3.8)\t1 (3.8)\t\nGrade 1\t3 (11.5)\t3 (11.5)\t8 (30.8)\t4 (15.4)\t\nGrade 2\t7 (26.9)\t5 (19.2)\t7 (26.9)\t4 (15.4)\t\nGrade 3\t6 (23.1)\t7 (26.9)\t9 (34.6)\t8 (30.8)\t\nGrade 4\t10 (38.5*)\t9 (34.6*)\t1 (3.8*)\t9 (34.6*)\t\nLD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.\n\n* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.\n\nThere was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.\n\nFollow-Up Outcome\n\nAt the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.\n\nThree patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).\n\nFigure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.\n\nDiscussion\n\nVarious studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).\n\nIn this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).\n\nIn recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.\n\nOf the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.\n\nThere were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).\n\nThe small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\n\nLW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Wang Y Chen H Chen J Han M Hu J Jiong Hu . The consensus on the monitoring, treatment, and prevention of leukemia relapse after hematopoietic stem cell transplantation in China. Cancer Lett. (2018) 438 :63–75. 10.1016/j.canlet.2018.08.030 30217562\n2. Kröger N Bacher U Bader P Böttcher S Borowitz MJ Dreger P . 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In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood. (2010) 116 :129–39. 10.1182/blood-2009-12-257253 20424188\n20. Lindblad KE Goswami M Hourigan CS Oetjen KA . Immunological effects of hypomethylating agents. Expert Rev Hematol. (2017) 10 :745–52. 10.1080/17474086.2017.1346470 28644756\n21. Gao L Zhang YQ Wang SB Kong PY Su Y Hu J . Effect of rhG-CSF combined with decitabine prophylaxis on relapse of patients with high-risk MRD-negative AML after HSCT: an open-label, multicenter, randomized controlled trial. J Clin Oncol. (2020) 38 :4249–59. 10.1200/JCO.19.03277 33108244\n22. Nollet F Billiet J Selleslag D Criel A . Standardisation of multiplex fluorescent short tandem repeat analysis for chimerism testing. Bone Marrow Transplant. (2001) 28 :511–8. 10.1038/sj.bmt.1703162 11593326\n23. Jung SH Lee TY Kim KM George SL . Admissible two-stage designs for phase II cancer clinical trials. Stat Med. (2004) 23 :561–9. 10.1002/sim.1600 14755389\n24. Ivanova A Qaqish BF Schell MJ . Continuous toxicity monitoring in phase II trials in oncology. Biometrics. (2005) 61 :540–5. 10.1111/j.1541-0420.2005.00311.x 16011702\n25. Kaplan EL Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc. (1958) 53 :457–80. 10.1080/01621459.1958.10501452\n26. Wethmar K Matern S Eßeling E Angenendt L Pfeifer H Brüggemann M . Monitoring minimal residual/relapsing disease after allogeneic haematopoietic stem cell transplantation in adult patients with acute lymphoblastic leukaemia. Bone Marrow Transplant. (2020) 55 :1410–20. 10.1038/s41409-020-0801-0 32001801\n27. Terwey TH Hemmati PG Nagy M Pfeifer H Gökbuget N Brüggemann M . Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant. (2014) 20 :1522–9. 10.1016/j.bbmt.2014.05.026 24907626\n28. Jacque N Nguyen S Golmard JL Uzunov M Garnier A Leblond V . Chimerism analysis in peripheral blood using indel quantitative real-time PCR is a useful tool to predict post-transplant relapse in acute leukemia. Bone Marrow Transplant. (2015) 50 :259–65. 10.1038/bmt.2014.254 25387089\n29. Caldemeyer LE Akard LP Edwards JR Tandra A Wagenknecht DR Dugan MJ . Donor lymphocyte infusions used to treat mixed-chimeric and high-risk patient populations in the relapsed and nonrelapsed settings after allogeneic transplantation for hematologic malignancies are associated with high five-year survival if persistent full donor chimerism is obtained or maintained. Biol Blood Marrow Transplant. (2017) 23 :1989–97. 10.1016/j.bbmt.2017.07.007 28712934\n30. Bar M Flowers MED Storer BE Chauncey TR Pulsipher MA Thakar MS . Reversal of low donor chimerism following hematopoietic cell transplantation using pentostatin and donor lymphocyte infusion: a prospective phase II multicenter trial. Biol Blood Marrow Transplant. (2018) 24 :308–13. 10.1016/j.bbmt.2017.10.016 29032276\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "allogeneic stem cell transplantation; low-dose decitabine; mixed chimerism; myeloablative conditioning regimen; pre-emptive therapy",
"medline_ta": "Front Med (Lausanne)",
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"pages": "627946",
"pmc": null,
"pmid": "33708780",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "20558311;24907626;29143282;11236950;11965233;12857560;16011702;22219225;33108244;25016197;12036896;26179902;27295272;29032276;15318247;24352219;30217562;24296490;32001801;14755389;27220637;26183077;28644756;11593326;25644958;20424188;25387089;17262061;28712934",
"title": "Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.",
"title_normalized": "low dose decitabine monotherapy reverses mixed chimerism in adult patients after allogeneic hematopoietic stem cell transplantation with myeloablative conditioning regimen a pilot phase ii study"
}
|
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{
"abstract": "As the number of older patients with cancer is increasing, oncology disciplines are faced with the challenge of managing patients with multiple chronic conditions who have difficulty maintaining independence, who may have cognitive impairment, and who also may be more vulnerable to adverse outcomes. National and international societies have recommended that all older patients with cancer undergo geriatric assessment (GA) to detect unaddressed problems and introduce interventions to augment functional status to possibly improve patient survival. Several predictive models have been developed, and evidence has shown correlation between information obtained through GA and treatment-related complications. Comprehensive geriatric evaluations and effective interventions on the basis of GA may prove to be challenging for the oncologist because of the lack of the necessary skills, time constraints, and/or limited available resources. In this article, we describe how the Geriatrics Service at Memorial Sloan Kettering Cancer Center approaches an older patient with colon cancer from presentation to the end of life, show the importance of GA at the various stages of cancer treatment, and how predictive models are used to tailor the treatment. The patient's needs and preferences are at the core of the decision-making process. Development of a plan of care should always include the patient's preferences, but it is particularly important in the older patient with cancer because a disease-centered approach may neglect noncancer considerations. We will elaborate on the added value of co-management between the oncologist and a geriatric nurse practitioner and on the feasibility of adapting elements of this model into busy oncology practices.",
"affiliations": "Memorial Sloan Kettering Cancer Center, New York, NY.;Memorial Sloan Kettering Cancer Center, New York, NY.;Memorial Sloan Kettering Cancer Center, New York, NY.;Memorial Sloan Kettering Cancer Center, New York, NY.",
"authors": "Shahrokni|Armin|A|;Kim|Soo Jung|SJ|;Bosl|George J|GJ|;Korc-Grodzicki|Beatriz|B|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1200/JOP.2016.017608",
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"issn_linking": "1554-7477",
"issue": "13(2)",
"journal": "Journal of oncology practice",
"keywords": null,
"medline_ta": "J Oncol Pract",
"mesh_terms": "D000367:Age Factors; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D003110:Colonic Neoplasms; D015577:Geriatric Assessment; D006801:Humans; D057240:Patient Preference; D018802:Patient-Centered Care; D011184:Postoperative Period; D011300:Preoperative Care",
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"pages": "95-102",
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"pmid": "28972834",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "23503516;21810685;10836348;22626912;16084735;24054409;16540616;26718329;23246499;21155144;23584423;27197915;25148556;25299146;26200581;25071125;9587123;24548926;11113982;20824372;19476884;1991946;6418786;27185838;19403886;27437646;20510798;5349366;18082416;10584605;27314191;26779363;22994865;20005123;20122034;27282296;6699671;20112252;22917646;10855596;25302022;15963180;19730176;8417639;27407124;28972835;24193075;11549951",
"title": "How We Care for an Older Patient With Cancer.",
"title_normalized": "how we care for an older patient with cancer"
}
|
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{
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},
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"literaturereference": "SHAHROKNI A, KIM SJ, BOSL GJ, KORC-GRODZICKI B. HOW WE CARE FOR AN OLDER PATIENT WITH CANCER. JOURNAL OF ONCOLOGY PRACTICE. 2017;13(2):95-102.",
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] |
{
"abstract": "There are limited data describing COVID-19 in lung transplant recipients. We performed a single center, retrospective case series study of lung transplant patients followed by the Columbia Lung Transplant program who tested positive for SARS-CoV-2 between March 19 and May 19, 2020. Thirty-two lung transplant patients developed mild (16%), moderate (44%), or severe (41%) COVID-19. The median age of patients was 65 years, and the median time from lung transplant was 5.6 years. Symptoms included cough (66%), dyspnea (50%), fever (47%), and gastrointestinal upset (44%). Patients received hydroxychloroquine (84%), azithromycin (75%), augmented steroids (44%), tocilizumab (19%), and remdesivir (9%). Eleven patients (34%) died at a median time of 14 days from admission. Complications during admission included: acute kidney injury (63%), transaminitis (31%), shock (31%), acute respiratory distress syndrome (25%), neurological events (25%), arrhythmias (22%), and venous thromboembolism (9%). Compared to patients with moderate COVID-19, patients with severe COVID-19 had higher peak white blood cell counts (15.8 vs 7 × 103 /uL, P = .019), C-reactive protein (198 vs. 107 mg/L, P = .010) and D-dimer (8.6 vs. 2.1 ug/mL, P = .004) levels, and lower nadir lymphocyte counts (0.09 vs. 0.4 × 103 /uL, P = .006). COVID-19 is associated with severe illness and a high mortality rate in lung transplant recipients.",
"affiliations": "Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Department of Pharmacy, New York-Presbyterian Hospital, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.;Division of Thoracic Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA.;Division of Thoracic Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA.;Division of Thoracic Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA.;Division of Thoracic Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA.;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, New York, USA.",
"authors": "Aversa|Meghan|M|0000-0002-7361-0024;Benvenuto|Luke|L|0000-0001-8005-8074;Anderson|Michaela|M|0000-0001-9274-7643;Shah|Lori|L|;Robbins|Hilary|H|;Pereira|Marcus|M|0000-0002-9214-9122;Scheffert|Jenna|J|;Carroll|Maggie|M|0000-0003-2477-6818;Hum|Jamie|J|;Nolan|Margaret|M|;Reilly|Genevieve|G|;Lemaitre|Philippe|P|;Stanifer|Bryan P|BP|;D'Ovidio|Frank|F|0000-0003-1678-2345;Sonett|Joshua|J|;Arcasoy|Selim|S|;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16241",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D000086382:COVID-19; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009519:New York City; D058873:Pandemics; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D015996:Survival Rate; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3072-3080",
"pmc": null,
"pmid": "32881315",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "COVID-19 in lung transplant recipients: A single center case series from New York City.",
"title_normalized": "covid 19 in lung transplant recipients a single center case series from new york city"
}
|
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"reaction": [
{
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Arrhythmia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Brain stem syndrome",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia klebsiella",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute kidney injury",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Candida infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia staphylococcal",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hallucination",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Enterococcal infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pneumonia pseudomonal",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Embolism venous",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Klebsiella test positive",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Morganella infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cytomegalovirus infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Transaminases increased",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Staphylococcus test positive",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Shock",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Mental status changes",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Migraine",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "COVID-19",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Delirium",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2020"
}
},
"primarysource": {
"literaturereference": "ANDERSON M. COVID?19 IN LUNG TRANSPLANT RECIPIENTS: A SINGLE CENTER CASE SERIES FROM NEW YORK CITY. AMERICAN JOURNAL OF TRANSPLANTATION. 2020?20:3072?3080",
"literaturereference_normalized": "covid 19 in lung transplant recipients a single center case series from new york city",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210519",
"receivedate": "20210519",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
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"transmissiondate": "20210717"
}
] |
{
"abstract": "Acanthamoeba keratitis (AK) is a sight threatening infection most commonly affecting contact lens wearers. The authors report a case of intractable A.polyphaga and A.castellanii, with extensive intraocular spread, managed using oral miltefosine. A 59-year old male contact lens wearer was referred to the tertiary corneal service at Bristol Eye Hospital. Vision was hand movements on the left and 6/6 on the right. Clinical examination was consistent with left AK (confirmed by corneal scrape). Management included biguanide (polyhexamethylene biguanide (PHMB) 0.02%, later 0.06%) and diamidine (hexamidine 0.1%). Further treatment included imidazole (guttae voriconazole, oral posaconazole) and fortified biguanide (chlorhexidine 0.2%). Therapeutic PKP was performed. Microscopy revealed Acanthamoeba throughout host stroma. Corneal scrape and anterior chamber tap revealed persistent infection with Acanthamoeba. Intracameral voriconazole was administered twice. Clinically there was scleritis, with concerns regarding posterior segment involvement. There was a severe necrotic keratitis with almost complete corneal melt, requiring enucleation. Oral miltefosine was commenced to reduce the risk of transmission of Acanthamoeba beyond ocular structures at the time of the enucleation. Histopathological analysis detected A.polyphaga and A.castellanii in vitreous but not retina, choroid or optic nerve suggesting that infection had not progressed posteriorly through the ocular structures and the central nervous system was not involved. The use of miltefosine as a component of combination anti-parasitic therapy is associated with long-term survival in cases of Acanthamoeba infection of the central nervous system. This case reports its first systemic use in the United Kingdom in a case of severe intractable AK with intraocular spread.",
"affiliations": "Bristol Eye Hospital, United Kingdom. Electronic address: [email protected].;Bristol Eye Hospital, United Kingdom.;Bristol Eye Hospital, United Kingdom.;Hospital for Tropical Diseases and the London School of Hygiene and Tropical Medicine, United Kingdom.;Bristol Eye Hospital, United Kingdom.",
"authors": "Tavassoli|Shokufeh|S|;Buckle|Miranda|M|;Tole|Derek|D|;Chiodini|Peter|P|;Darcy|Kieren|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.clae.2018.03.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1367-0484",
"issue": "41(4)",
"journal": "Contact lens & anterior eye : the journal of the British Contact Lens Association",
"keywords": "Acanthamoeba; Contact lens; Corneal ulcer; Keratitis; Miltefosine",
"medline_ta": "Cont Lens Anterior Eye",
"mesh_terms": null,
"nlm_unique_id": "9712714",
"other_id": null,
"pages": "400-402",
"pmc": null,
"pmid": "29580956",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The use of miltefosine in the management of refractory Acanthamoeba keratitis.",
"title_normalized": "the use of miltefosine in the management of refractory acanthamoeba keratitis"
}
|
[
{
"companynumb": "GB-ASTELLAS-2018US033039",
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{
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"activesubstancename": "TACROLIMUS"
},
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"drugdosageform": "FORMULATION UNKNOWN",
"drugdosagetext": null,
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"drugindication": "KERATOPLASTY",
"drugintervaldosagedefinition": "804",
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}
],
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"patientonsetage": "59",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Acanthamoeba infection",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Transplant rejection",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Scleritis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TAVASSOLI S, BUCKLE M, TOLE D, CHIODINI P, DARCY K. THE USE OF MILTEFOSINE IN THE MANAGEMENT OF REFRACTORY ACANTHAMOEBA KERATITIS.. CONTACT LENS AND ANTERIOR. 2018?41 (1):400?2",
"literaturereference_normalized": "the use of miltefosine in the management of refractory acanthamoeba keratitis",
"qualification": "3",
"reportercountry": "GB"
},
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"receiptdate": "20180726",
"receivedate": "20180726",
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},
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"sender": {
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"medicinalproduct": "PREDNISOLONE."
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],
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"patientonsetage": "59",
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"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adverse drug reaction",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acanthamoeba keratitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "3"
}
],
"summary": null
},
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"literaturereference": "TAVASSOLI S, BUCKLE M, TOLE D, CHIODINI P, DARCY K.. THE USE OF MILTEFOSINE IN THE MANAGEMENT OF REFRACTORY ACANTHAMOEBA KERATITIS.. CONTACT LENS + ANTERIOR EYE. 2018",
"literaturereference_normalized": "the use of miltefosine in the management of refractory acanthamoeba keratitis",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
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},
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "BACKGROUND\nInfections complicate a minority of orthopaedic arthroplasties but are the leading cause of malpractice claims. The basis for the claims is unclear. The objective of this study was to identify the main deviations from current recommendations by reviewing patient files recorded by a major French medical liability-specialized insurance company for private practitioners (MACSF [Mutuelle d'Assurance du Corps de Santé Français]) and to analyze legal claims and outcomes of litigation.\n\n\nMETHODS\nAll claims data for periprosthetic joint infections were analyzed retrospectively from 2010 to 2014. Treatment strategies were compared with therapeutic guidelines published by medical societies.\n\n\nRESULTS\nForty-five claims for periprosthetic joint infection were recorded; 82% of patients were men and the mean patient age was 63 years. Twenty-one patients (47%) had a knee arthroplasty, 21 had a hip arthroplasty, 2 had a shoulder arthroplasty, and 1 had an ankle arthroplasty. Twenty-three infections (51%) occurred within 1 month postoperatively. Staphylococcus aureus was isolated from intraoperative samples in 36% of the cases (including 25% of these with methicillin-resistant strains), and coagulase-negative staphylococci were isolated in 51% (44% methicillin-resistant strains) of the cases. Treatment lasted for a median of 9.5 months (range, 1.5 to 96 months), with a median of 6 months (range, 1.5 to 20 months) of antibiotics and 3 surgical procedures (range, 0 to 7 surgical procedures). A total of 18% of patients had antibiotic-related side effects, 2% of patients died, and 76% of patients had persistent sequelae. An infectious disease specialist's advice was required for 56% of the patients. Discordances with therapeutic guidelines were found in 76% of the patient files, including delay in diagnosis (44%) and inadequate medical treatment (18%) or medico-surgical treatment (13%).\n\n\nCONCLUSIONS\nLate diagnosis of early postoperative infections appears to be the major cause of inappropriate management and malpractice litigation. Discordance with current guidelines was identified. Early consultation with an infectious disease specialist may help to reduce malpractice claims.\n\n\nMETHODS\nTherapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.",
"affiliations": "Département de Maladies Infectieuses, Hôpital Raymond Poincaré, AP-HP, Université de Versailles, Versailles, France.;Mutuelle d'Assurance du Corps de Santé Français (MACSF), La Défense, Paris, France.;Service de Maladies Infectieuses, Hôpital Saint Louis, AP-HP, Université Paris 7, Paris, France.",
"authors": "Senard|Olivia|O|;Houselstein|Thierry|T|;Crémieux|Anne-Claude|AC|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.2106/JBJS.19.00101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9355",
"issue": "101(20)",
"journal": "The Journal of bone and joint surgery. American volume",
"keywords": null,
"medline_ta": "J Bone Joint Surg Am",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D019643:Arthroplasty, Replacement; D005260:Female; D005602:France; D019983:Guideline Adherence; D006801:Humans; D007595:Joint Prosthesis; D007603:Jurisprudence; D008297:Male; D008318:Malpractice; D008875:Middle Aged; D000072161:Orthopedic Surgeons; D017410:Practice Guidelines as Topic; D016459:Prosthesis-Related Infections; D012086:Reoperation; D012189:Retrospective Studies",
"nlm_unique_id": "0014030",
"other_id": null,
"pages": "1806-1811",
"pmc": null,
"pmid": "31626004",
"pubdate": "2019-10-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reasons for Litigation in Arthroplasty Infections and Lessons Learned.",
"title_normalized": "reasons for litigation in arthroplasty infections and lessons learned"
}
|
[
{
"companynumb": "NVSC2020FR124607",
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"occurcountry": "FR",
"patient": {
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"activesubstancename": "GENTAMICIN"
},
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"medicinalproduct": "GENTAMICIN."
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},
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}
],
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"reaction": [
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"reactionmeddrapt": "Renal failure",
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"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SENARD O, HOUSELSTEIN T, CREMIEUX AC. REASONS FOR LITIGATION IN ARTHROPLASTY INFECTIONS AND LESSONS LEARNED. THE JOURNAL OF BONE AND JOINT SURGERY. 2019?101:1806-11",
"literaturereference_normalized": "reasons for litigation in arthroplasty infections and lessons learned",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20200515",
"receivedate": "20200515",
"receiver": {
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},
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"safetyreportversion": 1,
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
}
] |
{
"abstract": "BACKGROUND\nFerric carboxymaltose (FCM) can induce hypophosphataemia in the general population and patients with chronic kidney disease (CKD). Less is known about the effect of FCM in the kidney transplant population. It has been suggested that fibroblast growth factor 23 (FGF-23)-mediated renal phosphate wasting may be the most likely cause of this phenomenon. In the current study, the effects of FCM on phosphate metabolism were studied in a cohort of kidney transplant recipients.\n\n\nMETHODS\nTwo index patients receiving FCM are described. Additionally, data of 23 kidney transplant recipients who received a single dose of FCM intravenously between 1 January 2014 and 1 July 2015 were collected. Changes in the serum phosphate concentration were analysed in all subjects. Change in plasma FGF-23 concentrations was analysed in the index patients.\n\n\nRESULTS\nIn the two index patients an increase in FGF-23 and a decrease in phosphate concentrations were observed after FCM administration. In the 23 kidney transplant patients, median estimated glomerular filtration rate was 42 ml/min/1.73 m2 ( range 10-90 ml/ min/1.73 m2). Mean phosphate concentration before and after FCM administration was 1.05 ±; 0.35 mmol/l and 0.78 ±; 0.41 mmol/l, respectively (average decrease of 0.27 mmol/l; p = 0.003). In the total population, 13 (56.5%) patients showed a transient decline in phosphate concentration after FCM administration. Hypophosphataemia following FCM administration was severe (i.e. < 0.5 mmol/l) in 8 (34.8%) patients.\n\n\nCONCLUSIONS\nAdministration of a single dose of FCM may induce transient and mostly asymptomatic renal phosphate wasting and hypophosphataemia in kidney transplant recipients. This appears to be explained by an increase in FGF-23 concentration.",
"affiliations": "Department of Internal Medicine, Division of Nephrology & Kidney Transplantation, Erasmus MC, University Medical Center Rotterdam, the Netherlands.",
"authors": "Sari|V|V|;Atiqi|R|R|;Hoorn|E J|EJ|;Heijboer|A C|AC|;van Gelder|T|T|;Hesselink|D A|DA|",
"chemical_list": "C000717427:FGF23 protein, human; D005290:Ferric Compounds; D010710:Phosphates; D005346:Fibroblast Growth Factors; C522335:ferric carboxymaltose; D008320:Maltose; D000089703:Fibroblast Growth Factor-23",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "75(2)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D005290:Ferric Compounds; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D006801:Humans; D017674:Hypophosphatemia; D016030:Kidney Transplantation; D008297:Male; D008320:Maltose; D010710:Phosphates; D011183:Postoperative Complications",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "65-73",
"pmc": null,
"pmid": "28276325",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ferric carboxymaltose-induced hypophosphataemia after kidney transplantation.",
"title_normalized": "ferric carboxymaltose induced hypophosphataemia after kidney transplantation"
}
|
[
{
"companynumb": "NL-STRIDES ARCOLAB LIMITED-2017SP006397",
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"occurcountry": "NL",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "FERROUS GLUCONATE"
},
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"drugauthorizationnumb": null,
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"drugindication": "IRON DEFICIENCY ANAEMIA",
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"medicinalproduct": "FERROUS GLUCONATE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Hypophosphataemia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "SARI V, ATIQI R, HOORN EJ, HEIJBOER AC, VAN GELDER T, HESSELINK DA. FERRIC CARBOXYMALTOSE-INDUCED HYPOPHOSPHATAEMIA AFTER KIDNEY TRANSPLANTATION. NETH-J-MED. 2017;75(2):65-73",
"literaturereference_normalized": "ferric carboxymaltose induced hypophosphataemia after kidney transplantation",
"qualification": "3",
"reportercountry": "NL"
},
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},
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},
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},
{
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},
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],
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},
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"medicinalproduct": "TACROLIMUS."
},
{
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"activesubstancename": "AMLODIPINE BESYLATE"
},
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"medicinalproduct": "AMLODIPINE"
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},
{
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},
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"medicinalproduct": "COLECALCIFEROL"
},
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{
"abstract": "OBJECTIVE\nAcute rejection continues to be a major clinical issue in renal transplantation. Three large multicenter trials have demonstrated a 50% decline in biopsy-proven rejection when mycophenolate mofetil (MMF) was given to renal transplant recipients with corticosteroids and cyclosporine. The purpose of this study was to compare the 6-month outcome of renal transplant recipients using MMF and non-MMF based immunosuppression protocols over a 4-year period at a single center.\n\n\nMETHODS\nThis retrospective study analyzed three patient groups defined by their immunosuppression protocol. The first group included patients who received a quadruple immunosuppression regimen of anti-lymphocyte induction (ATG), cyclosporine (CYA), azathioprine (AZA), and corticosteroids (CCS), and were transplanted between October 1993 and May 1995 (AZA group). The second group included patients who received a triple immunosuppression regimen of CYA, MMF, and CCS, and were transplanted between June 1995 and May 1996 (MMF group). The third group included patients who were transplanted between January 1997 and December 1997, and received an immunosuppression regimen of CYA and MMF with a reduced CCS dosing schema (reduced steroid group (RST)). Data were collected from a retrospective review of inpatient and outpatient clinical records.\n\n\nRESULTS\nA total of 325 patients were included in the study (106 AZA, 106 MMF, 113 RST). The demographic characteristics of the three groups were similar; however, the mean donor age for the AZA group was 40+/-15.1 years versus 33+/-14.1 years and 34+/-13.1 years for the MMF and RST groups, respectively (p<0.043). The incidence of acute, biopsy-proven rejection at 6 months was significantly less in the MMF group when compared with the AZA group [16 (15.1%) versus 35 (33%) patients, p = 0.002]. However, the incidence of acute, biopsy-proven rejection in the RST group (35 patients, 31%) was similar to that of the AZA group. Kaplan-Meier estimates for the cumulative incidence of acute rejection demonstrated a significant difference between the MMF group and the other two groups (p = 0.0059). The AZA group had more severe rejection as demonstrated by the more frequent use of antilymphocyte therapy for rejection treatment (68.4% episodes) compared with the MMF (38.9%) and RST (47.6%) groups. After 6 months of follow-up, 11 patients had lost their grafts (8, AZA; 1, MMF; 2, RST). One patient died in each of the AZA and RST groups due to hemorrhage and a pulmonary embolus, respectively. Four AZA patients were diagnosed with a malignancy (three post-transplant lymphoproliferative disorder, one squamous skin cell carcinoma) compared with 2 MMF patients (prostate cancer, basal skin cell carcinoma) and no RST patients. Herpes zoster was the only infection that occurred more frequently in the MMF group (p = 0.03). No other differences in infection rates were noted among the three groups. The initial length of hospital stay declined significantly over the 4-year study period [11+/-4.3 d (AZA), 7.0+/-4.0 d (MMF), 6.2+/-3.3 d (RST), p<0.001]. Total number of hospital days for the first 6 months also followed a similar declining pattern. Despite using intravenous cyclosporine immediately post-transplant in the MMF and RST groups, the incidence of delayed graft function was similar among the three groups. Average serum creatinine at 1 month was significantly lower in the MMF group (p = 0.008), but no difference was noted at 3 and 6 months when compared with the AZA and RST groups.\n\n\nCONCLUSIONS\nThis retrospective analysis indicates that MMF is an effective immunosuppressant. Decreased length of stay and less steroid resistant rejections with MMF is favorable for decreased hospital costs. However, the rebound in rejection rate with the RST group suggests that further study is needed to define the optimal use of this agent in combination with others to maximize effectiveness and minimize negative side effects.",
"affiliations": "Department of Pharmaceutical Services, Emory University Hospital Atlanta, GA, USA.",
"authors": "Triemer|H L|HL|;Pearson|T C|TC|;Odom|K L|KL|;Larsen|C P|CP|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "Denmark",
"delete": false,
"doi": "10.1034/j.1399-0012.2000.14041002.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "14(4 Pt 2)",
"journal": "Clinical transplantation",
"keywords": null,
"medline_ta": "Clin Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "413-20",
"pmc": null,
"pmid": "10946781",
"pubdate": "2000-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Analysis of a single-center experience with mycophenolate mofetil based immunosuppression in renal transplantation.",
"title_normalized": "analysis of a single center experience with mycophenolate mofetil based immunosuppression in renal transplantation"
}
|
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] |
{
"abstract": "Ado-trastuzumab emtansine (T-DM1) is a monoclonal antibody drug conjugate approved for the treatment of HER2-positive breast cancers. Presented here is a case report of a patient who developed fatal pulmonary toxicity in the form of acute eosinophilic pneumonia while undergoing treatment with T-DM1. Prior to beginning T-DM1 therapy, this patient had been treated with two HER2-targeted agents (trastuzumab, pertuzumab) per National Comprehensive Cancer Network (NCCN) guidelines. This case represents a novel presentation of toxicity associated with T-DM1 while perhaps demonstrating additive toxicity associated with multiple lines of HER2 targeted therapies.",
"affiliations": "Department of Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA [email protected].;Department of Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.;Department of Pulmonology and Critical Care, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.;Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.",
"authors": "LaMorte|Daniel|D|;Desmond|Daniel|D|;Ellis|John|J|;Lipkowitz|Stanley|S|",
"chemical_list": "D008453:Maytansine; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243881",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(9)",
"journal": "BMJ case reports",
"keywords": "breast cancer; chemotherapy; interstitial lung disease; pneumonia (respiratory medicine); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008453:Maytansine; D011657:Pulmonary Eosinophilia; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34479891",
"pubdate": "2021-09-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute eosinophilic pneumonia: a fatal reaction to ado-trastuzumab.",
"title_normalized": "acute eosinophilic pneumonia a fatal reaction to ado trastuzumab"
}
|
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"abstract": "This case report describes a 66-year-old male who presented to the emergency department with sepsis and jaundice. He reported that he had been eating seafood at local restaurants for the past two weeks. The medications that he was taking at the time of admission included esomeprazole (proton pump inhibitor (PPI)), which may have contributed to his infection with Raoultella planticola. In addition, the patient had a prior medical history of alcoholic liver cirrhosis, which may have contributed to the bacteremia based on his immunocompromised status.",
"affiliations": "Medical Student, University of Central Florida College of Medicine.;Infectious disease, University of Central Florida College of Medicine.;Medical Student, University of Central Florida College of Medicine.",
"authors": "Povlow|Michael R|MR|;Carrizosa|Jaime|J|;Jones|Adriana|A|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.1508Infectious DiseaseInternal MedicineGastroenterologyInfectious DiseaseRaoultella Planticola: Bacteremia and Sepsis in a Patient with Cirrhosis Muacevic Alexander Adler John R Povlow Michael R 1Carrizosa Jaime 2Jones Adriana 1\n1 \nMedical Student, University of Central Florida College of Medicine \n2 \nInfectious disease, University of Central Florida College of Medicine \nMichael R. Povlow [email protected] 7 2017 7 2017 9 7 e150830 1 2017 24 7 2017 Copyright © 2017, Povlow et al.2017Povlow et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/6413-raoultella-planticola-bacteremia-and-sepsis-in-a-patient-with-cirrhosisThis case report describes a 66-year-old male who presented to the emergency department with sepsis and jaundice. He reported that he had been eating seafood at local restaurants for the past two weeks. The medications that he was taking at the time of admission included esomeprazole (proton pump inhibitor (PPI)), which may have contributed to his infection with Raoultella planticola. In addition, the patient had a prior medical history of alcoholic liver cirrhosis, which may have contributed to the bacteremia based on his immunocompromised status.\n\nsepsisbacteremiaraoultella planticolaspontaneous bacterial peritonitiscirrhosisalcoholThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nRaoultella planticola is a gram negative rod, previously classified in the Klebsiella family [1]. It has been reported as a cause of upper gastrointestinal (GI) infection, pancreatitis, cholangitis, bacteremia, and sepsis following the consumption of seafood [2-5]. The current literature discusses the risk factors for human infection with this bacteria, which include an immunocompromised state and liver cirrhosis. Heavy alcohol use may be another major risk factor, which could be important for determining at-risk populations. \n\nCase presentation\nA 66-year-old male presented to the emergency department with two days of fever, chills, generalized weakness, and anuria. He had a history of alcoholic cirrhosis, chronic kidney disease, and Barrett’s esophagus. The patient reported drinking alcohol every day. The patient's relevant medications included esomeprazole (40 mg) and furosemide (40 mg).\n\nThe vital signs on presentation were: temperature: 97.6 F; heart rate: 89; respiration: 18; and blood pressure: 60/27. His physical exam was significant for jaundice, right upper quadrant pain, and abdominal distension.\n\nPertinent lab results on admission included a white blood cell (WBC) count of 7.4x109/L, a hemoglobin level of 6.9 g/dL, a platelet count of 70x109/L, an international normalized ratio (INR) of 6.54, and a partial thromboplastin time of 54.7 seconds. His serum lactic acid was 7.55, procalcitonin was 8.9, and bilirubin was 13.2 total. Aspartate aminotransferase/alanine aminotransferase was 203/70 with a blood urea nitrogen/creatinine of 55/4.7. Blood cultures were obtained.\n\nA computed tomography (CT) scan of the abdomen showed a cirrhotic liver with extensive portosystemic varices and a large right pleural effusion. An ultrasound of the abdomen showed findings consistent with liver cirrhosis, a large pleural fluid collection, and a thickening of the gallbladder wall.\n\nInitial treatment was started with piperacillin/tazobactam for a broad spectrum coverage of infection. Blood cultures reported the growth of a gram negative rod identified as Raoultella planticola. The patient was switched to ceftriaxone based on sensitivities and prior literature on the treatment of this infection [4]. A thoracentesis was performed due to hydrothorax from the ascites, and 1800 milliliters of serosanguinous fluid was removed and analyzed. The fluid tested was consistent with an effusion secondary to spontaneous bacterial peritonitis and was the suspected cause of sepsis. Blood cultures taken two days after the initial set showed no bacterial growth and the patient had begun recovering from sepsis. Before discharge, the patient was counseled on his alcohol intake and seafood intake, both risk factors for infection by Raoultella planticola.\n\nDiscussion\nIn this report, the patient stated that he had frequently consumed seafood in the weeks prior to the development of illness. His presentation suggested a picture of spontaneous bacterial peritonitis (SBP) with bacteremia in the presence of decompensated liver disease, cirrhosis, and massive ascites with the development of a large pleural effusion. The analysis of the pleural fluid did not show evidence of the most likely bacteria because of the early administration of appropriate antibiotics; however, the blood cultures taken two days earlier did show evidence of Raoultella planticola. There was no evidence of direct pulmonary infection. Unfortunately, the ascitic fluid was not examined.\n\nThere is a possible association of Klebsiella infection and Raoultella with alcohol abuse because of the colonization of the GI tract and the use of proton pump inhibitors (PPIs) in this setting [2-3,6]. Studies have shown that alcohol inhibits cytokines, which leads to a decrease in the host's defenses against bacteria, including Klebsiella [7]. Klebsiella and Raoultella are closely related bacteria [4] and, as a result, it is plausible that they would share some of these cytokine-releasing features, making alcoholics more prone to infection.\n\nCeftriaxone has shown excellent activity against Raoultella. In this case, the patient recovered well from this episode of sepsis. Some caution has to be taken because of recent reports of carbapenem-resistant strains [8].\n\nConclusions\nRaoultella planticola is an uncommon bacterium that is infectious. It is easy to be misidentified as the Klebsiella species during clinical laboratory testing. This is probably due to its prior history of being associated with Klebsiella and its more recent branching off as its own species. Now that we understand that this may be a potential cause of infection, especially in high-risk patients with many comorbidities, such as alcoholism, liver cirrhosis, PPI use, and immunocompromised state, it needs to be considered as a possible cause of the infection. This is especially true in patients with a recent history of seafood ingestion, as this has been identified as a possible source. Being able to identify the organism properly will help with more targeted treatments. It is also important to counsel patients on diet and alcohol intake to prevent future infections. In other reports, and in this case, ceftriaxone has been an effective choice for treatment, although individual sensitivities should be performed on a case-by-case basis to achieve the best results and decrease resistance.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Phylogenetic analyses of Klebsiella species delineate Klebsiella and Raoultella gen. nov., with description of Raoultella ornithinolytica comb. nov., Raoultella terrigena comb. nov. and Raoultella planticola comb. nov Int J Syst Evol Microbiol Drancourt M Bollet C Carta A 925 932 51 2001 11411716 \n2 Raoultella planticola bacteremia following consumption of seafood Can J Infect Dis Med Microbiol Lam PW Salit IE 83 84 25 2014 24855475 \n3 Raoultella planticola-associated cholangitis and sepsis: a case report and literature review QJM Salmaggi C Ancona F Olivetti J 911 913 107 2014 24733944 \n4 A case of severe pancreatitis complicated by Raoultella planticola infection J Med Microbiol Alves MS Riley LW Moreira BM 696 698 56 2007 17446297 \n5 Raoultella planticola bacteraemia secondary to gastroenteritis Clin Microbiol Infect Puerta-Fernandez S Miralles-Linares F Sanchez-Simonet MV 236 237 19 2013 \n6 Cholangitis with septic shock caused by Raoultella planticola J Med Microbiol Yokota K Gomi H Miura Y 446 449 61 2012 22096135 \n7 Acute alcohol intoxication suppresses the interleukin 23 response to Klebsiella pneumoniae infection Alcohol Clin Exp Res Happel KI Odden AR Zhang P 1200 1207 30 2006 16792568 \n8 A rare cause of infection, Raoultella planticola: emerging threat and new reservoir for carbapenem resistance Infection Demiray T Koroglu M Ozbek A 713 717 44 2016 27147419\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "9(7)",
"journal": "Cureus",
"keywords": "alcohol; bacteremia; cirrhosis; raoultella planticola; sepsis; spontaneous bacterial peritonitis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e1508",
"pmc": null,
"pmid": "28948128",
"pubdate": "2017-07-24",
"publication_types": "D002363:Case Reports",
"references": "22096135;17446297;11411716;23574552;25285133;16792568;27147419;24733944",
"title": "Raoultella Planticola: Bacteremia and Sepsis in a Patient with Cirrhosis.",
"title_normalized": "raoultella planticola bacteremia and sepsis in a patient with cirrhosis"
}
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"summary": null
},
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{
"abstract": "OBJECTIVE\nTo analyze the effect of disease-modifying antirheumatic drugs (DMARDs) on the outcome of interstitial lung disease secondary to rheumatoid arthritis (RA-ILD).\n\n\nMETHODS\nWe performed a multicenter, prospective, observational study of patients with RA-ILD receiving DMARDs between 2015 and 2017. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 24 months. The radiological assessment was centralized. The main outcome measure at 24 months was changed in lung function (improvement, stabilization, worsening, or death). We recorded the 28-joint Disease Activity Score 28 (DAS28) and adverse events. A logistic regression analysis was performed to identify factors associated with worsening of ILD.\n\n\nRESULTS\nAfter 24 months, lung disease was stabilized in 40 patients (57.1%), improved in 8 (11.4%), and worse in 21 (30.0%). One patient (1.4%) died. The factors associated with worsening of ILD in the multivariate analysis were treatment with abatacept, tocilizumab, or rituximab (OR, 0.102 [95%CI, 0.015-0.686]), DAS28 (OR, 1.969 [95%CI, 1.005-3.857]), and smoking (OR, 6.937 [95%CI, 1.378-4.900]). During follow-up, 30 patients (42.9%) experienced an adverse event, which was severe in 12 cases (17.1%).\n\n\nCONCLUSIONS\nLung function is stable and inflammatory activity well controlled in most patients with RA-ILD receiving treatment with DMARDs. Non-anti-TNF DMARDs reduce the risk of worsening of lung disease in 90% of patients. The inflammatory activity of RA and smoking, on the other hand, are associated with worsening. Key Points • We have performed prospectively evaluated lung and joint function in patients with RA-ILD receiving treatment with various DMARDs. • In our study, the lung function is stable and inflammatory activity well controlled in most patients with RA-ILD receiving treatment with DMARDs. • Neither csDMARDs nor anti-TNF agents were associated with a significant risk of worsening of lung disease, whereas non-anti-TNF bDMARDs could reduce the risk of worsening of lung disease. • Smoking and poor control of joint involvement were the main factors associated with worsening of lung disease.",
"affiliations": "Instituto de Investigación Biomédica de Málaga (IBIMA), 29010, Málaga, Spain. [email protected].;Instituto de Investigación Biomédica de Málaga (IBIMA), 29010, Málaga, Spain.;Instituto de Investigación Biomédica de Málaga (IBIMA), 29010, Málaga, Spain. [email protected].;UGC de Radiodiagnóstico, Hospital Regional Universitario de Málaga, 29009, Málaga, Spain.;UGC de Reumatología, Hospital Clínico Universitario Virgen de la Victoria, 29010, Málaga, Spain.;Instituto de Investigación Biomédica de Málaga (IBIMA), 29010, Málaga, Spain.;UGC de Neumología, Hospital Regional Universitario de Málaga, 29009, Málaga, Spain.;Hospital Universitario de Jaén, Jaén, Spain.;Hospital Universitario Virgen de las Nieves, Granada, Spain.;Hospital Universitario Virgen de Valme, Sevilla, Spain.;Instituto de Investigación Biomédica de Málaga (IBIMA), 29010, Málaga, Spain.;UGC de Radiodiagnóstico, Hospital Regional Universitario de Málaga, 29009, Málaga, Spain.;Instituto de Investigación Biomédica de Málaga (IBIMA), 29010, Málaga, Spain.",
"authors": "Mena-Vázquez|Natalia|N|http://orcid.org/0000-0001-6173-2051;Godoy-Navarrete|Francisco Javier|FJ|;Manrique-Arija|Sara|S|;Aguilar-Hurtado|María Carmen|MC|;Romero-Barco|Carmen María|CM|;Ureña-Garnica|Inmaculada|I|;Espildora|F|F|;Añón-Oñate|Isabel|I|;Pérez-Albaladejo|Lorena|L|;Gomez-Cano|Carmen|C|;Jimenez-Núñez|Francisco Gabriel|FG|;Padin-Martín|María Isabel|MI|;Fernández-Nebro|Antonio|A|",
"chemical_list": "D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-020-05227-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "40(1)",
"journal": "Clinical rheumatology",
"keywords": "Biologics; Interstitial lung disease; Non-anti-TNF biologics; Rheumatoid arthritis",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D006801:Humans; D017563:Lung Diseases, Interstitial; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "133-142",
"pmc": null,
"pmid": "32557255",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "27908307",
"title": "Non-anti-TNF biologic agents are associated with slower worsening of interstitial lung disease secondary to rheumatoid arthritis.",
"title_normalized": "non anti tnf biologic agents are associated with slower worsening of interstitial lung disease secondary to rheumatoid arthritis"
}
|
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"literaturereference": "MENA-VAZQUEZ N, GODOY-NAVARRETE, F, MANRIQUE-ARIJA S, AGUILAR-HURTADO M, ROMERO-BARCO C, URENA-GARNICA, I ET AL.. NON-ANTI-TNF BIOLOGIC AGENTS ARE ASSOCIATED WITH SLOWER WORSENING OF INTERSTITIAL LUNG DISEASE SECONDARY TO RHEUMATOID ARTHRITIS. CLINICAL RHEUMATOLOGY. 2020",
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{
"abstract": "BACKGROUND Bartonella infection is the causative organism of cat-scratch disease (CSD), which typically presents with self-limited localized lymphadenopathy. In HIV-infected patients, Bartonella infection can cause systemic illnesses with significant morbidity and mortality manifesting as bacillary angiomatosis (BA), hepatic peliosis, splenitis, bacteremic febrile illness, and other organ involvement. To the best of our knowledge, there have been no reports of HIV-infected patients presenting with generalized lymphadenopathy caused by Bartonella infection. We report an unusual case of CSD presenting with generalized lymphadenopathy in an AIDS patient with advanced immunosuppression. CASE REPORT A 44-year-old woman with AIDS, advanced immunosuppression, and intermittent adherence to antiretroviral therapy and medical care, presented with cough and increased generalized tender lymphadenopathy. A lymph node biopsy 1 year earlier was non-diagnostic for tuberculosis, fungal infection, and lymphoproliferative disorders. She remained with generalized lymphadenopathy. A repeat biopsy with the addition of Warthin-Starry silver staining suggested the diagnosis of cat-scratch lymphadenitis. She responded well to a long course of azithromycin antibiotic therapy, with the resolution of lymphadenopathy. CONCLUSIONS Cat-scratch disease may present with prolonged generalized lymphadenopathy, an unusual presentation in HIV patients with advanced immunosuppression. Awareness of the possibility of CSD in a similar clinical scenario may prompt early recognition and management of this disease.",
"affiliations": "Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"authors": "Mantis|Jazila|J|;Ali|Yasir|Y|;Junejo|Shoaib Zahoor|SZ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.909325",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3006890010.12659/AJCR.909325909325ArticlesCat-Scratch Disease in an AIDS Patient Presenting with Generalized Lymphadenopathy: An Unusual Presentation with Delayed Diagnosis Mantis Jazila ADEF1Ali Yasir ADEF2Junejo Shoaib Zahoor AEF2\n1 Division of Infectious Disease, Icahn School of Medicine at Mount Sinai, NYC Health + Hospital/Queens, New York, NY, U.S.A.\n2 Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, NYC Health + Hospital/Queens, New York, NY, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Jazila Mantis, e-mail: [email protected] 02 8 2018 19 906 911 02 2 2018 24 4 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 44\n\nFinal Diagnosis: Cat-scratch disease\n\nSymptoms: Lymfadenopathy\n\nMedication: —\n\nClinical Procedure: Lymph node biopsy\n\nSpecialty: Infectious Diseases\n\nObjective:\nUnusual clinical course\n\nBackground:\nBartonella infection is the causative organism of cat-scratch disease (CSD), which typically presents with self-limited localized lymphadenopathy. In HIV-infected patients, Bartonella infection can cause systemic illnesses with significant morbidity and mortality manifesting as bacillary angiomatosis (BA), hepatic peliosis, splenitis, bacteremic febrile illness, and other organ involvement. To the best of our knowledge, there have been no reports of HIV-infected patients presenting with generalized lymphadenopathy caused by Bartonella infection. We report an unusual case of CSD presenting with generalized lymphadenopathy in an AIDS patient with advanced immunosuppression.\n\nCase Report:\nA 44-year-old woman with AIDS, advanced immunosuppression, and intermittent adherence to antiretroviral therapy and medical care, presented with cough and increased generalized tender lymphadenopathy. A lymph node biopsy 1 year earlier was non-diagnostic for tuberculosis, fungal infection, and lymphoproliferative disorders. She remained with generalized lymphadenopathy. A repeat biopsy with the addition of Warthin-Starry silver staining suggested the diagnosis of cat-scratch lymphadenitis. She responded well to a long course of azithromycin antibiotic therapy, with the resolution of lymphadenopathy.\n\nConclusions:\nCat-scratch disease may present with prolonged generalized lymphadenopathy, an unusual presentation in HIV patients with advanced immunosuppression. Awareness of the possibility of CSD in a similar clinical scenario may prompt early recognition and management of this disease.\n\nMeSH Keywords:\nAngiomatosis, BacillaryCat-Scratch DiseaseHIV InfectionsLymphadenitis\n==== Body\nBackground\nCat-scratch disease (CSD) is an illness caused by Bartonella henselae infection following cat exposure, usually a cat-scratch or bite, most commonly occurring in children and young adults; with the median age of 21 years [1,2]. Typical CSD in immunocompetent patients presents as a regional lymphadenopathy accompanied by fever and other systemic symptoms of malaise, fatigue, and night sweats and is usually benign and self-limited. About 10% of patients have atypical CSD, mainly in older adults with manifestations including Parinaud oculo-glandular syndrome, neuroretinitis, granulomatous hepatitis, erythema nodosum, and, rarely, endocarditis, osteomyelitis, myalgias, and arthropathy [3,4].\n\nBartonella infections caused by B. henselae or B. quintana in immunocompromised patients primarily present as a systemic illness that may be characterized by angioproliferative lesions involving the skin, liver, and spleen. Bacillary angiomatosis (BA) lesions and fever are the most common manifestations of B. henselae and B. quintana in HIV/AIDS patients [5], with clinical manifestations, including cutaneous vascular lesions, subcutaneous nodules, and vascular-proliferative disease, affecting the liver and spleen, and systemic illness with fever, bacteremia, and weight loss [6,7].\n\nIsolation of Bartonella bacteria from blood and tissue is difficult, requiring prolonged incubation. The organisms can be seen on Warthin-Starry staining of histopathologic specimens, and PCR assay can be used in detecting Bartonella DNA in tissue [8,9].\n\nWe report a case of prolonged generalized lymphadenopathy of more than 1-year duration in an AIDS patient on intermittent antiretroviral therapy (ART) and Mycobacterium avium complex (MAC) prophylaxis.\n\nCase Report\nA 44-year-old woman was admitted with a few days’ history of cough, whitish sputum production, and acute increase in painful, enlarged neck lymph nodes. She was diagnosed with AIDS 7 years earlier and had previously been treated for oral thrush, genital herpes simplex infection, syphilis, and recurrent episodes of Pneumocystis jirovecii pneumonia (PCP). She received ART with a combination of rilpivirine/emtricitabine/tenofovir and raltegravir in addition to trimethoprim sulfamethoxazole and weekly azithromycin for PCP and MAC prophylaxis, respectively. She reported intermittent adherence to her medications and medical care. She reported stopping her ART and PCP prophylaxis 2 months prior to admission and then resuming her medications 6 weeks later. One year earlier, she was evaluated at a different facility for enlarged lymph nodes and underwent right epitrochlear lymph node biopsy that revealed non-necrotizing granuloma with negative fungal and mycobacterial stains and cultures. She remained with generalized lymphadenopathy with occasional febrile episodes and unquantified weight loss.\n\nOn presentation, she was afebrile. Results of a physical exam were significant for diffusely enlarged and tender anterior and posterior cervical lymphadenopathy, and bilateral epitrochlear, axillary, and inguinal lymphadenopathy. Laboratory findings were significant for a CD4 count of 77 (4%), HIV viral load 1370 copies/ml, and elevated LDH 450U/L. The result of a TB QuantiFERON test was negative. A chest x-ray was suggestive of hilar and subcarinal adenopathy (Figure 1A, 1B). A computed tomography (CT) scan of the neck and chest showed extensive cervical lymphadenopathy, nodes in the suboccipital region on the left, supraclavicular, axillary, subpectoral, paratracheal, and hilar lymphadenopathy, as well as celiac adenopathy in the visualized portion of the upper abdomen (Figure 2). The largest nodal mass in the subcarinal region measured 4×2.6 cm (Figures 3A–3C).\n\nThe patient received a 5-day course of azithromycin for bronchitis and an outpatient lymph node biopsy was scheduled for 2 weeks later. At the time of biopsy, she felt clinically improved, with decrease in cervical adenopathy and tenderness. A cervical lymph node biopsy showed necrotizing granuloma with palisaded epithelioid cells, partially preserved nodular pattern, thickened capsule, and vascular proliferation. Warthin-Starry staining revealed clumps of pleomorphic bacilli, consistent with Bartonella species, favoring cat-scratch lymphadenitis. She reported having a 2-year-old pet cat at home. She was started on a 12-week course of oral azithromycin 600 mg daily.\n\nOne week after starting the antibiotic course, a repeat chest CT and an abdomen CT revealed significantly decreased bilateral axillary, hilar, and mediastinal adenopathy (Figure 4). The dominant nodal mass in the subcarinal region measured 1.9 cm compared to 4 cm on the previous CT exam. There was extensive adenopathy in the region of the celiac axis, superior mesenteric artery and small bowel mesentery (Figure 5). She continued to improve clinically, with resolution of cervical, axillary, epitrochlear, and inguinal adenopathy. A planned repeat CT of chest and abdomen at the end of the 12-week azithromycin course was not done as the patient was lost to follow-up.\n\nDiscussion\nCat-scratch disease (CSD) is usually caused by Bartonella henselae [10–12] and cats are the main reservoir for the organism. The disease is linked to cat or flea exposure and in immunocompetent human hosts it is typically a local infection that manifests as cutaneous lesions at the site of inoculation and tender regional lymphadenopathy [13]. Localized disease is generally a self-limited illness. Generalized lymphadenopathy is rare. In a review of 1200 patients with CSD by Carithers, all patients in the series had lymphadenopathy; 85% had single-node involvement and the remainder had regional lymph node involvement, usually with only 2, occasionally 3, and rarely 4 or more nodes enlarged. None of the patients in this series had generalized lymphadenopathy [14]. In some individuals, CSD can include visceral organ involvement, an important manifestation in children, mainly the affecting the liver and spleen [15–17]. The diagnosis of CSD is often made presumptively based on characteristic clinical features and a history of recent cat or flea contact. Treatment, when indicated, is typically a 5-day course of azithromycin [18].\n\nBartonella infections in HIV-infected patients can cause serious morbidity and mortality, especially in those with significant immunosuppression [19]. Two species cause clinical infections in HIV-infected patients: Bartonella henselae, usually in patients who have a history of cat exposure, and Bartonella quintana, usually in homeless individuals with body lice. The clinical manifestations include BA, lesions involving the liver (hepatic peliosis) [20], splenitis, osteomyelitis, bacteremia, subcutaneous masses, and hemophagocytic lymphohistiocytosis [21,22]. BA is a common presentation in HIV-infected individuals with advanced immunosuppression, characterized by violaceous, friable, and vascular lesions that bleed profusely with trauma. These lesions most frequently involve the skin but can also involve internal organs, including the liver and spleen [23]. Constitutional symptoms are reported by almost all patients with BA.\n\nDefinitive diagnosis can be challenging since Bartonella species generally do not grow in routine cultures and isolation of the fastidious, slow-growing, gram-negative organism is difficult, requiring extended incubation with specific growth conditions [24]. The sensitivity of culture for Bartonella henselae from blood or lymph nodes has been reported to be as low as 20% [8]. Detection of Bartonella DNA in tissue specimens via polymerase chain reaction (PCR) assay is diagnostic, but the sensitivity is very low, especially when the duration of illness is more than 6 weeks [25]. Histopathological features in lymph nodes consistent with CSD include granuloma formation, stellate abscesses, and lymphocytic infiltrates. Warthin-Starry silver staining of tissue samples identifies the characteristic dark-staining masses of small curved bacteria. Treatment in immunocompromised patients with doxycycline or daily macrolide is generally for at least 3 months [26].\n\nOur patient, with advanced immunosuppression, presented with extensive generalized lymphadenopathy, raising the possibility of lymphoproliferative disorders, fungal infections, and tuberculosis in the differential diagnosis. She had no skin lesions, subcutaneous masses, or involvement of liver and spleen on CT scans, as might be expected in HIV-infected patients with Bartonella infection. One year prior to presentation, she had a lymph node biopsy that revealed necrotizing granuloma with negative fungal and mycobacterial stains and no evidence for lymphoproliferative disorders. A diagnosis of CSD was not made at that time as Warthin-Starry stain and Bartonella PCR were not performed. Warthin-Starry stains are not routinely performed on histologic specimens unless specifically asked for by clinicians. Our patient’s clinical presentation with prolonged generalized lymphadenopathy of over 1-year duration, neither typical of self-limited CSD nor of BA and other manifestations described in HIV-infected patients, is likely due to her intermittent adherence to ART and past exposure to macrolide therapy taken for MAC prophylaxis. Warthin-Starry staining on the second lymph node biopsy revealed typical findings on histopathology for CSD, and the patient responded well to azithromycin antibiotic therapy.\n\nConclusions\nCat-scratch disease may present with prolonged generalized lymphadenopathy, which is an unusual presentation in HIV patients with advanced immunosuppression. Awareness of the possibility of CSD in a similar clinical scenario may prompt early recognition and management of this disease.\n\nGenna Pearl, MD, St. George’s University School of Medicine reviewed and searched the literature.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Chest X-ray at presentation: (A) Frontal view, right hilar (arrow) opacities suggestive of lymphadenopathy; (B) Lateral view, subcarinal (arrow) opacities suggestive of lymphadenopathy.\n\nFigure 2. At presentation, contrast-enhanced CT scan of the neck, revealing bilateral cervical lymphadenopathy; the largest node was in the right supraclavicular region (arrow) with central low attenuation relative to periphery with enhancement.\n\nFigure 3. At Presentation, selected axial (A, B) and coronal (C) images from contrast-enhanced CT scan of the chest, demonstrating bilateral axillary (thick arrows), subcarinal (long arrows), and right hilar larger than left (short arrows) lymphadenopathy.\n\nFigure 4. One week after start of treatment, selected axial (A, B) and coronal (C, D) contrast-enhanced CT scan of the chest, demonstrating significant reduction in size of the right supraclavicular (arrow in C), bilateral axillary, hilar, and subcarinal lymphadenopathy, indicating a favorable response to treatment.\n\nFigure 5. One week after start of treatment, Axial contrast-enhanced CT image at level of lower pole of kidneys, demonstrating sub-centimeter and enlarged mesenteric lymph nodes (arrows).\n==== Refs\nReferences:\n1. Ridder GJ Boedeker CC Technau-Ihling K Role of cat-scratch disease lymphadenopathy in the head and neck Clin Infect Dis 2002 35 643 49 12203159 \n2. Windsor JJ Cat-scratch disease: epidemiology, aetiology and treatment Br J Biomed Sci 2001 58 101 10 11440202 \n3. Ben-Ami R Ephros M Avidor B Cat-scratch disease in elderly patients Clin Infect Dis 2005 41 969 74 16142661 \n4. Maman E Bickels J Ephros M Musculoskeletal Manifestations of cat-scratch disease Clin Infect Dis 2007 45 1535 40 18190312 \n5. Koehler JE Sanchez MA Tye S Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever Clin Infect Dis 2003 37 559 66 12905141 \n6. Koehler JE Quinn FD Berger TG Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis N Engl J Med 1992 327 1625 31 1435899 \n7. Cotell SL Noskin GA Bacillary angiomatosis. Clinical and histologic features, diagnosis and treatment Arch Intern Med 1994 154 524 28 8122945 \n9. Okaro U Addisu A Casanas B Anderson B Bartonella species, an emerging cause of blood-culture-negative endocarditis Clin Microbiol Rev 2017 30 709 49 28490579 \n9. Relman DA Loutit JS Schmidt TM The agent of bacillary angiomatosis. An approach to the identification of uncultured pathogens N Engl J Med 1990 323 1573 80 2233945 \n10. Regnery RL Olson JG Perkins BA Bibb W Serological response to “Rochalimaea henselae” antigen in suspected cat-scratch disease Lancet 1992 339 1443 45 1351130 \n11. Szelc-Kelly CM Goral S Perez-Perez Gl Serologic responses to Bartonella and Afipia antigens in patients with cat-scratch disease Pediatrics 1995 96 1137 42 7491236 \n12. Zangwill KM Hamilton DH Perkins BA Cat-scratch disease in Connecticut. Epidemiology, risk factors and evaluation of a new diagnostic test N Engl J Med 1993 329 8 13 8505963 \n13. Jacomo V Kelly PJ Raoult D Natural history of Bartonella infections (an exception to Koch’s Postulate) Clin Diagn Lab Immunol 2002 9 8 18 11777823 \n14. Carithers HA Cat-scratch disease. An overview based on a study of 1,200 patients Am J Dis Child 1985 139 11 1124 33 4061408 \n15. Lenoir AA Storch GA DeSchryver-Kecskemeti K Granulomatous hepatitis associated with cat-scratch disease Lancet 1988 1 1132 36 2896959 \n16. Delahoussaye PM Osborne BM Cat-scratch disease presenting as abdominal visceral granulomas J Infect Dis 1990 161 71 78 1688602 \n17. Fretzayas A Papadopoulos NG Moustaki M Unsuspected extralymphocutaneous dissemination in febrile cat-scratch disease Scand J Infect Dis 2001 33 599 603 11525355 \n18. Rolain JM Brouqui P Koehler JE Recommendations for treatment of human infections caused by Bartonella species Antimicrob Agents Chemother 2004 48 1921 33 15155180 \n19. Mohle-Boetani JC Koehler JE Berger TG Bacillary angiomatosis and bacillary peliosis in Patients infected with human immunodeficiency virus: Clinical characteristics in a case-control Study Clin Infect Dis 1996 22 794 800 8722933 \n20. Perkocha AL Geaghan MS Benedict Y Bacillary peliosis hepatis and HIV infection N Engl J Med 1990 323 1581 86 2233946 \n21. Le Joncour A Bidegain F Ziol M Hemophagocytic lymphohistiocytosis associated with Bartonella henselae infection in an HIV-infected patient Clin Infect Dis 2016 62 804 6 26646679 \n22. Poudel A Lew J Slayton W Dharnidharka VR Bartonella henselae infection inducing hemophagocytic lymphohistiocytosis in a kidney transplant recipient Pediatr Transplant 2014 18 E83 87 24829973 \n23. Tappero JW Perkins BA Wenger JD Berger TG Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus Clin Microbiol Rev 1995 8 440 50 7553576 \n24. Scott C Azwa A Cohen C Cat Scratch disease: A diagnostic conundrum Int J STD AIDS 2009 20 8 585 86 19625597 \n25. Vermeulen MJ Diederen BM Verbakel H Peeters MF Low sensitivity of Bartonella henselae PCR in serum samples of patients with cat-scratch disease lymphadenitis J Med Microbiol 2008 57 1049 50 18628513 \n26. Koehler JE Tappero JW Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus Clin Infect Dis 1993 17 612 24 8268340\n\n",
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"abstract": "IgG4-related disease (IgG4-RD) belongs to the group of rare diseases in which the identification of the characteristic histology and immunohistochemistry provides with the gold standard in the diagnosis. The variable organ dysfunction reflects the clinical presentation. The examples of different IgG4-RD presentations in the Rheumatology Unit were discussed in this article. The spectrum of IgG4-RD is wide-ranging and manifested in one or more organs synchronously or metachronously. In the presented article, we described five different cases of IgG4-RD. Four cases were reaffirmed in the histopathological assessment. The clinical and laboratory findings were analyzed and the assigned therapy was discussed. According to our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and variety of clinical forms of IgG4-RD shows that there is need of the cooperation among many specialists for the better and earlier recognition of the disease.",
"affiliations": "Department of Rheumatology and Internal Medicine, Wroclaw Medical Hospital, Borowska 213, 50-556, Wroclaw, Poland. [email protected].;Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical Hospital, Borowska 213, 50-556, Wroclaw, Poland.;Department of Rheumatology and Internal Medicine, Wroclaw Medical Hospital, Borowska 213, 50-556, Wroclaw, Poland.;Division of Pathomorphology and Clinical Cytology, Department of Pathomorphology, Wroclaw Medical University, Borowska 213, 50-556, Wroclaw, Poland.;Division of Pathomorphology and Clinical Cytology, Department of Pathomorphology, Wroclaw Medical University, Borowska 213, 50-556, Wroclaw, Poland.;Department of Rheumatology and Internal Medicine, Wroclaw Medical Hospital, Borowska 213, 50-556, Wroclaw, Poland.;Division of Pathomorphology and Clinical Cytology, Department of Pathomorphology, Wroclaw Medical University, Borowska 213, 50-556, Wroclaw, Poland.;Department of Rheumatology and Internal Medicine, Wroclaw Medical University, Borowska 213, 50-556, Wroclaw, Poland.",
"authors": "Sebastian|Agata|A|;Sebastian|Maciej|M|;Misterska-Skóra|Maria|M|;Donizy|Piotr|P|;Hałoń|Agnieszka|A|;Chlebicki|Arkadiusz|A|;Lipiński|Artur|A|;Wiland|Piotr|P|",
"chemical_list": "D005938:Glucocorticoids; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-017-3807-1",
"fulltext": "\n==== Front\nRheumatol IntRheumatol. IntRheumatology International0172-81721437-160XSpringer Berlin Heidelberg Berlin/Heidelberg 380710.1007/s00296-017-3807-1Cases with a MessageThe variety of clinical presentations in IgG4-related disease in Rheumatology Sebastian Agata +48 71 [email protected] 1Sebastian Maciej 2Misterska-Skóra Maria 1Donizy Piotr 3Hałoń Agnieszka 3Chlebicki Arkadiusz 1Lipiński Artur 3Wiland Piotr 41 Department of Rheumatology and Internal Medicine, Wroclaw Medical Hospital, Borowska 213, 50-556 Wroclaw, Poland 2 Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical Hospital, Borowska 213, 50-556 Wroclaw, Poland 3 0000 0001 1090 049Xgrid.4495.cDivision of Pathomorphology and Clinical Cytology, Department of Pathomorphology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland 4 0000 0001 1090 049Xgrid.4495.cDepartment of Rheumatology and Internal Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland 30 8 2017 30 8 2017 2018 38 2 303 309 22 4 2017 21 8 2017 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.IgG4-related disease (IgG4-RD) belongs to the group of rare diseases in which the identification of the characteristic histology and immunohistochemistry provides with the gold standard in the diagnosis. The variable organ dysfunction reflects the clinical presentation. The examples of different IgG4-RD presentations in the Rheumatology Unit were discussed in this article. The spectrum of IgG4-RD is wide-ranging and manifested in one or more organs synchronously or metachronously. In the presented article, we described five different cases of IgG4-RD. Four cases were reaffirmed in the histopathological assessment. The clinical and laboratory findings were analyzed and the assigned therapy was discussed. According to our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and variety of clinical forms of IgG4-RD shows that there is need of the cooperation among many specialists for the better and earlier recognition of the disease.\n\nKeywords\nIgG4TreatmentDifferential diagnosisPathologyissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2018\n==== Body\nIntroduction\nThe IgG4-related disease (IgG4-RD) is a chronic, inflammatory, multi-organ, systemic disease [1]. The name was first proposed by the Japanese investigators in 2010 [2], and the comprehensive diagnostic criteria for the IgG4‑RD were first determined and unified by Umehara et al. in 2011 [3]. The disease can affect many organs: most commonly the pancreas, liver, bile ducts, thyroid gland, aorta, retroperitoneum, lymph nodes, lacrimal glands, and occasionally the brain [4]. The variable organ dysfunction reflects the clinical presentation. Patients may be asymptomatic and only incidentally diagnosed at the physical examination or imaging. They may present a single or multiple organ involvement. The histopathological assessment is the diagnostic gold standard, hallmarked by the lymphoplasmacytic infiltrates of IgG4-plasma cells, the storiform fibrosis, tissue eosinophilia, and the obliterative phlebitis. Large epidemiologic studies are lacking. The exact frequency of IgG4-RD in Europe is still unknown. The prevalence of IgG4-RD in the Rheumatology Units is low, the diagnostic process is time-consuming, it may mimic other diseases and there is need for the specific histological assessment.\n\nThis article gives examples of different IgG4-RD presentations in the Rheumatology Unit in Eastern Europe.\n\nMaterials and methods\nThe patients were diagnosed with IgG4-RD in the Rheumatology and the Internal Medicine Department between 2014 and 2016. The data were collected retrospectively. The inclusion criteria were: age >18 years and the histopathological picture of IgG4-RD. The data included the time from the first symptoms to the establishment of IgG4-RD diagnosis, the age and gender of patients, the localization of lesions, histopathological biopsies, IgG4, IgG, and IgM concentration in blood samples, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values, C3 and C4 values treated with and the responsiveness to corticosteroids (CS), and the history of the atopic disease. Patients with the different IgG4-RD presentations were chosen to illustrate the complexity of IgG4-RD cases treated in the Rheumatology Unit. We performed the literature review following the methods specified by Gasparyan et al. [5]. The searches were conducted in the PubMed (part of the National Library of Medical Databases) and Cochrane Library. The search strategy was based on the publication since 2010. The key word included: IgG4 related disease or IgG4 or autoimmune pancreatitis or Mikulicz disease. Authors analyzed the review articles and case reports.\n\nResults\nFive cases of IgG4-RD were diagnosed. Four cases were reaffirmed in the histopathological assessment (Fig. 1). The main localization of IgG4-RD was the salivary glands (four cases). In two cases, the lacrimal gland enlargement was the first presentation of IgG4-RD (Fig. 2). In one case, it was the unilateral submandibular gland enlargement with the granulomatosis and polyangiitis (GPA) found in the biopsy. In case number four the pancreatitis was the first clinical presentation of IgG4-RD. The suspicion of IgG4-RD was made due to the increased IgG4 serum concentration, eosinophilia, concomitant parotid, the submandibular glands enlargement, peripheral lymphadenopathy, and the lack of specific antibodies, e.g., antinuclear antibodies. In case number five, the clinical presentation included the lacrimal enlargement, peripheral lymphadenopathy, and the clinical signs of ileus (Fig. 3). The characteristics of the clinical symptoms of the disease are demonstrated in Table 1 and Figs. 2, 3. None of the patients had the positive symptoms of dryness or the allergy history. Antinuclear antibodies (ANA) were positive only in case number one, but in a very low titer. The hypocomplementemia C3 and C4 were observed in case number three, where IgG4-RD and GPA were diagnosed. Three patients had the elevated blood IgG4 concentration, but not IgG fraction except case number three. In this case, the IgG4 fraction was not assessed because IgG4-RD was not suspected at the beginning of the diagnostic process. In the cases with the lacrimal gland enlargement, the IgM fraction in the serum was decreased. ESR and CRP concentrations were elevated in two patients. The laboratory findings of the patients with IgG4-RD are presented in Table 2. The therapy with CS was introduced in all the cases. In case number three, methotrexate was added due to the concomitant vasculitis. In case number five, mycophenolate mofetil was added due to the partial response to CS therapy and then changed into methotrexate due to leukopenia.Fig. 1 The lacrimal gland with the dense lymphoplasmacytic infiltration and advanced fibrosis, which are highly histologically suggestive for IgG4-related disease (a 200×, H&E staining). The inflammatory infiltration in the presented above lacrimal gland is predominantly consisted of the IgG4-positive plasma cells (b 200×, hematoxylin). Immunostaining for the IgG4 in the salivary gland in one high-power field (hpf), which is an accepted method for counting of the IgG4-positive plasma cells based on Deshpande et al. [6] (c 400×, hematoxylin). The increased number of IgG4-positive plasma cells in the salivary gland (d): 112 IgG4-positive plasma cells based on the detailed counting with Cell^D Program (Olympus, Poland)\n\n\nTable 1 Clinical characteristics of patients with IgG4-RD in rheumatology unit\n\nNumber of patient\t1\t2\t3\t4\t5\t\nAge (years)\t36\t43\t59\t42\t34\t\nGender\tFemale\tMale\tMale\tMale\tMale\t\nFirst manifestation\tLacrimal glands enlargement\tLacrimal glands enlargement\tUnilateral parotid gland enlargement\tPancreatitis\tIleus\t\nLocalization\tParotid and lacrimal glands\tParotid and lacrimal glands\tParotid glands, peripheral lymphadenopathy, mucosal ulcerations, weight lose\tParotid and submandibular glands, pancreas, (diabetes mellitus t2), peripheral lymphadenopathy\tIleus, lacrimal glands, lymphadenopathy\t\nProven in histopathology\tYes-lacrimal glands\tYes-lacrimal glands\tYes-salivary glands + GPA\tNo\tYes\t\nHistory of allergic diseases\tNo\tNo\tNo\tNo\tNo\t\nGlucocorticoid response\tYes\tYes\tYes + MTX 15 mg/w p.o.\tYes + AZA 100 mg/day\tPartial-(MMF leukopenia), MTX 15 mg/week\t\nTime to IgG4-RD diagnosis (months)\t132\t72\t4\t48\t17\t\n\nFig. 2 36-year-old female patient. The characteristic changes of IgG4-RD (a and b). It is the typical Mikulicz disease (MD) with the lacrimal glands enlargement and salivary glands enlargement which deformed normal features. The improvement after 3 weeks of the treatment with glucocorticoids (c and d)\n\n\nTable 2 Laboratory findings among patients with IgG4-RD\n\nNumber of patient\t1\t2\t3\t4\t5\t\nIgG4 in serum\n(n 0.11–1.57 g/l)\t3.77\t3.83\tNot done\t3.35\t0.54\t\nIgG in serum\n(n 7–16 g/l)\t10\t11.76\t48.14\t10.7\t6.1\t\nIgM in serum\n(n 0.4–2.3 g/l)\t0.25\t0.28\t0.76\t1.8\t0.68\t\nESR mm/hr\t39\t2\t86\t10\t8\t\nCRP\n(n 0–5 mg/l)\t19.1\t2.61\t14.6\t2\t2.35\t\nC3\n(n 0.9–1.8 g/l)\t1.93\t1.4\t0.57\t1.0\t0.65\t\nC4\n(n 0.1–0.4 g/l)\t0.76\t0.32\t0.08\t0.4\t0.18\t\nEosinophilia in blood\tNo\tNo\tNo\tYes\tNo\t\nANA dilution\t320 (specific-no)\tNo\tNo\tNo\tNegative\t\n\nGPA granulomatosis with polyangiitis, MTX methotrexate, AZA azathioprine, MMF mycophenolate mofetil, n normal value\n\n\nFig. 3 The lacrimal gland enlargement in the patient with the simultaneously diagnosed ileus pseudotumor\n\n\n\n\nDiscussion\nIgG4-RD belongs to the group of rare diseases. Three major histopathological features of IgG4-RD are: the lymphoplasmacytic infiltrates, storiform-type fibrosis of the irregularly whorled pattern resembling that of a straw mat, and the obliterative phlebitis. Sometimes the infiltration of eosinophils is observed in the affected tissues. Some lesions may be described as pseudotumors as in case number five with the first clinical presentation of ileus. Necrosis and granuloma are not found in IgG4-RD. When they are observed, the rheumatologists should think about the different diagnosis or alternative disease [6]. The diagnostic scheme of IgG4-RD includes the number of IgG4+ plasma cells in the affected tissue, and it depends on the localization and the type of biopsies (a needle biopsy or a surgical specimen) [6]. Important is that not all the histopathological features are observed in all the tissues and the histologically highly suggestive form of IgG4-RD or the probable features of IgG4-RD are distinguished [6]. The second step of the histopathological assessment is to determine the ratio of IgG4+ plasma cells to the general number of IgG cells, which should be more than 40%, except for the aorta where the ratio should be more than 50% [6]. The differential diagnosis includes lymphoma, tumor, vasculitis, and abscess and, therefore, the alternative diseases should be excluded at the beginning of the assessment. IgG4-RD may mimic the reactive lymphoid infiltrates and lymphoma, particularly MALT lymphoma. Both clinically and pathologically, IgG4-RD is manifested as the mass-forming lesion composed of the dense lymphoplasmacytic infiltrate [7–9]. IgG4-RD with the concomitant vasculitis, e.g., with GPA as in case number three, is rarely observed. In this patient, the clinical symptoms were more severe than in the other patients with the weight loss and mucosal ulcers in the nose and mouth.\n\nIn the non-biopsy-proven cases, e.g., the pancreas or brain localization, the measurement of the IgG4 concentration in blood samples is useful. Based on IgG4-RD definition, it should be elevated above 135 mg/dl [10] and it is observed in most patients. Nevertheless, 20–40% of the patients with IgG4-RD may have the IgG4 value in the normal ranges. On the other hand, the increased amount of IgG4 can be observed in different diseases: the primary Sjögren syndrome (7%), lupus erythematosus (10%), and rheumatoid arthritis, cancers and also in the healthy population (2%), but the criteria of IgG4-RD are fulfilled only by individuals [10, 11]. The IgG4 production depended on, among others, Il-10 and Il-6. Among 136 patients with the rheumatoid arthritis, the increased level of IgG4 in the serum was observed in 46% of patients and was correlated with the active disease [11].The elevated serum IgG4 levels were the most important laboratory features of IgG4-RD both in our and other publications [12, 13].The abnormal C3 and C4 complement levels were not observed in the presented cases, except the case with vasculitis, and they are not typical for IgG4-RD, but more frequently appear in other autoimmune disorders.\n\nIn one patient we observed eosinophilia, which occurs in one-third of the patients with IgG4-RD like the allergy history according to the recent publications [13]. Yu Chen et al. reported a higher frequency of allergic diseases (59%), but this was not correlated with the increased IgE serum concentration which was found in 83% of patients. In addition, the correlation between eosinophilia (33% of patients) and the allergy history was not observed [13]. The history of the atopic disease included, for example, the bronchial asthma, allergic rhinitis, nasal polyps, and atopic dermatitis [14]. In our group of patients, we did not observe this correlation between IgG4-RD symptoms and the history of allergic diseases. The IgE serum concentration was not measured because it was technically impossible.\n\nThe spectrum of IgG4-RD is wide-ranging, occurring in one or more organs synchronously or metachronously. Moreover, the patients with IgG4-RD usually do not have the constitutional symptoms, such as fever, malaise, night sweats, or the weight loss [15]. Malignancies were reported in 7.4% of patients with IgG4-RD [16].The extranodal marginal zone B cell lymphoma may occur in the ocular area, salivary glands or the meningeal dura up to 5 years after the diagnosis of IgG4-RD [17–19]. In our cohort, all of the patients had more than one organ involved. The most frequent localization was the head and neck area and the parotid glands. Two patients had the typical Mikulicz disease (MD) with the lacrimal gland enlargement. The orbital involvement in IgG4-RD is common and the orbit was the first extra pancreatic localization to be reported in the literature [20]. In the publication, MD was considered to be a subtype of IgG4-RD. In addition, it had a number of differences compared to the typical Sjögren syndrome, including not only the variety of the gender distribution (MD occurs in both men and women, while Sjögren syndrome occurs mainly in women) but the normal or mild salivary secretion dysfunction in MD [21]. The symptoms of dryness were not presented in our cohort and none of the patients met the criteria for the primary Sjögren syndrome (including the lack of the specific antibodies and normal salivary flow).\n\nBecause of the similarity to Sjögren syndrome (the lacrimal and salivary glands involvement, case numbers one to four), the diagnosis of the IgG4-RD was postponed for an average of 5 years (64 months). Generally, the clinical signs depended on the localization and organ damage caused by the main infiltration of IgG4 cells. They often formed pseudotumors as in patient number five. Nonetheless, the time for IgG4-RD diagnosis was 17 months late until the patient was admitted to the Rheumatology Unit. The shortest time for the diagnosis of IgG4-RD was in the patient with the unilateral parotid gland enlargement and the concomitant weight loss. The fast recognition of GPA caused the patient to be admitted to the Rheumatology Department. The first suspicion of lymphoma focused the diagnosis on tumor. In the presented paper, patients had been diagnosed by specialists in the general medicine, oncologists, surgeons, endocrinologists, specialists in the travel medicine, and hematologists before they were admitted to the Rheumatology Unit. In all the cases, the first diagnoses included the oncological diseases, e.g., the lacrimal lymphoma, salivary lymphoma, bowel tumor, lung cancer or hepatoma.\n\nIn the presented case series, the Type 1 (IgG4-related) autoimmune pancreatitis was observed in one patient. It is one of the most common disease manifestations that often devolves into the endocrine and exocrine insufficiency and may complicate the CS treatment. In the described patient, we started the therapy with CS in the recommended doses, despite the diabetes mellitus, with the good clinical response and improvement in the blood glucose level. In the case number four, the pancreatic biopsy was not performed because of the technical problem. In the diagnostic parameters, the IgG4 serum concentration, abdomen ultrasound, and the computed tomography were used, and the good clinical improvement after starting the CS treatment was observed. The diagnosis was ultimately made based on the classification criteria proposed by the Japanese Pancreas Society Revision in 2006 and Mayo Clinic [27–29].\n\nThe anti-nuclear antibodies were detected only in one case, but in a very low titer, without any specific antibodies, which is very typical for IgG4-RD compared to other autoimmune diseases. When the antibodies against the specific antigenes are present, the concomitant different disease is the most probable reason. The polyclonal hypergammaglobulinemia will not help in the diagnostic parameters; it is typical for Sjögren syndrome, but was often observed in IgG4-RD too [12].\n\nLymphadenopathy was very common in IgG4-RD patients, as in the paper of Chen [13], and occurred in most of the patients in the presented article.\n\nIn our series, the inflammatory markers ESR and CRP were elevated in two cases. The results were comparable with the other authors [12, 13, 22], who indicated that inflammatory factors did not play crucial role in IgG4-RD pathogenesis and its progression.\n\nIn the present study, all the patients were treated with the oral CS in the dose of prednisone of 0.6 mg/kg of the body weight/day. The response to this therapy was good, with the clinical and laboratory improvement. Nevertheless, in the previous publications, among the patients remaining on the long-term steroid therapy, the relapse was common after the cessation of CS [23]. Unfortunately, a large percentage of patients with this condition have the relative contraindications to the prolonged CS treatment, even in the moderate to low doses (for example, obesity, the glucose intolerance, hypertension, and osteoporosis) [24, 25]. Other therapies, such as radiation or the immunomodulating agents, are not well-described in the literature [26]. The paucity of data regarding the use of the disease-modifying anti-rheumatic drugs (DMARDs) provides with a little support for the use of these medications in the clinical practice, although they are often used in the hope of reducing the CS dependency. For this reason, DMARDs were added in patient numbers three, four, and five due to the partial responsiveness to the CS therapy. In one case (patient number five), who was treated with the mycophenolate mofetil, leukopenia was observed after 2 months of the treatment and the medication was changed into methotrexate. More recently, the B cell depletion has shown the evidence of the CS-sparing efficacy and has even been used as a monotherapy, with considerable success [24], but this therapy option is not commonly available in Eastern Europe.\n\nThere are some limitations of this study. First of all, there were a small number of patients enrolled only in one Rheumatology Unit. The time for the diagnosis of IgG4-RD was relatively long. In the presented cases, it was the mean of 5 years, suggesting that multicenter prospective study is needed to evaluate the clinical and laboratory features of IgG4-RD more broadly. Moreover, the benefits of the diagnostic methods in the diagnosis of IgG4-RD in the Rheumatology Units should be evaluated in a larger amount of patients. In our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and the variety of clinical forms of IgG4-RD confirmed that there is a need for the cooperation among many specialists for the better and earlier recognition of the disease.\n\nCompliance with ethical standards\nEthical approval\nFor this type of study a formal consent is not required.\n\nInformed consent\nThe additional informed consent was obtained from all the individual participants for whom the information identification is included in this article.\n\nConflict of interest\nAll authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1. Stone JH Khosroshahi A Deshpande V Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations Arthritis Rheumatol 2012 64 3061 3067 10.1002/art.34593 \n2. Takahashi H Yamamoto M Suzuki C The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity Autoimmun Rev 2010 9 591 594 10.1016/j.autrev.2010.05.003 20457280 \n3. Umehara H Okazaki K Masaki Y Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) Mod Rheumatol 2011 22 21 30 10.3109/s10165-011-0571-z \n4. Tanji H Okada H Igari R Inflammatory pseudotumor of the brain parenchyma with IgG4 Hypergammaglobulinemia Intern Med 2016 55 1911 1916 10.2169/internalmedicine.55.5854 27432102 \n5. Gasparyan AY Ayvazyan L Blackmore H Kitas GD Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors Rheumatol Int 2011 31 1409 1417 10.1007/s00296-011-1999-3 21800117 \n6. Deshpande V Zen Y Chan JK Consensus statement on the pathology of IgG4-related disease Mod Pathol 2012 25 181 192 10.1038/modpathol.2012.72 \n7. Karamchandani JR Younes SF Warnke RA IgG4-related systemic sclerosing disease of the ocular adnexa: a potential mimic of ocular lymphoma Am J Clin Pathol 2012 137 699 711 10.1309/AJCPE1G8DRHXRPIH 22523207 \n8. Lee FJ Varikatt W Kairaitis K IgG4-related dacryoadenitis Ophthalmology 2010 117 398 20141856 \n9. Ohta M Moriyama M Goto Y A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis World J Surg Oncol 2015 13 67 10.1186/s12957-015-0459-z 25889621 \n10. Mavragani CP Fragoulis GE Rontogianni D Elevated IgG4 serum levels among primary Sjögren’s syndrome patients: do they unmask underlying IgG4-related disease? Arthritis Care Res 2014 66 773 777 10.1002/acr.22216 \n11. Chen LF Mo YQ Ma JD Elevated serum IgG4 defines specific clinical phenotype of rheumatoid arthritis Med Inflamm 2014 \n12. Wallace ZS Deshpande V Mattoo H IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients Arthritis Rheumatol 2015 67 2466 2475 10.1002/art.39205 25988916 \n13. Chen Y Zhao JZ Feng RE Types of organ involvement in patients with immunoglobulin G4-related Disease Chin Med J 2016 129 1525 1532 10.4103/0366-6999.184459 27364787 \n14. Chen You Della Torre E Mattoo H Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease Allergy 2014 69 269 272 10.1111/all.12320 24266692 \n15. Yamamoto M Takahashi H Shinomura Y Mechanisms and assessment of IgG4- related disease: lessons for the rheumatologist Nat Rev Rheumatol 2014 10 148 159 10.1038/nrrheum.2013.183 24296677 \n16. Yamamoto M Yajima H Takahashi H Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: results from the SMART database Mod Rheumatol 2015 25 199 204 10.3109/14397595.2014.950036 25159154 \n17. Cheuk W Yuen HK Chan AC Ocular adnexal lymphoma associated with IgG4 + chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease Am J Surg Pathol 2008 32 1159 1167 10.1097/PAS.0b013e31816148ad 18580683 \n18. Oyama T Takizawa J Nakamura N Multifocal mucosa-associated lymphoid tissue lymphoma associated with IgG4-related disease: a case report J Ophthalmol 2011 55 304 306 \n19. Venkataraman G Rizzo KA Chavez JJ Marginal zone lymphomas involving meningeal dura: possible link to IgG4-related diseases Mod Pathol 2011 24 355 366 10.1038/modpathol.2010.206 21102421 \n20. Divatia M Kim SA Ro JY IgG4-related sclerosing disease, an emerging entity: a review of a multi-system disease Yonsei Med J 2012 53 15 34 10.3349/ymj.2012.53.1.15 22187229 \n21. Moriyama M Tanaka A Maehara T T helper subsets in Sjögren’s syndrome and IgG4-related dacryoadenitis and sialoadenitis: a critical review J Autoimmun 2014 51 81 88 10.1016/j.jaut.2013.07.007 23920005 \n22. Deshpande V Mattoo H Mahajan VS IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients Arthritis Rheumatol 2015 67 2466 2475 10.1002/art.39205 25988916 \n23. Matsushita M Ikeura T Fukui T Uchida K Refractory autoimmune pancreatitis: azathioprine or steroid pulse therapy? Am J Gastroenterol 2008 103 1834 1835 18691195 \n24. Perugino CA Stone JH Treatment of IgG4-related disease Z Rheumatol 2016 75 681 686 10.1007/s00393-016-0142-y 27431746 \n25. Peng T Hu Z Xie T IgG4-related disease: a case report with duration of more than 16 years and review of literature Springer Plus 2016 5 804 10.1186/s40064-016-2537-2 27390645 \n26. Lee CS Harocopos GJ Kraus CL IgG4-associated orbital and ocular inflammation J Ophthalmic Inflamm Infect 2015 5 15 10.1186/s12348-015-0047-y 26034515 \n27. Chari ST Smyrk TC Levy MJ Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience Clin Gastroenterol Hepatol 2006 4 1010 1016 10.1016/j.cgh.2006.05.017 16843735 \n28. Okazaki K Kawa S Kamisawa T Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal J Gastroenterol 2006 41 626 631 10.1007/s00535-006-1868-0 16932998 \n29. Chari ST Diagnosis of autoimmune pancreatitis using its five cardinal features: introducing the Mayo Clinic HISORt criteria J Gastroenterol 2007 42 39 41 10.1007/s00535-007-2046-8 17520222\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0172-8172",
"issue": "38(2)",
"journal": "Rheumatology international",
"keywords": "Differential diagnosis; IgG4; Pathology; Treatment",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000328:Adult; D001327:Autoimmune Diseases; D015551:Autoimmunity; D001706:Biopsy; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D042241:Early Diagnosis; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007074:Immunoglobulin G; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D011044:Poland; D011237:Predictive Value of Tests; D012074:Remission Induction; D012189:Retrospective Studies; D012219:Rheumatology; D016896:Treatment Outcome",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "303-309",
"pmc": null,
"pmid": "28856463",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27364787;25889621;22523207;25100215;21800117;18580683;20141856;17520222;27432102;18691195;16843735;22187229;21584726;24266692;22596100;21102421;24296677;25159154;22736240;27390645;20457280;25988916;27431746;16932998;23920005;22218969;26034515;25548435",
"title": "The variety of clinical presentations in IgG4-related disease in Rheumatology.",
"title_normalized": "the variety of clinical presentations in igg4 related disease in rheumatology"
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"abstract": "Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.",
"affiliations": "Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.;Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.;Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.;Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.;Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France.",
"authors": "Ghiringhelli|Francois|F|;Richard|Corentin|C|;Chevrier|Sandy|S|;Végran|Frédérique|F|;Boidot|Romain|R|",
"chemical_list": "D002272:Carcinoembryonic Antigen; D004268:DNA-Binding Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C448305:RAD51C protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C531550:olaparib",
"country": "United States",
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"doi": "10.3748/wjg.v22.i48.10680",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v22.i48.pg1068010.3748/wjg.v22.i48.10680Case ReportEfficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein Ghiringhelli Francois Richard Corentin Chevrier Sandy Végran Frédérique Boidot Romain Francois Ghiringhelli, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, FranceFrancois Ghiringhelli, Corentin Richard, Sandy Chevrier, Frédérique Végran, Romain Boidot, Platform of Transfer in Oncology, Center GF Leclerc, 21000 Dijon, FranceFrancois Ghiringhelli, Frederique Vegran, Romain Boidot, INSERM UMR866, 21000 Dijon, FranceFrancois Ghiringhelli, Corentin Richard, University of Bourgogne Franche Comte, 21000 Dijon, FranceAuthor contributions: Ghiringhelli F and Boidot R designed the report; Richard C, Chevrier S and Végran F performed the genetic analyses; Ghiringhelli F collected the patient’s clinical data; Ghiringhelli F and Boidot R analyzed the data and wrote the paper.\n\nCorrespondence to: Francois Ghiringhelli, MD, PhD, Professor, Department of Medical Oncology, Center GF Leclerc, 21000 Dijon, France. [email protected]\n\nTelephone: +33-380393371 Fax: +33-380393434\n\n28 12 2016 28 12 2016 22 48 10680 10686 7 7 2016 26 8 2016 28 9 2016 ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.2016This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.Precision medicine is defined by the administration of drugs based on the tumor’s particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.\n\nColorectal cancerExome analysisGenetic aberrationsHomologous repair deficiencyPrecision medicine\n==== Body\nCore tip: The role of genetic profiling in metastatic colorectal cancer for precision medicine is currently under investigation. This case report underlines for the first time, that olaparib may have some clinical efficiency in patients with homologous repair deficiency in colorectal tumor.\n\nINTRODUCTION\nColorectal cancer (CRC) is the third most common cancer worldwide with about 1 million new cases and over 500000 deaths every year[1]. Approximately 30% of patients with CRC develop an overt metastatic disease. Meanwhile, 40% to 50% of newly diagnosed patients already present a metastatic disease. For patients with non-operable metastatic CRC (mCRC), there are no curative options, but the use of palliative systemic chemotherapy dramatically enhances response rates, progression-free survival (PFS) and overall survival (OS)[2-4]. Currently, few drugs have demonstrated effectiveness in the treatment of metastatic colorectal disease and patients are treated based on the use of three cytotoxic chemotherapies: fluoropyrimidine, oxaliplatin and irinotecan, associated with targeted therapies [anti-EGFR (panitumumab and cetuximab) or anti-VEGF (bevacizumab) monoclonal antibodies].\n\nIn consequence, at the end of their treatment sequence, many patients still have a good performance status and would still be able to undergo treatment; unfortunately, we do not have any approved and efficient therapies to offer. Cancer cells are characterized by multiple genomic alterations. This finding has led to the development of molecularly targeted agents that inhibit mutated proteins. Such drugs are theoretically more specific for cancer cells bearing specific mutations. While such targeted agents have followed clinical development based on tumor location, most genetic molecular alterations exist across tumor types and histologies. This observation raises the possibility of shifting towards the administration of drugs based on molecular pattern rather than on histological status. Improvements in genetic sequencing have made possible the identification of multiple genomic molecular alterations in a timeframe compatible with clinical practice. Many retrospective and prospective trials have shown the usage and efficiency of off-label molecularly targeting agents. We report here the usage of exome testing in 2 patients with metastatic CRC and show for the first time that homologous repair deficiency could be targeted by poly ADP ribose polymerase (PARP) inhibitor in this pathology.\n\nSample preparation\nFormalin-fixed paraffin-embedded (FFPE) tumors were characterized by a pathologist to determine the tumor cell content and sent to the molecular biology platform for DNA extraction. Tumor cell content was 85% for Case 1 and 60% for Case 2. Seven 15-μm slices were extracted using the Maxwell 16 FFPE Plus LEV DNA purification kit (Promega) according to the manufacturer’s protocol. Corresponding normal DNA was extracted from 500 μL ethylenediaminetetraacetic acid blood samples with the Maxwell 16 Blood DNA Purification System (Promega) according to the manufacturer’s instructions. DNA quality was assessed by spectrophotometry with absorbance at 230, 260 and 280 nm. DNA was quantified using a fluorimetric assay with a Qubit device.\n\nTwo-hundred nanogram of genomic DNA from normal and cancer cells were fragmented with a Covaris device to obtain fragments around 180-200 bp. Then, libraries were constructed and captured by using SureSelect Human All Exon v5 kit (Agilent), following the manufacturer’s protocol. Paired-end (2 × 151 bases) sequencing was performed on a NextSeq500 device (Illumina). Obtained sequences were aligned and annotated with the human Hg19 genome based on the SureSelect Human All Exon v5 manifest by using Burrows-Wheeler Aligne (BWA) and Genome Analysis toolkit (GATK) algorithms. Only sequences with a read depth of 10 × and a mutation allele frequency superior to 5% were conserved for the analysis. The analysis is fostered on 137 clinically relevant genes related to biological pathways linked to cancer predisposition or available targeted therapies (Supplementary Table 1). Copy number variations were studied by using Control-FREEC software as described[5,6].\n\nCASE REPORT\nPatient 1\nA 58-year-old Caucasian male initially presented with abdominal pain. A CT scan, carried out in June 2011, revealed a metastatic sigmoid cancer with the following metastatic locations: mediastinal and lomboartic lymph nodes, lungs. A lymph node biopsy was performed and the diagnosis of wild-type KRAS, NRAS and BRAF, moderately differentiated Lieberkühn adenocarcinoma was made. From 2011 to 2015, the patient received different chemotherapeutic regimens. In July 2015, the patient’s lung metastases progressed and he started to show symptoms such as breathlessness and a permanent dry cough. As no approved chemotherapy or targeted therapy could be proposed, we performed somatic and constitutional exome analyses. We observed 479 somatic mutations. For clinical use, we analyzed a short list of 137 genes. It was interesting to see that among the 8 altered genes (Table 1), we observed a SMAD4 stop mutation, which is frequently found in CRC. An activating mutation of AKT1 was observed (Q79K). It could be targetable by protein kinase B (AKT)/mTor inhibitors. Surprisingly, we observed a constitutive Chek2 mutation (R117G), a gene involved in the homologous repair process. This mutation is cited in the public database for conferring a predisposition to cancer. Moreover, the analysis of copy number variation showed a loss of heterozygosity in chromosome 22 (from 29091114 to 29130709) (Figure 1A). This analysis suggested a complete deletion of Check2 function in tumor cells. After discussion of the case at the molecular tumor board, the patient was proposed to receive off-label PARP inhibitor olaparib which previously showed efficiency in patients with Chek2 mutation in metastatic prostate cancer[7]. One mo after beginning the therapy by PARP inhibitor, the patient declared reduction of cough and disappearance of breathlessness. After 3 mo we observed a reduction in carcinoembryonic antigen serum level (57 ng/mL to 25 ng/mL) and a tumor size reduction upon CT scan (Figure 2). No hematological toxicity was mentioned. Patient weight increased from 62 kg to 68 kg. However, despite this response, the patient died suddenly at home 4 mo after introduction of the therapy.\n\nTable 1 Alterations observed for Case 1 in the short list of clinically relevant genes\n\nGene\tNucleotide variation\tProtein variation\tOrigin\tImpact\t\nAKT1\tc.235C>A\tGln79Lys\tSomatic\tActivating\t\nCCNE1\tc.1022C>T\tThr341Met\tSomatic\tUnknown\t\nCHEK2\tc.478A>G\tArg117Gly\tConstitutive\tLikely pathogenic\t\nCUL2\tc.70C>T\tPro24Ser\tSomatic\tUnknown\t\nERCC6\tc.4179G>A\tMet1393Ile\tSomatic\tUnknown\t\nPMS2\tc.1531A>G\tThr511Ala\tConstitutive\tBenign\t\nSMAD4\tc.1091T>A\tLeu364X\tSomatic\tLoss of function\t\nSUFU\tc.1211T>C\tMet404Thr\tConstitutive\tUnknown\t\nFigure 1 Genetic data of targeted alterations. A: Patient 1 presented a T>C variation in the CHEK2 gene inducing a constitutive deleterious R117G mutation (left panel). At the chromosomal level, it appeared that chromosome 22 harbored a loss of heterozygosity inducing (right panel) a complete inactivation of CHEK2; B: Patient 2 presented a A>G variation in the RAD51C gene inducing a somatic loss of function T287A mutation (left panel). At the chromosomal level, it appeared that chromosome 17 harbored an important loss of heterozygosity at the RAD51C locus inducing a complete inactivation of RAD51C; C: Patient 2 also harbored an AG insertion resulting in a frameshift truncating mutation in the TP53BP1 gene.\n\nFigure 2 Computed tomography scan of patient 1 before and after 3 mo of olaparib (upper panel), and magnetic resonance imaging of liver metastasis of patient 2 before and after 3 mo of olaparib (lower panel).\n\nPatient 2\nA 49-year-old woman presented with rectal bleeding and diarrhea in March 2015. She underwent a colonoscopy with biopsies that revealed a KRAS mutated, well differentiated Lieberkühn rectal adenocarcinoma. The patient did not present any family history of CRC. The genetic testing did not show microsatellite instability. CT scan showed multiple, bilobar liver metastases. The patient was treated with FOLFIRINOX combination plus bevacizumab for 12 cycles. The CT scan showed major response in the liver and the rectum but no curative option could be proposed for the liver disease. Despite efficacy, the therapy had major toxicity with grade 3 peripheral neuropathy which precluded further usage of oxaliplatin. A therapeutic pause was proposed. The patient refused and asked for additional therapy. We performed somatic and constitutional exome analyses. We observed 905 somatic mutations. For clinical use, we analyzed a short list of 137 genes and interestingly, among the 13 altered genes (Table 2), we observed a potentially pathogenic APC mutation, which could predispose to CRC. Moreover, a KRAS activating mutation (G12D), commonly found in CRC, was observed. What was even more interesting is that we observed a somatic mutation of the homologous repair in RAD51C (T287A) previously reported to be associated with a loss of function[8]. Analysis of copy number variable showed a loss of heterozygosity in chromosome 17 from 56770004 to 56801461 (Figure 1B). This analysis suggested a complete deletion of RAD51C function in tumor cells. After discussion of the case at the molecular tumor board, the patient was proposed to receive off-label PARP inhibitor olaparib which previously showed efficacy in patients with RAD51 mutation in metastatic prostate cancer[7]. The patient received 3 mo of olaparib therapy without toxicity. Despite the absence of toxicity, the magnetic resonance imaging (Figure 2) showed tumor progression. Olaparib was stopped and the patient was included in a phase I clinical trial.\n\nTable 2 Alterations observed for Case 2 in the short list of clinically relevant genes\n\nGene\tNucleotide variation\tProtein variation\tOrigin\tImpact\t\nAPC\tc.3949G>C\tGlu1317Gln\tConstitutive\tPotentially Pathogenic\t\nBRCA1\tc.5180G>C\tGly1727Ala\tSomatic\tUnknown\t\nBRCA1\tc.3119G>A\tSer1040Asn\tConstitutive\tSNP\t\nBRCA1\tc.2521C>T\tArg841Trp\tSomatic\tNeutral\t\nFGFR4\tc.1676G>A\tArg559Gln\tSomatic\tUnknown\t\nGLI2\tc.1418G>A\tArg473His\tConstitutive\tUnknown\t\nJAK2\tc.195A>C\tGlu65Asp\tConstitutive\tUnknown\t\nJAK3\tc.2164G>A\tVal722Ile\tConstitutive\tActivating\t\nKDR\tc.2159G>A\tArg720Gln\tSomatic\tUnknown\t\nKRAS\tc.35G>A\tGly12Asp\tSomatic\tActivating\t\nMET\tc.2572G>A\tVal858Met\tConstitutive\tUnknown\t\nRAD51C\tc.859A>G\tThr287Ala\tSomatic\tLoss of function\t\nSLC28A1\tc.568G>T\tAla190Ser\tConstitutive\tSNP\t\nSLC28A1\tc.1152delG\tVal385Ser fsX16\tConstitutive\tLoss of function\t\nTHRA\tc.454C>T\tArg152X\tSomatic\tLoss of function\t\nUIMC1\tc.43C>T\tArg15Trp\tConstitutive\tUnknown\t\nSNP: Single nucleotide polymorphism.\n\nAs loss of TP53BP1 was previously described to be involved in PARP inhibitor resistance in homologous repair deficient breast cancer models in mice[9], we searched for the mutation of this gene in both patients. While patient 1 had a wild-type TP53PB1 gene, patient 2 had a frameshift truncating insertion in TP53BP1 (AG insertion at chromosomal position 17:43766919) (Figure 1C), thus suggesting a loss of function of the protein.\n\nDISCUSSION\nThe use of exome sequencing in cancer has largely taken place in the setting of research studies, such as The Cancer Genome Atlas. However, integration of exome sequencing into precision cancer care remains a challenging issue because samples issued from formalin-fixed tissues (i.e., FFPE) are difficult to analyze (due to small size and poor quality). Furthermore, bioinformatics approaches require detection of the wide-spectrum of mutations with the capacity to identify actionable mutations at an acceptable sensitivity and it remains an issue. This case report is the first to suggest efficacy of olaparib in CRC with homologous repair deficiency and to demonstrate that exome sequencing could be used to help drug repositioning. Accordingly, single-agent olaparib as well as combinations with irinotecan were previously tested in unselected CRC that is resistant to standard therapy without any clinical efficacy[10,11]. Such data raises the hypothesis that olaparib activity also requires molecular testing of homologous repair deficiency for CRC as requested for ovarian cancer.\n\nHomologous repair is an enzymatic complex aimed at repairing DNA double-strand breaks. CHEK2 and RAD51 play a central role in the repair of DNA double-strand breaks performed by homologous repair[12]. After the detection of DNA double-strand breaks by ATM and CHEK2, BRCA1 is phosphorylated by these proteins. Rad52 binds recombinase polymerase amplification and displaces it to allow Rad51 binding. BRCA2 binds to Rad51 until BRCA2 becomes phosphorylated, releasing Rad51 and allowing it to localize to the double strand break with Rad52. Homologous repair-mediated repair goes on; Rad51 then forms a nucleoprotein filament that invades a homologous sequence and activates strand exchange to generate a crossover between the juxtaposed DNA[13]. Several studies have shown that the level of RAD51 protein expression is elevated in immortalized cells as well as in a wide variety of human cancer cell lines[14,15]. It is generally suggested that RAD51 overexpression results in an increased cellular resistance to radiation and some chemotherapeutic drugs, such as topoisomerase inhibitors or crosslinking agents[15-17]. In CRC, high expression of RAD51 is associated with poor prognosis[18]. Several in vitro studies have shown that an increase in RAD51 expression stimulates homologous repair, resulting in greater cellular resistance to treatment with crosslinking agents, etoposide or irradiation[15-17]. High numbers of RAD51 foci in tumor biopsies were also positively associated with greater chemoresistance in breast cancer patients[19]. Chek2 is also involved in the colorectal oncogenesis and protein truncating mutations in CHEK2 have been reported to confer higher risks of cancer of the breast and the prostate but also CRC[20].\n\nBiallelic invalidation of homologous repair enzymes are still described to be a predictive marker of response to PARP inhibitor like olaparib in different diseases such as breast, ovarian and prostate cancer[7,21-23]. Our report is the first one that researched biallelic deficiency of homologous repair enzyme in metastatic CRC patients and underlines that such events could also occur in this pathology and could be targeted.\n\nResistance to PARP inhibitors is a key question and determining a predictive biomarker is important for the future design of clinical trials. Three mechanisms of resistance have been described: restoration of BRCA function by additional mutations[24-26], increased Mdr1 gene expression[27] or loss of TP53BP1[9]. Interestingly, TP53BP1 loss also induces resistance to the topoisomerase I inhibitor while tumor cells remain sensitive to DNA crosslinking agents like platinum, may thus explain the good response to FOLFIRINOX.\n\nTo conclude, we believe that this case report supports that large genetic characterization of metastatic CRC patients could be useful to find molecular hits that could be targeted by off-label targeted therapy. PARP inhibitors could be particularly useful is this context. Nevertheless, biallelic deficiency of homologous repair enzyme is a prerequisite to benefit from a PARP inhibitor therapy, but is not always associated to a PARP inhibitor response. Additional resistance pathways like TP53BP1 loss must be determined before prescribing PARP inhibitors.\n\nCOMMENTS\nCase characteristics\nTwo case of multitreated metastatic colorectal cancer patients that benefit from genetic testing.\n\nClinical diagnosis\nmetastatic colorectal cancer.\n\nLaboratory diagnosis\nWhole exome sequencing revealed inactivating mutation in the homologous repair gene with genetic deficiency in RAD51C or Check2.\n\nTreatment\nPatients were treated with the poly ADP ribose polymerase inhibitor olaparib.\n\nExperiences and lessons\nOne out the 2 patients gained clinical benefit from olaparib usage, thus suggesting that genetic testing could also be used in colorectal cancer to predict response to olaparib.\n\nPeer-review\nThis case report highlighting the importance of the exome sequencing analysis before administering targeted therapy.\n\nManuscript source: Invited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: France\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInstitutional review board statement: This study was approved by the local institutional review board.\n\nInformed consent statement: Patients gave their written consent to authorize genetic analyses.\n\nConflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.\n\nPeer-review started: July 11, 2016\n\nFirst decision: August 22, 2016\n\nArticle in press: September 28, 2016\n\nP- Reviewer: Lakatos PL, Matsuda A, Meshikhes AW S- Editor: Gong ZM L- Editor: Filipodia E- Editor: Liu WX\n==== Refs\n1 Parkin DM Bray F Ferlay J Pisani P Global cancer statistics, 2002 CA Cancer J Clin 2005 55 74 108 15761078 \n2 Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T, EORTC Gastro-Intestinal Tract Cancer Group, Cancer Research UK, Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO), Australasian Gastro-Intestinal Trials Group (AGITG), Fédération Francophone de Cancérologie Digestive (FFCD) Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial Lancet 2008 371 1007 1016 18358928 \n3 Van den Eynde M Hendlisz A Treatment of colorectal liver metastases: a review Rev Recent Clin Trials 2009 4 56 62 19149763 \n4 Douillard JY Cunningham D Roth AD Navarro M James RD Karasek P Jandik P Iveson T Carmichael J Alakl M Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial Lancet 2000 355 1041 1047 10744089 \n5 Boeva V 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recombination protein in tumor cells Cancer Res 2002 62 219 225 11782381 \n15 Hansen LT Lundin C Spang-Thomsen M Petersen LN Helleday T The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer Int J Cancer 2003 105 472 479 12712436 \n16 Slupianek A Hoser G Majsterek I Bronisz A Malecki M Blasiak J Fishel R Skorski T Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis Mol Cell Biol 2002 22 4189 4201 12024032 \n17 Vispé S Cazaux C Lesca C Defais M Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation Nucleic Acids Res 1998 26 2859 2864 9611228 \n18 Tennstedt P Fresow R Simon R Marx A Terracciano L Petersen C Sauter G Dikomey E Borgmann K RAD51 overexpression is a negative prognostic marker for colorectal adenocarcinoma Int J Cancer 2013 132 2118 2126 23065657 \n19 Asakawa H Koizumi H Koike A Takahashi M Wu W Iwase H Fukuda M Ohta T Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins Breast Cancer Res 2010 12 R17 20205718 \n20 Cybulski C Wokołorczyk D Kładny J Kurzawski G Suchy J Grabowska E Gronwald J Huzarski T Byrski T Górski B Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations? Eur J Hum Genet 2007 15 237 241 17106448 \n21 Lee JM Hays JL Annunziata CM Noonan AM Minasian L Zujewski JA Yu M Gordon N Ji J Sissung TM Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses J Natl Cancer Inst 2014 106 dju089 24842883 \n22 Oza AM Cibula D Benzaquen AO Poole C Mathijssen RH Sonke GS Colombo N Špaček J Vuylsteke P Hirte H Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial Lancet Oncol 2015 16 87 97 25481791 \n23 Kaufman B Shapira-Frommer R Schmutzler RK Audeh MW Friedlander M Balmaña J Mitchell G Fried G Stemmer SM Hubert A Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation J Clin Oncol 2015 33 244 250 25366685 \n24 Edwards SL Brough R Lord CJ Natrajan R Vatcheva R Levine DA Boyd J Reis-Filho JS Ashworth A Resistance to therapy caused by intragenic deletion in BRCA2 Nature 2008 451 1111 1115 18264088 \n25 Sakai W Swisher EM Karlan BY Agarwal MK Higgins J Friedman C Villegas E Jacquemont C Farrugia DJ Couch FJ Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers Nature 2008 451 1116 1120 18264087 \n26 Swisher EM Sakai W Karlan BY Wurz K Urban N Taniguchi T Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance Cancer Res 2008 68 2581 2586 18413725 \n27 Rottenberg S Jaspers JE Kersbergen A van der Burg E Nygren AO Zander SA Derksen PW de Bruin M Zevenhoven J Lau A High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs Proc Natl Acad Sci USA 2008 105 17079 17084 18971340\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1007-9327",
"issue": "22(48)",
"journal": "World journal of gastroenterology",
"keywords": "Colorectal cancer; Exome analysis; Genetic aberrations; Homologous repair deficiency; Precision medicine",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D015746:Abdominal Pain; D000230:Adenocarcinoma; D001706:Biopsy; D002272:Carcinoembryonic Antigen; D064447:Checkpoint Kinase 2; D002892:Chromosomes, Human, Pair 22; D015179:Colorectal Neoplasms; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D059472:Exome; D005260:Female; D006471:Gastrointestinal Hemorrhage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D056687:Off-Label Use; D010523:Peripheral Nervous System Diseases; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D057285:Precision Medicine; D012007:Rectum; D016896:Treatment Outcome; D000071857:Tumor Suppressor p53-Binding Protein 1",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "10680-10686",
"pmc": null,
"pmid": "28082821",
"pubdate": "2016-12-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20400964;22155870;17106448;18413725;15761078;26786262;27075016;21081509;18358928;20205718;11782381;12024032;23065657;18264087;18264088;19149763;25366685;9611228;9450758;12712436;25481791;10744089;26510020;24842883;12778123;18971340;23103855",
"title": "Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein.",
"title_normalized": "efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein"
}
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"abstract": "Coronavirus disease 2019 (COVID-19) may result in a life-threatening condition due to a hyperactive immune reaction to severe acute respiratory syndrome-coronavirus-2 infection, for which no effective treatment is available. Based on the potent immunomodulatory properties of mesenchymal stromal cells (MSCs), a growing number of trials are ongoing. This prompted us to carry out a thorough immunological study in a patient treated with umbilical cord-derived MSCs and admitted to the Intensive Care Unit for COVID-19-related pneumonia. The exploratory analyses were assessed on both peripheral blood and bronchoalveolar fluid lavage samples at baseline and after cellular infusion by means of single-cell RNA sequencing, flow cytometry, ELISA, and functional assays. Remarkably, a normalization of circulating T lymphocytes count paralleled by a reduction of inflammatory myeloid cells, and a decrease in serum levels of pro-inflammatory cytokines, mostly of interleukin-6 and tumor necrosis factor-α, were observed. In addition, a drop of plasma levels of those chemokines essential for neutrophil recruitment became evident that paralleled the decrease of lung-infiltrating inflammatory neutrophils. Finally, circulating monocytes and low-density gradient neutrophils acquired immunosuppressive function. This scenario was accompanied by an amelioration of respiratory, renal, inflammatory, and pro-thrombotic indexes. Our results provide the first immunological data possibly related to the use of umbilical cord-derived MSCs in severe COVID-19 context.",
"affiliations": "Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. [email protected].;Microbiology Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 \"Berica\", Vicenza, Italy.;Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 \"Berica\", Vicenza, Italy.;Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 \"Berica\", Vicenza, Italy.;Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 \"Berica\", Vicenza, Italy.;Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 \"Berica\", Vicenza, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.;Nuclear Medicine Unit, San Bortolo Hospital, A.U.L.S.S. 8 \"Berica\", Vicenza, Italy.;Microbiology Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.;Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 \"Berica\", Vicenza, Italy.;Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, A.O.U.I. Ospedale Maggiore & University of Verona, Verona, Italy.;Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.",
"authors": "Ciccocioppo|Rachele|R|0000-0002-6297-7576;Gibellini|Davide|D|;Astori|Giuseppe|G|;Bernardi|Martina|M|;Bozza|Angela|A|;Chieregato|Katia|K|;Elice|Francesca|F|;Ugel|Stefano|S|;Caligola|Simone|S|;De Sanctis|Francesco|F|;Canè|Stefania|S|;Fiore|Alessandra|A|;Trovato|Rosalinda|R|;Vella|Antonio|A|;Petrova|Varvara|V|;Amodeo|Giuseppe|G|;Santimaria|Monica|M|;Mazzariol|Annarita|A|;Frulloni|Luca|L|;Ruggeri|Marco|M|;Polati|Enrico|E|;Bronte|Vincenzo|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13287-021-02376-9",
"fulltext": "\n==== Front\nStem Cell Res Ther\nStem Cell Res Ther\nStem Cell Research & Therapy\n1757-6512\nBioMed Central London\n\n2376\n10.1186/s13287-021-02376-9\nShort Report\nThe immune modulatory effects of umbilical cord-derived mesenchymal stromal cells in severe COVID-19 pneumonia\nhttp://orcid.org/0000-0002-6297-7576\nCiccocioppo Rachele [email protected]\n\n1\nGibellini Davide 2\nAstori Giuseppe 3\nBernardi Martina 3\nBozza Angela 3\nChieregato Katia 3\nElice Francesca 4\nUgel Stefano 5\nCaligola Simone 5\nDe Sanctis Francesco 5\nCanè Stefania 5\nFiore Alessandra 5\nTrovato Rosalinda 5\nVella Antonio 5\nPetrova Varvara 5\nAmodeo Giuseppe 1\nSantimaria Monica 6\nMazzariol Annarita 2\nFrulloni Luca 1\nRuggeri Marco 4\nPolati Enrico 7\nBronte Vincenzo 5\n1 grid.5611.3 0000 0004 1763 1124 Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy\n2 grid.5611.3 0000 0004 1763 1124 Microbiology Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy\n3 grid.416303.3 0000 0004 1758 2035 Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 “Berica”, Vicenza, Italy\n4 grid.416303.3 0000 0004 1758 2035 Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 “Berica”, Vicenza, Italy\n5 grid.5611.3 0000 0004 1763 1124 Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy\n6 grid.416303.3 0000 0004 1758 2035 Nuclear Medicine Unit, San Bortolo Hospital, A.U.L.S.S. 8 “Berica”, Vicenza, Italy\n7 grid.411475.2 0000 0004 1756 948X Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, A.O.U.I. Ospedale Maggiore & University of Verona, Verona, Italy\n2 6 2021\n2 6 2021\n2021\n12 31627 11 2020\n9 5 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nCoronavirus disease 2019 (COVID-19) may result in a life-threatening condition due to a hyperactive immune reaction to severe acute respiratory syndrome-coronavirus-2 infection, for which no effective treatment is available. Based on the potent immunomodulatory properties of mesenchymal stromal cells (MSCs), a growing number of trials are ongoing. This prompted us to carry out a thorough immunological study in a patient treated with umbilical cord-derived MSCs and admitted to the Intensive Care Unit for COVID-19-related pneumonia. The exploratory analyses were assessed on both peripheral blood and bronchoalveolar fluid lavage samples at baseline and after cellular infusion by means of single-cell RNA sequencing, flow cytometry, ELISA, and functional assays. Remarkably, a normalization of circulating T lymphocytes count paralleled by a reduction of inflammatory myeloid cells, and a decrease in serum levels of pro-inflammatory cytokines, mostly of interleukin-6 and tumor necrosis factor-α, were observed. In addition, a drop of plasma levels of those chemokines essential for neutrophil recruitment became evident that paralleled the decrease of lung-infiltrating inflammatory neutrophils. Finally, circulating monocytes and low-density gradient neutrophils acquired immunosuppressive function. This scenario was accompanied by an amelioration of respiratory, renal, inflammatory, and pro-thrombotic indexes. Our results provide the first immunological data possibly related to the use of umbilical cord-derived MSCs in severe COVID-19 context.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s13287-021-02376-9.\n\nKeywords\n\nCOVID-19\nCytokines\nInflammatory response\nMesenchymal stromal cells\nScRNA-seq\nhttp://dx.doi.org/10.13039/501100006747 Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona ENACT Bronte Vincenzo issue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nIn a variable proportion of cases, severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 infection triggers a hyperacute inflammatory response that may ultimately lead to respiratory and multiorgan failure [1]. The immunological hallmarks comprise lymphopenia [2] and a flurry of active molecules which gives rise to the so-called “cytokine storm” [3], largely dominated by interleukin (IL)-6 and tumor necrosis factor (TNF)-α [4]. This causes disruption of both epithelial and endothelial barriers that magnifies inflammation and hampers gas exchange [5]. Despite there currently being a number of therapeutic approaches under investigation [6], none have substantially changed patients’ outcome. Following the results of early studies carried out in China showing the safety of applying mesenchymal stromal cells (MSCs) in patients with moderate to severe COVID-19-related pneumonia [7, 8], we offered this option to a patient admitted to the Intensive Care Unit for COVID-19 respiratory failure and unresponsive to current therapy. The rationale of this option lies on the evidence of a powerful and multifaceted action of MSCs on virtually all cell populations involved in inflammatory cascade [9]. Noteworthy, MSCs have also proven of benefit in experimental studies on acute respiratory distress syndrome [10], while the safety of this treatment option has been shown in a phase 2a trial carried out in this clinical setting [11]. Although these findings point to a potential role of MSCs even in COVID-19, no information is available on their immunological effects in this specific clinical setting. Therefore, we carried out an in-depth immune profiling at both bronchoalveolar and circulating levels to move the first step towards the understanding of their therapeutic effects in this dismal condition.\n\nMethods\n\nMesenchymal stromal cell administration\n\nThe advanced cell therapy medicinal product was supplied by the Laboratory for Advanced Cellular Therapies (Vicenza, Italy) in two bags as frozen, sterile, apyrogenic umbilical cord-derived MSC suspension (see Supplementary material). Upon receiving, the bags were thawed in succession under sterile conditions, diluted 1:1 (50 ml final) in a solution consisting of 38% saline, 10% human albumin, and 12% anticoagulant citrate dextrose solution (Terumo; Rome, Italy), connected to an infusion set, delivered to the Intensive Care Unit and then infused intravenously in 30 min each (Fig. 1a). The final dosage was of 1.1 × 106 cells/per kg body weight, in accordance with that used either in an early study on COVID-19 patients [7], or in further immune-mediated conditions, such as graft-versus-host disease [12, 13], and on personal experience [14, 15]. The patient was a 69-year-old Caucasian man who had been admitted to the Intensive Care Unit (A.O.U.I. Ospedale Maggiore; Verona, Italy) 2 weeks earlier for respiratory failure due to diagnosis of COVID-19 (see Supplementary material) pneumonia. The lack of amelioration upon a course of anti-viral agents (lopinavir-ritonavir) plus hydroxychloroquine and steroids, together with antiaggregant/coagulant therapy, vasoactive agents and nine rounds of prono-supination, and the failure at the screening assessment for further experimental therapies led us to offer him MSC infusion under the Hospital Exemption rule (art. 28 European Regulation 1394/2007), after approval by both the local Ethics Committee (no. 19464) and the Italian Drug Agency (no. 163516409) was obtained, and upon both the consent to participate and for publication were obtained by a relative since the patient was under pharmacological coma. The immunological analyses were performed on both bronchoalveolar lavage fluid (BALF) and peripheral blood samples before and after MSC infusion (Fig. 1a). Specifically, we decided to split the analyses using two different timeframes by considering that cytokines display a short life-span (estimated of hours), while circulating cell composition and myeloid cell function require a shift on myelopoiesis that need longer times (estimated of days). In parallel, a number of clinical and laboratory parameters were also assessed. Fig. 1 Study plan, serological and bronchoalveolar lavage fluid immune features. a Schematic representation of MSC administration and samples processing. b Plasma levels of anti-SARS-CoV-2 immunoglobulins at different time points (days 0, + 2, and + 8 after MSC infusion). c UMAP visualization of the six main cell types identified in the BALF by integrating the datasets of the days 0 and + 2 after MSC infusion. Dot plot graph shows the marker genes used to manually annotate each UMAP-associated cluster. Epithelial cells were discarded from further analyses. d Cell type frequencies in the days of observation. e The clustering of the BALF-derived neutrophils into five subgroups: S100+ neutrophils, CCL3+ neutrophils, IFN-activated neutrophils, IRAK3+ neutrophils, and HSP+ neutrophils. Dot plot graph shows the top five expressed genes by average log fold-change of each neutrophil sub-cluster. f The change in the proportion of each neutrophil sub-cluster in the days of observation. In b, d, and f, the red arrow indicates the time points in which MSC infusion was performed. For comments, see the text. BALF, bronchoalveolar lavage fluid; COVID, coronavirus disease; IFN, interferon; Ig, immunoglobulin; MSC, mesenchymal stromal cell; NK, natural killer; SARS-CoV, severe acute respiratory syndrome-coronavirus; scRNA-seq, single-cell RNA sequencing; UMAP, Uniform Manifold Approximation and Projection\n\nSingle-cell RNA sequencing\n\nAfter isolation of immune cells from both BALF and peripheral blood samples (see Supplementary material) at baseline and after 2 days from MSC infusion, the single-cell RNA sequencing was carried out on 12,000 cells after reverse transcription, cDNA amplification, and library construction were performed (see Supplementary material). Sequencing, alignment, barcode processing, and unique molecular identifier quantification were then assessed after checking the sample quality. Following integration and normalization of collected data [16], the clustering analysis was built up and the Wilcoxon rank-sum test was used for computing the statistically significant difference (see Supplementary material). Analysis was performed at baseline and after 2 days from MSC infusion.\n\nFlow cytometry\n\nPeripheral blood cell immunophenotyping was performed at baseline and 8 days after MSC infusion according to a standard no-wash procedure, using a PrepPlus™ 2 workstation (Beckman Coulter Inc.; Brea, CA, USA) by incubating the samples for 15 min at 20 °C with a panel of antibodies (all by Beckman Coulter Inc.) as listed in Supplementary material. Cytofluorimetric characterization of circulating immune cells was performed at baseline and after 8 days from MSC infusion.\n\nDetection of cytokines and serology\n\nThe following cytokines: IL-1β, IL-1RA, IL-2, IL-6, IL-8, IL-10, IL-15, interferon (IFN)-γ, TNF-α, vascular endothelial growth factor-A, and chemokines/ligands, CCL2, CCL3, CCL5, CXCL10, and CXCL12, were detected and quantified in the patient’s serum at baseline and after 2 days from MSC infusion by using the Human ProcartaPlex™ Panel 1 multiplex kit (Thermo Fisher Scientific; Waltham, MA, USA). Cytokine serum levels were detected at baseline and after 2 days from MSC infusion.\n\nThe ELISA assay to detect immunoglobulins (Ig) used fragment of the SARS-CoV2 spike glycoprotein (S-protein) as recently published [17].\n\nFunctional assay\n\nUpon Ficoll-Hypaque (GE Healthcare; Uppsala, Sweden) gradient centrifugation of peripheral blood samples harvested at baseline and 8 days after MSC infusion, monocytes and low-density gradient neutrophils (LDNs) were isolated by using CD14-microbeads (Miltenyi Biotec; Bergisch Gladbach, DE), and the sequential addition of CD66b-FITC antibody (BD Biosciences; NJ, USA) and microbeads anti-FITC (Miltenyi), respectively, following the manufacturers’ instructions. The purity of each fraction was evaluated at flow cytometry and a minimum cutoff of 95% was needed to perform the immunosuppressive assay [18]. A sample of 2 × 106 cells of each cell type was seeded in 24-well plates for 12 h; afterwards, both the supernatants and cells were collected and cultured with CellTrace (Thermo Fisher Scientific; Waltham, MA, USA). Labeled cells were then stimulated with coated anti-CD3 (OKT-3) and soluble anti-CD28 for 4 days at 37 °C in 8% CO2. For the co-cultures, a 3:1 (target to effector) ratio was used. Cells were finally stained with anti-CD3-PE/Cy7 and CellTrace signal was analyzed with FlowJo software (Tree Star, Inc., Ashland). This analysis was performed at baseline and after 8 days from infusion.\n\nResults\n\nClinical findings\n\nAlthough SARS-CoV-2 N gene was detected in BALF samples at very high cycle threshold throughout the observational period, an improvement of the inflammatory, respiratory, thrombotic, and renal parameters was observed after 2 and 8 days after MSC infusion (Table 1). No adverse events occurred during the same time frame. In addition, neither the serum level of class A and G immunoglobulins specific for the receptor-binding domain of the SARS-CoV-2 spike protein nor that of class G antibodies recognizing the nucleocapsid phosphoprotein of the virus underwent modification (Fig. 1b). Table 1 Clinical parameters\n\n\tDay 0\tDay + 2\tDay + 8\t\nSOFA score\t4\t3\t3\t\nCreatinine\t2.27\t0.99\t0.90\t\nHCO3−\t28.7\t32.9\t41.4\t\nD-Dimer\t3.83\t2.68\t1.32\t\nProthrombin time\t1.18\t1.09\t0.96\t\nP/F\t168\t136\t114\t\nFiO2\t0.50\t0.50\t0.70\t\npH\t7.31\t7.34\t7.38\t\nBase excess\t1.70\t5.90\t14.2\t\nWhite blood cells\t11.19\t10.14\t8.62\t\nNeutrophils\t9.29\t8.28\t6.59\t\nLymphocytes\t1.01\t1.11\t1.21\t\nMonocytes\t0.37\t0.44\t0.40\t\nBasophils\t0.06\t0.05\t0.04\t\nEosinophils\t0.46\t0.26\t0.38\t\nRed blood cells\t4.16\t4.13\t3.91\t\nPlatelet\t365\t327\t287\t\nC-reactive protein\t201\t139\t61\t\nSOFA Sequential Organ Failure Score, P/F oxygen partial pressure/oxygen inspiratory flow, FiO2 oxygen inspiratory flow\n\nNormal values: creatinine, 0.49–1.19 mg/dL; HCO3−, 24–28 mmol/L; D-Dimer, < 0.25 mg/L; prothrombin time, 0.8–1.17 INR%; P/F, > 300 mmHg; FiO2, > 21%; pH, 7.35–7.45; base excess, − 2 to + 2 mmol/L; white blood count, 4.30–10 × 109/L; neutrophils, 1.80–8 × 109/L; lymphocytes, 1.20–4 × 109/L; monocytes, 0.20–1 × 109/L; basophils, < 0.20 × 109/L; eosinophils, < 0.45 × 109/L; red blood count, 4.00–5.20 × 1012/L; platelet, 150–450 × 109/L; C-reactive protein, < 5 mg/L\n\nNotably, at baseline, the patient was in respiratory acidosis (pH, 7.31; PCO2, 57 mmHg; BE, 1.70; HCO3−, 28.7 mmol/L), partially compensated by metabolic alkalosis on the second day (pH, 7.34; PCO2, 61 mmHg; BE, 5.9; HCO3−, 32.9 mmol/L). Then, the patient underwent continuous infusion of furosemide which led to a mixed clinical picture of metabolic alkalosis and respiratory acidosis, as exemplified by parameters of day 8 (pH, 7.38; PCO2, 70 mmHg; BE, 14.2; HCO3−, 41.4 mmol/L).\n\nSingle-cell RNA sequencing of lung immune microenvironment\n\nAt total of 6362 high-quality single-cell transcriptomes for BALF cells were assessed and the overall population structure was visualized in two-dimensional space using Uniform Manifold Approximation and Projection (Fig. 1c). The unsupervised analysis identified six major clusters that were assigned to neutrophils (FCGR3B+, CSF3R+), macrophages (CD68+, FCGR3A+, CD14+), CD8+ T cells (CD3D+, CD8A+, CD8B+), CD4+ T cells (CD3D+, CD4+), natural killer (NK) cells (FCGR3A+, KLRD1+), and KRT18+ epithelial cells (Fig. 1d). In line with previously reported data on severe COVID-19 patients [19], BALF contained high proportions of neutrophils and macrophages with very limited number of T lymphocytes and NK cells (Fig. 1c). Notably, the frequency of lung-infiltrating immune cell populations did not substantially change during the observational time (Fig. 1d). However, a robust change became evident at a deeper analysis of neutrophils (Fig. 1e) since, according to the expression of typical markers, we identified two clusters of highly inflammatory neutrophils (S100+ neutro and CCL3+ neutro), one cluster of IFN-activated neutrophils (ISGs, GBPs) expressing CD274 (PD-L1) and one containing stressed/exhausted cells characterized by the production of heat shock proteins (HSP+ neutro), together with a small cluster of immature neutrophils (CD16−, CD10−) expressing IRAK3 (IRAK3+ neutro) (Fig. 1e). Interestingly, the frequency of highly inflammatory clusters along with the immature one underwent reduction after MSC infusion whereas a slight increase of the other two clusters occurred during the same interval (Fig. 1f).\n\nSingle-cell RNA sequencing of circulating immune cells\n\nA total of 3762 single-cell transcriptomes of peripheral blood cells were analyzed. The overall representation of each population showed 10 different clusters (Fig. 2a) and top three genes expressed in each cluster (Fig. 2b). Again, very few lymphoid cells were found in the following clusters: NK cells (FCGR3A+, KLRD1+, GZMA+, GZMB+), CD8+ T cells, T cells (CD4+, CD8+), and B cells (MS4A1+). The myeloid compartment was predominantly composed by classic monocytes (CD14+), inflammatory neutrophils (FCGR3B+), a small cluster of non-classic monocytes, and neutrophil precursors (CEACAM8+, ARG1+, MPO+). Interestingly, circulating neutrophils were mostly denoted by FCGR3B, CXCR2, and CSF3R resembling the BALF cluster of highly inflammatory neutrophils (S100+ neutro) (Fig. 2c) in line with previous reports [20, 21]. As shown in Fig. 2d, after MSC infusion, a contraction of the absolute number of circulating leukocytes occurred, mostly due to a decrease in neutrophils as well as NK and NKT cells, as evident at flow cytometry. By contrast, T cells increased as effect of expansion of both CD8+ and CD4+ subsets, mostly central memory CD8+ T cells (CD3+, CD8+, CD27+, CD45RA−) and effector memory CD8+ T cells (CD3+, CD8+, CD45RA−, CD57+), paralleled by a concurrent drop in naïve CD8+ T cells (CD3+, CD8+, CD27+, CD45RA+). Notably, a redistribution of monocyte subsets did occur since an increase of the absolute number of non-classic and intermediate monocytes and a decrease of classic ones were observed. By contrast, B-cell population was barely affected by MSC infusion. Fig. 2 Circulating immune cell population characterization. a UMAP visualization of the 10 cell types identified by integrating the datasets of the days 0 and + 2 after MSC infusion. b Dot plot graph showing the top three marker genes for each cell population used to manually annotate each UMAP-associated cluster. c Top 20 marker genes by average log fold-change of the blood-derived neutrophil cluster and heatmap with their mean normalized expression in the bronchoalveolar lavage fluid-derived neutrophil sub-clusters. The heatmap is scaled for rows. d Peripheral blood samples were analyzed at day 0 and at day + 8 after MSC infusion by flow cytometry. Numbers of cells/μl were reported for leukocytes, neutrophils, B cells, T cells, CD8+ T cells, CD4+ T cells, naïve CD8+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells, NK cells, NKT cells, monocytes, Cl. monocytes, intermediate monocytes and non-Cl. monocytes. In b, d, and f, the red arrow indicates the time points in which MSC infusion was performed. For comments, see the text. Cl., classic; IFN, interferon; Inter., intermediate; MSC, mesenchymal stromal cell; NK, natural killer; RBC, red blood cells; TEM, T-effector memory; UMAP, Uniform Manifold Approximation and Projection\n\nIn parallel, a critical reduction of IL-1β, IL-1RA, IL-6, and TNF-α concentration was evident 2 days after MSC infusion, mimicking the effectiveness of other immunomodulatory agents, such as baricitinib [17], in dampening COVID-19-associated inflammation. Moreover, a decrease in IL-10 in combination with an opposite trend for IL-2, IL-15, and IFN-γ was detected during the same time frame, strengthening the idea that MSCs might fuel a favorable environment for T-cell proliferation (Fig. 3a), as indeed found (Fig. 2d). In addition, we identified increased levels of CCL2 (an essential chemokine for both monocyte and memory CD8+ T-cell migration and function), CCL5 (a potent chemoattractant for effector memory CD8+ T cells), and CXCL10 (an IFN-γ-inducible protein associated with type 1 T-cell response) [22] (Fig. 3b). By contrast, a drop on plasma levels of such chemokines (CCL3, IL-8, and CXCL12) essential for neutrophil recruitment [22] was clearly evident (Fig. 3b). These data might explain the decrease of lung-infiltrating inflammatory neutrophils (S100+ neutro and CCL3+ neutro) emerging from the single-cell RNA sequencing (Fig. 1f). Fig. 3 Plasma cytokine/chemokine profile, and functional assay. a Plasma levels of cytokines at days 0 and + 2 after MSC infusion. b Plasma levels of chemokines at days 0 and + 2 after MSC infusion. c The immune suppressive ability of monocytes was tested in functional assay on activated T cells and shown as percentage of suppression. d Arginase1+ cells within the monocytes subsets were evaluated by flow cytometry at different time points. e The immune suppressive ability of CD66b+ LDNs was tested in functional assay on activated T cells and shown as percentage of suppression. f LDNs were counted and reported as number of cells/μl. The red arrow indicates the time point in which MSC infusion was performed. For comments, see the text. CCL, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand; Cl., classic; IL, interleukin; IFN, interferon; IL-1RA, interleukin-1 receptor A; LDN, low-density gradient neutrophil; MSC, mesenchymal stromal cell; PBMC, peripheral blood mononuclear cell; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor\n\nFunctional assay\n\nBecause the in vivo therapeutic effects of MSCs have been related to the ability of endogenous phagocytes to engulf apoptotic MSCs and activate an immunomodulatory program [23], we also performed an in vitro assay by using circulating monocytes (CD14+ cells) and LDNs harvested before and 8 days after MSC infusion. As shown in Fig. 3c, monocytes acquired the ability to suppress T-cells. This immunosuppressive feature seemed related to the increase of arginase1-expressing non-classic monocytes (Fig. 3d). Similarly, LDNs also acquired immunosuppressive properties (Fig. 3e), while their count gradually expanded (Fig. 3f).\n\nDiscussion\n\nReversing of the “cytokine storm” appears a key strategy to counterattack COVID-19 pneumonia [1, 24]. MSCs have been widely explored as a new treatment option for a number of immune-mediated conditions, including acute steroid-refractory graft-versus-host disease, where a “cytokine storm” is responsible for the high mortality rate [25]. It is conceivable, therefore, that MSCs may also have positive effects on the “cytokine storm” observed in critically ill COVID-19 patients. Therefore, we decided to treat a patient under mechanical ventilation for COVID-19-related respiratory failure with umbilical cord-MSCs under the Hospital Exemption rule. It is recognized that upon intravenous administration, MSCs lodge in the pulmonary vascular bed, where the majority of them are cleared within 24–48 h [26], although there can be longer persistence in inflamed lungs [27]. This is why we chose to analyze the immunological parameters before and after 2 and 8 days after MSC infusion, on the basis of their estimated half-life. While trapped in the lungs, MSCs are able to release a wide array of bioactive molecules, including anti-inflammatory cytokines [28], antimicrobial peptides [29], angiogenic growth factors, and extracellular vesicles [30], that guarantee the phenotypic and functional shift of both epithelial and immune cells [31, 32]. Moreover, despite the fact that the effects of systemic MSC administration in animal models of influenza respiratory infections are under debate [33], systemic infusion of MSCs in a mouse model of lipopolysaccharide-induced ARDS significantly ameliorated alveolar injury and inflammation [34]. In line with this evidence, further studies showed that MSCs promoted the regeneration of alveolar epithelial type II cells, prevented the apoptosis of endothelial cells, and contributed to the enhanced repair of the alveolar epithelial barrier in the ARDS-injured lungs [35–37]. Although we cannot exclude that the modification observed upon MSC treatment was unrelated to cellular therapy, it is conceivable that the reduction of the levels of chemokines and inflammatory cytokines in serum samples (Fig. 3a, b) and the contraction of pro-inflammatory neutrophil subset at pulmonary system (Fig. 1e, f) mirrored by an improvement of gas exchange and clinical parameters were the direct or indirect effects of MSC action. Moreover, our data suggest that MSCs administration was temporally associated with the development of favorable microenvironment for T-cell proliferation, while restraining the accumulation of pro-inflammatory neutrophils that could have actively fueled inflammation during the disease progression. In addition, monocytes underwent re-programming towards the intermediate/non-classical phenotype, a subset with more immunomodulatory function [38] and a higher propensity to become dendritic cells with a strong capacity to induce T-cell proliferation [39, 40]. This is an important point since there is growing evidence showing the relevant role played by monocytes in MSC-driven immunomodulation [41]. Further, our in vitro assay showed the ability of both monocytes and LDNs to acquire immunosuppressive abilities upon MSC treatment. In this regard, it should be emphasized that an expansion of arginase1-expressing CD14+ cells was found, a monocyte subset that we recently identified as immunosuppressive elements in pancreatic cancer patients [42].\n\nHowever, an important question that remains to be solved is whether protective MSC effects are directly against viral infection, perhaps by stimulating specific anti-viral T-cell action, or whether they are due to overall anti-inflammatory effects. Following the persistence of detectable levels of the N gene in the patient’s BALF samples, it is likely that MSCs favor the development of an anti-inflammatory and protective environment able to dampen the “cytokine storm” while contributing to the restoration of alveolar-capillary barrier, instead of having a direct anti-viral effect.\n\nAlthough the data presented here were obtained from a single patient, the completeness and depth of the immunological analyses carried out reinforces the idea of an altered myeloid compartment in the specific setting of COVID-19 severe pneumonia [21]. Moreover, the parameters identified may be of meaningful clinical utility as a potential platform to identify key biomarkers to design consistent and informative clinical trials on the use of MSC therapy in this dismal condition.\n\nSupplementary Information\n\nAdditional file 1: Supplementary methods.\n\nAbbreviations\n\nBALF Bronchoalveolar lavage fluid\n\nCCL C-C motif chemokine ligand\n\nCXCL C-X-C motif chemokine ligand\n\nCOVID Coronavirus disease\n\nIFN Interferon\n\nIL Interleukin\n\nLDNs Low-density neutrophils\n\nMSC Mesenchymal stromal cell\n\nNK Natural killer\n\nSARS-CoV Severe acute respiratory syndrome-coronavirus\n\nTNF Tumor necrosis factor\n\nAcknowledgements\n\nWe dedicate this work to the memory of all the health care professionals who gave their lives in the care of patients with COVID-19. We thank all the personnel involved in patient care and assistance. We also thank the members of the Immunology Section at the A.O.U.I. Policlinico G.B. Rossi in Verona (Italy) who actively worked during the pandemic: Cristina Anselmi, Roza Maria Barouni, Monica Brentegani, Nadia Brutti, Tiziana Cestari, Elena Chiesa, Giulio Fracasso, Cristina Frusteri, Oretta Gabrielli, Elisabetta Gallo, Francesca Hofer, Elena Lucchini, Morena Martini, Chiara Musiu, Fiorenza Paiola, Laura Pinton, Cristina Frusteri, Annalisa Adamo, Claudia Pizzoli, and Ornella Poffe for the excellent technical work; Selena Gomirato, Riccardo Ortolani, Silvia Sartoris, and Giovanna Zanoni for their help with the management of immunological data; and Claudia Italia, Daniel Lovato, and Antonella Valentini for the administrative support. We are also grateful to the mother who kindly donated the umbilical cord and to the nurses of the Obstetrics and Gynecology Unit of the Arzignano Hospital (Vicenza, Italy) for the collection of the umbilical cord.\n\nAuthors’ contributions\n\nRC: conception and design, full responsibility for cell therapy, data analysis and interpretation, manuscript writing, and final approval of the manuscript. DG: financial support, data analysis and interpretation, and final approval of the manuscript. GAs: full responsibility of manufacturing, testing and quality control of the advanced cell therapy medicinal product, manuscript writing, and final approval of the manuscript. MB: manufacturing, testing and quality control of the advanced cell therapy medicinal product, and final approval of the manuscript. AB: manufacturing, testing and quality control of the advanced cell therapy medicinal product, and final approval of the manuscript. KC: manufacturing, testing and quality control of the advanced cell therapy medicinal product, and final approval of the manuscript. FE: supervision of advanced cell therapy medicinal product administration and final approval of the manuscript. SU: collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of the manuscript. SCal: data analysis and interpretation, manuscript writing, and final approval of the manuscript. FDS: collection and assembly of data, data analysis and interpretation, and final approval of the manuscript. SCan: collection and assembly of data, data analysis and interpretation, and final approval of the manuscript. AF: collection and assembly of data, data analysis and interpretation, and final approval of the manuscript. RT: collection and assembly of data, data analysis and interpretation, manuscript writing, and final approval of the manuscript. AV: collection and assembly of data, data analysis and interpretation, and final approval of the manuscript. VP: collection and assembly of data, data analysis and interpretation, and final approval of the manuscript. GAm: collection and analysis of clinical data and final approval of the manuscript. MS: regulatory support and final approval of the manuscript. AM: collection and assembly of data, data analysis and interpretation, and final approval of the manuscript. LF: critical revision of the manuscript and final approval of the manuscript. MR: critical revision of the manuscript and final approval of the manuscript. EP: patient’s care and final approval of the manuscript. VB: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of the manuscript.\n\nFunding\n\nThis study was supported by a research grant from Fondazione CariVerona entitled: “ENACT” to Vincenzo Bronte and Davide Gibellini, and Fondazione TIM to Vincenzo Bronte. This source of funding was not in any way involved in the study design, collection, analysis and interpretation of data, writing of the manuscript, or in the decision to submit the article for publication.\n\nAvailability of data and materials\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was conducted according to the Hospital Exemption rule (art. 28 European Regulation 1394/2007) and after approval by both the local Ethics Committee (no. 19464) and the Italian Drug Agency (no. 163516409). Informed consent was obtained by a relative because of the patient was under pharmacological coma.\n\nConsent for publication\n\nConsent for publication of the data was obtained by a relative because of the patient was under pharmacological coma.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nRachele Ciccocioppo and Davide Gibellini contributed equally to this work.\n==== Refs\nReferences\n\n1. Vabret N Immunology of COVID-19: current state of the science Immunity 2020 52 6 910 941 10.1016/j.immuni.2020.05.002 32505227\n2. Tan L Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study Signal Transduct Target Ther 2020 5 1 33 10.1038/s41392-020-0148-4 32296069\n3. Gao Y-M, Xu G, Wang B, Liu B-C. Cytokine storm syndrome in coronavirus disease 2019: a narrative review. J Intern Med. 2020, 2021;10. 10.1111/joim.13144.\n4. Giamarellos-Bourboulis EJ Netea MG Rovina N Akinosoglou K Antoniadou A Antonakos N Damoraki G Gkavogianni T Adami ME Katsaounou P Ntaganou M Kyriakopoulou M Dimopoulos G Koutsodimitropoulos I Velissaris D Koufargyris P Karageorgos A Katrini K Lekakis V Lupse M Kotsaki A Renieris G Theodoulou D Panou V Koukaki E Koulouris N Gogos C Koutsoukou A Complex immune dysregulation in COVID-19 patients with severe respiratory failure Cell Host Microbe. 2020 27 6 992 1000 10.1016/j.chom.2020.04.009 32320677\n5. Vardhana SA Wolchok JD The many faces of the anti-COVID immune response J Exp Med. 2020 217 6 e20200678 10.1084/jem.20200678 32353870\n6. Wu R, et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Rep. 2020. 10.1007/s40495-020-00216-7.\n7. 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Stuart T Butler A Hoffman P Hafemeister C Papalexi E Mauck WM III Hao Y Stoeckius M Smibert P Satija R Comprehensive integration of single-cell data Cell. 2019 177 7 1888 1902 10.1016/j.cell.2019.05.031 31178118\n17. Bronte V Ugel S Tinazzi E Vella A de Sanctis F Canè S Batani V Trovato R Fiore A Petrova V Hofer F Barouni RM Musiu C Caligola S Pinton L Torroni L Polati E Donadello K Friso S Pizzolo F Iezzi M Facciotti F Pelicci PG Righetti D Bazzoni P Rampudda M Comel A Mosaner W Lunardi C Olivieri O Baricitinib restrains the immune dysregulation in patients with severe COVID-19 J Clin Invest. 2020 130 12 6409 6416 10.1172/JCI141772 32809969\n18. Solito S Pinton L de Sanctis F Ugel S Bronte V Mandruzzato S Marigo I Methods to measure MDSC immune suppressive activity in vitro and in vivo Curr Protoc Immunol. 2019 124 1 e61 10.1002/cpim.61 30303619\n19. Liao M Liu Y Yuan J Wen Y Xu G Zhao J Cheng L Li J Wang X Wang F Liu L Amit I Zhang S Zhang Z Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19 Nat Med. 2020 26 6 842 844 10.1038/s41591-020-0901-9 32398875\n20. Bost P Host-viral infection maps reveal signatures of severe COVID-19 patients Cell 2020 181 7 1475 88.e12 10.1016/j.cell.2020.05.006 32479746\n21. Schulte-Schrepping J Severe COVID-19 is marked by a dysregulated myeloid cell compartment Cell 2020 182 6 1419 40.e23 10.1016/j.cell.2020.08.001 32810438\n22. Turner MD Nedjai B Hurst T Pennington DJ Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease Biochim Biophys Acta. 2014 1843 11 2563 2582 10.1016/j.bbamcr.2014.05.014 24892271\n23. Galleu A Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation Sci Transl Med 2017 9 416 eaam7828 10.1126/scitranslmed.aam7828 29141887\n24. Fajgenbaum DC June CH Cytokine storm N Engl J Med 2020 383 23 2255 2273 10.1056/NEJMra2026131 33264547\n25. Blazar BR MacDonald KPA Hill GR Immune regulatory cell infusion for graft-versus-host disease prevention and therapy Blood. 2018 131 24 2651 2660 10.1182/blood-2017-11-785865 29728401\n26. Leibacher J Henschler R Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells Stem Cell Res Ther. 2016 7 1 7 10.1186/s13287-015-0271-2 26753925\n27. Armitage J Tan DBA Troedson R Young P Lam KV Shaw K Sturm M Weiss DJ Moodley YP Mesenchymal stromal cell infusion modulates systemic immunological responses in stable COPD patients: a phase I pilot study Eur Respir J. 2018 51 3 1702369 10.1183/13993003.02369-2017 29348155\n28. Lee RH Pulin AA Seo MJ Kota DJ Ylostalo J Larson BL Semprun-Prieto L Delafontaine P Prockop DJ Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6 Cell Stem Cell. 2009 5 1 54 63 10.1016/j.stem.2009.05.003 19570514\n29. Krasnodembskaya A Song Y Fang X Gupta N Serikov V Lee JW Matthay MA Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37 Stem Cells. 2010 28 12 2229 2238 10.1002/stem.544 20945332\n30. Hu S Park J Liu A Lee JH Zhang X Hao Q Lee JW Mesenchymal stem cell microvesicles restore protein permeability across primary cultures of injured human lung microvascular endothelial cells Stem Cells Transl Med. 2018 7 8 615 624 10.1002/sctm.17-0278 29737632\n31. Court AC Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response EMBO Rep 2020 21 2 e48052 10.15252/embr.201948052 31984629\n32. Islam MN Das SR Emin MT Wei M Sun L Westphalen K Rowlands DJ Quadri SK Bhattacharya S Bhattacharya J Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury Nat Med. 2012 18 5 759 765 10.1038/nm.2736 22504485\n33. Khoury M Cuenca J Cruz FF Figueroa FE Rocco PRM Weiss DJ Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19 Eur Respir J. 2020 55 6 2000858 10.1183/13993003.00858-2020 32265310\n34. Gupta N Su X Popov B Lee JW Serikov V Matthay MA Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice J Immunol. 2007 179 3 1855 1863 10.4049/jimmunol.179.3.1855 17641052\n35. Lee JW Fang X Gupta N Serikov V Matthay MA Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung Proc Natl Acad Sci U S A. 2009 106 38 16357 16362 10.1073/pnas.0907996106 19721001\n36. Yang Y Hu S Xu X Li J Liu A Han J Liu S Liu L Qiu H The vascular endothelial growth factors-expressing character of mesenchymal stem cells plays a positive role in treatment of acute lung injury in vivo Mediators Inflamm. 2016 2016 2347938 2347912 10.1155/2016/2347938 27313398\n37. Hu S Li J Xu X Liu A He H Xu J Chen Q Liu S Liu L Qiu H Yang Y The hepatocyte growth factor-expressing character is required for mesenchymal stem cells to protect the lung injured by lipopolysaccharide in vivo Stem Cell Res Ther. 2016 7 1 66 10.1186/s13287-016-0320-5 27129877\n38. Ziegler-Heitbrock L Hofer TPJ Toward a refined definition of monocyte subsets Front Immunol. 2013 4 23 10.3389/fimmu.2013.00023 23382732\n39. Randolph GJ Sanchez-Schmitz G Liebman RM Schakel K The CD16(+) (Fcgam- maRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting J Exp Med. 2002 196 4 517 527 10.1084/jem.20011608 12186843\n40. Bajana S Differential CD4(+) T-cell memory responses induced by two subsets of human monocyte-derived dendritic cells Immunology. 2007 122 3 381 393 10.1111/j.1365-2567.2007.02650.x 17608690\n41. Allen A Vaninov N Li M Nguyen S Singh M Igo P Tilles AW O’Rourke B Miller BLK Parekkadan B Barcia RN Mesenchymal stromal cell bioreactor for ex vivo reprogramming of human immune cells Sci Rep. 2020 10 1 10142 10.1038/s41598-020-67039-w 32576889\n42. Trovato R Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3 J Immunother Cancer 2019 7 1 255 10.1186/s40425-019-0734-6 31533831\n\n",
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"abstract": "There are numerous studies presenting the beneficial effect of bisphosphonates (BPs) on bone disease of patients suffering from beta-thalassemia major (TM). Although BPs have been widely used, adverse events have been described including atypical femoral fractures (AFF). In the present case, a male adult patient suffering from TM sustained an AFF fulfilling all major and two minor criteria. Before AFF, the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy. To our knowledge, this is the first reported case of AFF in a patient suffering from TM, probably due to the small sample size of patients with thalassemia. The purpose of the present case is to increase the awareness amongst haematologists, who mainly deal with TM patients, of the adverse events of BP use.",
"affiliations": "Laboratory for Research of the Musculoskeletal System 'Th. Garofalidis', Medical School, University of Athens, General Hospital of Athens KAT, Greece.",
"authors": "Lampropoulou-Adamidou|K|K|;Tournis|S|S|;Triantafyllopoulos|I K|IK|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
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"fulltext": "\n==== Front\nJ Musculoskelet Neuronal InteractJ Musculoskelet Neuronal InteractJournal of Musculoskeletal & Neuronal Interactions1108-7161International Society of Musculoskeletal and Neuronal Interactions Greece 26944826JMNI-16-75Case Report ArticleAtypical femoral fracture in a beta-thalassemia major patient with previous bisphosphonate use: case report and a review of the literature Lampropoulou-Adamidou K. 12Tournis S. 1Triantafyllopoulos I.K. 11 Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, Medical School, University of Athens, General Hospital of Athens KAT, Greece2 3rd Orthopaedic Department, Medical School, University of Athens, General Hospital of Athens KAT, GreeceCorresponding author: Kalliopi Lampropoulou-Adamidou, M.D., M.Sc., Ph.D., Laboratory for Research of the Musculoskeletal System “Th. Garofalidis” Medical School, University of Athens, General Hospital of Athens KAT, 10 Athinas Str., Kifissia, PC: 14561, Athens, Greece E-mail: [email protected] authors have no conflict of interest.\n\n3 2016 16 1 75 78 05 1 2016 Copyright: © Journal of Musculoskeletal and Neuronal Interactions2016This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.There are numerous studies presenting the beneficial effect of bisphosphonates (BPs) on bone disease of patients suffering from beta-thalassemia major (TM). Although BPs have been widely used, adverse events have been described including atypical femoral fractures (AFF). In the present case, a male adult patient suffering from TM sustained an AFF fulfilling all major and two minor criteria. Before AFF, the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy. To our knowledge, this is the first reported case of AFF in a patient suffering from TM, probably due to the small sample size of patients with thalassemia. The purpose of the present case is to increase the awareness amongst haematologists, who mainly deal with TM patients, of the adverse events of BP use.\n\nThalassemiaBone DiseaseAtypical FractureBisphosphonatesAdverse Event\n==== Body\nIntroduction\nBeta-thalassemia major (TM) affects 0.44 per 1,000 births worldwide[1]. It is an inherited recessive of beta hemoglobin synthesis due to beta globin genes mutations on chromosome 11, leading to ineffective erythropoiesis and anaemia requiring regular blood transfusions[2]. Chronic transfusion therapy results to iron overload that cause a wide spectrum of complications due to heart, liver and endocrine glands damage[3]. Although improvement of management of patients with TM have increased life span, other comorbidities of the disease including bone disease have emerged. There are numerous studies presenting the beneficial effect of bisphosphonates (BPs) on bone disease and their use is widespread in TM patients with low bone mass (BMD) and high fracture risk[4-6].\n\nAlthough bisphosphonates have been widely used, they present several adverse events including osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF)[7]. Only recently 3 cases of ONJ have been reported in these patients following BP therapy[8]. To our knowledge, this is the first reported case of a male adult patient suffering from TM that sustained an AFF after previous zoledronic acid use.\n\nCase report\nA 36-year-old male patient with beta-thalassemia major sustained a left tibial medial condyle and shaft fracture after a motor vehicle accident (Figure 1). The tibial fractures were treated with two free cannulated screws and a reamed static locked intramedullary nail. Rehabilitation started on forth postoperative day with partial weight bearing on the left leg using crutches. On the eleventh postoperative day, the patient felt a sudden acute pain, with no reported prodromal pain, when walking on his right thigh and became unable to walk on his right leg. Radiographs revealed a short oblique femoral shaft fracture without comminution, and absence of cortical thickness and cortical beaking (Figure 2). This fracture was also treated with a reamed static locked intramedullary nail.\n\nFigure 1 Anteroposterior radiograph of the left tibia after a motor vehicle accident presents a tibial medial condyle and shaft fracture.\n\nFigure 2 Anteroposterior radiograph of the right femur, eleven days after operation of the tibial fracture, reveals a short oblique femoral shaft fracture without comminution.\n\nThe patient suffers from beta-thalassemia major requiring transfusion twice a month since childhood and iron chelating-therapy with desferoxamine until 2007 and deferiprone since that time. Other comorbidities include type 2 diabetes mellitus, hypertension, osteoporosis with a compressive fracture of the lumbar spine (L4) sustained 6 years earlier, esophageal varices treated with banding and cholochystectomy. His medications consisted of metformin, glyclazide, magnesium, sotalol and ramipril/hydrochlorothiazide. As for the osteoporosis treatment, after the occurrence of the vertebral fracture, the patient had been treated with intranasal calcitonin 200 IU daily for one year followed by intravenous zoledronic acid 5 mg once yearly for 3 years along with calcium and vitamin D supplementation. Thus, the patient at the time of the tibial and femoral fractures had remained without osteoporosis treatment for one year. Four months postoperatively, teriparatide (TRP) treatment was initiated.\n\nBone densitometry measured by Lunar Prodigy dual-energy X-ray absorptiometry (DXA) was consistent with BMD lower than that expected for age in the left hip 5 and one year before tibial and femoral fracture (Z-score, -3.4 and 3.5, respectively). Biochemical evaluation revealed normal testosterone levels, acceptable levels of 25(OH) vitamin D (27 ng/mL), while bone markers were within normal range (P1NP and sCTX) three months after tibial and femoral fracture, similarly with values reported in most of the patients with AFF treated with BPs[9] (Table 1).\n\nTable 1 Laboratory tests of the patient three months after tibial and femoral fracture.\n\nValues\t\tNormal range values\t\nCreatinine (mg/dL)\t0.65\t0.7-1.3\t\nCalcium (mg/dL)\t8.8\t8.4-10.2\t\nPhosphate (mg/dL)\t3.6\t2.5-4.7\t\nALP (IU/L)\t126\t40-150\t\nAlbumin (gr/dL)\t3.6\t3.5-5.0\t\nTestosterone (ng/dL)\t320\t280-1100\t\nTSH (µIU/mL)\t2.4\t0.55-4.78\t\n25(OH)D (ng/mL)\t27\t30-60 (deficiency <20)\t\nPTH (pg/mL)\t15.7\t15-65\t\nPINP (ng/mL)\t26\t15-59\t\nsCTX (ng/mL)\t0.335\t<0.584\t\nALP, alkaline phosphatase; TSH, thyroid-stimulating hormone; 25(OH)D, 25-hydroxy vitamin D; PTH, parathyroid hormone; PINP, procollagen type I N-terminal propeptide; sCTX, serum C-telopeptide cross-link of type-I collagen.\n\nAfter the second operation, patient’s rehabilitation included lower-extremity isometric and range of motion exercises for 4 weeks and initiation of a weight-bearing as tolerated ambulation with bilateral axillary crutches on the first postoperative week. Six weeks postoperatively, full-weight-bearing was started. Patient returned to work and was able to perform activities of daily living on forth postoperative month.\n\nDiscussion\nThalassemia-related bone disease had been first described by Cooley et al as “peculiar bone changes” consisted by cranial, facial and limb marked deformities mainly due to bone marrow expansion[10]. The introduction of transfusion therapy in 1960 have been resulted to amelioration of such bone deformities[11]. Nowadays, bone disease is characterised by low BMD, increased risk of fractures and bone pain. Possible risk factors for fracture are age older than 20 years, male gender, hypothyroidism, hypogonadism, lack of spontaneous puberty in females, active hepatitis, heart disease and diabetes[12,13]. Most of the fractures are presented in the upper extremity and spine mainly caused by a fall[14,15].\n\nPathogenesis of bone disease in TM is complex and some of the underlying mechanisms are still unclear. Multiple genetic and acquired factors are involved. Already known genetic factors include polymorphisms at the Sp1 site of the collagen type Ia1 (COLIA 1) gene, at FokI and BsmI of vitamin D receptor (VDR) gene and at 713-8delC of transforming growth factor-beta (TGF-b) gene. Acquired factors include ineffective erythropoiesis and subsequent bone marrow expansion due to increased erythropoietin levels, iron overload and iron chelation therapy (particularly deferoxamine), endocrine complications such as hypogonadism, hypothyroidism, dysfunction of GH/IGF-1 axis, diabetes, calcium and vitamin C and D deficiencies, as well as decreased physical activity[12,13]. These factors lead to an imbalance in bone remodelling by inhibiting bone formation and increasing bone resorption.\n\nGeneral principles of management of TM patients are regular blood transfusions and iron chelation therapy with deferasirox, hormone replacement therapy, adequate calcium and vitamin D supplementation and increase of physical activity[16]. Annual BMD measurement, starting in adolescence, is recommended for the early diagnosis of BMD below the expected values for age and initiation of antiosteoporotic treatment[13]. The increased bone resorption observed in TM patients could justify the use of BPs. BPs are the most widely used drugs for the prevention and treatment of bone loss[4]. A systematic review of randomised controlled trials have concluded that reliable clinical studies in TM patients showed improved BMD, reduced bone and back pain and decreased bone turnover markers without causing any severe or unexpected adverse event after various dose regimens of an amino-BP (alendronate, neridronate, or zoledronic acid) compared to baseline and to placebo. However, long-term studies are required to answer about the reduction of fracture risk[5]. There is lack of evidence on the treatment of patients suffering from TM with other antiosteoporotic agents such as TRP. To our knowledge, there is only one case presenting encouraging results of TRP use in TM associated bone disease in the English literature[17].\n\nAccording to the updated Task Force of the ASBMR, an AFF should present all the major features that include its location in the subtrochanteric region and femoral diaphysis, association with no or minimal trauma, transverse or short oblique configuration and lack of comminution. Complete AFFs extend through both cortices and incomplete only in the lateral cortex. These fractures may present also some of the minor features that include periosteal reaction of the lateral cortex, prodromal symptoms, fractures or symptoms bilaterally, delayed healing, comorbid conditions and use of certain pharmaceutical agents such as BPs[18]. Recently, AFFs have been considered as stress/ fatigue or insufficiency fractures that develop over the time and present specific features[18,19]. They have been described mostly as a potent complication of BP use[7], while the risk remains albeit decreased by about 70% per year after BP discontinuation[18,19].\n\nAlthough the causal association between BP use and AFF remains uncertain, the most likely mechanisms relate to the suppression of bone turnover include increase of degree and homogenicity of mineralization, collagen maturity, microcrack accumulation, propagation and impairment of crack repair. Finally, anti-angiogenic effects of BPs may be implicated[20]. Empirical management for AFF includes application of intramedullary full-length nails, discontinuation of BP treatment, adequate supplementation with calcium and vitamin D and anabolic therapy with TRP or strontium ranelate[18,21-23].\n\nThere are many aspects needing to be addressed regarding treatment of bone disease of TM patients. Although there is evidence that BPs demonstrate beneficial effects in bone disease of TM, the dose regimen, duration of therapy and drug-free holidays have not yet been clarified[6]. Given the young age of patients, there is concern about their safety in use in reproductive age[24] and their effect on reducing morbidity and mortality of such patients. There is also lack of evidence in prediction of fracture risk by using DXA in TM patients[25,26]. Furthermore, existing data support that haemoglobin levels are positively correlated with BMD, however it is still unclear if regular blood transfusions and preservation of haemoglobin at a higher level could lead to higher BMD by reduction of hypoxia and erythropoietin levels that participate in the pathogenesis of bone disease[15].\n\nIn the present case, a male adult patient suffering from TM sustained an AFF fulfilling all major and two minor criteria (comorbid conditions and use of BPs). Biochemical evaluation revealed normal levels of bone markers three months after tibial and femoral fracture that could be a cause of concern. Before AFF, the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy. To our knowledge, this is the first reported case of AFF in a patient suffering from TM, probably due to the small sample size of patients with thalassemia in the general population. The purpose of the present case is to increase the awareness amongst haematologists, who mainly deal with TM patients, of the adverse events of BP use.\n\nEdited by: F. Rauch\n==== Refs\nReferences\n1 Rund D Rachmilewitz E Beta-thalassemia N Engl J Med 2005 353 1135 46 16162884 \n2 Cappellini MD Goldman L Schafer AI The Thalassemias Goldman-Cecil Medicine: Expert Consult - Online 2015 25 ed Elsevier Health Sciences 1089 95 \n3 Taher AT Musallam KM Inati A Iron overload: consequences, assessment, and monitoring Hemoglobin 2009 33 Suppl 1 S46 57 20001632 \n4 Nancollas GH Tang R Phipps RJ Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite Bone 2006 38 617 27 16046206 \n5 Giusti A Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials J Bone Miner Metab 2014 32 606 15 24748165 \n6 Terpos E Voskaridou E Treatment options for thalassemia patients with osteoporosis Ann N Y Acad Sci 2010 1202 237 43 20712799 \n7 Papapetrou PD Bisphosphonate-associated adverse events Hormones (Athens) 2009 8 96 110 19570737 \n8 Chatterjee R Bajoria R Shah FT Porter JB Fedele S High index of suspicion for early diagnosis of alendronate-induced stage zero osteonecrosis of jaw in thalassaemia major Br J Haematol 2014 166 292 4 24628574 \n9 Giusti A Hamdy NA Papapoulos SE Atypical fractures of the femur and bisphosphonate therapy: A systematic review of case/case series studies Bone 2010 47 169 80 20493982 \n10 Cooley TB Lee P A series of cases of splenomegaly in children with anemia and peculiar bone changes Trans Am Pediatr Soc 1925 37 29 30 \n11 Piomelli S The management of patients with Cooley’s anemia: transfusions and splenectomy Semin Hematol 1995 32 262 8 8560283 \n12 Vogiatzi MG Macklin EA Fung EB Bone disease in thalassemia: a frequent and still unresolved problem J Bone Miner Res 2009 24 543 57 18505376 \n13 Haidar R Musallam KM Taher AT Bone disease and skeletal complications in patients with beta thalassemia major Bone 2011 48 425 32 21035575 \n14 Fung EB Harmatz PR Milet M Fracture prevalence and relationship to endocrinopathy in iron overloaded patients with sickle cell disease and thalassemia Bone 2008 43 162 8 18430624 \n15 Wong P Fuller PJ Gillespie MT Thalassemia bone disease: a 19-year longitudinal analysis J Bone Miner Res 2014 29 2468 73 24764138 \n16 Voskaridou E Terpos E New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia Br J Haematol 2004 127 127 39 15461618 \n17 Tournis S Dede AD Savvidis C Triantafyllopoulos IK Kattamis A Papaioannou N Effects of teriparatide retreatment in a patient with beta-thalassemia major Transfusion 2015 \n18 Shane E Burr D Abrahamsen B Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research J Bone Miner Res 2014 29 1 23 23712442 \n19 Schilcher J Michaelsson K Aspenberg P Bisphosphonate use and atypical fractures of the femoral shaft N Engl J Med 2011 364 1728 37 21542743 \n20 Compston J Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw Osteoporos Int 2011 22 2951 61 21997225 \n21 Lampropoulou-Adamidou K Tournis S Balanika A Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with atypical femoral fractures after long-term bisphosphonate administration Hormones (Athens) 2013 12 591 7 24457408 \n22 Gomberg SJ Wustrack RL Napoli N Arnaud CD Black DM Teriparatide, vitamin D, and calcium healed bilateral subtrochanteric stress fractures in a postmenopausal woman with a 13-year history of continuous alendronate therapy J Clin Endocrinol Metab 2011 96 1627 32 21430030 \n23 Carvalho NN Voss LA Almeida MO Salgado CL Bandeira F Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium ranelate and teriparatide J Clin Endocrinol Metab 2011 96 2675 80 21752890 \n24 Stathopoulos IP Liakou CG Katsalira A The use of bisphosphonates in women prior to or during pregnancy and lactation Hormones (Athens) 2011 10 280 91 22281884 \n25 Fung EB Vichinsky EP Kwiatkowski JL Characterization of low bone mass in young patients with thalassemia by DXA, pQCT and markers of bone turnover Bone 2011 48 1305 12 21443975 \n26 Wong P Fuller PJ Gillespie MT Thalassemia bone disease: the association between nephrolithiasis, bone mineral density and fractures Osteoporos Int 2013 24 1965 71 23291906\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7161",
"issue": "16(1)",
"journal": "Journal of musculoskeletal & neuronal interactions",
"keywords": null,
"medline_ta": "J Musculoskelet Neuronal Interact",
"mesh_terms": "D000328:Adult; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005264:Femoral Fractures; D006801:Humans; D007093:Imidazoles; D008297:Male; D010024:Osteoporosis; D000077211:Zoledronic Acid; D017086:beta-Thalassemia",
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"pages": "75-8",
"pmc": null,
"pmid": "26944826",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24457408;21430030;21542743;15461618;23712442;24764138;21752890;21035575;16162884;20712799;22281884;20493982;23291906;24748165;21997225;26174236;18505376;8560283;16046206;18430624;24628574;20001632;19570737;21443975",
"title": "Atypical femoral fracture in a beta-thalassemia major patient with previous bisphosphonate use: case report and a review of the literature.",
"title_normalized": "atypical femoral fracture in a beta thalassemia major patient with previous bisphosphonate use case report and a review of the literature"
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{
"abstract": "The evaluation of new-onset seizure activity must raise a much broader differential than just epilepsy. This case study highlights that broad differential and identifies an important, but less common, cause of seizure activity in specific patient populations. Information is summarized from recent primary research, case series, literature reviews, and meta-analyses. In the appropriate clinical context, the diagnosis of posterior reversible encephalopathy syndrome (PRES) should be considered as a cause of seizures. Posterior reversible encephalopathy syndrome is a neurotoxic syndrome characterized by posterior cerebral edema on imaging and triggered by a variety of inciting or predisposing factors. This article reviews suggestions for the identification and management of PRES. Because of the myriad factors, nurse practitioners should be familiar with PRES and may encounter it through primary care, emergency or urgent care, hospitalist medicine, or a variety of specialty roles.",
"affiliations": "Crouse Testing Center, Crouse Hospital, Syracuse, New York.;Department of Emergency Services, Ellis Hospital, Schenectady, New York.",
"authors": "Gersch|Kathryn|K|;Spencer|Taylor R|TR|",
"chemical_list": "D017984:Enoxaparin; D007166:Immunosuppressive Agents; D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.1097/JXX.0000000000000331",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2327-6886",
"issue": "32(12)",
"journal": "Journal of the American Association of Nurse Practitioners",
"keywords": null,
"medline_ta": "J Am Assoc Nurse Pract",
"mesh_terms": "D003550:Cystic Fibrosis; D004636:Emergency Service, Hospital; D017984:Enoxaparin; D004827:Epilepsy; D005260:Female; D006470:Hemorrhage; D006801:Humans; D006973:Hypertension; D007166:Immunosuppressive Agents; D007328:Insulin; D008279:Magnetic Resonance Imaging; D055815:Young Adult",
"nlm_unique_id": "101600770",
"other_id": null,
"pages": "824-828",
"pmc": null,
"pmid": "31764400",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New-onset seizure activity in a transplant patient on immunosuppressive therapy.",
"title_normalized": "new onset seizure activity in a transplant patient on immunosuppressive therapy"
}
|
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{
"abstract": "OBJECTIVE\nTo assess the safety and efficacy of intravitreal dexamethasone implants in the treatment of macular edema secondary to infectious uveitis.\n\n\nMETHODS\nWe retrospectively reviewed clinical records from three uveitis referral units in Spain. The main outcome measures were rate of reactivation of infection, improvements in visual acuity and resolution of macular edema, as measured by optical coherence tomography.\n\n\nRESULTS\nWe included eight eyes from seven patients with a median age of 64 years (30-75). Etiologies of the infections were Herpes simplex virus-type 1, Varicela-Zoster virus, Treponema pallidum, Brucella mellitensis, Borrelia burgdorferi, Toxoplasma gondii, and cytomegalovirus. Median visual acuity was 20/160 (20/30-20/400) at baseline and 20/70 (20/25-20/200) at the last follow-up visit. Mean macular thickness was 516 μm (115) at baseline and 266.3 μm (40) at the last follow-up visit. Visual acuity improved in 100% of the eyes and none of the eyes showed macular edema at the last follow-up visit. Five patients required reinjections of the implant. Only one patient required antiglaucoma drops for a temporary increase in ocular pressure. There were no cases of reactivation of the infectious ocular disease. Median follow-up time was 18 months.\n\n\nCONCLUSIONS\nIn this small case series of eyes with macular edema secondary to infectious uveitis, treatment with dexamethasone intravitreal implants was not associated with reactivation of the infectious ocular disease. Furthermore, significant improvements in visual acuity and macular thickness were observed in our patients.",
"affiliations": "*Begiker-Ophthalmology Research Group, Ophthalmology Department, BioCruces Health Research Institute, Cruces Hospital, University of the Basque Country, Bilbao, Spain; †Ophthalmology Institute, Hospital Clinic of Barcelona, Barcelona, Spain; ‡Autoimmune Diseases Research Unit, Department of Internal Medicine, BioCruces Health Research Institute, Cruces Hospital, University of the Basque Country, Bilbao, Spain; §Infectious Disease Department, BioCruces Health Research Institute, Cruces Hospital, University of the Basque Country, Bilbao, Spain; and ¶Uveitis Unit, Ophthalmology Department, León Hospital, IBIOMED, León University, León, Spain.",
"authors": "Fonollosa|Alex|A|;Llorenç|Victor|V|;Artaraz|Joseba|J|;Jimenez|Beatriz|B|;Ruiz-Arruza|Ioana|I|;Agirrebengoa|Koldo|K|;Cordero-Coma|Miguel|M|;Costales-Mier|Felipe|F|;Adan|Alfredo|A|",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000001001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "36(9)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000328:Adult; D000368:Aged; D003907:Dexamethasone; D004343:Drug Implants; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014605:Uveitis",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "1778-85",
"pmc": null,
"pmid": "27183031",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "SAFETY AND EFFICACY OF INTRAVITREAL DEXAMETHASONE IMPLANTS IN THE MANAGEMENT OF MACULAR EDEMA SECONDARY TO INFECTIOUS UVEITIS.",
"title_normalized": "safety and efficacy of intravitreal dexamethasone implants in the management of macular edema secondary to infectious uveitis"
}
|
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{
"abstract": "Hepatitis E virus genotype 3 is not rare in developed countries, and may cause chronic hepatitis in immunocompromised patients. This may not only lead to abnormalities in liver test and malaise, but to severe neurological symptoms as well. In this case, chronic hepatitis E infection caused encephalopathy, an atactic gait, Lhermitte's sign, incomplete bladder emptying and peripheral sensory neuropathy in a renal transplant recipient. The diagnosis was not performed until years after the onset of first symptoms and several months after the onset of neurological symptoms. If treated adequately, viral load can be reduced in over two-thirds of patients and neurological symptoms are often resolved. More widespread knowledge about this virus and its extrahepatic manifestations may lead to a quicker diagnosis, and may limit pathology. Serological screening should be added to standard pretransplant virological screening, so that, in the future, patients without antibodies could be vaccinated.",
"affiliations": "Department of Internal Medicine, Maasstad Hospital, Rotterdam, The Netherlands.",
"authors": "de Vries|Marijke A|MA|;Samijn|Johnny P A|JP|;de Man|Rob|R|;Boots|Johannes M M|JM|",
"chemical_list": "D012254:Ribavirin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D001707:Biopsy, Needle; D002908:Chronic Disease; D018450:Disease Progression; D004576:Electromyography; D005260:Female; D005500:Follow-Up Studies; D006085:Graft Survival; D006501:Hepatic Encephalopathy; D016751:Hepatitis E; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging; D012254:Ribavirin; D012720:Severity of Illness Index; D066027:Transplant Recipients; D014181:Transplantation Immunology; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24789162",
"pubdate": "2014-04-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18651907;23929229;21291585;21316404;18992406;22516170;17329696;21192851;23013075;17913730;22172156;22947521;16623913;20728932;22549046",
"title": "Hepatitis E-associated encephalopathy in a renal transplant recipient.",
"title_normalized": "hepatitis e associated encephalopathy in a renal transplant recipient"
}
|
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{
"abstract": "Post-transplant lymphoproliferative disorder (PTLD) is defined as a heterogeneous group of lymphoid and plasmocytic proliferations with variable malignant potential. They often arise in immunocompromised post solid organ transplant (SOT) patients linked with Epstein-Barr virus (EBV) infection. Clinical manifestations include fever, lymphadenopathy and organ involvement. Diagnosis of PTLD requires morphopathological tissue examination. Treatment of EBV-related PTLD in SOT patients includes immunosuppressive (IS) agents' reduction, use of antiviral medication, anti-B-lymphocyte antibodies and chemotherapy for high-risk patients. We report a case of late EBV-related PTLD occurring in a young female, coming from twins, nine years after renal transplant from deceased donor. Both sisters were diagnosed at the age of 10 with chronic kidney disease (CKD) based on nephronophthisis and underwent the first simultaneous renal transplant from deceased donor in Romania. PTLD Hodgkin's-like lymphoma and EBV-positive lesions were to be found in autopsy. Routine EBV viral load testing and immune condition in SOT patients could identify PTLD risk factors therefore early treatment can be applied. Monitoring EBV serology and immunological parameters are preferred as strategy for PTLD prevention.",
"affiliations": "Department of Pediatrics, \"Victor Babes\" University of Medicine and Pharmacy, Timisoara, Romania; [email protected]; Department of Pediatrics, \"Iuliu Hatieganu\" University of Medicine and Pharmacy, Cluj-Napoca, Romania; [email protected].",
"authors": "Isac|Raluca|R|;Costa|Rodica|R|;Lăzureanu|Dorela CodruŢa|DC|;Olariu|Cristina Ioana|CI|;Muntean|Adriana Milena|AM|;Aldea|Cornel Olimpiu|CO|;Doroş|Gabriela Simona|GS|;Gafencu|Mihai|M|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1220-0522",
"issue": "58(3)",
"journal": "Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie",
"keywords": null,
"medline_ta": "Rom J Morphol Embryol",
"mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders",
"nlm_unique_id": "9112454",
"other_id": null,
"pages": "1041-1045",
"pmc": null,
"pmid": "29250687",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lymphoproliferative disorder in a twin female teenager post kidney transplantation.",
"title_normalized": "lymphoproliferative disorder in a twin female teenager post kidney transplantation"
}
|
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"abstract": "Bone cement implantation syndrome (BCIS) typically occurs during bone cementation and prosthesis insertion. Almost all of the models used to explain BCIS are based on studies related to hip arthroplasty. BCIS induced by bone cement implantation in superficial wounds has not been reported.\n\n\nMETHODS\nWe report the case of a 37-year-old man with chronic osteomyelitis of the left tibia (Cierny - Mader type II), who developed BCIS after covering the infected bone surface with antibiotic-loaded bone cement. BCIS presented as acute massive pulmonary exudation and hypoxemia. Early application of awake prone positioning effectively improved oxygenation and lung injury, and prevented the need for a more advanced means of respiratory support. The patient was discharged without any clinical complications on postoperative day 15.\nWe assessed the cause of acute respiratory events in this patient using Naranjo Adverse Drug Reaction Probability Scale, and BCIS was finally considered. Despite the lack of \"driving force\" (e.g., increased intramedullary pressure), the bone cement monomer may be absorbed into circulation through the wound surface due to its penetrability. Subsequent immune-mediated amplification resulted in pulmonary exudation and hypoxemia. As a pathophysiologically change-oriented strategy, effective drainage after awake prone positioning significantly improved clinical outcomes.\n\n\nCONCLUSIONS\nBone cement monomer absorbed through the wound should be of concern, and pathophysiological change-oriented management should be emphasized in BCIS.",
"affiliations": "Intensive Care Unit, Sichuan Provincial Orthopedic Hospital, Chengdu 610041, Sichuan Province, China. Electronic address: [email protected].;Intensive Care Unit, Sichuan Provincial Orthopedic Hospital, Chengdu 610041, Sichuan Province, China.;Intensive Care Unit, Sichuan Provincial Orthopedic Hospital, Chengdu 610041, Sichuan Province, China.;Department of Anesthesia, Sichuan Provincial Orthopedic Hospital, Chengdu 610041, Sichuan Province, China.",
"authors": "Qin|Zhijun|Z|;Deng|Yang|Y|;Li|Xia|X|;Li|Man|M|",
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"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612\nElsevier\n\nS2210-2612(21)01129-9\n10.1016/j.ijscr.2021.106627\n106627\nCase Report\nBone cement implantation syndrome induced by antibiotic-loaded bone cement covering the infected bone surface: A case report\nQin Zhijun [email protected]\na⁎\nDeng Yang a\nLi Xia a\nLi Man b\na Intensive Care Unit, Sichuan Provincial Orthopedic Hospital, Chengdu 610041, Sichuan Province, China\nb Department of Anesthesia, Sichuan Provincial Orthopedic Hospital, Chengdu 610041, Sichuan Province, China\n⁎ Corresponding author at: Intensive Care Unit, Sichuan Provincial Orthopedic Hospital, No. 132, West First Section, First Ring Road, Chengdu City, Sichuan Province 610041, China. [email protected]\n25 11 2021\n12 2021\n25 11 2021\n89 10662724 10 2021\n20 11 2021\n21 11 2021\n© 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction and importance\n\nBone cement implantation syndrome (BCIS) typically occurs during bone cementation and prosthesis insertion. Almost all of the models used to explain BCIS are based on studies related to hip arthroplasty. BCIS induced by bone cement implantation in superficial wounds has not been reported.\n\nCase presentation\n\nWe report the case of a 37-year-old man with chronic osteomyelitis of the left tibia (Cierny - Mader type II), who developed BCIS after covering the infected bone surface with antibiotic-loaded bone cement. BCIS presented as acute massive pulmonary exudation and hypoxemia. Early application of awake prone positioning effectively improved oxygenation and lung injury, and prevented the need for a more advanced means of respiratory support. The patient was discharged without any clinical complications on postoperative day 15.\n\nClinical discussion\n\nWe assessed the cause of acute respiratory events in this patient using Naranjo Adverse Drug Reaction Probability Scale, and BCIS was finally considered. Despite the lack of “driving force” (e.g., increased intramedullary pressure), the bone cement monomer may be absorbed into circulation through the wound surface due to its penetrability. Subsequent immune-mediated amplification resulted in pulmonary exudation and hypoxemia. As a pathophysiologically change-oriented strategy, effective drainage after awake prone positioning significantly improved clinical outcomes.\n\nConclusion\n\nBone cement monomer absorbed through the wound should be of concern, and pathophysiological change-oriented management should be emphasized in BCIS.\n\nHighlights\n\n• Bone cement monomer absorbed through the wound surface should be of concern.\n\n• Even a small amount of bone cement monomer can trigger severe organ damage due to immune amplification.\n\n• Prone position can be used for the management of bone cement implantation syndrome characterized by pulmonary exudation.\n\nKeywords\n\nBone cement implantation syndrome\nChronic osteomyelitis\nAwake prone positioning\nPulmonary exudation\nHypoxemia\n==== Body\npmc1 Introduction\n\nBone cement implantation syndrome (BCIS) is considered a unique complication of cemented orthopedic surgeries, and is characterized by varying degrees of respiratory and circulatory dysfunctions [1]. To date, the mechanisms of BCIS are still unclear and cannot be explained by a single model. However, the preventive and therapeutic measures for BCIS are largely based on the theories of pathogenesis [2], [3]. Elucidating the mechanisms from multiple perspectives, as well as the etiology and pathophysiology and prophylaxis and treatment, will be beneficial for the management of BCIS.\n\nWe highlight a case of BCIS caused by antibiotic-loaded bone cement implant, in which awake prone positioning (PP) played a pivotal role in improving oxygenation and facilitating recovery from lung injury. This case report has been reported in line with the SCARE Criteria [4].\n\n2 Case-report\n\n2.1 Case presentation\n\nA 37-year-old man with no family, drug, psychosocial or personal histories, was referred to the Sichuan Provincial Orthopedic Hospital for postoperative osteomyelitis following tibial fracture fixation. He had a left tibiofibular fracture due to a fall, and underwent internal fixation of a tibial fracture with screw/plate osteosynthesis in a local hospital about 10 mo prior. More than 6 mo ago, the skin of the left calf appeared red and swollen and an ulcer had formed. He was treated with antibiotics and dressing changes for several months at several medical institutions, but his symptoms did not improve.\n\nPhysical examination revealed a mildly swollen left calf with a 3 mm ulcer on the medial aspect of its lower segment. Laboratory tests on admission revealed higher triglycerides (5.61 mmol/L; normal range: <2.3 mmol/L), total cholesterol (7.49 mmol/L; normal range: <2.55 mmol/L), low-density lipoprotein (4.33 mmol/L; normal range: <3.37 mmol/L), and apolipoprotein B (1.58 g/L; normal range: 0.6–1.1 g/L) compared to reference values. Fatty liver was detected by abdominal ultrasound. Radiological examination showed thinning cortical bone in the lower tibia as well as bone heterogeneity (Fig. 1A). Chronic osteomyelitis of the left tibia (Cierny - Mader type II) was diagnosed.Fig. 1 Radiographic images of the left tibiofibula. A: Preoperative; B: Postoperative.\n\nFig. 1\n\n2.2 Treatment\n\nSurgical treatment was determined by both the patient and the surgeons. After blocking the left femoral and sciatic nerve with 0.2% ropivacaine, anesthesia was induced by administration of propofol, sufentanil, and rocuronium, and a No. 4 laryngeal mask was placed. Sevoflurane inhalation and continuous injection of propofol were applied for the maintenance of anesthesia. The original internal fixation device was removed and the chronically-infected membrane between the plate and bone was scraped. The wound surface was cleaned with normal saline, and vancomycin-loaded bone cement was used to cover the bone wound (approximately 2 cm × 5 cm). After the procedure, the tourniquet was deflated. The surgical duration was 95 min, the blood loss was 50 mL, intravenous infusion volume was 1200 mL, and urine volume was 200 mL. The laryngeal mask was removed when the patient awakened from anesthesia. He complained of mild dyspnea. The heart rate was 110 beats/min, blood pressure was 130/82 mmHg, respiratory rate was 28 breaths/min, and pulse oxygen saturation (SpO2) was 90%–91% (O2 was administered via face mask at 10 L/min). Considering the unstable oxygenation, the patient was transferred to an intensive care unit (ICU) under O2 therapy and monitoring.\n\nArterial blood gas analysis showed hypoxemia (Table 1). Ultrasound showed no abnormalities in the size, chamber, valve, and systolic and diastolic function of the heart. However, diffuse B-lines were found in the lungs. Hydrocortisone and furosemide were administered, but the patient's oxygenation status did not improve. A chest CT examination was implemented under monitoring and showed multiple patchy shadows and ground-glass opacities scattered around the texture, with extensive consolidation in the lower lobes of the lung (Fig. 2B). Based on the radiographic findings, awake PP was considered. As soon as the patient was transferred to the prone position, a choking cough occurred. Subsequently, a large amount of pink foamy sputum was expectorated, followed by a significant increase in SpO2. After 2 h of awake PP, SpO2 was maintained at 97% to 98% with 5 L/min O2 administered with nasal cannula. The first awake PP lasted 8 h. During the next 48 h, PP was intermittently performed for a total of 12 h, according to the patient's tolerance.Table 1 Postoperative laboratory findings and oxygen therapy.\n\nTable 1Parameter\t1 h\tDay 1\tDay 2\tDay 3\tDay 4\t\nArterial pH\t7.34\t7.34\t7.36\t7.41\t7.47\t\nPaO2 (mmHg)\t51\t79\t79\t83\t194\t\nPaCO2 (mmHg)\t44\t43\t48\t44\t37\t\nSaO2 (%)\t83\t95\t95\t96\t100\t\nSB (mmol/L)\t22.8\t22.8\t25.7\t27.9\t27.5\t\nLactate (mmol/L)\t3.2\t3.4\t2.6\t3.7\t2.1\t\nWBC (×109 per L)\t–\t15.8\t10.8\t11.2\t–\t\nHemoglobin (g/L)\t–\t149\t130\t140\t–\t\nPlatelets (×109 per L)\t–\t291\t214\t237\t–\t\nhs-TnT (ng/mL)\t–\t0.005\t–\t0.007\t–\t\npro-BNP (pg/mL)\t–\t84.16\t–\t667.8\t–\t\nPCT (ng/mL)\t–\t0.936\t–\t0.301\t–\t\nOxygen therapy\tFM\tNC\tNC\tNC\tNC\t\nFlow (L/min)\t10\t5\t3\t3\t3\t\nAbbreviations: FM, Face mask; hs-TnT, High-sensitivity cardiac troponin T; NC, Nasal catheter; PaCO2, Partial pressure of carbon dioxide; PaO2, Arterial partial pressure of oxygen; PCT, Procalcitonin; pro-BNP, pro-brain natriuretic peptide; SaO2, Blood oxygen saturation; SB, Standard bicarbonate; WBC, White blood cell.\n\nFig. 2 Chest computed tomography scan obtained during hospitalization. A: Before surgery; B: 3 h after surgery; C: 3 d after surgery; D: 12 d after surgery. Before and after surgery, significant changes occurred as well as the gradual dissipation of pulmonary lesions over time.\n\nFig. 2\n\n2.3 Outcome and follow-up\n\nOn the third postoperative day, the patient was transferred to the general ward because his oxygenation status was markedly improved and most of the lung lesions had dissipated (Table 1, Fig. 2C). Chest CT showed almost no abnormalities on postoperative day 12 (Fig. 2D). The patient was discharged on postoperative day 15 without any clinical complications. His outpatient follow-up at 4 wk. after surgery showed no clinical symptoms or chest abnormalities upon physical examination. Despite the unexpected perioperative complication, the patient was satisfied with our treatment because his lower limb lesions had improved markedly.\n\n3 Discussion and conclusion\n\n3.1 Discussion\n\nThe patient developed serious pulmonary edema after debridement and vancomycin-loaded bone cement implantation, and cardiogenic and airway obstruction-related factors were excluded. These symptoms were puzzling. Referring to a previous study [3], Naranjo Adverse Drug Reaction Probability Scale was used to assess the association between intraoperative drug use (including vancomycin) and subsequent symptoms. This scoring system clearly defines the causal relationship between drugs and adverse events at four levels: definite, probable, possible, and doubtful [5]. The bone cement was given a score of 6 in this scoring system, corresponding to probable. Therefore, BCIS was diagnosed.\n\nCurrent perspectives on the mechanisms of BCIS mainly include embolic and immunological models. Embolization is commonly used to explain BCIS occurring in hip arthroplasty. This theory is based on the fact that some amount of emboli, which may be composed of bone cement microparticle, bone, fat, marrow, or air, has been detected by ultrasonography or autopsy of the right heart and pulmonary vessels [3], [6]. The driving force for emboli to enter the circulation is related to the increased intramedullary pressure during the procedure. In our case, as the surgeon only used a “flaky” vancomycin-loaded bone cement to cover the bone wound, “pressure” contributing to the embolization appeared to be lacking. It is worth noting that the bone cement monomer may be absorbed through the wound due to its penetrating properties [7].\n\nHowever, a causal relationship between bone cement monomer and lung injury in this patient based solely on the above explanation seems far-fetched, as asymptomatic embolic events are not uncommon [8], [9]. Immunological models may be a bridge connecting the wound-absorbed bone cement monomer to acute pulmonary exudation. As the possibility of hydrostatic pulmonary edema was ruled out in this case, massive exudation of the lungs were attributed to hyperpermeability of the pulmonary capillaries. The direct effects of bone cement monomer, hypersensitivity, complement-mediated cytotoxicity, and waterfall release of cytokines may play important roles in this amplification effect, further illustrating that cement emboli may act as a mediator rather than a single mechanical force to promote BCIS development.\n\nPP, first proposed in the 1970s, facilitates the drainage of secretions, increases ventilation for pulmonary atelectasis, and optimizes ventilation-perfusion matching. The physiological improvements and clinical benefits based on PP have been a subject of debate [10]. In 2013, the PROSEVA trial demonstrated a significant benefit of PP in reducing 28-d and 90-d mortality in patients with severe acute respiratory distress syndrome (ARDS), and PP has mainly been applied to cases of severe ARDS with PaO2/FiO2 < 100 mmHg in subsequent clinical practice [11], [12]. With the COVID-19 pandemic, awake PP has been tentatively used in hypoxemic non-intubated COVID-19 patients, and significant improvement in oxygenation has been found. However, more clinical evidence is needed to determine whether non-sedated, non-intubated patients with COVID-19 really benefit from this therapy [13].\n\nBCIS in the reported patient presented as acute massive pulmonary exudation and hypoxemia without significant circulatory disturbance. Implementation of awake PP is, on the one hand, a pathophysiology-oriented management protocol, and on the other hand, a concern about the adverse effects of inadequate pulmonary drainage on long-term lung function. The rapid improvements in oxygenation and chest imaging of this patient were largely attributed to effective drainage after awake PP.\n\n3.2 Conclusion\n\nBone cement monomer absorbed through the wound surface should be of concern, which may also cause serious organ damage due to immune amplification. Pathophysiological change-oriented management should be emphasized in BCIS.\n\nFunding\n\nNo financial support was received for the completion of this study.\n\nEthical approval\n\nThis study is exempt from ethnical approval in our institution.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nRegistration of research studies\n\nNone.\n\nGuarantor\n\nZhijun Qin takes full responsibility of the work.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nCRediT authorship contribution statement\n\nZhijun Qin, Yang Deng and Man Li managed the patient and wrote the first draft.\n\nXia Li reviewed the manuscript.\n\nAll authors read and approved the final manuscript.\n\nDeclaration of competing interest\n\nNo conflict of interest exits in the submission of this manuscript.\n==== Refs\nReferences\n\n1 Hamal P.K. Poudel P.R. Singh J. Grade III bone cement implantation syndrome in malignant lung cancer patient: a case report BMC Anesthesiol. 18 2018 28 10.1186/s12871-018-0492-x 29499640\n2 Dradjat R.S. Pradana A.S. Putra D.P. Hexa Pandiangan R.A. Cendikiawan F. Mustamsir E. Successful management of severe manifestation bone cemented implantation syndrome during hemiarthroplasty surgery in patient with multiple comorbidities: a case report Int. J. Surg. Case Rep. 78 2021 331 335 10.1186/s12871-018-0492-x 33388512\n3 Kalra A. Sharma A. Palaniswamy C. El-Oshar S. Desai P. Yazbeck M. Diagnosis and management of bone cement implantation syndrome: case report and brief review Am. J. Ther. 20 2013 121 125 10.1097/MJT.0b013e31820b3de3 21317615\n4 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. SCARE Group The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 10.1016/j.ijsu.2020.10.034 33181358\n5 Liang R. Borgundvaag B. McIntyre M. Thwaites C. Ragan K. Wyllie A. Evaluation of the reproducibility of the Naranjo adverse drug reaction probability scale score in published case reports Pharmacotherapy 34 2014 1159 1166 10.1002/phar.1496 25266970\n6 Razuin R. Effat O. Shahidan M.N. Shama D.V. Miswan M.F. Bone cement implantation syndrome Malays. J. Pathol. 35 2013 87 90 23817399\n7 Hines C.B. Understanding bone cement implantation syndrome AANA J. 86 2018 433 441 31584416\n8 Sultan P. Seligman K. Carvalho B. Amniotic fluid embolism: update and review Curr. Opin. Anaesthesiol. 29 2016 288 296 10.1097/ACO.0000000000000328 27153475\n9 Rothberg D.L. Makarewich C.A. Fat embolism and fat embolism syndrome J. Am. Acad. Orthop. Surg. 27 2019 e346 e355 10.5435/JAAOS-D-17-00571 30958807\n10 Scholten E.L. Beitler J.R. Prisk G.K. Malhotra A. Treatment of ARDS with prone positioning Chest 151 2017 215 224 10.1016/j.chest.2016.06.032 27400909\n11 Guérin C. Reignier J. Richard J.C. Beuret P. Gacouin A. Boulain T. Prone positioning in severe acute respiratory distress syndrome N. Engl. J. Med. 368 2013 2159 2168 10.1056/NEJMoa1214103 23688302\n12 Ding L. Wang L. Ma W. He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study Crit. Care 24 2020 28 10.1186/s13054-020-2738-5 32000806\n13 Alhazzani W. Evans L. Alshamsi F. Møller M.H. Ostermann M. Prescott H.C. Surviving sepsis campaign guidelines on the Management of Adults with Coronavirus Disease 2019 (COVID-19) in the ICU: first update Crit. Care Med. 49 2021 e219 e234 10.1097/CCM.0000000000004899 33555780\n\n",
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"keywords": "Awake prone positioning; Bone cement implantation syndrome; Chronic osteomyelitis; Hypoxemia; Pulmonary exudation",
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"title": "Bone cement implantation syndrome induced by antibiotic-loaded bone cement covering the infected bone surface: A case report.",
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"literaturereference": "Qin Z, Deng Y, Li X, Li M.. Bone cement implantation syndrome induced by antibiotic-loaded bone cement covering the infected bone surface: A case report. International Journal of Surgery Case Reports. 2021;89:106627",
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},
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] |
{
"abstract": "Carbohydrate antigen 19-9 (CA 19-9) is a well-known tumor marker of adenocarcinoma (reference range, 37 U/mL). It can also be used, together with computed tomography, to monitor responses and resistance to chemotherapy in cancer patients. False elevation of CA 19-9 levels is often seen in conditions such as biliary tract obstruction and cholangitis. However, whether medication might induce false elevation of CA 19-9 levels has not yet been reported. A 74-year-old man was treated with third-line CPT-11 (irinotecan) plus panitumumab for stage IV cancer of the ascending colon. The patient developed chemotherapy-induced dysgeusia and was treated with polaprezinc. After polaprezinc administration, his CA 19-9 levels gradually increased from 18.9 to 1,699.4 U/mL. He developed deep vein thrombosis (DVT), although it was not associated with progressive disease or metastasis. Upon discontinuation of polaprezinc, CA 19-9 levels gradually decreased. This case demonstrates that polaprezinc may not only induce false elevation of CA 19-9 levels but also cause development of DVT induced by increased CA 19-9 levels, both of which are very rare events.",
"affiliations": "Department of Pharmacy, Saiseikai Hyogo Hospital, Kobe, Japan.;Department of Pharmacy, Saiseikai Hyogo Hospital, Kobe, Japan.;Department of Pharmacy, Saiseikai Hyogo Hospital, Kobe, Japan.;Department of Gastroenterology, Saiseikai Hyogo Hospital, Kobe, Japan.;Department of Gastroenterology, Saiseikai Hyogo Hospital, Kobe, Japan.;Department of Gastroenterology, Saiseikai Hyogo Hospital, Kobe, Japan.;Department of Gastroenterology, Saiseikai Hyogo Hospital, Kobe, Japan, [email protected].;Department of Surgery, Saiseikai Hyogo Hospital, Kobe, Japan.",
"authors": "Naito|Masahito|M|;Torii|Ryota|R|;Hashimoto|Yuki|Y|;Kawamoto|Yuki|Y|;Hayashi|Kenichi|K|;Shinoda|Hiroaki|H|;Honjo|Yumiko|Y|;Hiroyoshi|Motoki|M|",
"chemical_list": "D018395:CA-19-9 Antigen; D009942:Organometallic Compounds; D017967:Zinc Compounds; C061957:polaprezinc; D002336:Carnosine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000503221",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "64(3)",
"journal": "Chemotherapy",
"keywords": "CA 19-9; Chemotherapy; Deep vein thrombosis; Polaprezinc",
"medline_ta": "Chemotherapy",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D018395:CA-19-9 Antigen; D002336:Carnosine; D003110:Colonic Neoplasms; D004408:Dysgeusia; D005268:Femoral Vein; D006801:Humans; D008297:Male; D009942:Organometallic Compounds; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis; D017967:Zinc Compounds",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "163-166",
"pmc": null,
"pmid": "31655804",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Increase in Carbohydrate Antigen 19-9 Levels without Tumor Progression after Polaprezinc Administration that Induced Deep Vein Thrombosis in a Colon Cancer Patient.",
"title_normalized": "increase in carbohydrate antigen 19 9 levels without tumor progression after polaprezinc administration that induced deep vein thrombosis in a colon cancer patient"
}
|
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{
"abstract": "We performed a phase 1 study to evaluate the safety and feasibility of bortezomib (BOR) with melphalan and dexamethasone (BMD) in patients with light chain amyloidosis (AL) without severe cardiac failure. Patients received BOR on a twice-weekly schedule (days 1, 4, 8, and 11 of 28-day treatment cycles) at planned doses of 1.0 (dose level 1) and 1.3 (dose level 2) mg/m(2) in combination with melphalan 8 mg/m(2) on days 1-4 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Dose-limiting toxicity (DLT) was evaluated at the end of cycle one, and treatment was continued for four cycles. Six patients were enrolled at dose level 1, and one showed DLT (grade 3: herpes zoster). Further 3 patients were enrolled at dose level 2, and none experienced DLT. Thus, the maximum tolerated dose was defined as BOR doses of 1.3 mg/m(2) for the twice-weekly schedule. A total of 32 cycles of BMD therapy were given, and the most common hematologic toxicity was thrombocytopenia (47%). Peripheral neuropathy was the most common non-hematologic toxicity (16%). We demonstrated that BMD is safe and tolerable for Japanese AL patients without severe cardiac damage.\n\n\nBACKGROUND\nUMIN000006604.",
"affiliations": "Department of Hematology, Japan Community Healthcare Organization, Kyoto Kuramaguchi Medical Center, Kyoto, Japan. [email protected].;Department of Hematology, Japan Community Healthcare Organization, Kyoto Kuramaguchi Medical Center, Kyoto, Japan.;Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Hematology, National Hospital Organization Nishigunma National Hospital, Shibukawa, Japan.;Department of Hematology, Kanazawa University School of Medicine, Kanazawa, Japan.;Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.;Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.;Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.;Department of Neurology, Kumamoto University School of Medicine, Kumamoto, Japan.",
"authors": "Shimazaki|Chihiro|C|;Fuchida|Shin-Ichi|S|;Suzuki|Kenshi|K|;Ishida|Tadao|T|;Imai|Hirokazu|H|;Sawamura|Morio|M|;Takamatsu|Hiroyuki|H|;Abe|Masahiro|M|;Miyamoto|Toshihiro|T|;Hata|Hiroyuki|H|;Yamada|Masahito|M|;Ando|Yukio|Y|",
"chemical_list": "D000069286:Bortezomib; D003907:Dexamethasone; D008558:Melphalan",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-015-1901-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "103(1)",
"journal": "International journal of hematology",
"keywords": "AL amyloidosis; Bortezomib; Dexamethasone; Melpahaln",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000686:Amyloidosis; D000069286:Bortezomib; D003907:Dexamethasone; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008558:Melphalan; D008875:Middle Aged; D012008:Recurrence; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "79-85",
"pmc": null,
"pmid": "26588925",
"pubdate": "2016-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25059496;21752867;25027514;20375312;9302305;25430082;15070667;24213149;16990593;21483018;17561972;17768110;18245653;20085941;21507715;17606766;12036853;18024367;17855669;17008538;15180858;15572585;18711175;19090004;25492370;18024372;21533608;25827161;22331188;22331187;22964848;14734330;18633693;18753647;16044444;15365071;19498019;15958804;25248716;21562045",
"title": "Phase 1 study of bortezomib in combination with melphalan and dexamethasone in Japanese patients with relapsed AL amyloidosis.",
"title_normalized": "phase 1 study of bortezomib in combination with melphalan and dexamethasone in japanese patients with relapsed al amyloidosis"
}
|
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MELPHALAN"
},
{
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"activesubstance": {
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},
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"medicinalproduct": "BORTEZOMIB"
},
{
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"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
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"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1.3 MG/M2 DAYS (1, 4, 8, AND 11 OF 28-DAY TREATMENT)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BORTEZOMIB"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuropathy peripheral",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHIMAZAKI C, FUCHIDA S-I, SUZUKI K, ISHIDA T, IMAI H, SAWAMURA M, ET AL. PHASE 1 STUDY OF BORTEZOMIB IN COMBINATION WITH MELPHALAN AND DEXAMETHASONE IN JAPANESE PATIENTS WITH RELAPSED AL AMYLOIDOSIS. INT-J-HEMATOL 2016?103(1):79-85.",
"literaturereference_normalized": "phase 1 study of bortezomib in combination with melphalan and dexamethasone in japanese patients with relapsed al amyloidosis",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20160222",
"receivedate": "20160222",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160526"
}
] |
{
"abstract": "The addition of Sc(OTf)3 and Al(OTf)3 to the mononuclear MnIII-hydroxo complex [MnIII(OH)(dpaq)]+ (1) gives rise to new intermediates with spectroscopic properties and chemical reactivity distinct from those of [MnIII(OH)(dpaq)]+. The electronic absorption spectra of [MnIII(OH)(dpaq)]+ in the presence of Sc(OTf)3 (1-ScIII) and Al(OTf)3 (1-AlIII) show modest perturbations in electronic transition energies, consistent with moderate changes in the MnIII geometry. A comparison of 1H NMR data for 1 and 1-ScIII confirm this conclusion, as the 1H NMR spectrum of 1-ScIII shows the same number of hyperfine-shifted peaks as the 1H NMR spectrum of 1. These 1H NMR spectra, and that of 1-AlIII, share a similar chemical-shift pattern, providing firm evidence that these Lewis acids do not cause gross distortions to the structure of 1. Mn K-edge X-ray absorption data for 1-ScIII provide evidence of elongation of the axial Mn-OH and Mn-N(amide) bonds relative to those of 1. In contrast to these modest spectroscopic perturbations, 1-ScIII and 1-AlIII show greatly enhanced reactivity toward hydrocarbons. While 1 is unreactive toward 9,10-dihydroanthracene (DHA), 1-ScIII and 1-AlIII react rapidly with DHA (k2 = 0.16(1) and 0.25(2) M-1 s-1 at 50 °C, respectively). The 1-ScIII species is capable of attacking the much stronger C-H bond of ethylbenzene. The basis for these perturbations to the spectroscopic properties and reactivity of 1 in the presence of these Lewis acids was elucidated by comparing properties of 1-ScIII and 1-AlIII with the recently reported MnIII-aqua complex [MnIII(OH2)(dpaq)]2+ ( J. Am. Chem. Soc. 2018, 140, 12695-12699). Because 1-ScIII and 1-AlIII show 1H NMR spectra essentially identical to that of [MnIII(OH2)(dpaq)]2+, the primary effect of these Lewis acids on 1 is protonation of the hydroxo ligand caused by an increase in the Brønsted acidity of the solution.",
"affiliations": "Department of Chemistry and Center for Environmentally Beneficial Catalysis, The University of Kansas, 1567 Irving Hill Road, Lawrence, Kansas 66045, United States.;Department of Chemistry and Center for Environmentally Beneficial Catalysis, The University of Kansas, 1567 Irving Hill Road, Lawrence, Kansas 66045, United States.;Department of Chemistry and Center for Environmentally Beneficial Catalysis, The University of Kansas, 1567 Irving Hill Road, Lawrence, Kansas 66045, United States.;Department of Chemistry and Center for Environmentally Beneficial Catalysis, The University of Kansas, 1567 Irving Hill Road, Lawrence, Kansas 66045, United States.",
"authors": "Rice|Derek B|DB|;Grotemeyer|Elizabeth N|EN|;Donovan|Anna M|AM|;Jackson|Timothy A|TA|http://orcid.org/0000-0002-3529-2715",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1021/acs.inorgchem.9b02980",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-1669",
"issue": "59(5)",
"journal": "Inorganic chemistry",
"keywords": null,
"medline_ta": "Inorg Chem",
"mesh_terms": null,
"nlm_unique_id": "0366543",
"other_id": null,
"pages": "2689-2700",
"pmc": null,
"pmid": "32045220",
"pubdate": "2020-03-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of Lewis Acids on the Structure and Reactivity of a Mononuclear Hydroxomanganese(III) Complex.",
"title_normalized": "effect of lewis acids on the structure and reactivity of a mononuclear hydroxomanganese iii complex"
}
|
[
{
"companynumb": "US-OTSUKA-2020_012537",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
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"drugdosageform": "Suspension for injection",
"drugdosagetext": "UNK",
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"medicinalproduct": "ABILIFY MAINTENA"
}
],
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"reaction": [
{
"reactionmeddrapt": "No adverse event",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Rice DB, Grotemeyer EN, Donovan AM, Jackson TA,. Effect of Lewis Acids on the Structure and Reactivity of a Mononuclear Hydroxomanganese(III) Complex. Inorganic chemistry. 2020;59(56):2689-700",
"literaturereference_normalized": "effect of lewis acids on the structure and reactivity of a mononuclear hydroxomanganese iii complex",
"qualification": "3",
"reportercountry": "US"
},
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"receiptdate": "20211004",
"receivedate": "20211004",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
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},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Complaints of hypoglycemia resemble the sedative effect of antipsychotics. As such, clinicians may overlook hypoglycemia in patients with psychiatric disorders. Here, a case of hypoglycemia associated with hyperinsulinemia induced by quetiapine in a female patient with bipolar disorder is reported. The case suggests that clinicians should be aware of the potential for hypoglycemia induced by second-generation antipsychotics.",
"affiliations": "Department of Psychiatry, Faculty of Medicine, Saga University, Saga City, Japan.;Department of Psychiatry, Faculty of Medicine, Saga University, Saga City, Japan.;Department of Psychiatry, Faculty of Medicine, Saga University, Saga City, Japan.;Department of Psychiatry, Faculty of Medicine, Saga University, Saga City, Japan.;Department of Psychiatry, Faculty of Medicine, Saga University, Saga City, Japan.;Department of Neuropsychiatry, Faculty of Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Japan.;Department of Psychiatry, Faculty of Medicine, Saga University, Saga City, Japan.",
"authors": "Fujita|Tomonari|T|;Mizoguchi|Yoshito|Y|;Kunitake|Yutaka|Y|;Tateishi|Hiroshi|H|;Inaba|Takayoshi|T|;Kato|Takahiro A|TA|;Monji|Akira|A|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2155-7780",
"issue": "20(1)",
"journal": "The primary care companion for CNS disorders",
"keywords": null,
"medline_ta": "Prim Care Companion CNS Disord",
"mesh_terms": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D003865:Depressive Disorder, Major; D003951:Diagnostic Errors; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D008875:Middle Aged; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "101547532",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29372938",
"pubdate": "2018-01-25",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Second-Generation Antipsychotic-Induced Hypoglycemia.",
"title_normalized": "second generation antipsychotic induced hypoglycemia"
}
|
[
{
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"occurcountry": "JP",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
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"drugstructuredosagenumb": "25",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "QUETIAPINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
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"drugadministrationroute": "048",
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"drugindication": "DEPRESSIVE SYMPTOM",
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"medicinalproduct": "MIRTAZAPINE."
}
],
"patientagegroup": null,
"patientonsetage": "62",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hyperinsulinaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypoglycaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nutritional condition abnormal",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "FUJITA T, MIZOGUCHI Y, KUNITAKE Y, TATEISHI H, INABA T, KATO TA, ET AL. SECOND-GENERATION ANTIPSYCHOTIC-INDUCED HYPOGLYCEMIA. PRIM CARE COMPANION CNS DISORD. 2018 JAN 25?20(1). PII: 17BR02186.",
"literaturereference_normalized": "second generation antipsychotic induced hypoglycemia",
"qualification": "1",
"reportercountry": "JP"
},
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"receiptdate": "20190312",
"receivedate": "20180209",
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},
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},
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
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{
"actiondrug": "1",
"activesubstance": {
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},
"drugadditional": "1",
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"drugindication": "MAJOR DEPRESSION",
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"medicinalproduct": "MIRTAZAPINE."
},
{
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},
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"drugindication": "MAJOR DEPRESSION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosagenumb": "25",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "QUETIAPINE."
}
],
"patientagegroup": null,
"patientonsetage": "62",
"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
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"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
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},
"primarysource": {
"literaturereference": "FUJITA T, MIZOGUCHI Y, KUNITAKE Y, TATEISHI H, INABA T, KATO TA, ET AL. SECOND-GENERATION ANTIPSYCHOTIC-INDUCED HYPOGLYCEMIA. PRIM-CARE-COMPAN-J-CLIN-PSYCHIATRY 2018?20(1):17BR02186.",
"literaturereference_normalized": "second generation antipsychotic induced hypoglycemia",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180522",
"receivedate": "20180522",
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},
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},
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"seriousnesscongenitalanomali": null,
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"seriousnessother": 1,
"transmissiondate": "20180711"
},
{
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{
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},
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"drugindication": "DEPRESSIVE SYMPTOM",
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"medicinalproduct": "MIRTAZAPINE."
}
],
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"patientonsetage": "62",
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"reaction": [
{
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}
],
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},
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"literaturereference_normalized": "second generation antipsychotic induced hypoglycemia",
"qualification": "1",
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},
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20181010"
},
{
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "202295",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
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"drugdosagetext": "2.5 MG, QD",
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"drugindication": "ANOREXIA NERVOSA",
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"medicinalproduct": "OLANZAPINE."
},
{
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"activesubstancename": "PAROXETINE"
},
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] |
{
"abstract": "The use of venovenous extracorporeal membrane oxygenation (VV-ECMO) has traditionally been limited to a narrow set of clinical circumstances, such as acute hypoxic respiratory failure, submassive pulmonary embolism, and cardiopulmonary collapse. Within the pediatric population, there have been cases of VV-ECMO in the context of extrinsic airway compression by a mediastinal mass, typically in the setting of either a lymphoma or germ cell tumors. However, the use of VV-ECMO for adults with extrinsic airway compression is comparatively limited. More specifically, VV-ECMO has been used as a bridge for tracheal reconstruction in both children and adults. Although, it has not been used in adults in the context of palliative endobronchial stent placement. We present a case of a 49-year-old woman with refractory multiple myeloma and extramedullary plasmacytoma presenting with acute hypoxic respiratory failure from extrinsic airway compression by a mediastinal plasmacytoma. We were able to use VV-ECMO to assist with endobronchial stent placement, followed by radiation therapy, and ultimately hospital discharge. In this article, we also review the literature surrounding VV-ECMO for extrinsic airway compression.",
"affiliations": "Departments of Internal Medicine.;Division of Pulmonary Medicine, Mayo Clinic, Phoenix, AZ.;Cardiothoracic Surgery.;Division of Pulmonary Medicine, Mayo Clinic, Phoenix, AZ.",
"authors": "Nokes|Brandon T|BT|;Vaszar|Laszlo|L|;Jahanyar|Jama|J|;Swanson|Karen L|KL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/LBR.0000000000000435",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1948-8270",
"issue": "25(2)",
"journal": "Journal of bronchology & interventional pulmonology",
"keywords": null,
"medline_ta": "J Bronchology Interv Pulmonol",
"mesh_terms": "D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D010954:Plasmacytoma; D012131:Respiratory Insufficiency; D015607:Stents",
"nlm_unique_id": "101496866",
"other_id": null,
"pages": "144-147",
"pmc": null,
"pmid": "28906275",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "VV-ECMO-Assisted High-Risk Endobronchial Stenting as Rescue for Asphyxiating Mediastinal Mass.",
"title_normalized": "vv ecmo assisted high risk endobronchial stenting as rescue for asphyxiating mediastinal mass"
}
|
[
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},
{
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},
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"drugindication": "PLASMA CELL MYELOMA",
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}
],
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{
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}
],
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},
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"literaturereference": "NOKES B, VASZAR L, JAHANYAR J, SWANSON K. VV-ECMO-ASSISTED HIGH-RISK ENDOBRONCHIAL STENTING AS RESCUE FOR ASPHYXIATING MEDIASTINAL MASS. JOURNAL OF BRONCHOLOGY AND INTERVENTIONAL PULMONOLOGY. 2018 APR?25 (2):144-147.",
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
}
] |
{
"abstract": "To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to a dolutegravir-based regimen, regardless of the genotypic susceptibility score (GSS).\n\n\n\nThis was an observational single-centre study assessing ART-treated patients with plasma viral load (pVL) <50 copies/mL who were switched to a dolutegravir-based regimen with 1 year of follow-up. PCR negative was defined as an undetected PCR signal. Trough plasma concentration (C24) was determined using UPLC-MS/MS.\n\n\n\nTwo hundred and thirty-nine patients initiated a dolutegravir-based regimen: 12%, 29% and 59% had a total GSS of 1 or 1.5 (group 1), 2 or 2.5 (group 2) and 3 (group 3), respectively. At switch initiation, the median time since first ART and the median duration with pVL <50 copies/mL were 13 years (IQR = 6-19) and 3 years (IQR = 1-6), respectively. Median times since last genotype were 9, 10 and 5 years for groups 1, 2 and 3, respectively. Twenty patients (8.4%) discontinued the dolutegravir-based regimen due to adverse events. During the study, 96.4% (n = 661/686) of all pVL were <50 copies/mL. Four patients (1.7%) experienced virological failure (two pVL >50 copies/mL) without emergence of resistance; these patients' GSSs were 2, 2.5, 3 and 3. The median dolutegravir C24 was 1545 ng/mL (IQR = 1150-2097). Of the patients with pVL <20 copies/mL, 72% were PCR negative during the follow-up, with no difference between the three groups of patients.\n\n\n\nThis observational cohort study showed a high level of virological suppression maintenance in the first year following the switch to a dolutegravir-based regimen, even in patients with GSS ≤2.",
"affiliations": "IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Virologie, Hôpital Bichat, AP-HP, Paris, France.;IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Pharmacologie-Toxicologie, Hôpital Bichat, AP-HP, Paris, France.;IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Pharmacologie-Toxicologie, Hôpital Bichat, AP-HP, Paris, France.;IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Service de Maladies Infectieuses et Tropicales, Hôpital Bichat, AP-HP, Paris, France.;AP-HP, Hôpital Bichat-Claude Bernard, Service de Maladies Infectieuses et Tropicales, 75018 Paris, France.;IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Virologie, Hôpital Bichat, AP-HP, Paris, France.;AP-HP, Hôpital Bichat-Claude Bernard, Service de Maladies Infectieuses et Tropicales, 75018 Paris, France.;AP-HP, Hôpital Bichat-Claude Bernard, Service de Maladies Infectieuses et Tropicales, 75018 Paris, France.;IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Service de Maladies Infectieuses et Tropicales, Hôpital Bichat, AP-HP, Paris, France.;IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Virologie, Hôpital Bichat, AP-HP, Paris, France.;IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Service de Maladies Infectieuses et Tropicales, Hôpital Bichat, AP-HP, Paris, France.",
"authors": "Charpentier|Charlotte|C|;Peytavin|Gilles|G|;Lê|Minh P|MP|;Joly|Véronique|V|;Cabras|Ornella|O|;Perrier|Marine|M|;Le Gac|Sylvie|S|;Phung|Bao|B|;Yazdanpanah|Yazdan|Y|;Descamps|Diane|D|;Landman|Roland|R|",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; C562325:dolutegravir",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dky062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "73(6)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D057915:Drug Substitution; D005260:Female; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D019562:Viral Load",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "1665-1671",
"pmc": null,
"pmid": "29528412",
"pubdate": "2018-06-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort.",
"title_normalized": "high virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir based regimen week 48 results in an observational cohort"
}
|
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"activesubstancename": "DOLUTEGRAVIR"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "50 MG, QD, MG, ONCE DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTIRETROVIRAL THERAPY",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "50",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOLUTEGRAVIR"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABACAVIR SULFATE\\LAMIVUDINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021652",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTIRETROVIRAL THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ABACAVIR SULFATE + LAMIVUDINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Virologic failure",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHARPENTIER C, PEYTAVIN G, L? MP, JOLY V, CABRAS O, PERRIER M.ET.AL. HIGH VIROLOGICAL SUPPRESSION REGARDLESS OF THE GENOTYPIC SUSCEPTIBILITY SCORE AFTER SWITCHING TO A DOLUTEGRAVIR-BASED REGIMEN: WEEK 48 RESULTS IN AN OBSERVATIONAL COHORT. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. 2018?73(6):1665-1671. DOI: 10.1093/JAC/DKY062",
"literaturereference_normalized": "high virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir based regimen week 48 results in an observational cohort",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20180618",
"receivedate": "20180618",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 15022551,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "OBJECTIVE\nNeoadjuvant chemotherapy (NAC) followed by esophagectomy has become a standard treatment for esophageal squamous cancer (ESCC) in Japan. We used propensity-matching analysis to clarify the safety and efficacy of NAC in daily clinical practice.\n\n\nMETHODS\nWe reviewed the medical records of 335 patients with clinical Stage II/III ESCC diagnosed between 2007 and 2012, including 191 who received preoperative NAC (NAC group) and 144 treated by upfront surgery (US group). After propensity score matching, there were 118 patients in each group. We compared the postoperative complications and long-term outcomes between the groups.\n\n\nRESULTS\nSeven patients in the NAC group underwent replacement therapy. Complications occurred in 76 (68.5%) and 76 (64.4%) patients in NAC and US groups, respectively (p = 0.51), and severe complications occurred in 17 (22.4%) and 30 (39.5%) patients, respectively (p = 0.057). One (0.8%) and three patients (2.5%) from the US group died within 30 days and 90 days after surgery, respectively, but none of the patients from the NAC group died within the same period. The 5-year survival rate was 54.9% in the NAC group and 41.2% in the US group (p = 0.024).\n\n\nCONCLUSIONS\nNAC is a safe and effective treatment to improve prognosis in the clinical setting.",
"affiliations": "Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.;Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.;Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.;Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.;Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.;Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.;Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.;Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. [email protected].",
"authors": "Kurogochi|Takanori|T|;Honda|Michitaka|M|;Yamashita|Kotaro|K|;Hayami|Masaru|M|;Okamura|Akihiko|A|;Imamura|Yu|Y|;Mine|Shinji|S|;Watanabe|Masayuki|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s00595-018-1718-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-1291",
"issue": "49(2)",
"journal": "Surgery today",
"keywords": "Complications; Daily clinical practice; Esophageal cancer; Neoadjuvant chemotherapy",
"medline_ta": "Surg Today",
"mesh_terms": "D000368:Aged; D002294:Carcinoma, Squamous Cell; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D005260:Female; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011183:Postoperative Complications; D011300:Preoperative Care; D011379:Prognosis; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9204360",
"other_id": null,
"pages": "150-157",
"pmc": null,
"pmid": "30276466",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "23830137;28111535;20931620;23274278;28063028;25620903;18673563;15273542;16822992;21879261;24982463;22239958;21296855;26330238;26095389;21444866;20229072;28033447;17383866;27280509;12049861;27689845",
"title": "Safety and efficacy of preoperative chemotherapy followed by esophagectomy versus upfront surgery for resectable esophageal squamous cell carcinoma.",
"title_normalized": "safety and efficacy of preoperative chemotherapy followed by esophagectomy versus upfront surgery for resectable esophageal squamous cell carcinoma"
}
|
[
{
"companynumb": "JP-HQ SPECIALTY-JP-2019INT000086",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "018057",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "80 MG/M2, DAY 1 PLANNED",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugstructuredosagenumb": "80",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "800 MG/M2, DAYS 1-5 PLANNED",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OESOPHAGEAL SQUAMOUS CELL CARCINOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "800",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "5-FLUOROURACIL /00098801/"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatic function abnormal",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KUROGOCHI T, HONDA M, YAMASHITA K, HAYAMI M, OKAMURA A, IMAMURA Y, ET AL.. SAFETY AND EFFICACY OF PREOPERATIVE CHEMOTHERAPY FOLLOWED BY ESOPHAGECTOMY VERSUS UPFRONT SURGERY FOR RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA. SURG-TODAY. 2019?49(2):150-157",
"literaturereference_normalized": "safety and efficacy of preoperative chemotherapy followed by esophagectomy versus upfront surgery for resectable esophageal squamous cell carcinoma",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190404",
"receivedate": "20190404",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "This study aimed to characterize chemotherapy-induced transient increase and surge of CA 19-9 level to treatment response in patients with advanced pancreatic ductal adenocarcinoma (PDAC). A retrospective case series was performed of advanced PDAC patients treated with first-line chemotherapy at City of Hope Comprehensive Cancer Center from Jan 2017 to May 2020. CA 19-9 surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CA 19-9 levels compared to baseline. Out of 106 advanced PDAC patients, 38 were evaluable for CA 19-9 surge. Fourteen (51.9%) patients treated with FOLFIRINOX and 3 (27.3%) patients treated with nab-P + Gem chemotherapy demonstrated an early transient rise in CA 19-9 level. A CA 19-9 surge was documented in 9 (23.7%) patients, all with duration of surge lasting < 16 weeks. Five out of 9 (55.6%) patients (4: FOLFIRINOX, 1: nab-P + Gem) with CA 19-9 surge demonstrated partial objective response rate on surveillance cross-sectional imaging. One patient (FOLFIRINOX) had stable disease, and 2 patients (1: FOLFIRINOX, 1: nab-P + Gem) were found to have disease progression after treatment interruption. The initial early rise of CA 19-9 levels during chemotherapy in patients with advanced PDAC may not indicate tumor progression. Rather, it may represent a chemotherapy-induced transient increase or surge phenomenon of the tumor marker in patients responding to treatment.",
"affiliations": "Department of Surgery, MercyOne Medical Center, Des Moines IA United States. Electronic address: [email protected].;Department of Surgery, MercyOne Medical Center, Des Moines IA United States. Electronic address: [email protected].;Department of Surgery, City of Hope National Medical Center, Duarte CA United States. Electronic address: [email protected].;Department of Surgery, City of Hope National Medical Center, Duarte CA United States. Electronic address: [email protected].;Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center, Duarte CA United States. Electronic address: [email protected].;Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center, Duarte CA United States. Electronic address: [email protected].",
"authors": "Le|Viet H|VH|;Franko|Jan|J|;Paz|Benjamin I|BI|;Singh|Gagandeep|G|;Fakih|Marwan|M|;Chung|Vincent|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.ctarc.2021.100397",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2468-2942",
"issue": "28()",
"journal": "Cancer treatment and research communications",
"keywords": "CA 19–9 surge; Chemo-induced CA 19–9 surge; FOLFIRINOX-induced CA 19–9; Nab-P + Gem-induced CA 19–9; Transient CA 19–9 increase",
"medline_ta": "Cancer Treat Res Commun",
"mesh_terms": null,
"nlm_unique_id": "101694651",
"other_id": null,
"pages": "100397",
"pmc": null,
"pmid": "34023768",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chemotherapy-induced early transient increase and surge of CA 19-9 level in patients with pancreatic Adenocarcinoma✰.",
"title_normalized": "chemotherapy induced early transient increase and surge of ca 19 9 level in patients with pancreatic adenocarcinoma"
}
|
[
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-04033",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "UNKNOWN",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ADENOCARCINOMA PANCREAS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "5?FU"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "091032",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "UNKNOWN",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ADENOCARCINOMA PANCREAS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "IRINOTECAN"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "089384",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "UNKNOWN",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ADENOCARCINOMA PANCREAS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEUCOVORIN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "UNKNOWN",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ADENOCARCINOMA PANCREAS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OXALIPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Metastases to peritoneum",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Carbohydrate antigen 19-9 increased",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LE V, FRANKO J, PAZ B, SINGH G, FAKIH M, CHUNG V. CHEMOTHERAPY?INDUCED EARLY TRANSIENT INCREASE AND SURGE OF CA 19?9 LEVEL IN PATIENTS WITH PANCREATIC ADENOCARCINOMA. CANCER TREATMENT AND RESEARCH COMMUNICATIONS. 2021 JAN 01?28:. DOI:HTTPS://DOI.ORG/10.1016/J.CTARC.2021.100397",
"literaturereference_normalized": "chemotherapy induced early transient increase and surge of ca 19 9 level in patients with pancreatic adenocarcinoma",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "US",
"receiptdate": "20210921",
"receivedate": "20210921",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19860650,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "Severe intraoperative hypotension has been reported in patients on angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 antagonists. We describe a patient on lisinopril who developed refractory intraoperative hypotension associated with increased serum tryptase level suggesting mast cell activation (allergic reaction). However, allergology workup ruled out an allergic etiology as well as mastocytosis, and hypotension recalcitrant to treatment was attributed to uninterrupted lisinopril therapy. Elevated serum tryptase was attributed to our patient's chronic renal insufficiency.",
"affiliations": "Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.;Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.;Department of Internal Medicine, Mayo Clinic Program for the Study of Mast Cell and Eosinophil Disorders, Mayo Clinic, Rochester, MN 55905, USA.;Division of Rheumatology, Allergy & Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.;Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.",
"authors": "Sprung|Juraj|J|;Larson|Kelly J|KJ|;Divekar|Rohit D|RD|;Butterfield|Joseph H|JH|;Schwartz|Lawrence B|LB|;Weingarten|Toby N|TN|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5415/apallergy.2015.5.1.47",
"fulltext": "\n==== Front\nAsia Pac AllergyAsia Pac AllergyAPAAsia Pacific Allergy2233-82762233-8268Asia Pacific Association of Allergy, Asthma and Clinical Immunology 10.5415/apallergy.2015.5.1.47Educational & Teaching MaterialRefractory intraoperative hypotension with elevated serum tryptase Sprung Juraj 1Larson Kelly J. 1Divekar Rohit D. 2Butterfield Joseph H. 3Schwartz Lawrence B. 4Weingarten Toby N. 11 Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.2 Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.3 Department of Internal Medicine, Mayo Clinic Program for the Study of Mast Cell and Eosinophil Disorders, Mayo Clinic, Rochester, MN 55905, USA.4 Division of Rheumatology, Allergy & Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.\nCorrespondence: Juraj Sprung. Department of Anesthesiology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN 55905, USA. Tel: +1-507-255-3298, Fax: +1-507-255-6463, [email protected] 2015 28 1 2015 5 1 47 50 14 8 2014 25 12 2014 Copyright © 2015. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Severe intraoperative hypotension has been reported in patients on angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 antagonists. We describe a patient on lisinopril who developed refractory intraoperative hypotension associated with increased serum tryptase level suggesting mast cell activation (allergic reaction). However, allergology workup ruled out an allergic etiology as well as mastocytosis, and hypotension recalcitrant to treatment was attributed to uninterrupted lisinopril therapy. Elevated serum tryptase was attributed to our patient's chronic renal insufficiency.\n\nAnaphylaxisRenal insufficiency, ChronicHypotensionLisinoprilMastocytosisTryptase\n==== Body\nINTRODUCTION\nPreoperative use of angiotensin-converting enzyme inhibitors (ACEI) has been associated with intraoperative hypotension [1]. We describe a patient on the ACEI lisinopril who developed severe intraoperative hypotension, but because hypotension was associated with increased serum tryptase levels a comprehensive allergology work-up was conducted.\n\nCASE REPORT\nThe Mayo Clinic Institutional Review Board gave written permission for the authors to publish this report. A 66-year-old male with chronic renal insufficiency (serum creatinine, 2.0 mg/dL) and hypertension was scheduled for cryoablation of recurrent renal carcinoma on a solitary kidney. Two hours before the procedure the patient took propranolol (120 mg) and lisinopril (10 mg). Anesthesia was induced with lidocaine, fentanyl, propofol, and succinylcholine, and he immediately developed hypotension recalcitrant to treatment with intravenous crystalloids, ephedrine, phenylephrine and vasopressin and bradycardia recalcitrant to ephedrine and glycopyrrolate. Only epinephrine, 20 µg every 3 minutes, would transiently increase blood pressure and heart rate. Epinephrine and phenylephrine infusions were initiated, both at 0.05 µg/kg/min. Though clinical features of an allergic reaction were absent (urticaria, bronchospasm, etc.), anaphylaxis was still considered as a part of differential diagnosis and hydrocortisone, diphenhydramine, and famotidine were administered. Transesophageal echocardiography showed good ventricular filling (therefore hypotension was unrelated to hypovolemia) and myocardial contractility (therefore unrelated to decreased myocardial contractility). The procedure was aborted and patient was transferred to the intensive care unit where cardiac troponins, and the adrenocorticotropic hormone stimulation test were normal. Three hours after the hypotensive event the total serum tryptase level was measured 16.2 µg/L (reference, <11.5 µg/L), raising the possibility of an allergic reaction. After 6 hours the patient was weaned from vasopressors. A baseline total tryptase level, measured 72 hours after the hypotension remained high (16.5 µg/L), but both 24-hour urinary N-methylhistamine (NMH), 67 µg/g creatinine, (reference, 30-200 µg/g creatinine) and 11-β prostaglandin F2α (11-β PGF2α), 874 ng per 24 hours (reference, <1,000 ng per 24 hours) were normal.\n\nAllergology consult was obtained and patient interview revealed that 2 years earlier he underwent 2 uneventful anesthetics with the same agents as during the present anesthetic, but at that time he was not receiving lisinopril, which pointed to its potential role in encountered hypotension. Cryoablation was rescheduled one week later, and the lisinopril had been withheld for the entire week. In addition, preoperatively our patient received prednisone (50 mg) 13, 7 , and 1 hour prior to the procedure; montelukast (10 mg) and cetirizine (10 mg) both day before and on the morning of surgery; and diphenhydramine (50 mg) and famotidine (10 mg) both on the morning of surgery. The procedure was uneventful. Six weeks later the patient was scheduled for allergy testings. Surprisingly, the serum tryptase remained elevated (23.9 µg/L). Allergy testings for medications used perioperatively (midazolam, propofol, succinylcholine, lidocaine, dexamethasone, penicillin, benzylpenicilloyl moiety, alkaline hydrolysis product, cefazolin, povidone-iodine swab stick, and chlorhexidine) were all negative. Repeat NMH and 11-β PGF2α were normal along with negative c-kit D816V mutation analysis on peripheral blood.\n\nDISCUSSION\nWe describe a patient on the ACEI, lisinopril, who developed refractory hypotension after anesthetic induction, with elevated serum tryptase which suggested a possibility for allergic etiology. However, although the acute serum tryptase level was elevated, so was the baseline level (level remote from event), making an acute mast cell activation event an unlikely culprit. This notion was further supported by normal urine NMH and 11-β PGF2α levels [2]. The fact that the patient underwent subsequent uneventful anesthetic using the same drugs but with lisinopril withheld, reiterated the likelihood that the ACEI therapy was the likely culprit. The persistently elevated tryptase was attributed to renal insufficiency.\n\nThe enzyme tryptase is secreted from mast cells in immature proforms (α- and β-protryptases). Protryptases undergo processing within the cell to become mature tryptase, which is stored in mast cell granules and released only during mast cell activation. Portions of the protryptases that do not mature are constitutively secreted from mast cells and are always present in 'normal' plasma. Total tryptase serum assay measures both pro- and mature (β)-forms of tryptase [3]. In the absence of mast cell activation, nearly all of the serum tryptase is the proform, and reflects the mast cell burden, which is typically elevated in systemic mastocytosis. During severe anaphylaxis mature β-tryptase is released from store granule, raising total tryptase levels above baseline. Furthermore, prostaglandin D2 and histamine are also released and their degradation products appear in the urine as 11-β PGF2α and NMH [4].\n\nTo diagnose the cause for increased serum tryptase one should ideally know the total and mature β-tryptase, unfortunately testing for mature β-tryptase is available in only one center in the United States [5]. When both total (>11.5 µg/L) and mature β (>1 µg/L) tryptases are elevated, anaphylaxis may be considered [3]. In patients with mastocytosis associated with mast cell activation, acute total tryptase levels are increased above baseline (Table 1). Comparison of acute (within 4 hours of event) to baseline levels (at least 24 hours after signs have resolved) of total tryptase are necessary to distinguish between an increased mast cell burden (mastocytosis with an cute mast cell degranulation) and mast cell degranulation [3]. Therefore, if the baseline total tryptase remains chronically elevated a nonanaphylactic causes, such as mastocytosis, may be considered. The Red Española de Mastocytosis or Spanish Network on Mastocytosis (REMA) score may be used to assess the probability of systemic mastocytosis [6]. The REMA score assigns positive or negative points: male (+1), female (-1), serum baseline tryptase levels <15 µg/L (-1) or >25 µg/L (+2), presence (-2) or absence (+1) of pruritus, hives or angioedema and presence (+3) of presyncope or syncope [7]. A REMA score of ≥2 indicates a high likelihood of bone marrow mast cell clonality. In our case, the REMA score was 2, but mastocytosis was excluded because of the atypical clinical history, negative NMH and PGF2α on two independent occasions, and a negative D816V c-kit mutation [8]. Finally, in our patient elevated serum tryptase was attributed to renal insufficiency [9]. The proposed mechanism of elevated serum tryptase in patients with renal insufficiency is based on decreased clearance of stem cell factor which causes mast cell hyperplasia resulting in serum tryptase elevation [10].\n\nIn our patient severe hypotension refractory to treatment was likely associated with lisinopril therapy. Angiotensin system inhibitors (as well as angiotensin receptor blockers) interfere with regulation of blood pressure and have a vasodilatory action via multiple mechanisms. These drugs induce a direct sympathetic blockade and reduce the responsiveness to alpha-adrenergic agonists, inhibit the vasoconstrictor effects of angiotensin II by binding to its receptor, and impair the degradation of vasodilators such as bradykinin. Patients receiving chronic antihypertensive therapy with angiotensin system inhibitors are at higher risk for refractory hypotension during anesthesia [1, 11, 12, 13].\n\nThis case emphasizes that the presence of elevated serum tryptase cannot be taken as a definitive diagnostic proof of mast cell activation, and other conditions associated with increased tryptase production, in our case chronic renal insufficiency, should be considered.\n\nTable 1 Tryptase, N-methylhistamine (NMH) and 11-β prostaglandin F2α (11-β PGF2α) as tests for differentiating the etiology of increased serum tryptase\n\nReference: total serum tryptase, <11.5 µg/L; Mature β tryptases, <1 µg/L; 24-Hour urinary NMH, 30-200 µg/g creatinine; 24-Hour urinary 11-β PGF2α, <1,000 ng.\n\n*Measured from urine collected over 24 hours. †Elevations are transient; a clinically-significant acute tryptase elevation has been recommended as more than 2 + 1.2 (µg/L) × baseline tryptase level. ‡Elevations in urinary metabolites may be transient, either one or the other or be persistent. §Systemic mastocytosis is typically associated with normal levels of mature tryptase, except in patients who have recently experienced a mast-cell activation, in which case acute NMH and 11-β PGF2α should also be elevated.\n==== Refs\n1 Comfere T Sprung J Kumar MM Draper M Wilson DP Williams BA Danielson DR Liedl L Warner DO Angiotensin system inhibitors in a general surgical population Anesth Analg 2005 100 636 644 15728043 \n2 Moreno F Blanca M Fernandez J Ferrer A Mayorga C del Cano A Aguilar F Juarez C Garcia J Determination of inflammatory markers in allergic reactions to drugs Allergy Proc 1995 16 119 122 7557369 \n3 Schwartz LB Diagnostic value of tryptase in anaphylaxis and mastocytosis Immunol Allergy Clin North Am 2006 26 451 463 16931288 \n4 Ono E Taniguchi M Mita H Fukutomi Y Higashi N Miyazaki E Kumamoto T Akiyama K Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis Clin Exp Allergy 2009 39 72 80 19128354 \n5 Schwartz LB Laboratory tests to support the clinical diagnosis of anaphylaxis Waltham, MA UpToDate 2014 \n6 van Doormaal JJ van der Veer E van Voorst Vader PC Kluin PM Mulder AB van der Heide S Arends S Kluin-Nelemans JC Oude Elberink JN de Monchy JG Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions Allergy 2012 67 683 690 22435702 \n7 Alvarez-Twose I Gonzalez-de-Olano D Sanchez-Munoz L Matito A Jara-Acevedo M Teodosio C Garcia-Montero A Morgado JM Orfao A Escribano L Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms Int Arch Allergy Immunol 2012 157 275 280 22042301 \n8 Valent P Akin C Arock M Brockow K Butterfield JH Carter MC Castells M Escribano L Hartmann K Lieberman P Nedoszytko B Orfao A Schwartz LB Sotlar K Sperr WR Triggiani M Valenta R Horny HP Metcalfe DD Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal Int Arch Allergy Immunol 2012 157 215 225 22041891 \n9 Sirvent AE Gonzalez C Enríquez R Fernandez J Millan I Barber X Amoros F Serum tryptase levels and markers of renal dysfunction in a population with chronic kidney disease J Nephrol 2010 23 282 290 20349428 \n10 Kitoh T Ishikawa H Ishii T Nakagawa S Elevated SCF levels in the serum of patients with chronic renal failure Br J Haematol 1998 102 1151 1156 9753036 \n11 Brabant SM Eyraud D Bertrand M Coriat P Refractory hypotension after induction of anesthesia in a patient chronically treated with angiotensin receptor antagonists Anesth Analg 1999 89 887 888 10512259 \n12 Wheeler AD Turchiano J Tobias JD A case of refractory intraoperative hypotension treated with vasopressin infusion J Clin Anesth 2008 20 139 142 18410871 \n13 Bjerregaard J Jaffe RA Intraoperative cardiac arrest: was it the ACE inhibitor? J Clin Anesth 2014 26 62 64 24444993\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2233-8276",
"issue": "5(1)",
"journal": "Asia Pacific allergy",
"keywords": "Anaphylaxis; Hypotension; Lisinopril; Mastocytosis; Renal insufficiency, Chronic; Tryptase",
"medline_ta": "Asia Pac Allergy",
"mesh_terms": null,
"nlm_unique_id": "101561954",
"other_id": null,
"pages": "47-50",
"pmc": null,
"pmid": "25653920",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports",
"references": "20349428;22041891;9753036;16931288;22435702;15728043;19128354;7557369;18410871;24444993;10512259;22042301",
"title": "Refractory intraoperative hypotension with elevated serum tryptase.",
"title_normalized": "refractory intraoperative hypotension with elevated serum tryptase"
}
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{
"abstract": "Disseminated candidiasis in immunosuppressed patients has been classically associated with an erythematous papular eruption, however more severe presentations are possible. We present a patient who developed disseminated Candida tropicalis that presented with hemorrhagic bullae that progressed to large necrotic ulcers.",
"affiliations": "University of Texas Southwestern Medical Center. [email protected].",
"authors": "Beasley|Knox|K|;Panach|Kamaldeep|K|;Dominguez|Arturo R|AR|",
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"country": "United States",
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"issn_linking": "1087-2108",
"issue": "22(1)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D041022:Candida tropicalis; D002177:Candidiasis; D002179:Candidiasis, Cutaneous; D003937:Diagnosis, Differential; D004473:Ecthyma; D006801:Humans; D008297:Male; D012867:Skin; D055815:Young Adult",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26990472",
"pubdate": "2016-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated Candida tropicalis presenting with Ecthyma-Gangrenosum-like Lesions.",
"title_normalized": "disseminated candida tropicalis presenting with ecthyma gangrenosum like lesions"
}
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{
"abstract": "In this paper, a clinical case of combination of chronic myeloid leukemia and T-lymphoblastic lymphoma is present-ed, which is currently a rather rare finding for a clinician. The diagnosis of T-lymphoblastic lymphoma is establishedafter 2 years from the verification of chronic myeloid leukemia. The course of diseases and approaches to treatmentare described.The pathogenetic relationship between myeloid and lymphoid diseases remains unclear and is likely to be the resultof several factors - radiation, chemical and, consequently, genetic disorders.",
"affiliations": "State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.;State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine.",
"authors": "Dyagil|I S|IS|;Sholoyko|V V|VV|;Silayev|Yu O|YO|;Martina|Z V|ZV|;Dmytrenko|I V|IV|;Tovstogan|A O|AO|;Fedorenko|V G|VG|;Shlyakhtychenko|T Yu|TY|;Minchenko|Zh M|ZM|",
"chemical_list": "D000970:Antineoplastic Agents; D014750:Vincristine; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide; D011241:Prednisone; D006918:Hydroxyurea",
"country": "Ukraine",
"delete": false,
"doi": "10.33145/2304-8336-2018-23-517-523",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2304-8336",
"issue": "23()",
"journal": "Problemy radiatsiinoi medytsyny ta radiobiolohii",
"keywords": "Chornobyl catastrophe; T-lymphoblastic lymphoma; chemical loading; chronic myeloid leukemia; small doses of ionizing radiation",
"medline_ta": "Probl Radiac Med Radiobiol",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D047852:Chernobyl Nuclear Accident; D003520:Cyclophosphamide; D004317:Doxorubicin; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D006918:Hydroxyurea; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D016399:Lymphoma, T-Cell; D008875:Middle Aged; D011241:Prednisone; D000069079:Radiation Exposure; D011839:Radiation, Ionizing; D016896:Treatment Outcome; D014455:Ukraine; D014750:Vincristine",
"nlm_unique_id": "101560511",
"other_id": null,
"pages": "517-523",
"pmc": null,
"pmid": "30582869",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "CASE OF DEVELOPMENT OF NON-HODGKIN'S MALIGNANT LYMPHOMA ON THE BACKGROUND OF CHRONIC MYELOID LEUKEMIA IN A PATIENT WHO SUFFERED OF THE CHORNOBYL ACCIDENT.",
"title_normalized": "case of development of non hodgkin s malignant lymphoma on the background of chronic myeloid leukemia in a patient who suffered of the chornobyl accident"
}
|
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"abstract": "BACKGROUND\nDuchenne muscular dystrophy (DMD) is a progressive muscle condition starting in childhood, leading to severe disability and a shortened life span. It is due to severe deficiency of the protein dystrophin which performs both structural and signalling roles within skeletal and cardiac myocytes. Calcium accumulates in dystrophic muscle cells and plays a role in cell damage. It has been hypothesised that use of calcium antagonists might reduce this calcium load and its toxic effect on muscle cells.\n\n\nOBJECTIVE\nTo evaluate the effects of calcium antagonists on muscle function and muscle strength in people with DMD.\n\n\nMETHODS\nThe Cochrane Neuromuscular Disease Group Trials Register (February 2008), MEDLINE (from January 1950 to March 2008) and EMBASE (from January 1947 to March 2008) were searched. Search terms were 'calcium antagonists' or 'calcium channel blocker' or 'dantrolene' or 'verapamil' or 'nifedipine' or 'flunarizine' or 'diltiazem' or 'amlodipine' or 'nicardipine' and 'Muscular Dystrophy, Duchenne'. Bibliographies in reports of any trials were also searched.\n\n\nMETHODS\nAll randomised or quasi-randomised controlled trials of any calcium antagonist in people with DMD.\n\n\nMETHODS\nBoth authors assessed all identified trials for inclusion in the study on the basis of whether they fulfilled the selection criteria. Both authors extracted data from the trials and assessed the methodological quality. Had there been more than one trial of the same intervention and outcome of sufficient methodological quality, we had planned to undertake a meta-analysis.\n\n\nRESULTS\nFive randomised or quasi-randomised double-blind trials fulfilled the selection criteria, but were not sufficiently comparable to undertake a meta-analysis. The drugs studied were verapamil (8 participants), diltiazem (56 participants), nifedipine (105 participants) and flunarizine (27 participants). There were limitations in the description of blinding and randomisation, and definition of outcome measures. One trial, using verapamil, showed a difference between groups in muscle force measured by ergometry, but also revealed cardiac side effects. The numbers of people included in the trials were low, and so the studies may not have included enough people for sufficient power to detect small differences in muscle force or function between placebo and control groups. In addition, calcium antagonists were in an early stage of development and some of the second generation drugs that have a better side effect profile, such as amlodipine, have not been studied.\n\n\nCONCLUSIONS\nThere is no evidence to show a significant beneficial effect of calcium antagonists on muscle function in DMD.",
"affiliations": "Division of Rehabilitation Medicine, University of Nottingham, Arkwright House, Derby City Hospital, Derby, UK, DE22 3NE. [email protected]",
"authors": "Phillips|Margaret F|MF|;Quinlivan|Rosaline|R|",
"chemical_list": "D002121:Calcium Channel Blockers; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; D005444:Flunarizine",
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"journal": "The Cochrane database of systematic reviews",
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"mesh_terms": "D002121:Calcium Channel Blockers; D004110:Diltiazem; D005444:Flunarizine; D006801:Humans; D053580:Muscle Strength; D018482:Muscle, Skeletal; D020388:Muscular Dystrophy, Duchenne; D009543:Nifedipine; D016032:Randomized Controlled Trials as Topic; D014700:Verapamil",
"nlm_unique_id": "100909747",
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"pubdate": "2008-10-08",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Calcium antagonists for Duchenne muscular dystrophy.",
"title_normalized": "calcium antagonists for duchenne muscular dystrophy"
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"abstract": "Parieto-occipital region is the most commonly involved site in posterior reversible encephalopathy syndrome (PRES). Cerebellar involvement has been reported with the predominant involvement of posterior cerebral regions, but isolated cerebellar involvement in PRES has been reported only once in English literature. We report here a 7-year-old boy with acute lymphoblastic leukemia who had PRES with isolated cerebellar involvement during induction chemotherapy. He presented with sudden onset headache, vomiting and hypertension followed by seizures, unconsciousness, and involuntary movements. Computed tomography scan revealed bilateral cerebellar hypodensities. He improved within few hours and reversibility of the lesions was documented on magnetic resonance imaging after 2 weeks. Awareness of atypical patterns in distribution of imaging abnormalities is important to recognize PRES more accurately and to avoid unnecessary diagnostic procedures and treatment.",
"affiliations": "Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.",
"authors": "Chaudhary|Narendra|N|;Majeed|Rubeena|R|;Borker|Anupama|A|",
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"fulltext": "\n==== Front\nIndian J Med Paediatr OncolIndian J Med Paediatr OncolIJMPOIndian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology0971-58510975-2129Medknow Publications & Media Pvt Ltd India IJMPO-32-21110.4103/0971-5851.95143Case ReportIsolated cerebellar involvement in posterior reversible encephalopathy syndrome in a child with acute lymphoblastic leukemia Chaudhary Narendra Majeed Rubeena 1Borker Anupama Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India1 Department of Radiodiagnosis, Kasturba Medical College, Manipal University, Manipal, Karnataka, IndiaAddress for correspondence: Dr. Anupama Borker, Department of Pediatrics, Kasturba Medical College, Madhav Nagar, Manipal - 576 104, Karnataka, India. E-mail: [email protected] 2011 32 4 211 213 Copyright: © Indian Journal of Medical and Paediatric Oncology2011This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Parieto-occipital region is the most commonly involved site in posterior reversible encephalopathy syndrome (PRES). Cerebellar involvement has been reported with the predominant involvement of posterior cerebral regions, but isolated cerebellar involvement in PRES has been reported only once in English literature. We report here a 7-year-old boy with acute lymphoblastic leukemia who had PRES with isolated cerebellar involvement during induction chemotherapy. He presented with sudden onset headache, vomiting and hypertension followed by seizures, unconsciousness, and involuntary movements. Computed tomography scan revealed bilateral cerebellar hypodensities. He improved within few hours and reversibility of the lesions was documented on magnetic resonance imaging after 2 weeks. Awareness of atypical patterns in distribution of imaging abnormalities is important to recognize PRES more accurately and to avoid unnecessary diagnostic procedures and treatment.\n\nIsolated cerebellar involvementposterior reversible encephalopathyreversible occipito-parietal leukoencephalopathy\n==== Body\nINTRODUCTION\nPosterior reversible encephalopathy syndrome (PRES) is a reversible clinicoradiological syndrome characterized clinically by acute onset headache, altered alertness, seizures, vomiting, and abnormalities of visual perception, and neuroradiologically by edema predominantly involving the parieto-occipital regions. Cerebellar involvement has been reported with the predominant involvement of posterior cerebral regions, but review of published English literature revealed only one case report with isolated cerebellar involvement in PRES.[1] We report here a case of PRES with isolated cerebellar involvement in a child with acute lymphoblastic leukemia (ALL) during induction chemotherapy.\n\nCASE REPORT\nA 7-years-old boy presented with slowly progressive bilateral cervical lymphadenopathy of few months’ duration. There were no constitutional symptoms. He had pallor, nontender generalized lymphadenopathy, and splenomegaly. Biopsy from cervical lymph node revealed lymphoblastic lymphoma. Laboratory investigations at admission revealed pancytopenia with 20% blasts in peripheral blood. Bone marrow aspiration revealed 65% blasts. Immunophenotyping of bone marrow aspirate suggested T-cell ALL. Central nervous system was uninvolved on cerebrospinal fluid examination. Induction chemotherapy was initiated as per MCP 841 protocol which includes prednisolone, 40 mg/m2 for 29 days; L-asparaginase, 6 000 IU/m2 on alternate days for 10 doses; vincristine, 1.4 mg/m2 weekly for 5 doses; daunorubicin, 30 mg/m2 at day 8, 15, and 29; and weekly intrathecal injections of methotrexate for 4 weeks. After documentation of febrile neutropenia on 14th day of induction, piperacillin-tazobactam and amikacin were initiated. He responded well and became afebrile within 24 hours of initiation of antibiotics.\n\nOn 19th day of induction, he complained of sudden onset headache and projectile vomiting. He was lethargic but well oriented and did not have signs of meningitis, abnormal movements, or visual disturbances. Fundus examination was normal bilaterally. He was hypertensive initially (blood pressure, 150/110 mmHg; >99th centile), but subsequent records were within normal range. A few hours later, the patient had two episodes of left focal tonic-clonic seizures at one-hour interval which were managed with midazolam and phenytoin. The seizure was followed by loss of consciousness and some involuntary movements. Computed tomography (CT) of brain revealed diffuse hypodensity involving bilateral cerebellar hemispheres [Figure 1a]. Patient became fully conscious after about 3 to 4 hours without any neurological deficit. Follow-up cranial magnetic resonance imaging (MRI) examination performed 2 weeks after the episode showed almost complete resolution of cerebellar lesions [Figure 1b]. He achieved remission after induction and received two cycles of high-dose cytarabine (I2A) and repeat induction (RI1) cycle. He did not develop any neurological symptom during subsequent chemotherapy, but unfortunately succumbed to infective endocarditis after the third cycle of chemotherapy.\n\nFigure 1 (a) CT scan brain showing bilateral cerebellar edema; (b) MRI after 2 weeks showing complete resolution of cerebellar edema\n\nDISCUSSION\nThe reversible syndrome of altered mental status, headache, seizures, visual disturbances, and hypertension has been described in literature with different terminologies like hypertensive encephalopathy, reversible posterior leukoencephalopathy, and reversible occipitoparietal leukoencephalopathy.[2]\n\nThis syndrome has been recognized without hypertension or with only mild increase in blood pressure; there is usually no accompanying destructive process of the white matter; and neuroradiologically, the involvement is not strictly restricted to parieto-occipital regions. Hence, PRES is more acceptable and popular terminology.[34]\n\nPRES is seen exclusively in the setting of a significant systemic process or condition, including sudden hypertension, bone marrow or solid organ transplantation (specially on cyclosporine immunosuppression), infection/sepsis/shock, toxemia of pregnancy, autoimmune disease, and during cancer chemotherapy (e.g., l-asparaginase, prednisolone, high-dose cytarabine, etc.). A case series from India revealed induction chemotherapy, hypertension, high-dose cytarabine, and cyclosporine as the triggers for PRES in 13 leukemic patients.[5]\n\nCerebral hypoperfusion and cytotoxic edema secondary to underlying systemic condition or drugs seems to be the principle pathophysiologic process leading to development of encephalopathy. Hypertension may have a modulating effect to this process.[3] An obvious risk factor in our patient was induction chemotherapy for ALL, but he also had one record of sudden onset hypertension at the time of neurotoxicity, which might have modulating effect. Furthermore, despite receiving high-dose cytarabine and repeat induction cycle subsequently, PRES did not recur, probably due to absence of hypertension during subsequent therapy.\n\nAlthough MRI is the most sensitive imaging test to diagnose PRES, it is not necessary for the diagnosis if CT is suggestive. CT usually shows bilateral hypodensities in the posterior white matter, with some involvement of the overlying cortex. On MRI, these lesions appear hyperintense on T2-weighted images, and are usually hypointense or isointense on diffusion-weighted images, with an increase of the apparent diffusion coefficient, indicating vasogenic edema. Mckinney et al. reported two cases of completely unilateral involvement in their series, which is difficult to distinguish from infarction.[6] The calcarine and paramedian occipital-lobe structures are usually spared, a fact that distinguishes PRES from bilateral infarction of the posterior-cerebral-artery territory.[4] The posterior part of the brain is more frequently involved due to poor sympathetic innervation of the vertebrobasilar system.\n\nFugate et al. found the parieto-occipital regions as the most commonly involved site (94%) on MRI in a large prospective study, followed by the frontal lobe (77%), temporal lobe (64%), and cerebellum (53%). Cerebellar involvement was significantly more frequent in patients with a history of autoimmunity, and patients with sepsis were more likely to have cortical involvement.[7] Although parieto-occipital involvement was found in 99% of the cases, McKinney et al. noted higher incidence of atypical distributions (posterior frontal, 78.9%; temporal, 68.4%; thalamus, 30.3%; cerebellum, 34.2%; brainstem, 18.4%; and basal ganglia, 11.8%) than commonly perceived. Only one patient lacked parieto-occipital edema, but this patient had severe brainstem, thalamic, and deep white matter edema.[6] “Atypical” cases with only frontal, temporal, or brain stem lesions have been reported in literature. Only one case of PRES with isolated cerebellar involvement has been reported in the English literature, ours being the second.[1]\n\nAlthough the reversibility of the clinicoradiological features is most characteristic, it should be noted that prolonged seizures, hypertension, or both may result in permanent neurologic deficits and cerebral infarction. Hence, PRES must be managed with good supportive care including antihypertensive and antiepileptic medications to prevent any irreversible damage. A follow-up scan in a period of 1 to 2 weeks is needed to document the reversibility.[8]\n\nCONCLUSION\nAwareness of atypical patterns and variations in distribution of imaging abnormalities is important to recognize PRES more accurately, to avoid expensive or potentially invasive work-ups for other primary cerebral diseases.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Soysal DD Caliskan M Aydin K Nayir A Karaböcüoglu M Citak A Isolated cerebellar involvement in a case of posterior reversible leukoencephalopathy Clin Radiol 2006 61 983 6 17018313 \n2 Pavlakis SG Frank Y Chusid R Hypertensive encephalopathy, reversible occipitoparietal encephalopathy, or reversible posterior leukoencephalopathy: Three names for an old syndrome J Child Neurol 1999 14 277 81 10342593 \n3 Bartynski WS Posterior reversible encephalopathy syndrome, part 2: Controversies surrounding pathophysiology of vasogenic edema AJNR Am J Neuroradiol 2008 29 1043 9 18403560 \n4 Hinchey J Chaves C Appignani B Breen J Pao L Wang A A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 8559202 \n5 Dongre A Gulia S Arora B Kurkure PA Banavali SD Posterior reversible encephalopathy syndrome (PRES) in pediatric cancer patients Last accessed on 2010 Dec 26 PHOCON 2009/OP1 [Abstract]. Available from:\nhttp://www.phoindia.org/pdf/all-abstracts-PHOCON-2009-chandigarh.pdf \n6 McKinney AM Short J Truwit CL McKinney ZJ Kozak OS SantaCruz KS Posterior reversible encephalopathy syndrome: Incidence of atypical regions of involvement and imaging findings AJR Am J Roentgenol 2007 189 904 12 17885064 \n7 Fugate JE Claassen DO Cloft HJ Kallmes DF Kozak OS Rabinstein AA Posterior reversible encephalopathy syndrome: Associated clinical and radiologic findings Mayo Clin Proc 2010 85 427 32 20435835 \n8 Prasad N Gulati S Gupta RK Kumar R Sharma K Sharma RK Is reversible posterior leukoencephalopathy with severe hypertension completely reversible in all patients? Pediatr Nephrol 2003 18 1161 6 14505162\n\n",
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{
"abstract": "A 66-year-old Japanese male presented with thirst, polyuria, and hemoglobin A1c and postprandial glucose levels (13.1% and 529 mg/dL, respectively) that indicated severe hyperglycemia. Based on his high immunoglobulin G4 level and the results of magnetic resonance imaging and magnetic resonance cholangiopancreatography, we diagnosed him with autoimmune pancreatitis. Insulin was initiated to control his diabetes. One month later, the patient commenced on prednisolone therapy for the treatment of autoimmune pancreatitis, after which his total insulin dosage increased to a maximum of 52 units/day. When the prednisolone dosage was later tapered, the patient's total dosage of insulin was reduced to 42 units/day. However, he had gained 3.6 kg from the start of prednisolone therapy, and 42 units/day was insufficient for maintaining glycemic control. Thus, empagliflozin, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, was added. Thereafter, we were able to reduce the patient's total dosage of insulin; it was eventually discontinued with good glycemic control and weight loss. Such results suggest that the combination of insulin with an SGLT2 inhibitor may be a viable option for the treatment of diabetic patients on prednisolone therapy.",
"affiliations": "Clinical Research Center, Department of Medicine, International University of Health and Welfare, Tochigi, Japan.;Clinical Research Center, Department of Medicine, International University of Health and Welfare, Tochigi, Japan.;Clinical Research Center, Department of Medicine, International University of Health and Welfare, Tochigi, Japan.",
"authors": "Kishimoto|Miyako|M|0000-0003-3043-2720;Yamaoki|Kazuhide|K|;Adachi|Masayuki|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/9415347",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2019/9415347Case ReportCombination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment http://orcid.org/0000-0003-3043-2720Kishimoto Miyako [email protected]\n1\n\n2\nYamaoki Kazuhide \n1\n\n2\nAdachi Masayuki \n1\n\n2\n\n1Clinical Research Center, Department of Medicine, International University of Health and Welfare, Tochigi, Japan\n2Department of Internal Medicine, Sanno Hospital, 8-10-16 Akasaka, Minato, Tokyo 107-0052, JapanAcademic Editor: John Broom\n\n2019 14 2 2019 2019 941534714 12 2018 1 2 2019 Copyright © 2019 Miyako Kishimoto et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 66-year-old Japanese male presented with thirst, polyuria, and hemoglobin A1c and postprandial glucose levels (13.1% and 529 mg/dL, respectively) that indicated severe hyperglycemia. Based on his high immunoglobulin G4 level and the results of magnetic resonance imaging and magnetic resonance cholangiopancreatography, we diagnosed him with autoimmune pancreatitis. Insulin was initiated to control his diabetes. One month later, the patient commenced on prednisolone therapy for the treatment of autoimmune pancreatitis, after which his total insulin dosage increased to a maximum of 52 units/day. When the prednisolone dosage was later tapered, the patient's total dosage of insulin was reduced to 42 units/day. However, he had gained 3.6 kg from the start of prednisolone therapy, and 42 units/day was insufficient for maintaining glycemic control. Thus, empagliflozin, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, was added. Thereafter, we were able to reduce the patient's total dosage of insulin; it was eventually discontinued with good glycemic control and weight loss. Such results suggest that the combination of insulin with an SGLT2 inhibitor may be a viable option for the treatment of diabetic patients on prednisolone therapy.\n==== Body\n1. Introduction\nSodium-dependent glucose transporter 2 (SGLT2) is a protein in the early proximal tubule that reabsorbs the majority of filtered glucose. Inhibitors of SGLT2 enhance urinary glucose excretion, thereby lowering blood glucose levels in an insulin-independent manner. SGLT2 inhibitors have pleiotropic actions, including reduced glomerular hyperfiltration, hypertension, and weight loss [1], which may correlate with reduced cardiovascular risk. In a recent study of patients with type 2 diabetes who were at high risk for cardiovascular events, those who received empagliflozin (an SGLT2 inhibitor) in addition to standard care had lower rates of the primary composite cardiovascular outcome and death from any cause than did those on placebo [2, 3]. As a result of mounting evidence, the American Diabetes Association and the European Association for the Study of Diabetes recently updated their position statements on the management of type 2 diabetes in adults [4, 5]. In their statements, an SGLT2 inhibitor with proven benefit is recommended for the treatment of patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease.\n\nAutoimmune pancreatitis (AIP) is a chronic and progressive inflammatory pancreatic disease that is uniquely characterized by diagnostic images of pancreatic enlargement and irregularly narrowed main pancreatic ducts. It is a condition that responds dramatically to corticosteroid therapy [6–8]. Corticosteroids are frequently used for the treatment of inflammatory conditions and autoimmune diseases, but are widely recognized to cause hyperglycemia and insulin resistance when used at high doses and for long durations [9, 10].\n\nHerein, we report the case of a patient in whom uncontrolled diabetes as a direct result of AIP and subsequent steroid treatment was successfully treated by the addition of empagliflozin to his insulin therapy.\n\n2. Case Report\nA 66-year-old Japanese man, 177 cm tall and weighing 66 kg (body mass index of 21.1), had been treated for hypertension for more than seven years. He had yearly medical evaluations but was never diagnosed with diabetes (postprandial glucose and hemoglobin A1c [HbA1c] levels in March 2017: 141 mg/dL and 5.4%, respectively). However, results of an annual medical check-up in March 2018 showed remarkable elevation of postprandial glucose and HbA1c levels (265 mg/dL and 11.4%, respectively). The following month (April), he reported symptoms of thirst and polyuria. His postprandial glucose and HbA1c levels on that day were 529 mg/dL and 13.1%, respectively. A high glycoalbumin level (43.2%) also suggested acute glucose elevation (Table 1). The patient's anti-glutamic acid decarboxylase antibody test was negative; however, because his postprandial C-peptide level was low (1.15 ng/mL), the patient's pancreas presumably had reduced insulin-secreting capacity. We noted that the patient's daily life had not changed in years; and he had no diabetic complications such as retinopathy, nephropathy, or neuropathy.\n\nTo identify the cause of hyperglycemia, we performed several imaging studies. Abdominal computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography (MRCP) revealed diffuse swelling that extended from the pancreatic body to tail (Figures 1(a)–1(c)). In addition, MRCP showed narrowing of the associated main pancreatic duct (Figure 1(c)). The patient did not complain of any digestive symptoms such as upper abdominal pain; however, based on the imaging scans and elevation of serum immunoglobulin G4 (IgG4) levels (141.0 mg/dL), we diagnosed him with type 1 AIP.\n\nTo control diabetes, the patient began self-administering insulin injections: insulin aspart (Novo Nordisk) three times per day before each meal and insulin degludec (Novo Nordisk) before going to bed. Because tight adjustment of insulin dosage is required for achieving good glycemic control, the patient received a flash glucose monitoring system (Freestyle Libre™; Abbott Diabetes Care, Witney, UK) [11] upon initiation of insulin. He initially had considerable ketosis (Table 1), but, soon after, the levels of total ketone bodies, acetoacetate, and β-hydroxybutyrate declined to the normal range (36 μmol/L, 12 μmol/L, and 24 μmol/L, respectively). By the end of April, the patient's total insulin dosage was 36 units/day (Figure 2(a)). In May, prednisolone (35 mg/day) was initiated for the treatment of AIP. At that time, 42 units/day of insulin was not sufficient to control glucose elevation (Figure 2(b)); the patient required a maximum of 52 units/day (Figure 2(c)). One month later, IgG4 levels declined to 54.3 mg/dL. The dosage of prednisolone, which was being tapered by 5 mg/day every 2 weeks, was 20~25 mg/day; and the total dosage of insulin was also lower than that of the previous month. However, 42 units/day of insulin was required to maintain glycemic control (Figure 2(d)). In addition, the combination of high-dose insulin and prednisolone caused our patient to gain 3.6 kg weight from the start of prednisolone initiation.\n\nTo improve glycemic control, empagliflozin was added to insulin therapy. Because we expected empagliflozin to lower blood glucose levels, we reduced the dosage of insulin to 29 units/day beforehand. Nevertheless, the patient experienced hypoglycemia 1 hour after breakfast and 1 hour after dinner on the day of empagliflozin initiation (Figure 2(e)). By the end of June, 20 days after the addition of empagliflozin, the patient had lost 1.2 kg and his total insulin dosage had declined to 20 units/day (Figure 2(f)). In July, the prednisolone dosage was reduced to 10 mg/day. Because the patient had achieved good glycemic control (postprandial glucose, HbA1c, and glycoalbumin levels: 159 mg/dL, 6.9%, and 14.3%, respectively), the total dosage of insulin was further reduced and then eventually discontinued (Figure 2(g)). Thereafter, he maintained good glycemic control (postprandial glucose and HbA1c levels: 130–180mg/dL and 5.4–5.8%, respectively) despite receiving only empagliflozin for diabetes (Figure 3). However, his postprandial C-peptide level remained low (1.84 ng/mL), revealing that although the insulin-secreting capacity of his pancreas had slightly recovered, it remained insufficient.\n\nIn October, the patient's prednisolone dosage was 4 mg/day. His follow-up magnetic resonance imaging and MRCP showed that both the diffuse swelling of the pancreatic tail and narrowing of the associated main pancreatic duct had been ameliorated (Figures 4(a) and 4(b)). To date, the patient's AIP is well controlled and has not relapsed.\n\n3. Discussion\nThe international consensus diagnostic criteria for AIP identify two subtypes: type 1 is characterized by serum IgG4 elevation and the classic histopathological patterns of lymphoplasmacytic sclerosing pancreatitis; type 2 is characterized by idiopathic duct-centric pancreatitis and is not associated with IgG4 levels [12–14]. Although the clinical findings in AIP are nonspecific, the most common presentation is obstructive jaundice and upper abdominal pain [6, 7]. Approximately 40–80% of patients with AIP reportedly also present with diabetes—some with simultaneous onset with AIP and some with exacerbation of preexisting diabetes [8, 14–21]. In addition, some patients develop diabetes after the start of steroid therapy, the outcome of which varies with regard to glycemic control [17, 18, 20, 22–24].\n\nThe diabetes associated with AIP is assumed to be caused by a reduction in insulin secretion. This may be the result of various mechanisms. For one, AIP is characterized by infiltration of cluster of differentiation (CD)8 and CD4 T lymphocytes, which surround ductal cells and secrete cytokines to suppress and destroy β-islet cells of the pancreas [22, 23]. In addition, inflammation and fibrosis of exocrine glands is associated with the obstruction of blood flow in the endocrine glands, that results in ischemia of islet cells and dysfunctional insulin secretion. Furthermore, extensive destruction of the pancreatic islets caused by direct infiltration of inflammatory cells and fibroblasts proliferation also leads to dysfunctional insulin secretion [14, 16, 20, 23–27].\n\nGlucocorticoids are counterhormones against insulin [9, 10], with mechanisms that include reduction of glucose uptake, induction of hepatic glucose production, and direct inhibition of insulin release [28–30]. Glucocorticoid-induced hyperglycemia is a common condition, which is often considered postprandial hyperglycemia [31, 32]. Prominent hyperglycemia is most often observed when individuals with known diabetes take high doses of glucocorticoids, but may also occur with intake of moderate and low doses in individuals without a known risk [29, 31, 33]. The odds ratio for new-onset diabetes mellitus in patients treated with glucocorticoids ranges from approximately 1.5 to 2.5, and the total glucocorticoid dose and duration of therapy are strong predictors of diabetes induction [32].\n\nThus, initiation of steroid therapy in patients with AIP may induce the onset of diabetes or worsen glycemic control in those with preexisting diabetes [34]. However, steroid therapy also inactivates inflammatory cells and fibroblast function, and may improve insulin secretion by controlling a series of autoimmune mechanisms, including cytokine production [16, 25]. It has been reported that pancreatic endocrine function improves after treatment with steroids in 25–45% of patients with AIP [20, 24, 35], with some patients eventually achieving a medication-free status [34]. Indeed, Miyamoto et al. reported that three months after the start of steroid therapy in patients with AIP and simultaneous onset of diabetes mellitus, 54% of patients experience improvement in diabetes, 36% do not have any change, and 9% have worsening of diabetes [16]. In addition, they noted that the long-term positive effect of corticosteroid therapy on glucose tolerance might be greater than its short-term negative effect on insulin [16].\n\nApproximately half of patients with AIP-associated pancreatic diabetes are treated with insulin [35]. Such therapy is effective in lowering blood glucose. However, patients must be monitored for hypoglycemia and undesirable weight gain, especially when insulin dosage is increased. SGLT2 inhibitors may have glycemic benefits in patients with type 1 or type 2 diabetes who are on insulin therapy [36]. Accumulating reports indicate that SGLT2 inhibitors are well tolerated, and their addition to insulin therapy improves glycemic control and reduces body weight such that insulin dosages could sometimes be reduced [37–52]. The mechanism was explained by Ferrannini et al., who reported that empagliflozin lowers fasting and postprandial glycemia by inducing glycosuria, which improves β cell function and insulin sensitivity in patients with type 2 diabetes [53]. This was noted despite the fall in insulin secretion and tissue glucose disposal, and the rise in endogenous glucose production that occurs after a single dose of 25 mg empagliflozin [53]. We were able to reduce our patient's total insulin dosage upon initiation of empagliflozin. This lowered his risk of hypoglycemia and suppressed weight gain. Although improvement in glycemic control and reduction in total insulin dosage could have been the result of AIP amelioration alone, we believe that empagliflozin accelerated improvement of glycemic control in our patient.\n\nOne of the risks of SGLT2 inhibitors is diabetic ketoacidosis (DKA) [4, 5]. Similar to classic DKA, ketone accumulation in SGLT2 inhibitor-associated DKA is downstream of insulin deficiency and glucagon elevation, promoting lipolysis and hepatic ketogenesis. SGLT2 inhibitor-enhanced glucosuria effectively lowers plasma glucose levels, which decreases insulin secretion from pancreatic β cells. SGLT2 inhibitor-mediated glucosuria and attenuation of sodium reabsorption in the kidneys may also indirectly expand the ketone reservoir by enhancing renal ketone reabsorption [54–56]. Although our patient initially had prominent ketosis, the ketosis improved soon after initiation of insulin therapy. Although we rechecked for ketosis throughout his treatment with empagliflozin, no further signs of ketosis were detected.\n\nIn conclusion, this case report suggests that the combination of insulin and SGLT2 inhibitor can be effective for the treatment of secondary diabetes, such as prednisolone-induced diabetes associated with the treatment of AIP in our patient. Further studies on a larger scale are required to confirm the effectiveness of this combination for the treatment of diabetes in patients on corticosteroid therapy.\n\nEthical Approval\nAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1975, as revised in 2000 and 2008. In addition, this case report was approved by the Ethics Committee of Sanno Hospital.\n\nConsent\nThe authors obtained written informed consent from the patient for publication.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 (a) An abdominal computed tomography scan performed on the patient's first visit shows diffuse swelling extending from the pancreatic body to tail. The arrow indicates the affected portion of the pancreas. (b) Magnetic resonance image (T2 weighted image) of the abdomen prior to prednisolone therapy reveals diffuse swelling extending from the pancreatic body to tail. (c) MRCP prior to prednisolone therapy shows narrowing of the main pancreatic duct extending from the pancreatic body to tail.\n\nFigure 2 The results of continuous glucose monitoring (CGM) with the flash glucose monitoring system. Closed arrowheads indicate the timing of the patient's meals and insulin injections. Open arrowheads indicate the timing of the patient's insulin injections before sleep. Values adjacent to the arrowheads indicate the number of units of insulin injected. (a) One representative pattern of CGM prior to initiation of prednisolone. (b) Initiation of 35 mg/day of oral prednisolone. (c) Two days after initiation of prednisolone. Total dosage of insulin was increased to 52 units/day. (d) Because of the amelioration of AIP, prednisolone dosage was reduced to 25 mg/dL; however, 42 units/day of insulin was required to maintain glycemic control. (e) First day of empagliflozin administration. Hypoglycemia recorded at 5 AM to 6 AM and approximately 8 PM. (f) Twenty days after empagliflozin initiation. (g) CGM pattern of patient on empagliflozin only.\n\nFigure 3 Changes in glycemic control and clinical course of AIP during prednisolone therapy. HbA1c levels (circles) and serum IgG4 levels (squares) declined over the course of treatment.\n\nFigure 4 (a) Magnetic resonance image (T2 weighted image) of the abdomen after prednisolone therapy reveals amelioration of the diffuse swelling that had affected the pancreas from body to tail. (b) MRCP after prednisolone therapy revealed amelioration of the narrowing of the main pancreatic duct.\n\nTable 1 Postprandial laboratory results on patient's first visit.\n\n\nHematology\n\t \t\nAuto-antibody tests\n\t \t\nWhite blood cells\t7400/μL\tAntinuclear antibodies\t< 40\t\nRed blood cells\t473×104/μL\t \t \t\nHemoglobin\t15.9 g/dL\t\nImmunoglobulin\n\t \t\nHematocrit\t44.9%\tImmunoglobulin A\t186 mg/dL\t\nPlatelets\t22.5×104/μL\tImmunoglobulin M\t90 mg/dL\t\n \t \tImmunoglobulin G\t1104 mg/dL\t\n\nBlood chemistry\n\t \tImmunoglobulin G4\t141 mg/dL\t\nAlbumin\t4.9 g/dL\t \t \t\nT-bilirubin\t0.8 mg/dL\t\nTumor markers\n\t \t\nAspartate aminotransferase\t18 IU/L\tCEA\t5.7 ng/mL\t\nAlanine aminotransferase\t20 IU/L\tCA19-9\t1.2 U/mL\t\nLactate dehydrogenase\t162 IU/L\tSpan-1\t< 1.0 U/mL\t\nAlkaline phosphatase\t448 IU/L\tDUPAN-2\t57 U/mL\t\n\nγ-Glutamyl transpeptidase\t47 IU/L\t \t \t\nPancreatic amylase\t13 IU/L\t\nGlycometabolism tests\n\t \t\nLipase\t18 IU/L\tPlasma glucose\t529 mg/dL\t\nTrypsin\t111 ng/mL\tHbA1c\t13.1%\t\nElastase-1\t93 IU/L\tGlycoalbumin\t43.2%\t\nCholinesterase\t290 IU/L\tC-peptide reactivity\t1.15 ng/mL\t\nCreatinine kinase\t115 IU/L\tAnti-GAD antibodies\t< 5.0 U/mL\t\nUric acid\t4.3 mg/dL\t \t \t\nBlood urea nitrogen\t11.5 mg/dL\t\nKetone body fractions\n\t \t\nCreatinine\t0.64 mg/dL\tTotal ketone bodies\t895 μmol/L\t\neGFR\t95 ml/min/1.73m2\tAcetoacetate\t218 μmol/L\t\nSodium\t135 mEq/L\t\nβ-Hydroxybutyrate\t677 μmol/L\t\nPotassium\t4.1 mEq/L\t \t \t\nChloride\t98 mEq/L\t\nUrinalysis\n\t \t\nTriglycerides\t195 mg/dL\tProtein\t( – )\t\nHDL cholesterol\t65 mg/dL\tGlucose\t4+\t\nLDL cholesterol\t115 mg/dL\tOccult blood\t( – )\t\nC-reactive protein\t0.13 mg/dL\tKetones\t(+/–)\n==== Refs\n1 Gallo L. 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Empagliflozin as adjunct to insulin in patients with type 1 diabetes: A 4-week, randomized, placebo-controlled trial (EASE-1) Diabetes, Obesity and Metabolism 2015 17 10 928 935 2-s2.0-84942258219 10.1111/dom.12494 \n46 Araki E. Onishi Y. Asano M. Kim H. Yajima T. Efficacy and safety of dapagliflozin over 1 year as add-on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial Diabetes, Obesity and Metabolism 2017 19 4 562 570 2-s2.0-85013648197 10.1111/dom.12853 \n47 Das G. Surya A. Abusahmin H. Use of dapagliflozin as an add-on to insulin therapy in patients with suboptimally controlled type 2 diabetes Therapeutic Advances in Endocrinology and Metabolism 2018 9 8 269 270 2-s2.0-85046673084 10.1177/2042018818771434 30181853 \n48 Terauchi Y. Tamura M. Senda M. Gunji R. Kaku K. Long-term safety and efficacy of tofogliflozin as add-on to insulin in patients with type 2 diabetes: Results from a 52-week, multicentre, randomized, double-blind, open-label extension, Phase 4 study in Japan (J-STEP/INS) Diabetes, Obesity and Metabolism 2018 20 5 1176 1185 2-s2.0-85041703052 10.1111/dom.13213 \n49 Neal B. Perkovic V. De Zeeuw D. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes Diabetes Care 2015 38 3 403 411 10.2337/dc14-1237 2-s2.0-84930844091 25468945 \n50 Araki E. Onishi Y. Asano M. Efficacy and safety of dapagliflozin in addition to insulin therapy in Japanese patients with type 2 diabetes: Results of the interim analysis of 16-week double-blind treatment period Journal of Diabetes Investigation 2016 7 4 555 564 2-s2.0-84977589113 10.1111/jdi.12453 27181422 \n51 Suzuki K. Mitsuma Y. Sato T. Anraku T. Hatta M. Comparison of combined tofogliflozin and glargine, tofogliflozin added to insulin, and insulin dose-increase therapy in uncontrolled type 2 diabetes Journal of Clinical Medicine Research 2016 8 11 805 814 10.14740/jocmr2741w 27738482 \n52 Mathieu C. Dandona P. Gillard P. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the depict-2 study): 24-week results from a randomized controlled trial Diabetes Care 2018 41 9 1938 1946 10.2337/dc18-0623 2-s2.0-85052622868 30026335 \n53 Ferrannini E. Muscelli E. Frascerra S. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients The Journal of Clinical Investigation 2014 124 2 499 508 2-s2.0-84893872877 10.1172/JCI72227 24463454 \n54 Ogawa W. Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: Possible mechanism and contributing factors Journal of Diabetes Investigation 2016 7 2 135 138 2-s2.0-84959366596 10.1111/jdi.12401 27042263 \n55 Goldenberg R. M. Berard L. D. Cheng A. Y. SGLT2 inhibitor–associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis Clinical Therapeutics 2016 38 12 2654 2664.e1 10.1016/j.clinthera.2016.11.002 28003053 \n56 Rosenstock J. Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors Diabetes Care 2015 38 9 1638 1642 10.2337/dc15-1380 26294774\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-651X",
"issue": "2019()",
"journal": "Case reports in endocrinology",
"keywords": null,
"medline_ta": "Case Rep Endocrinol",
"mesh_terms": null,
"nlm_unique_id": "101576457",
"other_id": null,
"pages": "9415347",
"pmc": null,
"pmid": "30895163",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11036899;11522716;12021096;14508128;15492613;16628078;16702740;17130214;17312466;17520224;19454391;20124412;20736934;21412117;21562755;21615876;21973241;22249131;23170157;23911013;24463454;24639057;24929430;25468945;25481618;25616707;26040302;26080652;26294774;26370106;26378978;27042263;27181422;27294040;27316668;27436788;27738482;27987240;28003053;28025462;28027896;28197205;28502112;28538386;29110384;29166415;29316236;29725970;29858981;30026335;30181853;30288571;30291106;30800562;9329975",
"title": "Combination Therapy with Empagliflozin and Insulin Results in Successful Glycemic Control: A Case Report of Uncontrolled Diabetes Caused by Autoimmune Pancreatitis and Subsequent Steroid Treatment.",
"title_normalized": "combination therapy with empagliflozin and insulin results in successful glycemic control a case report of uncontrolled diabetes caused by autoimmune pancreatitis and subsequent steroid treatment"
}
|
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"summary": null
},
"primarysource": {
"literaturereference": "KISHIMOTO M, YAMAOKI K, ADACHI M. COMBINATION THERAPY WITH EMPAGLIFLOZIN AND INSULIN RESULTS IN SUCCESSFUL GLYCEMIC CONTROL: A CASE REPORT OF UNCONTROLLED DIABETES CAUSED BY AUTOIMMUNE PANCREATITIS AND SUBSEQUENT STEROID TREATMENT. CASE-REP-ENDOCRINOL 2019?:.",
"literaturereference_normalized": "combination therapy with empagliflozin and insulin results in successful glycemic control a case report of uncontrolled diabetes caused by autoimmune pancreatitis and subsequent steroid treatment",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190420",
"receivedate": "20190420",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16219462,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "BACKGROUND\nLung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination.\n\n\nMETHODS\nWe conducted a retrospective chart review of all lung and heart-lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined.\n\n\nRESULTS\nDuring the study period, 193 patients underwent lung or heart-lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post-transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P = 0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P < 0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P < 0.05).\n\n\nCONCLUSIONS\nItraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota.;William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota.;William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota.",
"authors": "Pennington|Kelly M|KM|https://orcid.org/0000-0003-1187-5059;Razonable|Raymund R|RR|https://orcid.org/0000-0001-5248-0227;Peters|Steve|S|;Scott|John P|JP|;Wylam|Mark|M|;Daly|Richard C|RC|;Kennedy|Cassie C|CC|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole; D065819:Voriconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "antifungal; lung transplant; prophylaxis; triazole",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000072742:Invasive Fungal Infections; D017964:Itraconazole; D016040:Lung Transplantation; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D009181:Mycoses; D012189:Retrospective Studies; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13067",
"pmc": null,
"pmid": "30866168",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "12535262;15614697;17062003;17251531;18462102;19645709;19712081;21272239;21803962;22484291;24992954;25604399;29110351",
"title": "Why do lung transplant patients discontinue triazole prophylaxis?",
"title_normalized": "why do lung transplant patients discontinue triazole prophylaxis"
}
|
[
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "POSACONAZOLE"
},
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"drugadministrationroute": "048",
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"drugdosageform": "TABLET",
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{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatic function abnormal",
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"reactionoutcome": "6"
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{
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}
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},
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{
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],
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"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PENNINGTON K, RAZONABLE R, PETERS S, SCOTT J, WYLAM M, DALY R, KENNEDY C. WHY DO LUNG TRANSPLANT PATIENTS DISCONTINUE TRIAZOLE PROPHYLAXIS?. TRANSPLANT INFECTIOUS DISEASE. 2019 JUN?.",
"literaturereference_normalized": "why do lung transplant patients discontinue triazole prophylaxis",
"qualification": "3",
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},
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"transmissiondate": "20191004"
},
{
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},
{
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},
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},
{
"reactionmeddrapt": "Product use in unapproved indication",
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}
],
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},
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"literaturereference": "PENNINGTON KM, RAZONABLE RR, PETERS S, SCOTT JP, WYLAM M, DALY RC ET AL.. WHY DO LUNG TRANSPLANT PATIENTS DISCONTINUE TRIAZOLE PROPHYLAXIS?. TRANSPLANT INFECTIOUS DISEASE. 2019?21(3):1-5",
"literaturereference_normalized": "why do lung transplant patients discontinue triazole prophylaxis",
"qualification": "3",
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},
"primarysourcecountry": "US",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20191004"
},
{
"companynumb": "US-JNJFOC-20190717850",
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"occurcountry": "US",
"patient": {
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"actiondrug": "1",
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},
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"drugadministrationroute": "065",
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"drugdosageform": "UNKNOWN",
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"drugindication": "ANTIFUNGAL PROPHYLAXIS",
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"medicinalproduct": "SPORANOX"
}
],
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{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PENNINGTON K, PETERS S, SCOTT J, WYLAM M, DALY R, KENNEDY C, RAZONABLE R, PENNINGTON K. WHY DO LUNG TRANSPLANT PATIENTS DISCONTINUE TRIAZOLE PROPHYLAXIS?. TRANSPL INFECT DIS. 2019 JUN?21(3):.",
"literaturereference_normalized": "why do lung transplant patients discontinue triazole prophylaxis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190807",
"receivedate": "20190807",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "BACKGROUND\nLarge-scale clinical trials have analyzed risk factors for any ischemic stroke in patients with atrial fibrillation (AF). However, the risk factors for cardioembolic stroke (CES), specifically, have not been reported. To clarify the risk factors for CES and clinically significant cardioembolic infarction, we examined the incidence of CES and larger infarct volume (IV) (> 30 mL) CES, employing the Fushimi AF Registry, a community-based prospective cohort of AF patients in the Fushimi ward, Kyoto, Japan.\n\n\nMETHODS\nA total of 4,182 Fushimi AF patients were enrolled from March 2011 to December 2014. The risk factors for CES were evaluated using multivariate analysis.\n\n\nRESULTS\nOf 4,182 patients enrolled, 3,749 patients were observed for ≥1 year. During the follow-up period (mean duration, 979 ± 7.7 days), 91/3,749 patients experienced a CES (2.43%). Significant risk factors associated with CES were older age (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.01-1.72; p = 0.046), low body weight (OR, 1.30; 95% CI, 1.03-1.65; p = 0.033), sustained AF (OR, 1.67; 95% CI, 1.05-2.71; p = 0.034), and previous stroke or transient ischemic attack (TIA) (OR, 1.94; 95% CI, 1.22-3.06; p = 0.004). Predictors of a large IV were chronic kidney disease (CKD) (OR, 2.08; 95% CI, 1.09-4.05; p = 0.027) and previous stroke/TIA (OR, 2.27; 95% CI, 1.19-4.24; p = 0.011).\n\n\nCONCLUSIONS\nIn this population-based cohort of Japanese patients with AF, in addition to previous stroke/TIA and older age, sustained AF and low body weight emerged as risk factors for CES, as opposed to any stroke, which may have a different risk profile. Patients with CKD or previous stroke/TIA who developed cardioembolic infarction exhibited more advanced severity. There is a need for direct oral anticoagulants that can be used safely in patients with comorbid AF and CKD.",
"affiliations": "Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Biostatistics, School of Public Health, Kyoto University, Kyoto, Japan.;Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.;Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.",
"authors": "Yasuda|Ken|K|;Fukuda|Shunichi|S|;Nakamura|Michikazu|M|;Ohtani|Ryo|R|;Kuwata|Yasuhiro|Y|;Takata|Masaki|M|;Sainouchi|Makoto|M|;Gotou|Masahiro|M|;Masuda|Yuichi|Y|;Kawarazaki|Satoru|S|;Kawabata|Yasuhiro|Y|;Murase|Nagako|N|;Aoki|Tomokazu|T|;Yonemoto|Naohiro|N|;Akao|Masaharu|M|;Tsukahara|Tetsuya|T|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000488206",
"fulltext": "\n==== Front\nCerebrovasc Dis ExtraCerebrovasc Dis ExtraCEECerebrovascular Diseases Extra1664-5456S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, [email protected] 2978802110.1159/000488206cee-0008-0050Original PaperPredictors of Cardioembolic Stroke in Japanese Patients with Atrial Fibrillation in the Fushimi AF Registry Yasuda Ken abFukuda Shunichi c*Nakamura Michikazu aOhtani Ryo aKuwata Yasuhiro aTakata Masaki aSainouchi Makoto aGotou Masahiro aMasuda Yuichi aKawarazaki Satoru cKawabata Yasuhiro cMurase Nagako aAoki Tomokazu cYonemoto Naohiro eAkao Masaharu dTsukahara Tetsuya caDepartment of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, JapanbDepartment of Neurology, Kyoto University, Graduate School of Medicine, Kyoto, JapancDepartment of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto, JapandDepartment of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, JapaneDepartment of Biostatistics, School of Public Health, Kyoto University, Kyoto, Japan*Shunichi Fukuda, Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555 (Japan), E-Mail [email protected] 2018 22 5 2018 22 5 2018 8 2 50 59 19 8 2017 7 3 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.Background\nLarge-scale clinical trials have analyzed risk factors for any ischemic stroke in patients with atrial fibrillation (AF). However, the risk factors for cardioembolic stroke (CES), specifically, have not been reported. To clarify the risk factors for CES and clinically significant cardioembolic infarction, we examined the incidence of CES and larger infarct volume (IV) (> 30 mL) CES, employing the Fushimi AF Registry, a community-based prospective cohort of AF patients in the Fushimi ward, Kyoto, Japan.\n\nMethods\nA total of 4,182 Fushimi AF patients were enrolled from March 2011 to December 2014. The risk factors for CES were evaluated using multivariate analysis.\n\nResults\nOf 4,182 patients enrolled, 3,749 patients were observed for ≥1 year. During the follow-up period (mean duration, 979 ± 7.7 days), 91/3,749 patients experienced a CES (2.43%). Significant risk factors associated with CES were older age (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.01–1.72; p = 0.046), low body weight (OR, 1.30; 95% CI, 1.03–1.65; p = 0.033), sustained AF (OR, 1.67; 95% CI, 1.05–2.71; p = 0.034), and previous stroke or transient ischemic attack (TIA) (OR, 1.94; 95% CI, 1.22–3.06; p = 0.004). Predictors of a large IV were chronic kidney disease (CKD) (OR, 2.08; 95% CI, 1.09–4.05; p = 0.027) and previous stroke/TIA (OR, 2.27; 95% CI, 1.19–4.24; p = 0.011).\n\nConclusions\nIn this population-based cohort of Japanese patients with AF, in addition to previous stroke/TIA and older age, sustained AF and low body weight emerged as risk factors for CES, as opposed to any stroke, which may have a different risk profile. Patients with CKD or previous stroke/TIA who developed cardioembolic infarction exhibited more advanced severity. There is a need for direct oral anticoagulants that can be used safely in patients with comorbid AF and CKD.\n\nKeywords\nAtrial fibrillationCardioembolic strokeRisk factorsStroke subtypeInfarct volumeCohort study\n==== Body\nIntroduction\nAtrial fibrillation (AF), which is the most common type of arrhythmia, increases the risk of thromboembolic events [1], and in particular, cardioembolic stroke (CES), which is the severest ischemic stroke subtype. Stroke risk has been examined in patients with AF in several studies [2, 3, 4, 5, 6], wherein various risk score rubrics were advocated, such as the CHADS2 scoring system [3] and, more recently, the CHA2DS2-VASc scoring system [4]. However, these scoring systems assess the risk for any stroke, including noncardioembolic ischemic stroke (i.e., lacunar or atherothrombotic infarction) and/or hemorrhagic stroke (i.e., cerebral, subarach noid, or chronic subdural hemorrhage), without specificity for CES [5, 6]. This may be partly because diagnostic imaging examinations were not usually performed at the onset of stroke in these clinical studies. Thus, it is unclear what factors are closely associated with CES in AF patients. For the same reason, the risk factors associated with infarct volume (IV) have not been determined in most clinical studies either, although the clinical outcome, as indexed by clinical stroke scales, has been found to be correlated with the lesion volume [7].\n\nThe Fushimi ward is located in southern Kyoto, Japan. It is a densely populated region with a total population of 283,000 and can be considered representative of a typical urban community in Japan. The Fushimi AF Registry includes a community-based prospective cohort of Japanese patients with AF. Investigators have already developed several lines of evidence based on this resource [8, 9, 10, 11].\n\nThe aims of this study were (1) to identify predictors specific to CES in Japanese AF patients and (2) to clarify risk factors associated with clinically meaningful large cardioembolic IV. Towards these aims, we used the Fushimi AF Registry to enroll all AF patients in the Fushimi ward in our analysis of stroke incidence and risk factors [8].\n\nMaterials and Methods\nFor further details, refer to online supplementary methods (for all online suppl. material, see www.karger.com/doi/10.1159/000488206).\n\nFushimi AF Registry Data Sources\nThe detailed study design, patient enrollment, definition of the measurements, and Fushimi AF Registry subjects' baseline clinical characteristics have been described previously. All Fushimi AF Registry patients who had undergone 12-lead electrocardiography or Holter monitoring at any of the 80 participating institutions (all Fushimi Ishi-Kai [Fushimi Medical Association] members) since March 2011 were consecutively enrolled without exclusion. Patients without at least 1 year of follow-up were excluded. Most of the patients had undergone brain magnetic resonance imaging (MRI) examinations at stroke onset, enabling us to determine the ischemic stroke type and measure IV with diffusion-weighted imaging. Cases for which MRI or computed tomography (CT) data from stroke events were unavailable were excluded (Fig. 1).\n\nThe study protocol conformed to the ethical guidelines of the 2000 Declaration of Helsinki and was approved by the ethics committees of both the National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital.\n\nStroke Ascertainment and Definitions\nWe identified stroke cases and determined stroke subtypes based on brain MRI or CT images obtained at stroke onset. Because all registry patients had cardiac-originated AF, we could not use a standard classification. Several independent neurologists reviewed each case and confirmed the stroke diagnoses, as informed by the literature [12]. The underlying stroke etiology was classified as CES, large-artery atherosclerosis, lacunar infarction, or undetermined etiology (see suppl. methods). Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2.\n\nIV Measurement\nIVs were measured manually in diffusion-weighted imaging or CT images, section by section, using the ITK-SNAP 2.2.0 software (http://www.itksnap.org/pmwiki/pmwiki.php?n=Main.Downloads). IV was classified as large (> 30 mL) or small (≤30 mL), based on a study that showed that lesion volume is correlated with functional status [13]. Clinical background data were compared between the resulting large and small IV groups.\n\nStatistical Analysis\nMeans are reported with standard deviations. We compared binary and categorical variables using the χ2 test when appropriate; otherwise, the Fisher exact test was applied. We compared continuous variables using the Student t test or the Wilcoxon rank-sum test. We performed univariate and multivariate logistic regression for identified risk factors and calculated odds ratios (ORs) and 95% confidence intervals (CIs). A set of potential risk factors was chosen a priori based on biological plausibility and a priori knowledge [2, 3, 4, 5, 6]. A two-sided p value < 0.05 was considered statistically significant. The rationales for risk factor selection are described in the online supplementary methods. All analyses were performed with JMP, version 11 (SAS Institute, Cary, NC, USA).\n\nResults\nOf 4,182 patients that were enrolled from March 2011 to December 2014, 3,749 patients were observed for at least 1 year (follow-up rate, 90.7%). The mean follow-up period for these 3,749 patients was 979 ± 7.7 days (median, 1,099 days; range 553–1,470 days). CES occurred in 91/3,749 (2.43%) during follow-up. Twenty-eight cases for which we could not obtain MRI or CT data were excluded.\n\nBaseline Clinical Characteristics\nThe baseline clinical characteristics of the 91 patients who experienced CES are summarized and are compared with the characteristics of non-CES patients (Table 1). Compared to those without CES, AF patients with CES tended to be older, shorter, and with a lower body weight, and were more likely to have a history of heart failure, prior stroke/transient ischemic attack (TIA), CKD, hypertrophic cardiomyopathy, and sustained AF. The average CHADS2 and CHA2DS2-VASc scores were higher while average estimated glomerular filtration rate and hemoglobin levels were lower in CES than in non-CES patients. CES patients were less likely to be taking an oral anticoagulant (OAC) than non-CES patients, with the most common OAC being warfarin (alternative OACs were limited when the majority of patients were enrolled). Compared to patients with a smaller IV (≤30 mL), patients with a larger IV (> 30 mL) were, on average, older, of lower body weight, and more likely to have a history of heart failure, previous stroke/TIA, or CKD.\n\nUnivariate and Multivariate Analysis\nThe univariate analysis results for CES and IV are reported in online supplementary Tables 1 and 2. Subsequent multivariate analysis after adjustment indicated that age (per decade; OR, 1.31; 95% CI, 1.10–1.72), low body weight (LBW; i.e., body mass ≤50 kg) (OR, 1.30; 95% CI, 1.03–1.65), sustained AF (OR, 1.67; 95% CI, 1.05–2.71), and previous stroke/TIA (OR, 1.94; 95% CI, 1.22–3.06) were risk factors for CES (Table 2). CKD (OR, 2.08; 95% CI, 1.09–4.05) and previous stroke/TIA (OR, 2.27; 95% CI, 1.19–4.24) were found to be associated with a larger IV (Table 3).\n\nCES Cases\nOf the 91 patients who experienced CES during the follow-up period (Table 4), 8 (9.7%) received recombinant tissue plasminogen activator (rt-PA); the mean modified Rankin Scale score of these patients was 3.27 ± 2.05. Notably, 41 of the 91 CES patients (45%) received warfarin at the time of stroke onset, although only 34 (37%) had a follow-up prothrombin time-international normalized ratio (PT-INR) value maintained within the warfarin therapeutic target range as established in the Japanese guidelines (PT-INR of 1.6–2.6 for patients ≤70 years old and PT-INR of 2.0–3.0 for patients < 70 years old) [14]. Most of the remaining patients (61%) had a PT-INR under the therapeutic range, indicating OAC underdosage. Sixteen (39%) of the patients were not administered an OAC at the time of CES onset.\n\nDiscussion\nPredictors of CES\nPredictors of CES identified in this study were of an older age, had an LBW, sustained AF, and prior stroke/TIA.\n\nSustained AF\nSeveral studies have reported that patients with paroxysmal AF have a risk of thromboembolic events similar to those with sustained (persistent and permanent) AF [6]. However, a recent meta-analysis reported that patients with sustained AF had a higher rate of stroke/systemic embolism than patients with paroxysmal AF [15]. AF events lasting longer than 1 day have been shown to be independently associated with embolism, and AF burden (i.e., time spent in AF) has been shown to be associated with an increased risk of stroke [16]. AF presence, duration, and burden status data may be integrated to obtain improved clinical risk stratification with continuous arrhythmia burden monitoring [17]. A previous study based on a Fushimi AF Registry cohort showed that sustained AF was independently associated with a higher incidence of stroke/systemic embolism than paroxysmal AF [9]. The present findings suggest that patients with sustained AF are also at a greater risk than patients with paroxysmal AF for CES, in particular.\n\nLow Body Weight\nIn the Fushimi AF Registry, patients with LBW (body mass ≤50 kg) had high-risk profiles and showed a higher incidence of any stroke and systemic embolism [10]. The inverse relationship between obesity and prognosis in AF patients has been termed an “obesity paradox.” Several large studies have found that AF patients who were overweight (body mass index, 25–30) or obese (body mass index, ≤30) tended to have a better prognosis in terms of cardiovascular hospitalizations, global mortality risk, and cardiovascular mortality risk [18]. We also found that LBW was a risk factor for CES in Japanese AF patients. Hence, there may be an inverse relationship between body weight and prognosis in AF patients, which extends beyond the normal weight versus obesity range into the LBW versus normal body weight range of comparison.\n\nAsian AF patients are generally leaner and smaller than European and North American AF patients; relative to Europeans and North Americans in the RE-LY [19], ROCKET-AF [20], and ARISTOTLE [21] studies, Asian patients were, on average, 20, 16 and 17 kg lighter, respectively. The proportions of Fushimi AF Registry enlistees with a body weight < 50 and < 60 kg have been reported to be 25.7 and 55.0%, respectively [8]. According to the National Health and Nutrition Survey, the mean body weights of Japanese men and women over 70 years old in 2014 were 50.7 and 50.1 kg, respectively (http://www.mhlw.go.jp/).\n\nThere are several possible explanations for the association of LBW with a higher risk of stroke [22]. First, LBW may be due to poor nutritional status or illness-related weight loss (e.g., malignancy, chronic obstructive pulmonary disease, and gastrointestinal disease). Second, underweight patients may have advanced atrial fibrosis and remodeling involving the activation of the renin-angiotensin system.\n\nOther Risk Factors\nAdvanced age and previous stroke/TIA are widely recognized as risk factors for stroke in patients with AF, including in the CHADS2 rubric [3] and CHADS2-VASc rubric [4]. The present study confirmed these two factors as independent risk factors for CES. In contrast, diabetes mellitus, hypertension, or congestive heart failure, which are commonly listed as risk factors for any ischemic stroke in AF patients, were not found to be significant risk factors for CES.\n\nIn a previous study, diabetes mellitus was associated with a significantly increased risk of AF (+26%) among women, but not among men [23]. It is still controversial whether diabetes mellitus is [2] or is not [23] a risk factor even for any ischemic stroke in patients with AF. The present study supports the view that diabetes mellitus is not a risk factor for CES.\n\nHypertension was not identified as an independent predictor of CES in the present study despite its common description as an important risk factor for any stroke. It may be that hypertension is associated with atherothrombotic cerebral infarction, lacunar infarction, hypertensive cerebral hemorrhage, and subarachnoid hemorrhage, but not with CES. Another possibility is that blood pressure (BP) was well controlled in the Fushimi AF Registry cohort (systolic BP 124.7 ± 19.1 mm Hg, diastolic BP 70.6 ± 12.8 mm Hg, n = 3,719). Future investigations are needed to clarify the possible role of hypertension in CES.\n\nPredictors of IV\nIV has been proposed as an alternative criterion (surrogate endpoint) to classical dis ability scales [24]. However, IV has not been associated with predictors of disability. The present study, to our knowledge, is the first to demonstrate that CKD and previous stroke/TIA are significant predictors of a larger IV. Notably, LBW, sustained AF, hypertension, and diabetes mellitus were not identified as significant risk factors for a larger IV.\n\nCKD is characterized by endothelial dysfunction and increased coagulation in association with factor VIII activity [25]. The abnormal hemostatic profiles of patients with CKD may be related to an elevated risk of thrombotic events. Thus, CKD has been associated with an increased risk of stroke or systemic thromboembolism among patients with AF [5]. The mechanism of this increased risk may be related to anemia, oxidative stress, elevated plasma asymmetrical dimethylarginine (an inhibitor of nitric oxide synthesis), inflammation, and coagulation-promoting conditions [26].\n\nTherefore, anticoagulation therapy should be sufficiently performed for AF patients with CKD. However, there are concerns regarding OAC prescriptions in these patients because of the increased risk of bleeding associated with CKD [27], which may lead to OAC underuse or underdosage. In addition, the metabolism of direct OAC drugs is largely dependent on the kidneys for elimination and little is known regarding the safety and efficacy of these drugs in patients with a creatinine clearance rate < 25 mL/min because they were excluded from all pivotal phase-3 direct OAC trials [27]. Because direct OAC use is often restricted in patients with advanced CKD, it has not been shown which direct OACs, if any, are safe for CKD patients at risk of large infarction [27].\n\nCES Cases\nKim et al. [12] found that 81.2% of ischemic stroke patients had AF-related stroke. Similarly, in the present study, CES patients accounted for 67.4% of all stroke patients and 83.5% of all ischemic stroke patients. The proportion of patients receiving rt-PA was larger in the present study than in other studies [28, 29], perhaps because Japan has a relatively high MRI delivery capacity (http://www.oecd.org/), with a large portion of hospitals capable of supporting rt-PA therapy, particularly in the Fushimi ward, where these capacities exceed the national average. Accordingly, it might be that education for stroke in the Fushimi ward has been widely dispersed among our patients.\n\nIn the present study, the absence of an OAC prescription was not a significant risk factor. This negative finding may be related to inappropriate OAC use in the study region. The Fushimi AF Registry has been demonstrated to encompass inappropriate OAC use in AF management, including OAC overuse among low-risk patients, OAC underuse among at-risk patients, and underdosing of warfarin [30]. Such inappropriate OAC use may be related to the narrow therapeutic range of OACs, drug and food interactions, the need for better monitoring, and/or concerns regarding bleeding risk [8]. Regardless, there is discordance between recommended guidelines and real-world clinical practice.\n\nLimitations\nThis study has several limitations. First, there were a limited number of stroke patients in the study population during the observation period. Second, antithrombotic drugs and doses were determined at the discretion of the attending physician. These limitations are intrinsic to most large multicenter registry studies.\n\nConclusions\nIn this population-based cohort of Japanese patients with AF, older age, sustained AF, previous stroke/TIA, and LBW were independently associated with the incidence of CES, as opposed to any stroke, which may have a different risk profile. Patients with CKD or previous stroke/TIA who developed cardioembolic infarction exhibited more advanced severity. There is a need for direct OACs that can be used safely in patients with comorbid AF and CKD.\n\nDisclosure Statement\nThe Fushimi AF Registry is supported by research funding from Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Novartis Pharma, MSD, Sanofi-Aventis, and Takeda Pharmaceutical. This research was supported in part by the Practical Research Project for Lifestyle-Related Diseases, including cardiovascular diseases and diabetes mellitus, from the Japanese Agency for Medical Research and Development, AMED (18ek0210082h0002, 18ek0210056h0003). Dr. Akao has received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare, and Daiichi-Sankyo.\n\nSupplementary Material\nSupplementary data\n\nClick here for additional data file.\n\n Supplementary data\n\nClick here for additional data file.\n\n Supplementary data\n\nClick here for additional data file.\n\n Acknowledgements\nWe sincerely appreciate the help of all of the institutions that participated in the Fushimi AF Registry and the contributions of the institutions' clinical research coordinators (T. Shi nagawa, M. Mitamura, M. Fukahori, M. Kimura, M. Fukuyama, and C. Kamata).\n\nFig. 1 Flowchart of this study.\n\nTable 1 Comparison of baseline clinical characteristics between patients with and without CES\n\n\tCES\tCES large IV\tCES small IV\tNon-CES\tp value\t\nNumber\t91\t45\t46\t3,658\t\t\nMale\t45 (49.5)\t22 (24.2)\t23 (25.3)\t2,178 (59.5)\t0.053\t\nAge, years\t78.9±8.4\t79.6±1.63\t78.1±1.61\t73.5±11.0\t<0.001\t\nHeight, cm\t156.1±10.8\t155.3±1.5\t156.9±1.5\t160.0±10.1\t<0.001\t\nBody weight, kg\t53.5±12.7\t52.3±2.0\t54.8±2.0\t59.3±13.2\t<0.001\t\nBMI\t21.7±3.7\t21.5±0.6\t22.1±0.6\t23.1±4.0\t0.003\t\nSystolic blood pressure, mm Hg\t121.4±21.5\t118.0±2.8\t124.7±2.8\t124.8±19.0\t0.092\t\nDiastolic blood pressure, mm Hg\t67.5±15.3\t64.0±1.9\t70.9±1.9\t70.7±12.8\t0.018\t\nSustained AF\t61 (67.3)\t31 (34.0)\t30 (33.3)\t1,851 (50.6)\t0.002\t\nParoxysmal AF Comorbidities\t30 (33.0)\t14 (15.3)\t16 (17.7)\t1,807 (49.4)\t0.002\t\nCHADS2 score\t2.69±1.30\t2.76±0.20\t2.63±0.20\t2.01±1.33\t<0.001\t\nCHA2DS2-VASc score\t4.28±1.60\t4.31±0.25\t4.26±0.25\t3.34±1.70\t<0.001\t\nCongestive heart failure\t35 (38.5)\t18 (19.7)\t17 (18.8)\t973 (26.6)\t0.012\t\nHypertension\t59 (64.8)\t30 (33.0)\t29 (31.8)\t2,270 (62.1)\t0.589\t\nDiabetes mellitus\t19 (21.0)\t5 (5.5)\t14 (15.5)\t841 (23.0)\t0.636\t\nDyslipidemia\t35 (38.5)\t16 (17.6)\t19 (20.9)\t1,583 (43.3)\t0.360\t\nChronic kidney disease\t46 (50.6)\t26 (28.6)\t20 (22.0)\t1,277 (34.9)\t0.002\t\neGFR\t46.2±17.5\t44.9±3.1\t47.3±3.0\t51.2±20.7\t0.022\t\nHemoglobin, g/dL\t12.4±2.0\t12.0±0.30\t12.8±0.30\t12.9±2.02\t0.014\t\nPrevious stroke/TIA\t33 (36.3)\t18 (19.7)\t15 (16.6)\t707 (19.3)\t<0.001\t\nDilated cardiomyopathy\t0 (0)\t0 (0)\t0 (0)\t51 (1.39)\t\t\nHypertrophic cardiomyopathy\t3 (3.3)\t1 (1.1)\t2 (2.2)\t37 (1.01)\t0.036\t\nEjection fraction\t63.0±10.7\t63.5±1.9\t62.4±1.8\t63.0±11.7\t0.603\t\nLeft atrial dilation, mm\t46.4±7.6\t46.8±1.4\t46.1±1.32\t43.7±8.3\t0.006\t\nOAC prescription at baseline\t54 (59.3)\t29 (31.9)\t25 (27.4)\t1,944 (53.4)\t0.262\t\nWarfarin\t50 (55.0)\t26 (28.5)\t24 (26.5)\t1,678 (46.1)\t0.095\t\nDabigatran\t3 (3.3)\t2 (2.2)\t1 (1.1)\t133 (3.64)\t0.864\t\nRivaroxaban\t1 (1.1)\t1 (1.1)\t0 (0)\t84 (2.3)\t0.449\t\nApixaban\t0 (0)\t0 (0)\t0 (0)\t49 (1.34)\t\t\nAntiplatelet drugs prescription at baseline\t41 (45.1)\t20 (22.0)\t21 (23.1)\t1,041 (27.7)\t<0.001\t\nCategorical data are presented as number (%) and continuous data as mean ± SD. We compared categorical variables using the χ2 test when appropriate; otherwise, we used the Fisher exact test. Continuous variables were compared using the Student t test or Wilcoxon rank-sum test based on the distribution. p values were used for comparison between CES and non-CES. CKD was defined as eGFR <60 mL/min/1.73 m2. Sustained AF referred to persistent and permanent AF. Infarct volume was classified as large (>30 mL) or small (≤30 mL). AF, atrial fibrillation; BMI, body mass index; CES, cardioembolic stroke; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IV, infarct volume; OAC; oral anticoagulant; TIA, transient ischemic attack.\n\nTable 2 Predictors of CES during follow-up: multivariate analysis after adjustment for CHADS2 score components, body weight loss (per 10 kg), prevalence of sustained AF, CKD, and OAC prescription at baseline\n\nVariable (n = 3,343)\tOdds ratio\t95% CI\tp value\t\nAge (per 10 years)\t1.31\t1.01–1.72\t0.046\t\nBody weight loss (per 10 kg)\t1.30\t1.03–1.65\t0.033\t\nPrevious stroke/TIA\t1.94\t1.22–3.06\t0.004\t\nHypertension\t1.00\t0.64–1.60\t0.969\t\nCongestive heart failure\t1.06\t0.66–1.70\t0.797\t\nDiabetes mellitus\t0.92\t0.53–1.53\t0.754\t\nSustained AF\t1.67\t1.05–2.71\t0.034\t\nOAC prescription at baseline\t1.10\t0.70–1.74\t0.676\t\nChronic kidney disease\t1.52\t0.96–2.41\t0.072\t\nMale\t1.04\t0.63–1.76\t0.857\t\nAF, atrial fibrillation; CES, cardioembolic stroke; CI, confidence interval; CKD, chronic kidney disease; OAC, oral anticoagulant; TIA, transient ischemic attack.\n\nTable 3 Predictors of large infarct volume CES (≥30 mL) during follow-up: multivariate analysis after adjustment for CHADS2 score components, sex, body weight loss (per 10 kg), prevalence of sustained AF, CKD, and OAC prescription at baseline\n\nVariable (N = 3,343)\tCES large IV\tCES small IV\t\n\todds ratio\t95% CI\tp value\todds ratio\t95% CI\tp value\t\nAge (per 10 years)\t1.34\t0.92–1.99\t0.141\t1.29\t0.91–1.88\t0.166\t\nBody weight loss (per 10 kg)\t1.40\t1.00–2.00\t0.054\t1.21\t0.88–1.68\t0.256\t\nPrevious stroke/TIA\t2.27\t1.19–4.24\t0.011\t1.65\t0.83–3.12\t0.138\t\nHypertension\t1.15\t0.61–2.26\t0.662\t0.88\t0.47–1.69\t0.700\t\nCongestive heart failure\t0.96\t0.49–1.84\t0.894\t1.18\t0.60–2.27\t0.620\t\nDiabetes mellitus\t0.42\t0.14–0.99\t0.074\t1.60\t0.80–3.05\t0.167\t\nSustained AF\t1.86\t0.96–3.81\t0.074\t1.50\t0.79–2.93\t0.220\t\nOAC prescription at baseline\t1.33\t0.70–2.59\t0.393\t0.92\t0.49–1.74\t0.798\t\nChronic kidney disease\t2.08\t1.09–4.05\t0.027\t1.12\t0.58–2.13\t0.737\t\nMale\t1.16\t0.56–2.42\t0.691\t0.96\t0.47–1.96\t0.903\t\nAF, atrial fibrillation; CES, cardioembolic stroke; CI, confidence interval; CKD, chronic kidney disease; IV, infarct volume; OAC, oral anticoagulant; TIA, transient ischemic attack.\n\nTable 4 CES case characteristics\n\nNumber of patients\t91\t\nmRS at discharge\t3.27±2.05\t\nICA/M1 occlusion\t28 (31)\t\nrt-PA\t8 (9.7)\t\nMedian infarct volume, mL\t29.75 [4.47–88.2]\t\nOAC prescription at onset\t49 (54)\t\nWarfarin prescription at onset\t41 (45)\t\n PT-INR under therapeutic range\t25 (27)\t\n PT-INR within optimal range\t15 (16)\t\n PT-INR over therapeutic range\t2 (o.02)\t\nDOAC prescription at onset\t8 (9)\t\n Apixaban\t1\t\n Dabigatran\t4\t\n Rivaroxaban\t3\t\nWithout OAC at onset\t36 (40)\t\nUnknown OAC use at onset\t6 (6)\t\nCategorical data are presented as number (%) and continuous data as mean ± SD. ICA/M1 occlusion were disclosed on magnetic resonance imaging at the onset. CES, cardioembolic stroke; CKD, chronic kidney disease; DOAC, direct oral anticoagulant; ICA, internal carotid artery; M1, M1 segment of middle cerebral artery; mRS, modified Rankin Scale; OAC, oral anticoagulant; PT-INR, prothrombin time-international normalized ratio; rt-PA, recombinant tissue plasminogen activator.\n==== Refs\nReferences\n1 Wolf PA Abbott RD Kannel WB Atrial fibrillation as an independent risk factor for stroke: the Framingham study Stroke 1991 22 983 988 1866765 \n2 Stroke Risk in Atrial Fibrillation Working Group: Independent predictors of stroke in patients with atrial fibrillation: a systematic review Neurology 2007 69 546 554 17679673 \n3 Gage BF Waterman AD Shannon W Boechler M Rich MW Radford MJ Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation JAMA 2001 285 2864 2870 11401607 \n4 Lip GY Frison L Halperin JL Lane DA Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort Stroke 2010 41 2731 2738 20966417 \n5 Olesen JB Lip GY Kamper AL Hommel K Kober L Lane DA Stroke and bleeding in atrial fibrillation with chronic kidney disease N Engl J Med 2012 367 625 635 22894575 \n6 Hohnloser SH Pajitnev D, Pogue J, Healey JS Pfeffer MA Yusuf S Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W substudy J Am Coll Cardiol 2007 50 2156 2161 18036454 \n7 Tong DC Yenari MA Albers GW O'Brien M Marks MP Moseley ME Correlation of perfusion- and diffusion-weighted MRI with NIHSS score in acute (< 6.5 h) ischemic stroke Neurology 1998 50 864 870 9566364 \n8 Akao M Chun YH Wada H Esato M Hashimoto T Abe M Current status of clinical background of patients with atrial fibrillation in a community-based survey: the Fushimi AF registry J Cardiol 2013 61 260 266 23403369 \n9 Takabayashi K Hamatani Y Yamashita Y Takagi D Unoki T Ishii M Incidence of stroke or systemic embolism in paroxysmal versus sustained atrial fibrillation: the Fushimi Atrial Fibrillation Registry Stroke 2015 46 3354 3361 26514188 \n10 Hamatani Y Ogawa H Uozumi R Iguchi M Yamashita Y Esato M Low body weight is associated with the incidence of stroke in atrial fibrillation patients - insight from the Fushimi AF Registry Circ J 2015 79 1009 1017 25740669 \n11 Yamashita Y Hamatani Y Esato M Chun YH Tsuji H Wada H Clinical characteristics and outcomes in extreme elderly (age ≥85 years) Japanese patients with atrial fibrillation: the Fushimi AF Registry Chest 2016 149 401 412 26181726 \n12 Kim SJ Ryoo S Kwon S Park YK Kim JP Lee GY Is atrial fibrillation always a culprit of stroke in patients with atrial fibrillation plus stroke? Cerebrovasc Dis 2013 36 373 382 24217395 \n13 Schiemanck SK Post MW Witkamp TD Kappelle LJ Prevo AJ Relationship between ischemic lesion volume and functional status in the 2nd week after middle cerebral artery stroke Neurorehabil Neural Repair 2005 19 133 138 15883357 \n14 Group JJW: Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013) Circ J 2014 78 1997 2021 24965079 \n15 Ganesan AN Chew DP Hartshorne T Selvanayagam JB Aylward PE Sanders P The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-analysis Eur Heart J 2016 37 1591 1602 26888184 \n16 Capucci A Santini M Padeletti L Gulizia M Botto G Boriani G Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers J Am Coll Cardiol 2005 46 1913 1920 16286180 \n17 Boriani G Botto GL Padeletti L Santini M Capucci A Gulizia M Improving stroke risk stratification using the CHADS2 and CHA2DS2-VASc risk scores in patients with paroxysmal atrial fibrillation by continuous arrhythmia burden monitoring Stroke 2011 42 1768 1770 21493904 \n18 Cambeiro G Cristina M Rodríguez-Mañero Moisés Raposeiras-Roubin Assi A Review of obesity and atrial fibrillation: exploring the paradox J Atr Fibrillation 2015 8 1259 27957191 \n19 Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009 361 1139 1151 19717844 \n20 Patel MR Mahaffey KW Garg J Pan G Singer DE Hacke W Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med 2011 365 883 891 21830957 \n21 Granger CB Alexander JH McMurray JJ Lopes RD Hylek EM Hanna M Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med 2011 365 981 992 21870978 \n22 Novo G Guttilla D Fazio G Cooper D Novo S The role of the renin-angiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS Br J Clin Pharmacol 2008 66 345 351 18782141 \n23 Suzuki S Yamashita T Okumura K Atarashi H Akao M Ogawa H Incidence of ischemic stroke in Japanese patients with atrial fibrillation not receiving anticoagulation therapy: pooled analysis of the Shinken Database, J-RHYTHM registry, and Fushimi AF registry Circ J 2015 79 432 438 25501800 \n24 Warach S Pettigrew LC Dashe JF Pullicino P Lefkowitz DM Sabounjian L Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging Citicoline 010 investigators Ann Neurol 2000 48 713 722 11079534 \n25 Huang M-J, Wei R Wang Y Su T Di P Li Q Blood coagulation system in patients with chronic kidney disease: a prospective observational study BMJ Open 2017 7 e014294 \n26 Yahalom G Schwartz R Schwammenthal Y Merzeliak O Toashi M Orion D Chronic kidney disease and clinical outcome in patients with acute stroke Stroke 2009 40 1296 1303 19182072 \n27 Di Lullo L Ronco C Cozzolino M Russo D Russo L Di Iorio B Nonvitamin K-dependent oral anticoagulants (NOACs) in chronic kidney disease patients with atrial fibrillation Thromb Res 2017 155 38 47 28482261 \n28 Kleindorfer D Kissela B Schneider A Woo D Khoury J Miller R Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study Stroke 2004 35 e27 e29 14739423 \n29 Skolarus LE Meurer WJ Shanmugasundaram K Adelman EE Scott PA Burke JF Marked regional variation in acute stroke treatment among medicare beneficiaries Stroke 2015 46 1890 1896 26038520 \n30 Akao M Chun YH Esato M Abe M Tsuji H Wada H Hasegawa K Inappropriate use of oral anticoagulants for patients with atrial fibrillation: 1-year outcomes of the Fushimi AF Registry Circ J 2014 78 2166 2172 24976391\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "8(2)",
"journal": "Cerebrovascular diseases extra",
"keywords": "Atrial fibrillation; Cardioembolic stroke; Cohort study; Infarct volume; Risk factors; Stroke subtype",
"medline_ta": "Cerebrovasc Dis Extra",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D001835:Body Weight; D016009:Chi-Square Distribution; D015897:Comorbidity; D005260:Female; D006801:Humans; D015994:Incidence; D020766:Intracranial Embolism; D007564:Japan; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012042:Registries; D012307:Risk Factors; D020521:Stroke; D013997:Time Factors",
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"title": "Predictors of Cardioembolic Stroke in Japanese Patients with Atrial Fibrillation in the Fushimi AF Registry.",
"title_normalized": "predictors of cardioembolic stroke in japanese patients with atrial fibrillation in the fushimi af registry"
}
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"abstract": "The triple negative cancer is an unusual, and at the same time, a unique entity where the discordance rate is almost 18%. That means 18% of Her2 negative results will transform into a Her2 positive status and will have the affinity to spread to the central nervous system (CNS). With the identification of CD44, CD24, and ALDH1, we may be able to determine which group of triple negative breast cancer patients will have CNS metastasis. This case illustrates the Her2 expressing cells have higher CNS affinity. As the original tumor was Her2 negative, if a genomic assay was then done on this patient, we would have identified the potential of CNS involvement. In conclusion, genomic assays should be routinely done on triple negative cancers.",
"affiliations": "Regional Medical Oncology Hematology Leader, Centre for the North, BC Cancer Agency, Prince George, British Columbia, Canada.",
"authors": "Katakkar|Suresh B|SB|",
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"keywords": "breast cancer; claudin high or low; genomic microassay; triple negative",
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"title": "A triple negative breast cancer: what it is not!",
"title_normalized": "a triple negative breast cancer what it is not"
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{
"abstract": "A 46-year-old woman with quiescent lupus presented with worsening pleuritic chest pain and dyspnoea. Bedside echocardiogram confirmed large pericardial effusion with cardiac tamponade. Emergency bedside pericardiocentesis was performed. Pericardial fluid cytology confirmed diffuse large B cell lymphoma, stage four on positron emission tomography. Conventional rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy achieved good response in all sites except the pericardium. Progressive cardiac involvement was complicated by atrioventricular conduction block requiring permanent pacemaker. Second-line palliative chemotherapy was performed.",
"affiliations": "Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia.;Department of Haematology, Royal Perth Hospital, Perth, Western Australia, Australia.;Department of Cardiology, Royal Perth Hospital, Perth, Western Australia, Australia.",
"authors": "Giudicatti|Lauren Christina|LC|;Cirillo|Melita|M|http://orcid.org/0000-0001-9881-0260;King|Benjamin|B|",
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"keywords": "cancer - see oncology; cardiovascular medicine; haematology (incl blood transfusion); pacing and electrophysiology; pericardial disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D054537:Atrioventricular Block; D004452:Echocardiography; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged; D009367:Neoplasm Staging; D010138:Pacemaker, Artificial; D010166:Palliative Care; D010490:Pericardial Effusion; D020519:Pericardiocentesis; D049268:Positron-Emission Tomography",
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"references": "26551877;24126323;26320112;22571682;2040331;9134285;17098886;7037154;26184750;18765314;26935129",
"title": "Pericardial effusion as first presentation of disseminated non-Hodgkin's lymphoma.",
"title_normalized": "pericardial effusion as first presentation of disseminated non hodgkin s lymphoma"
}
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],
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"reaction": [
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute kidney injury",
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"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "GIUDICATTI LC, CIRILLO M, KING B. PERICARDIAL EFFUSION AS FIRST PRESENTATION OF DISSEMINATED NON-HODGKIN^S LYMPHOMA. BMJ-CASE-REP 2018?2018:225926.",
"literaturereference_normalized": "pericardial effusion as first presentation of disseminated non hodgkin s lymphoma",
"qualification": "1",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20181115",
"receivedate": "20181115",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15621282,
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},
"serious": 1,
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"seriousnesslifethreatening": 1,
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}
] |
{
"abstract": "Objective The objective of this study was to compare clinical outcomes in children undergoing hematopoietic cell transplantation who received levetiracetam versus those who received phenytoin for the prevention of busulfan-induced seizures. Methods This study was an IRB-approved, single-center, retrospective analysis of pediatric patients receiving intravenous busulfan for hematopoietic cell transplantation conditioning from January 2009 to July 2014. The primary study endpoint was the incidence of seizure during busulfan administration (day -8 to 0). Key transplant related-outcomes were also collected, including the incidence of graft rejection, sinusoidal obstruction syndrome, relapse, and death. Results A total of 20 patients met criteria for inclusion in the study. The population was heterogeneous with regard to the indication for hematopoietic cell transplantation, donor type, stem cell source, and conditioning regimen. Nine patients (45%) received levetiracetam and 11 (55%) received phenytoin for seizure prophylaxis. No seizures or graft rejections were observed in the study population. One relapse, one case of sinusoidal obstruction syndrome, and two deaths occurred in the levetiracetam group, while no relapses, two cases of sinusoidal obstruction syndrome, and one death occurred in the phenytoin group. Conclusion These data suggest similar safety and effectiveness between levetiracetam and phenytoin for the prevention of busulfan-induced seizures in a small, heterogeneous pediatric hematopoietic cell transplantation population.",
"affiliations": "1 Department of Pharmacy Services, Oregon Health & Science University, Portland, USA.;2 Department of Pharmacy and Department of Pharmaceutics, University of Washington, Seattle, USA.",
"authors": "Floeter|Abby E|AE|;McCune|Jeannine S|JS|",
"chemical_list": "D000927:Anticonvulsants; D019653:Myeloablative Agonists; D000077287:Levetiracetam; D010672:Phenytoin; D002066:Busulfan; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": "10.1177/1078155216651128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "23(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Antiepileptic drug; busulfan; levetiracetam; phenytoin; seizures",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D005260:Female; D006084:Graft Rejection; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007223:Infant; D000077287:Levetiracetam; D008297:Male; D019653:Myeloablative Agonists; D010672:Phenytoin; D010889:Piracetam; D012008:Recurrence; D012189:Retrospective Studies; D012640:Seizures; D019172:Transplantation Conditioning; D055815:Young Adult",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "344-349",
"pmc": null,
"pmid": "27208016",
"pubdate": "2017-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Levetiracetam for the prevention of busulfan-induced seizures in pediatric hematopoietic cell transplantation recipients.",
"title_normalized": "levetiracetam for the prevention of busulfan induced seizures in pediatric hematopoietic cell transplantation recipients"
}
|
[
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{
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"drugindication": "BONE MARROW CONDITIONING REGIMEN",
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{
"abstract": "BACKGROUND\nGermline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood.\n\n\nOBJECTIVE\nThis study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis.\n\n\nMETHODS\nPatients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing.\n\n\nRESULTS\nBoth patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization.\n\n\nCONCLUSIONS\nComplete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.",
"affiliations": "Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.;Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.;Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, Emory University, Atlanta, Ga.;Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.;Section of Oncology/Bone Marrow Therapy, Departments of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.;Department of Pathology and Laboratory Medicine, University of Calgary, Alberta Precision Laboratories, Calgary, Alberta, Canada.;Department of Pathology and Laboratory Medicine, University of Calgary, Alberta Precision Laboratories, Calgary, Alberta, Canada.;Department of Pathology and Laboratory Medicine, University of Calgary, Alberta Precision Laboratories, Calgary, Alberta, Canada.;Centre for Blood Research, The University of British Columbia, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.;Section of Oncology/Bone Marrow Therapy, Departments of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.;Section of Oncology/Bone Marrow Therapy, Departments of Oncology and Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.;Department of Pediatrics, Division of Immunology, Hematology, Oncology and Palliative Care (iHOPE), University of Alberta, Edmonton, Alberta, Canada.;Department of Pediatrics, Division of Immunology, Hematology, Oncology and Palliative Care (iHOPE), University of Alberta, Edmonton, Alberta, Canada.;Department of Pediatrics, Division of General and Community Pediatrics, University of Alberta, Edmonton, Alberta, Canada.;Section of Pediatric Hematology-Immunology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.;Section of Pediatric Hematology-Immunology, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.;Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.;Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.;Centre for Blood Research, The University of British Columbia, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.;Department of Pediatrics, Division of Immunology, Hematology, Oncology and Palliative Care (iHOPE), University of Alberta, Edmonton, Alberta, Canada.;Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: [email protected].",
"authors": "Lu|Henry Y|HY|;Sharma|Mehul|M|;Sharma|Ashish A|AA|;Lacson|Atilano|A|;Szpurko|Ashley|A|;Luider|Joanne|J|;Dharmani-Khan|Poonam|P|;Shameli|Afshin|A|;Bell|Peter A|PA|;Guilcher|Gregory M T|GMT|;Lewis|Victor A|VA|;Vasquez|Marta Rojas|MR|;Desai|Sunil|S|;McGonigle|Lyle|L|;Murguia-Favela|Luis|L|;Wright|Nicola A M|NAM|;Sergi|Consolato|C|;Wine|Eytan|E|;Overall|Christopher M|CM|;Suresh|Sneha|S|;Turvey|Stuart E|SE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaci.2021.04.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-6749",
"issue": "148(6)",
"journal": "The Journal of allergy and clinical immunology",
"keywords": "B-cell development; CARD11; CBM complex; Combined immunodeficiency; hematopoietic stem cell transplantation",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": null,
"nlm_unique_id": "1275002",
"other_id": null,
"pages": "1559-1574.e13",
"pmc": null,
"pmid": "33872653",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency.",
"title_normalized": "mechanistic understanding of the combined immunodeficiency in complete human card11 deficiency"
}
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"drugindication": "Bone marrow conditioning regimen",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "ALEMTUZUMAB"
},
{
"actiondrug": "5",
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"activesubstancename": "ALEMTUZUMAB"
},
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"drugindication": "Combined immunodeficiency",
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"medicinalproduct": "ALEMTUZUMAB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
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"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "DAYS - 6 TO - 2 (30 MG/M 2 /DAY, DOSE ADJUSTED FOR RENAL FUNCTION)",
"drugenddate": null,
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"drugindication": "Allogenic stem cell transplantation",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"medicinalproduct": "FLUDARABINE"
},
{
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"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
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"drugcharacterization": "1",
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"drugindication": "Bone marrow conditioning regimen",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "FLUDARABINE"
},
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Combined immunodeficiency",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"medicinalproduct": "FLUDARABINE"
}
],
"patientagegroup": null,
"patientonsetage": "18",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cytomegalovirus infection reactivation",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Norovirus infection",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Gastrointestinal haemorrhage",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Lu HY, Sharma M, Sharma AA, Lacson A, Szpurko A, Luider J et al.. Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency. J Allergy Clin Immunol. 2021;148(6):1559-74",
"literaturereference_normalized": "mechanistic understanding of the combined immunodeficiency in complete human card11 deficiency",
"qualification": "3",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20211221",
"receivedate": "20211221",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20213664,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Ablation of the acardiac twin umbilical cord in the TRAP protects the normal donor twin.\n\n\n\nTwo case descriptions, one of interstitial laser photocoagulation and one of laser umbilical cord occlusion (L-UCO) of the acardiac twin in monochorionic monoamniotic pregnancies are reported.\n\n\n\nL-UCO in two pregnancies with TRAP syndrome in the second trimester resulted in intrauterine fetal death in both cases after 1 month. Case 1 had no detectable cause of fetal death. Case 2 had rupture of the amniotic sac causing anhydramnios and acute chorioamnionitis. A groove on the umbilical cord of the normal twin indicated a cord stricture due to cord entanglement.\n\n\n\nOur experience confirms that the best timing and optimal treatment of MC/MA twins complicated by TRAP sequence still remains a controversial clinical issue. Cord entanglement may continue be a potential clinical risk factor for adverse perinatal outcome even after ablation therapy.",
"affiliations": "a Department of Obstetric and Gynecology, Prenatal Diagnostic Service , Reggio Emilia , Italy.;b Azienda Socio Sanitaria Territoriale di Mantova, Department of Obstetrics and Gynecology , Carlo Poma Hospital , Mantova , Italy.;b Azienda Socio Sanitaria Territoriale di Mantova, Department of Obstetrics and Gynecology , Carlo Poma Hospital , Mantova , Italy.;c Department of Obstetrics and Gynecology , Brescia , Italy.;d Universita degli Studi di Brescia Sezione Materno Infantile, Obstetrics and Gynecology , Brescia , Italy.;e Arcispedale S.Maria Nuova , Reggio Emilia , Italy.;f Hopital Universitaire Robert-Debre, Unite de Foetopathologie , Paris , France.;f Hopital Universitaire Robert-Debre, Unite de Foetopathologie , Paris , France.;f Hopital Universitaire Robert-Debre, Unite de Foetopathologie , Paris , France.;g Hopital Universitaire Robert-Debre, Obstetrics and Gynecology , Paris , France.;h Paulista School of Medicine - Federal University of São Paulo, Obstetrics , São Paulo , Brazil.",
"authors": "Tonni|Gabriele|G|0000-0002-2620-7486;Grisolia|Gianpaolo|G|;Zampriolo|Paolo|P|;Prefumo|Federico|F|0000-0001-7793-714X;Fichera|Anna|A|;Bonasoni|Paola|P|;Lefebvre|Mathilde|M|;Khung-Savatovsky|Suonavy|S|;Guimiot|Fabien|F|;Rosenblatt|Jonathan|J|;Araujo Júnior|Edward|E|0000-0002-6145-2532",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/15513815.2018.1526240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-3815",
"issue": "37(6)",
"journal": "Fetal and pediatric pathology",
"keywords": "Cristal and Realistic Vue; TRAP sequence; fetal pathology; fetoscopic laser photocoagulation; monochorionic/monoamiotic twins",
"medline_ta": "Fetal Pediatr Pathol",
"mesh_terms": "D005260:Female; D005330:Fetofetal Transfusion; D005332:Fetoscopy; D006801:Humans; D017075:Laser Coagulation; D053685:Laser Therapy; D011247:Pregnancy; D014430:Twins, Monozygotic",
"nlm_unique_id": "101230972",
"other_id": null,
"pages": "433-447",
"pmc": null,
"pmid": "30636554",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "TRAP Sequence in Monochorionic/Monoamniotic (MC/MA) Discordant Twins: Two Cases Treated with Fetoscopic Laser Surgery.",
"title_normalized": "trap sequence in monochorionic monoamniotic mc ma discordant twins two cases treated with fetoscopic laser surgery"
}
|
[
{
"companynumb": "IT-STRIDES ARCOLAB LIMITED-2019SP006712",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "210958",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10ML OF 2%",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "LOCAL ANAESTHESIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LIDOCAINE."
}
],
"patientagegroup": null,
"patientonsetage": "31",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Foetal death",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TONNI G, GRISOLIA G, ZAMPRIOLO P, PREFUMO F, FICHERA A, BONASONI P, ET AL. TRAP SEQUENCE IN MONOCHORIONIC/MONOAMNIOTIC (MC/MA) DISCORDANT TWINS: TWO CASES TREATED WITH FETOSCOPIC LASER SURGERY. FETAL AND PEDIATRIC PATHOLOGY. 2018?37:433-447",
"literaturereference_normalized": "trap sequence in monochorionic monoamniotic mc ma discordant twins two cases treated with fetoscopic laser surgery",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20190801",
"receivedate": "20190801",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16656072,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "BACKGROUND\nAntipsychotics are a treatment option for delirium in the intensive care unit. Atypical antipsychotics are preferred over first-generation antipsychotics because of their lower incidence of extrapyramidal adverse effects. The most common such effect is akathisia or restlessness. This report describes a case of atypical antipsychotic-induced akathisia and addresses the clinical distinction between extrapyramidal movements and movements due to intensive care unit delirium.\n\n\nRESULTS\nA 56-year-old man who had a prolonged hospital stay after orthotopic liver transplant complicated by multisystem organ failure, primary graft failure requiring a second transplant, and enterocutaneous fistula developed agitated delirium on hospital day 28. Initial treatment included intravenous haloperidol and scheduled sublingual olanzapine (5 mg daily). His delirium and insomnia persisted, requiring dexmedetomidine infusion. Olanzapine dosing was increased to 10 mg daily on hospital day 34 and 15 mg daily on hospital day 45. The following day, his mentation improved; however, he exhibited asynchronous, nonrhythmic, involuntary rolling motions of his hands and choreiform gait.\nAntipsychotics were immediately discontinued owing to acute akathisia. All symptoms resolved within 2 days, and the patient was transferred out of the intensive care unit on hospital day 52.\n\n\nCONCLUSIONS\nAlthough extrapyramidal adverse effects are less common with olanzapine than with typical antipsychotics, they sometimes occur and can mimic manifestations of delirium. Restlessness should alert the nurse to assess for possible extrapyramidal adverse effects. If they are suspected, antipsychotic medications should be reduced or discontinued to prevent progression to functional disability.",
"affiliations": "Christan D. Santos is a nurse practitioner, Department of Critical Care Medicine, Mayo Clinic, Jacksonville, Florida.;Mariah Q. Rose is a nurse practitioner, Department of Critical Care Medicine, Mayo Clinic.",
"authors": "Santos|Christan D|CD|;Rose|Mariah Q|MQ|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.4037/ccn2021765",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0279-5442",
"issue": "41(3)",
"journal": "Critical care nurse",
"keywords": null,
"medline_ta": "Crit Care Nurse",
"mesh_terms": "D014150:Antipsychotic Agents; D003693:Delirium; D006220:Haloperidol; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine",
"nlm_unique_id": "8207799",
"other_id": null,
"pages": "50-54",
"pmc": null,
"pmid": "34061189",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extrapyramidal Symptoms Induced by Treatment for Delirium: A Case Report.",
"title_normalized": "extrapyramidal symptoms induced by treatment for delirium a case report"
}
|
[
{
"companynumb": "US-MYLANLABS-2021M1039339",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "5 MILLIGRAM GIVEN ON DAY 28",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DELIRIUM",
"drugintervaldosagedefinition": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HALOPERIDOL."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "1",
"drugadministrationroute": "060",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "ORODISPERSIBLE TABLET",
"drugdosagetext": "10 MILLIGRAM, QD STARTED ON HOSPITAL DAY 34",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OLANZAPINE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
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"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INFUSION",
"drugdosagetext": "2 MICROG/KG/H INFUSION WAS ADMINISTERED NIGHTLY FROM 8PM TO 5AM FROM HOSPITAL DAY 34?41",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INSOMNIA",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "DEXMEDETOMIDINE."
},
{
"actiondrug": "1",
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"activesubstancename": "OLANZAPINE"
},
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"drugdosagetext": "15 MILLIGRAM, QD STARTED ON HOSPITAL DAY 45",
"drugenddate": null,
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"drugindication": null,
"drugintervaldosagedefinition": "804",
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"drugstructuredosagenumb": "15",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "OLANZAPINE."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
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"drugcharacterization": "2",
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"drugdosagetext": "ADMINISTERED AT NIGHT",
"drugenddate": null,
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"drugindication": "INSOMNIA",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PROPOFOL."
},
{
"actiondrug": "6",
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"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
"drugadministrationroute": "042",
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"drugdosageform": "INJECTION",
"drugdosagetext": "50 MILLIGRAM ON HOSPITAL DAY 43",
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DIPHENHYDRAMINE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "1",
"drugadministrationroute": "060",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "ORODISPERSIBLE TABLET",
"drugdosagetext": "5 MILLIGRAM, QD AT BEDTIME; STARTED ON HOSPITAL DAY 28",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INSOMNIA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
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"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OLANZAPINE."
}
],
"patientagegroup": null,
"patientonsetage": "56",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Akathisia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SANTOS CD, ROSE MQ. EXTRAPYRAMIDAL SYMPTOMS INDUCED BY TREATMENT FOR DELIRIUM: A CASE REPORT. CRIT?CARE?NURSE 2021?41(3):50?54.",
"literaturereference_normalized": "extrapyramidal symptoms induced by treatment for delirium a case report",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210707",
"receivedate": "20210707",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20211014"
},
{
"companynumb": "US-APOTEX-2021AP016002",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INFUSION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
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}
],
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"reaction": [
{
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "24.0",
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},
{
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},
{
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
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},
"primarysource": {
"literaturereference": "SANTOS C, ROSE M. EXTRAPYRAMIDAL SYMPTOMS INDUCED BY TREATMENT FOR DELIRIUM: A CASE REPORT. CRIT CARE NURSE. 2021?41(3):50?4. DOI:10.4037/CCN2021765",
"literaturereference_normalized": "extrapyramidal symptoms induced by treatment for delirium a case report",
"qualification": "3",
"reportercountry": "US"
},
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"receivedate": "20210630",
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},
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},
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
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"transmissiondate": "20211014"
}
] |
{
"abstract": "The outcome of immunosuppressive therapy (IST) and prognosis in patients with aplastic anaemia (AA) secondary to chemotherapy or radiotherapy for cancers remains unknown. A total of 43 of 2559 patients with AA referred to our hospital had previously received chemoradiotherapy for various types of solid tumours (n = 25) or haematological malignancies (n = 18). Their cancer status was complete remission (CR) in 27, non-CR in 13, and unknown in three. Small populations of glycosylphosphatidylinositol-anchored protein-deficient [GPI(-)] granulocytes were detected in 16 patients (37·2%). Of 18 patients who were treated with IST, 50% improved regardless of the presence of GPI(-) cells. The overall survival (OS) rate was significantly higher in patients with a history of solid tumours patients than in those of haematological malignancies (median OS, 87 vs. 11 months, P = 0·0003), and in patients treated with IST than in those of untreated patients (median OS, 115 vs. 20 months, P = 0·028). Cancer aggravation occurred in two of four patients who were treated with IST while in non-CR of their original cancers. Progression to myelodysplastic syndromes was observed in two patients not possessing GPI(-) cells. IST should thus be considered for patients with AA secondary to chemoradiotherapy for cancers, particularly when their original solid tumours are in CR.",
"affiliations": "Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.;Department of Transfusion Medicine, Kanazawa University Hospital, Kanazawa, Japan.;Department of Hematology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.",
"authors": "Nakagawa|Noriharu|N|https://orcid.org/0000-0001-8520-9142;Ishiyama|Ken|K|https://orcid.org/0000-0002-6189-0620;Tanabe|Mikoto|M|;Yoroidaka|Takeshi|T|;Mizumaki|Hiroki|H|;Imi|Tatsuya|T|;Zaimoku|Yoshitaka|Y|https://orcid.org/0000-0002-4108-5245;Maruyama|Hiroyuki|H|;Hosokawa|Kohei|K|https://orcid.org/0000-0002-3423-1523;Yamazaki|Hirohito|H|;Nakao|Shinji|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17802",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "195(5)",
"journal": "British journal of haematology",
"keywords": "aplastic anaemia; cancer; chemoradiotherapy; glycosylphosphatidylinositol-anchored protein-deficient cells; immunosuppressive therapy",
"medline_ta": "Br J Haematol",
"mesh_terms": null,
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "770-780",
"pmc": null,
"pmid": "34476805",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The effectiveness of immunosuppressive therapy in patients with aplastic anaemia secondary to chemoradiotherapy for cancers.",
"title_normalized": "the effectiveness of immunosuppressive therapy in patients with aplastic anaemia secondary to chemoradiotherapy for cancers"
}
|
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},
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},
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},
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"transmissiondate": "20220721"
}
] |
{
"abstract": "Hydralazine is a commonly prescribed antihypertensive agent. Some of its labelled adverse reactions include lupus-like syndrome, tachycardia, headache and fever. Despite its well-known side effects, little is known about hydralazine's hepatotoxic effects. We report the case of a 54-year-old female patient who was started on hydralazine for hypertension management but later presented with hydralazine-induced liver injury. Her initial presentation consisted of non-specific symptoms and a hepatocellular injury pattern. Liver biopsy revealed hepatic steatosis. Three weeks after discontinuation of hydralazine, the patient's liver enzymes normalised, and her symptoms resolved. Few studies have examined the incidence and mechanism by which hydralazine induces a liver injury pattern. With this case, we review the literature, the pathogenesis involved and the eventual management of hydralazine-induced liver injury. We propose close monitoring of liver enzymes for patients on hydralazine throughout their treatment course.",
"affiliations": "Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA.;Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA.;Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA.;Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA [email protected].",
"authors": "Bhardwaj|Meeta|M|http://orcid.org/0000-0002-4083-3395;Bhardwaj|Nakul Jay|NJ|;Cueto|Kendra|K|;Killeen|T Colin|TC|",
"chemical_list": "D000959:Antihypertensive Agents; D006830:Hydralazine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "drugs; gastroenterology; gastrointestinal system; liver disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000959:Antihypertensive Agents; D056486:Chemical and Drug Induced Liver Injury; D056487:Chemical and Drug Induced Liver Injury, Chronic; D005260:Female; D006801:Humans; D006830:Hydralazine; D006973:Hypertension; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34404652",
"pubdate": "2021-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydralazine-induced liver injury: a review and discussion.",
"title_normalized": "hydralazine induced liver injury a review and discussion"
}
|
[
{
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{
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},
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},
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},
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"drugindication": "HYPERTENSION",
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"medicinalproduct": "HYDRALAZINE HYDROCHLORIDE."
}
],
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
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},
"primarysource": {
"literaturereference": "BHARDWAJ M, BHARDWAJ NJ, CUETO K, KILLEEN TC. HYDRALAZINE?INDUCED LIVER INJURY: A REVIEW AND DISCUSSION. BMJ CASE REPORTS. 2021?14:1?5",
"literaturereference_normalized": "hydralazine induced liver injury a review and discussion",
"qualification": "3",
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},
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},
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},
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},
{
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"fulfillexpeditecriteria": "1",
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"patient": {
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{
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},
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}
],
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"reactionmeddraversionpt": "24.1",
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},
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
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],
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},
{
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}
],
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},
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"literaturereference": "1: BHARDWAJ M, BHARDWAJ NJ, CUETO K, KILLEEN TC. HYDRALAZINE?INDUCED LIVER?INJURY: A REVIEW AND DISCUSSION. BMJ CASE REP. 2021 AUG 17?14(8):E243278.",
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},
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},
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},
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}
] |
{
"abstract": "Bimatoprost is a prostaglandin analogue used topically in the treatment of glaucoma. Commonly known side effects include eyelash growth, iris pigmentation and conjunctival hyperemia. While pseudomyopia is reported to be caused by parasympathomimetics, such an effect precipitated by bimatoprost has not yet been reported. We report a case demonstrating pseudomyopia and accommodative spasm caused after starting bimatoprost 0.03% in a young patient with glaucoma.",
"affiliations": "LV Prasad Eye Institute, Bhubaneswar, Odisha, India.;Glaucoma Services, LV Prasad Eye Institute, Bhubaneswar, Odisha, India.",
"authors": "Padhy|Debananda|D|;Rao|Aparna|A|",
"chemical_list": "D000959:Antihypertensive Agents; D000069580:Bimatoprost",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000959:Antihypertensive Agents; D000069580:Bimatoprost; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009216:Myopia; D009801:Oculomotor Muscles; D013035:Spasm; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26598527",
"pubdate": "2015-11-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15334011;10958605;11328719;19107053;9479285;15710814;9780112;11231772;15980234;12614748;9683147",
"title": "Bimatoprost (0.03%)-induced accommodative spasm and pseudomyopia.",
"title_normalized": "bimatoprost 0 03 induced accommodative spasm and pseudomyopia"
}
|
[
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2016-00257",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BIMATOPROST"
},
"drugadditional": null,
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"drugauthorizationnumb": "203991",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"drugindication": "OPEN ANGLE GLAUCOMA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": ".03",
"drugstructuredosageunit": "030",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BIMATOPROST."
}
],
"patientagegroup": null,
"patientonsetage": "47",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pseudomyopia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Accommodation disorder",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RAO A, PADHY D. BIMATOPROST (0.03%)-INDUCED ACCOMMODATIVE SPASM AND PSEUDOMYOPIA. BMJ CASE REPORTS. 2015?1-3.",
"literaturereference_normalized": "bimatoprost 0 03 induced accommodative spasm and pseudomyopia",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20160308",
"receivedate": "20160308",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 12157413,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
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"seriousnesslifethreatening": null,
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"transmissiondate": "20160526"
}
] |
{
"abstract": "Role of prophylactic anticoagulation in acutely ill medical patients has been extensively probed with the development of guidelines which made it convenient for the physicians to adopt a particular anticoagulation regimen for thromboprophylaxis. Intermingled with the guidelines are the development of modern anticoagulants like direct factor Xa inhibitors which are being studied for their role in the prevention of venous thromboembolism (VTE) in medically ill patients and have been concluded so far with the positive note. We are going to discuss a case of a patient who was admitted in the medical ICU with hospital acquired pneumonia. As her immediate risk of VTE was low (Wells criteria), she was advised mechanical measures to prevent VTE along with continuation of rivaroxaban therapy which had already been prescribed for her avalvular atrial fibrillation. While mechanically ventilated, she developed pulmonary venous thromboembolism. It is the first case report of VTE in adequately anticoagulated patient with rivaroxaban.",
"affiliations": "Department of Medicine, Khan Research Laboratories Hospital, Islamabad.",
"authors": "Saleem|Ayesha|A|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "Pakistan",
"delete": false,
"doi": "285",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "27(9)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000925:Anticoagulants; D001281:Atrial Fibrillation; D001777:Blood Coagulation; D016638:Critical Illness; D065427:Factor Xa Inhibitors; D006801:Humans; D012121:Respiration, Artificial; D012307:Risk Factors; D000069552:Rivaroxaban; D054556:Venous Thromboembolism; D020246:Venous Thrombosis",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "S129-S130",
"pmc": null,
"pmid": "28969751",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary Venous Thromboembolism in an Acutely Ill Medical Patient Receiving Rivaroxaban.",
"title_normalized": "pulmonary venous thromboembolism in an acutely ill medical patient receiving rivaroxaban"
}
|
[
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},
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"medicinalproduct": "THYROXIN"
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{
"abstract": "Eribulin mesylate (Halaven®) is a novel inhibitor of microtubule dynamics that has demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received at least two chemotherapeutic regimens including an anthracycline and a taxane. Although trastuzumab is indicated for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, a phase 1 study to evaluate tolerability/safety of eribulin mesylate with trastuzumab has not been conducted. Therefore, a study of eribulin mesylate in combination with trastuzumab was conducted to evaluate dose limiting toxicity (DLT), tolerability/safety, pharmacokinetics (PK), and efficacy and to estimate the recommended dose in Japanese patients with advanced or recurrent HER2+ breast cancer. Eribulin mesylate (1.4 mg/m(2)) was administered on days 1 and 8 of every 3 week cycle. Trastuzumab was administered with a 4 mg/kg loading dose followed by 2 mg/kg weekly doses or with an 8 mg/kg loading dose followed by 6 mg/kg tri-weekly doses. A total of 12 patients (six for each regimen) received eribulin mesylate and trastuzumab. No DLT was observed and the recommended dose of eribulin mesylate in combination with trastuzumab was estimated as 1.4 mg/m(2). Common adverse events were neutropenia, leukopenia, anaemia and alopecia. This combination therapy was well tolerated and the neutropenia observed was manageable. No PK drug-drug interaction between eribulin and trastuzumab was observed. Since a transient ejection fraction decreased was observed in two patients, cardiac function should be routinely assessed in patients receiving the combination therapy of eribulin mesylate with trastuzumab (ClinicalTrials.gov Identifier: NCT01432886).",
"affiliations": "Department of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan, [email protected].",
"authors": "Mukai|Hirofumi|H|;Saeki|Toshiaki|T|;Shimada|Ken|K|;Naito|Yoichi|Y|;Matsubara|Nobuaki|N|;Nakanishi|Tadashi|T|;Obaishi|Hiroshi|H|;Namiki|Masayuki|M|;Sasaki|Yasutsuna|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005663:Furans; D007659:Ketones; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C490954:eribulin; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-014-0161-y",
"fulltext": "\n==== Front\nInvest New Drugs\nInvest New Drugs\nInvestigational New Drugs\n0167-6997\n1573-0646\nSpringer US Boston\n\n25242374\n161\n10.1007/s10637-014-0161-y\nPhase I Studies\nPhase 1 combination study of Eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer\nMukai Hirofumi +81-4-7133-1111 [email protected]\n\n1\nSaeki Toshiaki 2\nShimada Ken 3\nNaito Yoichi 1\nMatsubara Nobuaki 1\nNakanishi Tadashi 4\nObaishi Hiroshi 4\nNamiki Masayuki 4\nSasaki Yasutsuna 5\n1 Department of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan\n2 Department of Breast Oncology Cancer Center, International Medical Center Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298 Japan\n3 Department of Internal Medicine, Showa University Northern Yokohama Hospital, 35-1 Chigasaki-chuo, Tsuzuki-ku, Yokohama, Kanagawa 224-8503 Japan\n4 Eisai Co., Ltd, 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, 112-8088 Japan\n5 Division of Medical Oncology-Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666 Japan\n23 9 2014\n23 9 2014\n2015\n33 1 119127\n9 7 2014\n8 9 2014\n© The Author(s) 2014\nOpen Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nSummary\n\nEribulin mesylate (Halaven®) is a novel inhibitor of microtubule dynamics that has demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received at least two chemotherapeutic regimens including an anthracycline and a taxane. Although trastuzumab is indicated for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, a phase 1 study to evaluate tolerability/safety of eribulin mesylate with trastuzumab has not been conducted. Therefore, a study of eribulin mesylate in combination with trastuzumab was conducted to evaluate dose limiting toxicity (DLT), tolerability/safety, pharmacokinetics (PK), and efficacy and to estimate the recommended dose in Japanese patients with advanced or recurrent HER2+ breast cancer. Eribulin mesylate (1.4 mg/m2) was administered on days 1 and 8 of every 3 week cycle. Trastuzumab was administered with a 4 mg/kg loading dose followed by 2 mg/kg weekly doses or with an 8 mg/kg loading dose followed by 6 mg/kg tri-weekly doses. A total of 12 patients (six for each regimen) received eribulin mesylate and trastuzumab. No DLT was observed and the recommended dose of eribulin mesylate in combination with trastuzumab was estimated as 1.4 mg/m2. Common adverse events were neutropenia, leukopenia, anaemia and alopecia. This combination therapy was well tolerated and the neutropenia observed was manageable. No PK drug-drug interaction between eribulin and trastuzumab was observed. Since a transient ejection fraction decreased was observed in two patients, cardiac function should be routinely assessed in patients receiving the combination therapy of eribulin mesylate with trastuzumab (ClinicalTrials.gov Identifier: NCT01432886).\n\nKeywords\n\nEribulin mesylate\nHER2 positive breast cancer\nJapanese patients\nPhase 1 study\nTrastuzumab\nissue-copyright-statement© Springer Science+Business Media New York 2015\n==== Body\nIntroduction\n\nOverexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 25 to 30 % of breast cancers and is associated with a poor prognosis [1, 2]. Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the HER2 protein. The studies of weekly trastuzumab monotherapy (4 mg/kg loading dose followed by 2 mg/kg weekly) and combination with paclitaxel was active, well tolerated and prolonged survival in patients with HER2+ metastatic breast cancer [3–5]. Also, comparison of tri-weekly trastuzumab (8 mg/kg loading dose followed by 6 mg/kg tri-weekly dose) with weekly trastuzumab has shown comparable results in both monotherapy and combination therapy with paclitaxel [6, 7]. The combination therapy of a tubulin-targeted drug and trastuzumab appeared to have a superior antitumor effect and a well-tolerated safety profile in the treatment of HER2 + breast cancer [5, 7–9].\n\nEribulin mesylate, a non-taxane microtubule dynamics inhibitor, is a structurally simplified synthetic analog of the marine natural product halichondrin B. The inhibitory effects of eribulin on microtubule dynamics lead to G2/M cell-cycle blocks, disruption of normal mitotic spindle formation, and prolonged mitotic blockage followed by apoptotic cell death [10, 11].\n\nA phase 1 study has been completed in Japanese patients with solid tumors to evaluate the safety and pharmacokinetics (PK) of eribulin mesylate administration on days 1 and 8 of a 21-day cycle. Dose-limiting toxicities (DLTs) were neutropenia/febrile neutropenia, and the recommended dose of eribulin mesylate was determined as 1.4 mg/m2 [12]. Based on the results of this phase 1 study in Japan, a phase 2 study was conducted to evaluate the efficacy and safety of eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with anthracycline and taxane. Eribulin mesylate demonstrated antitumor activity with an objective response rate (ORR) of 21.3 % (17/80 patients) and a manageable safety profile [13]. This study supported the previous phase 2 study of eribulin mesylate that demonstrated its antitumor activity and safety profile in extensively pretreated breast cancer patients [14, 15].\n\nIn a randomized phase 3 study of patients with locally recurrent or metastatic breast cancer who previously received at least two chemotherapeutic regimens including an anthracycline and a taxane, the efficacy and safety of eribulin mesylate (1.4 mg/m2, days 1 and 8 of a 21-day cycle) were compared with the treatment of the physician’s choice (TPC). Overall survival (OS) was statistically significantly longer in the eribulin mesylate group than in the TPC group (median OS: 13.1 months vs. 10.6 months, hazard ratio [HR]: 0.81, p = 0.041). Furthermore, an updated analysis of OS confirmed the significant increase in OS of the eribulin mesylate group compared with the TPC group (median OS: 13.2 months vs. 10.5 months, HR: 0.81, p = 0.014) [16].\n\nBased on these results, the combination therapy of eribulin mesylate and trastuzumab was also expected to provide a superior antitumor effect and favorable safety profile.\n\nTherefore, a phase 1 study of eribulin mesylate in combination with trastuzumab in Japanese patients with advanced or recurrent HER2+ breast cancer was carried out.\n\nMaterials and methods\n\nStudy design and treatment\n\nThis was a multi-center, open-label phase 1 study of eribulin mesylate with trastuzumab combination therapy in Japanese patients with advanced or recurrent HER2+ breast cancer (NCT01432886). This study consisted of Part 1 (weekly dose of trastuzumab) and Part 2 (tri-weekly dose of trastuzumab) to evaluate DLT, tolerability/safety, efficacy and PK, and to estimate the recommended dose of eribulin mesylate in this combination therapy.\n\nEribulin mesylate was administered by 2- to 5-minute i.v. injection on days 1 and 8 of a 21-day cycle. The initial dose of eribulin mesylate was 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin expressed as free base) in combination with trastuzumab treatment. Eribulin mesylate was administered on days 1 and 8, if all of the following criteria were met: (1) neutrophil count ≥1.0 × 103/μL, (2) platelet count ≥7.5 × 104/μL, and (3) non-hematologic toxicity ≤grade 2 (except grade 3 nausea, vomiting, and diarrhea controllable with anti-emetic or anti-diarrheal medication and abnormal laboratory parameters not requiring treatment). If the patient did not meet the criteria, the administration of the next dose was delayed. If the patient met the criteria within a 1-week delay, the 2nd administration of the cycle was implemented, and the next cycle had to be initiated no sooner than 2 weeks after the 2nd administration. If the patient did not meet the criteria within a 1-week delay, the 2nd administration was skipped. Dose reduction of eribulin mesylate could be exercised at the discretion of the investigator if the 2nd administration in a cycle was delayed or skipped. If dose reduction was necessary, the 1.4 mg/m2 dose of eribulin mesylate was initially reduced to 1.1 mg/m2 and then further reduced to 0.7 mg/m2.\n\nIn Part 1, trastuzumab was administered by i.v. infusion at 4 mg/kg as a loading dose and at 2 mg/kg weekly. In Part 2, trastuzumab was administered by i.v. infusion at 8 mg/kg as a loading dose and at 6 mg/kg tri-weekly. The infusion time of trastuzumab was 90 min or longer at initial administration and could be shortened to 30 min from the 2nd administration and later. Trastuzumab was administered immediately after eribulin mesylate administration when used in the same day. Concomitant use of other medications or treatments was allowed. However, other anti-cancer drugs, investigational drugs and prophylactic administration of granulocyte-colony stimulating factor (G-CSF) were not permitted during the study.\n\nDLT was evaluated in the first cycle, and if DLTs were observed in none or one of the first three patients, an additional three patients were to be added at the same dose level. If none or one of a total of six patients experienced a DLT, the investigated dose level of eribulin mesylate was to be regarded as tolerable with the trastuzumab combination. In the event that two of six patients reported a DLT, the investigators were to obtain written or verbal advice from an Independent Safety Committee on whether to investigate a decreased dose level of eribulin mesylate (1.1 mg/m2) as the initial dose. The initial eribulin mesylate dose level was planned to decrease to 1.1 mg/m2 if a DLT was reported in three or more patients. Patients were to continue to receive eribulin mesylate until they no longer received clinical benefit, had progressive disease (PD), or experienced unacceptable toxicity.\n\nThe protocol was approved by the Institutional Review Board and conducted in accordance with the Declaration of Helsinki.\n\nPatient eligibility\n\nKey inclusion criteria included: 20–74 years of age; histologically or cytologically confirmed advanced or recurrent breast cancer; HER2+ tumor score of 3+ by immunohistochemistry staining or gene amplification by fluorescence in situ hybridization (FISH); and any of the following, 1) evidence of recurrence during adjuvant chemotherapy with trastuzumab and taxane, 2) evidence of recurrence within 6 months after adjuvant chemotherapy with trastuzumab and taxane or 3) prior chemotherapy including trastuzumab and taxane for advanced or recurrent breast cancer; normal function in major organs; left ventricular ejection fraction (LVEF) ≥60 % by multigated acquisition scan or echocardiogram (B or M mode); and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\nKey exclusion criteria included: brain metastasis accompanied by clinical symptoms or requiring treatment; severe active infection requiring treatment; pleural effusions, ascites or pericardial effusions requiring drainage; pregnancy or breastfeeding; and refusal of supportive therapy by blood transfusion. All patients provided written informed consent prior to any study procedure.\n\nAssessments\n\nDLTs\n\nThe following toxicities were to be regarded as DLTs if they occurred in the first cycle and their causal relationship with the study treatment could not be ruled out: grade 4 neutropenia persistent for more than 7 days; grade 3 or above febrile neutropenia; grade 4 thrombocytopenia or grade 3 thrombocytopenia requiring blood transfusion; and non-hematologic toxicity ≥grade 3 (unless grade 3 nausea, vomiting and diarrhea was controllable with an anti-emetic and anti-diarrheal medication, or clinical laboratory abnormalities did not require treatment). It would also be regarded as a DLT if the 2nd eribulin mesylate administration per cycle was delayed and the study treatment could not be resumed from day 22 of cycle 1.\n\nSafety\n\nThe demographic and disease characteristics of breast cancer were recorded at baseline and included HER2 status, estrogen receptor status, progesterone receptor status, and prior therapy complications. Safety assessments were made throughout the study. The factors that were assessed include adverse events (AEs), vital signs, bodyweight, 12-lead electrocardiogram, multigated acquisition scan or echocardiogram, concomitant medications, and clinical laboratory values (hematology, blood biochemistry and urinalysis). AEs were assessed on days 1, 8 and 15 of each cycle. AE severity was classified according to the Japanese version of Common Terminology Criteria for Adverse Events v4.0. QT interval corrected for heart rate using Fridericia’s formula (QTcF) and LVEF assessment were conducted before the treatment, on day 15 of cycle 1, on day 1 of every 4th cycle, and if clinically indicated.\n\nPK and biochemical methodology\n\nBlood samples were taken for eribulin PK analysis on days 1 and 8 of the first treatment cycle, pre-dose, end of infusion, 30 min, and 1, 2, 4, 24, 72 and 168 h after drug administration. Plasma concentrations of eribulin, measured as the free-base (i.e. non-mesylate) equivalent, were determined by using the validated liquid chromatography- tandem mass spectrometry method. The lower limit of quantitation was 0.2 ng/mL.\n\nIn Part 1, blood samples were taken for trastuzumab PK analysis on day 1 (pre-dose, end of infusion, and 3, 4, 24 and 72 h after drug administration) and day 8 and 15 (pre-dose) of cycle 1, and on day 1 (pre-dose) of cycle 2 and later. In Part 2, blood samples of day 1 (pre-dose and 3, 4, 24, 72, 168 and 336 h after drug administration) of cycle 1 and day 1 (pre-dose) of cycle 2 and later cycles were taken. Serum concentrations of trastuzumab were determined by using the validated enzyme-linked immunosorbent assay method. The lower limit of quantitation was 10 μg/mL.\n\nPK parameters for eribulin and trastuzumab were calculated by a non-compartmental approach by using WinNonlin software version 6.2 (Pharsight Corporation, CA, USA). The calculated parameters included: area under the curve extrapolated to infinity (AUC(0-inf)), terminal half-life (t1/2), total clearance (CL) and volume of distribution at steady state (Vss). The maximum observed plasma concentration (Cmax) and time to Cmax (tmax) were directly derived from the data.\n\nTumor assessment\n\nTumor response was assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [17]. Tumor assessments were performed within 28 days prior to the start of treatment, 6 weeks after the first dose and every 6 weeks thereafter, or sooner, if there was clinical suspicion of disease progression.\n\nResults\n\nResults are based on data collected until an August 2, 2013, cutoff date.\n\nPatient characteristics\n\nA total of 12 patients received eribulin mesylate and trastuzumab, 6 in Part 1 and 6 in Part 2. These patients were extensively pretreated with a median of 4.5 (range, 1–14) prior chemotherapy regimens. Patient demographics and baseline characteristics are shown in Table 1.Table 1 Patient demographics and baseline characteristics\n\nParameter\tPart 1 (N = 6)\tPart 2 (N = 6)\tTotal (N = 12)\t\nAge, median (range), years\t64.5 (58–72)\t47.0 (39–64)\t60.0 (39–72)\t\nRace, n (%)\t\n Japanese\t6\t6\t12 (100.0)\t\nECOG performance status, n (%)\t\n 0\t3\t2\t5 (41.7)\t\n 1\t3\t4\t7 (58.3)\t\nER + and/or PR + disease, n (%)\t2\t3\t5 (41.7)\t\nNumber of prior anti-cancer drug treatment, n (%)a\t\n 1\t0\t1\t1 (8.3)\t\n 2\t0\t1\t1 (8.3)\t\n 3\t2\t0\t2 (16.7)\t\n 4\t1\t1\t2 (16.7)\t\n ≥5\t3\t3\t6 (50.0)\t\n Median (range)\t5.0 (3–14)\t4.5 (1–6)\t4.5 (1–14)\t\nPrior trastuzumab treatment, n (%)\t6\t6\t12 (100.0)\t\nNumber of prior trastuzumab treatment, n (%)a\t\n 1\t2\t1\t3 (25.0)\t\n 2\t1\t3\t4 (33.3)\t\n ≥3\t3\t2\t5 (41.7)\t\n Median (range)\t2.5 (1–5)\t2.0 (1–4)\t2.0 (1–5)\t\nPrior taxane treatment, n (%)\t6\t6\t12 (100.0)\t\nNumber of prior taxane treatment, n (%)a\t\n 1\t3\t4\t7 (58.3)\t\n 2\t2\t2\t4 (33.3)\t\n 3\t1\t0\t1 (8.3)\t\nPrior anthracycline treatment, n (%)\t3\t3\t6 (50.0)\t\nECOG Eastern Cooperative Oncology Group, ER estrogen receptor, PR progesterone receptor\n\naIncluding the number of neoadjuvant, adjuvant and therapeutic therapy\n\nTreatment\n\nFor the overall population, eribulin mesylate and trastuzumab were administered for a median of 7 (range, 2–23) cycles, with eight patients receiving five or more cycles. The numbers of treatment cycles by patients are shown in Table 2. Treatment was discontinued in seven patients (58.3 %) due to PD, and two patients (16.7 %) withdrew due to AEs. Three patients (25.0 %) continued to receive the study drug treatment at the time of the cutoff date. Dose adjustment (reduction, delay or skip) of eribulin mesylate occurred in ten patients (83.3 %); eight patients (66.7 %) had dose reduction, eight patients (66.7 %) had dose delay, and five patients (41.7 %) had to skip one dose per cycle.Table 2 Numbers of treatment cycles by patients\n\nNumber of cycles received, n (%)\tPart 1 (N = 6)\tPart 2 (N = 6)\tTotal (N = 12)\t\n1–2\t–\t1\t1 (8.3)\t\n3–4\t2\t1\t3 (25.0)\t\n5–8\t–\t3a\t3 (25.0)a\t\n9–12\t2\t–\t2 (16.7)\t\n13–16\t–\t1a\t1 (8.3)a\t\n17–20\t–\t–\t–\t\n≥21\t2a\t–\t2 (16.7)a\t\na3 patients in total were on treatment as of 2 August 2013\n\nDLTs\n\nDLTs were evaluated on the first cycle, and none of the 12 patients experienced DLT. In cycle 1, grade 3 or 4 neutropenia that led to a dose delay of the day 8 administration of eribulin mesylate occurred in two patients (16.7 %), and a dose was skipped in two patients (16.7 %). Two patients (16.7 %) received concomitant treatment with G-CSF for grade 4 neutropenia. The median time from day 1 of cycle 1 to the nadir in neutrophil count was 15 days (95 % CI:14, 23), and the median time to recovery from the nadir to ≤grade 2 neutropenia was 8 days (95 % CI: 4, 9). One of six patients (16.7 %) skipped a dose of trastuzumab due to an ejection fraction decreased (grade 2) in Part 1 (weekly dose of trastuzumab).\n\nAdverse events\n\nThe AEs (all grades) experienced by ≥10 % of patients and the total grade 3 or 4 AEs are shown in Table 3. The common AEs were similar in Part 1 and 2. Frequently observed hematologic AEs were neutropenia [100 % (grade 3/4: 100 %)], leukopenia [100 % (grade 3/4: 83 %)] and anaemia [67 % (grade 3/4: 0 %)]. G-CSF was administered to three patients (25.0 %). Frequently observed non-hematologic AEs, which were generally mild and manageable, included alopecia (67 %), pyrexia (42 %), decreased appetite (42 %) and rash (42 %) (all grade 1 or 2). Peripheral neuropathy occurred in four patients (33.3 %), including one patient (8.3 %) with grade 3 neuropathy. The AEs that led to study discontinuation were peripheral neuropathy in one patient (8.3 %) and tumour pain in one patient (8.3 %). An ejection fraction decreased (grade 2) occurred in two patients (16.7 %) (both patients on day 15 of cycle 1 with one patient also in cycle 19), but the patients recovered after 1 week without treatment. The mean LVEF transition is shown in Fig. 1. The other cardiac disorders were second degree atrioventricular block (grade 2) in one patient (8.3 %) and palpitation (grade 1) in two patients (16.7 %); no treatments were required for these adverse advents. No grade 5 AEs or serious AEs were observed.Table 3 Adverse events (All grades in ≥10 % of patients and grades 3/4 in total)\n\n\tPart 1\tPart 2\tTotal\t\nAll grades\tGrade 3/4 AEs\tAll grades\tGrade 3/4 AEs\tAll grades\tGrade 3/4 AEs\t\nAE preferred term\tN = 6\tN = 6\tN = 6\tN = 6\tN = 12\tN = 12\t\nBlood and lymphatic system disorders\t\n Neutropenia\t6\t6\t6\t6\t12 (100.0)\t12 (100.0)\t\n Leukopenia\t6\t4\t6\t6\t12 (100.0)\t10 (83.3)\t\n Anaemia\t4\t0\t4\t0\t8 (66.7)\t0\t\n Lymphopenia\t0\t0\t3\t3\t3 (25.0)\t3 (25.0)\t\n Febrile neutropenia\t0\t0\t1\t1\t1 (8.3)\t1 (8.3)\t\nCardiac disorders\t\n Palpitations\t2\t0\t0\t0\t2 (16.7)\t0\t\nGastrointestinal disorders\t\n Nausea\t1\t0\t2\t0\t3 (25.0)\t0\t\n Vomiting\t0\t0\t3\t0\t3 (25.0)\t0\t\n Constipation\t2\t0\t0\t0\t2 (16.7)\t0\t\n Stomatitis\t1\t0\t1\t0\t2 (16.7)\t0\t\nGeneral disorders and administration site conditions\t\n Pyrexia\t2\t0\t3\t0\t5 (41.7)\t0\t\n Malaise\t3\t0\t0\t0\t3 (25.0)\t0\t\n Chest discomfort\t1\t0\t1\t0\t2 (16.7)\t0\t\n Injection site reaction\t2\t0\t0\t0\t2 (16.7)\t0\t\nInfections and infestations\t\n Lung infection\t0\t0\t2\t0\t2 (16.7)\t0\t\n Tonsillitis\t1\t0\t1\t0\t2 (16.7)\t0\t\nInvestigations\t\n Alanine aminotransferase increased\t2\t0\t1\t0\t3 (25.0)\t0\t\n Aspartate aminotransferase increased\t2\t0\t1\t0\t3 (25.0)\t0\t\n Blood creatine phosphokinase increased\t3\t0\t0\t0\t3 (25.0)\t0\t\n Ejection fraction decreased\t1\t0\t1\t0\t2 (16.7)\t0\t\nMetabolism and nutrition disorders\t\n Decreased appetite\t4\t0\t1\t0\t5 (41.7)\t0\t\n Hypertriglyceridaemia\t1\t1\t2\t2\t3 (25.0)\t3 (25.0)\t\n Hypophosphataemia\t0\t0\t1\t1\t1 (8.3)\t1 (8.3)\t\nMusculoskeletal and connective tissue disorders\t\n Myalgia\t4\t0\t0\t0\t4 (33.3)\t0\t\n Muscle spasms\t2\t0\t0\t0\t2 (16.7)\t0\t\nNervous system disorders\t\n Dysgeusia\t2\t0\t2\t0\t4 (33.3)\t0\t\n aPeripheral neuropathy\t4\t1\t0\t0\t4 (33.3)\t1 (8.3)\t\n Headache\t0\t0\t2\t0\t2 (16.7)\t0\t\nSkin and subcutaneous tissue disorders\t\n Alopecia\t5\t–\t3\t–\t8 (66.7)\t–\t\n Rash\t4\t0\t1\t0\t5 (41.7)\t0\t\naPeripheral neuropathy includes neuropathy peripheral and peripheral sensory neuropathy in preferred terms\n\nFig. 1 Mean LVEF transition assessed by echocardiogram: Assessment by B mode echocardiogram at the indicated times. Baseline LVEF was ≥60 % by B or M mode echocardiogram in all patients, as defined in the inclusion criteria\n\nPK\n\nFigure 2 shows the mean plasma eribulin concentration time profile up to 168 h and Table 4 shows the PK parameters of eribulin after eribulin mesylate (1.4 mg/m2) administration over 2 to 5 min with trastuzumab on day 1 of cycle 1 in Part 1 and Part 2, as well as previously reported phase 1 study results of eribulin mesylate monotherapy in Japanese patients [12].Fig. 2 PK analysis of the relationship between mean plasma eribulin concentration versus time profiles for Parts 1 and 2 of the study and for a previous phase 1 study [12] (cycle 1, day 1)\n\nTable 4 Pharmacokinetic parameters of eribulin (cycle 1, day 1)\n\nPK Parameter (unit)\tPart 1 (n = 6)\tPart 2 (n = 6)\tMonotherapy (n = 6)\t\nCmax (ng/mL)\t547 ± 128\t582 ± 61.0\t519.4 ± 107.2\t\nAUC(0-inf) (ng⋅h/mL)\t524 ± 137\t631 ± 271\t672.7 ± 113.7\t\nt1/2 (h)\t38.1 ± 7.80\t35.0 ± 10.8\t39.4 ± 8.3\t\nCL (L/h/m2)\t2.47 ± 0.774\t2.12 ± 0.754\t1.89 ± 0.33\t\nVss (L/m2)\t101 ± 45.3\t69.8 ± 11.8\t76.3 ± 19.2\t\nMean ± SD\n\nAUC (0-inf) area under the concentration-time curve from time zero to infinity, CL total clearance, C max maximum plasma concentration, t ½ terminal half-life, V ss steady-state volume of distribution\n\nIn Part 1, the mean values for t1/2, CL and Vss after administration of eribulin mesylate on day 1 (Table 4) and Day 8 were 38.1 ± 7.80 and 30.3 ± 3.29 h, 2.47 ± 0.774 and 2.44 ± 0.967 L/h/m2, and 101 ± 45.3 and 77.9 ± 37.6 L/ m2, respectively. In Part 2, the mean values for t1/2, CL and Vss after administration of eribulin mesylate on day 1 (Table 4) and Day 8 were 35.0 ± 10.8 and 31.7 ± 8.58 h, 2.12 ± 0.754 and 1.95 ± 0.721 L/h/m2, and 69.8 ± 11.8 and 58.0 ± 6.99 L/m2, respectively.\n\nAfter trastuzumab was administered intravenously in combination with eribulin, trastuzumab was eliminated from the serum biphasically after reaching the Cmax in both Part 1 and 2. In Part 1, the mean values for t1/2, CL and Vss after administration of trastuzumab (4 mg/kg) on day 1 were 115 ± 28.0 h, 0.369 ± 0.0297 mL/h/kg and 62.4 ± 17.9 mL/kg, respectively. In Part 2, the mean values of t1/2, CL and Vss after administration of trastuzumab (8 mg/kg) on day 1 were 173 ± 26.7 h, 0.271 ± 0.0343 mL/h/kg and 62.0 ± 4.04 mL/kg, respectively (Table 5).Table 5 Pharmacokinetic parameters of trastuzumab (cycle 1, day 1)\n\nPK parameter (unit)\tPart 1 (4 mg/kg) (n = 6)\tPart 2 (8 mg/kg) (n = 6)\t\nCmax (μg/mL)\t74.9 ± 25.9\t194 ± 33.1\t\nAUC (μg⋅h/mL)\t10900 ± 868\t29800 ± 3740\t\nt1/2 (h)\t115 ± 28.0\t173 ± 26.7\t\nCL (mL/h/kg)\t0.369 ± 0.0297\t0.271 ± 0.0343\t\nVss (mL/kg)\t62.4 ± 17.9\t62.0 ± 4.04\t\nMean ± SD\n\nAUC (0-inf) area under the concentration-time curve from time zero to infinity, CL total clearance, C max maximum plasma concentration, t ½ terminal half-life, V ss steady-state volume of distribution\n\nAntitumor activity\n\nTumor responses were evaluated by RECIST version 1.1 in all 12 patients. The ORR was 8.3 % (95 % CI: 0.2, 38.5) and tumor responses consisted of a partial response (PR) in one patient (8.3 %), stable disease (SD: including non-complete response (CR)/non-PD) ≥5 weeks) in ten patients (83.3 %) and PD in one patient (8.3 %). The disease control rate (CR + PR + SD ≥11 weeks) was 83.3 % (95 % CI: 51.6, 97.9) and the clinical benefit rate (CR + PR + SD ≥23 weeks) was 50.0 % (95 % CI: 21.1, 78.9) (Table 6).Table 6 Best tumor responses\n\n\tPart 1\tPart 2\tTotal\t\nResponse category, n (%)\tN = 6\tN = 6\tN = 12\t\nBest tumor response, n (%)\t\n CR\t0\t0\t0\t\n PR\t1 (16.7)\t0\t1 (8.3)\t\n SD (including non-CR/non-PD)\t4 (66.7)\t6 (100.0)\t10 (83.3)\t\n PD\t1 (16.7)\t0\t1 (8.3)\t\n Not evaluable\t0\t0\t0\t\nObjective response rate\t1 (16.7)\t0\t1 (8.3)\t\n 95 % CI\t0.4, 64.1\t0.0, 45.9\t0.2, 38.5\t\nDisease Control Rate\t5 (83.3)\t5 (83.3)\t10 (83.3)\t\n 95 % CI\t35.9, 99.6\t35.9, 99.6\t51.6, 97.9\t\nClinical Benefit Rate\t4 (66.7)\t2 (33.3)\t6 (50.0)\t\n 95 % CI\t22.3, 95.7\t4.3, 77.7\t21.1, 78.9\t\nCI confidence interval, CR complete response, PR partial response, SD stable disease, PD progressive disease\n\nDiscussion\n\nThis phase 1 study established the recommended dose of eribulin mesylate as 1.4 mg/m2 when administered on days 1 and 8 of a 21-day cycle with appropriate dose adjustment in combination with either weekly trastuzumab (4 mg/kg loading dose, 2 mg/kg/weekly) or tri-weekly trastuzumab (8 mg/kg loading dose, 6 mg/kg/tri-weekly) in Japanese patients with advanced or recurrent HER2+ breast cancer. Eribulin mesylate was suggested to be safe and tolerable in combination with trastuzumab with the same recommended dose as monotherapy [12].\n\nThere were no DLTs, grade 5 AEs or serious AEs in this study. The most common AEs of grade 3 or 4 reported in this study were neutropenia and leukopenia, which were hematologic toxicities also found in prior clinical studies of eribulin mesylate monotherapy in Japanese patients [12, 13]. All 12 patients experienced neutropenia, but all events were reversible and easily managed with appropriate dose reduction or a skipped dose. The median time of 8 days required for resolution from nadir in neutrophil count to ≤grade 2 neutropenia in cycle 1 and the low requirement for G-CSF use (25 %) supported the safety of the defined eribulin mesylate administration procedure. The non-hematologic AEs were consistent with the known safety profile of eribulin, with only one grade 3 or higher AE with clinical symptoms (grade 3 peripheral neuropathy). The low incidence of neuropathy was consistent with previous eribulin mesylate studies and the incidence was also lower when compared with taxane studies [12–16, 18].\n\nA retrospective review of seven phase 2 and phase 3 trastuzumab clinical trials reported that the patients treated with trastuzumab were at an increased risk of cardiac dysfunction. The incidence of cardiac dysfunction was highest in patients receiving concomitant trastuzumab and anthracycline/cyclophosphamide (27 %). The risk was substantially lower in patients receiving paclitaxel and trastuzumab (13 %), trastuzumab alone (3 to 7 %), anthracycline/cyclophosphamide alone (8 %), or paclitaxel alone (1 %) [19]. To evaluate the risk of cardiac dysfunction in patients receiving the combination therapy of eribulin mesylate and trastuzumab, periodic assessments of QTcF and LVEF were conducted. Although an ejection fraction decreased (grade 2) was observed in two patients (16.7 %), these patients recovered after 1 week without treatment. The mean LVEF transition was ≥55 % in either part 1 or 2 of the study (Fig. 1). The other cardiac disorders experienced by patients were second-degree atrioventricular block and palpitation, which did not require treatment. Therefore, a clear increased risk of severe cardiac dysfunction resulting from the addition of eribulin mesylate to trastuzumab was not suggested from this study. Since a few cardiac events were observed, cardiac function should be routinely assessed in patients receiving eribulin mesylate in combination with trastuzumab, which is consistent with the recommendation for patients receiving trastuzumab in other combination therapies. The neutropenia observed was manageable, and the non-hematologic AEs were generally mild. Thus, treatment with eribulin mesylate (1.4 mg/m2) on days 1 and 8 of a 21-day cycle with appropriate dose adjustment was regarded as tolerable in combination with trastuzumab (either weekly or tri-weekly) in Japanese patients.\n\nThe PK profile of eribulin in combination with trastuzumab was similar between the present study and the previously reported phase 1 study of eribulin mesylate monotherapy in Japanese patients [12], including the mean t1/2, volume of distribution, and renal and systemic clearance (Fig. 2, Table 4), and as in those studies, the parameters were consistent between days 1 and 8 of the first cycle. The PK profile of trastuzumab (Table 5) was also similar to that in the previous reported phase 1 study of trastuzumab [20]. Combination therapy of trastuzumab with eribulin mesylate did not appear to change the PK profile of either eribulin or trastuzumab. Therefore, no pharmacokinetic drug-drug interaction between eribulin and trastuzumab was indicated.\n\nAlthough efficacy was not a primary objective, 8 of 12 patients completed more than 5 cycles of treatment and the clinical benefit rate (CBR) was 50.0 % (95 % CI: 21.1, 78.9), which also supports the long-term efficacy and safety of this combination therapy. Recently, the final results of a phase 2 study of eribulin mesylate (1.4 mg/m2) in combination with trastuzumab (8 mg/kg as a loading dose followed by a 6 mg/kg tri-weekly dose) as a first-line therapy for locally recurrent or metastatic HER2+ breast cancer was reported. Those results showed: ORR of 71.2 % (37/52 patients), CBR of 84.6 % (95 % CI: 71.9, 93.1), median progression free survival of 11.6 months (95 % CI: 9.1, 13.9) and an acceptable safety profile. The most common AEs of grade 3 or 4 were neutropenia (38.5 %) with clinical laboratory hematologic abnormalities of neutrophils (55.8 %) and peripheral neuropathy (26.9 %) [21]. The low incidence of severe neutropenia compared with that of the present study (100 %) was considered to be due to the difference of prior chemotherapy regimen numbers. The high incidence of severe peripheral neuropathy compared with that of the present study (8.3 %) was likely due to the prolonged duration of treatment in a first-line setting.\n\nIn conclusion, 1.4 mg/m2 eribulin mesylate administered on days 1 and 8 of a 21-day cycle in combination with either weekly or tri-weekly trastuzumab was well tolerated in extensively pre-treated Japanese patients with advanced or recurrent HER2+ breast cancer. The safety profile shown in the present study and the reported phase 2 study [21] indicates that further evaluation of eribulin mesylate and trastuzumab combination therapy is warranted.\n\nWe gratefully acknowledge the commitment of participating patients, their families, and the study investigators for their invaluable contribution to this research.\n\nEthical standards\n\nThe protocol was approved by the Institutional Review Board and conducted in accordance with the Declaration of Helsinki.\n\nConflict of interest\n\nHirofumi Mukai received lecture fees from Eisai Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Sanofi K.K., and Taiho Pharmaceutical Co., Ltd. Toshiaki Saeki received lecture fees from Eisai Co., Ltd., AstraZeneca K.K., Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Fuji Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mochida Pharmaceutical Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K. and Taiho Pharmaceutical Co., Ltd. Yasutsuna Sasaki received lecture fees from Eisai Co., Ltd. and Chugai Pharmaceutical Co., Ltd. Hirofumi Mukai, Yoichi Naito and Nobuaki Matsubara received research funding from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Glaxo SmithKline K.K., Nippon Boehringer Ingelheim Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Phizer Japan Inc. and the Public Health Research Foundation. Toshiaki Saeki received research funding from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Yasutsuna Sasaki received research funding from Eisai Co., Ltd. and Chugai Pharmaceutical Co., Ltd. Tadashi Nakanishi and Hiroshi Obaishi are employees and own stock of Eisai Co., Ltd. Masayuki Namiki is an employee of Eisai Co., Ltd. Ken Shimada has no disclosures. The study was designed under the responsibility of Eisai Co., Ltd.; The study was funded by Eisai Co., Ltd.; Eribulin mesylate was provided by Eisai Co., Ltd.; Eisai Co., Ltd. collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication.\n\nPresented in poster format at the European Cancer Congress 2013, Amsterdam, the Netherlands, 27 September–1 October 2013.\n==== Refs\nReferences\n\n1. Slamon DJ Godolphin W Jones LA Holt JA Wong SG Keith DE Levin WJ Stuart SG Udove J Ullrich A Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer Science 1989 244 707 712 10.1126/science.2470152 2470152\n2. Slamon DJ Clark GM Wong SG Levin WJ Ullrich A McGuire WL Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene Science 1987 235 177 182 10.1126/science.3798106 3798106\n3. Vogel CL Cobleigh MA Tripathy D Gutheil JC Harris LN Fehrenbacher L Slamon DJ Murphy M Novotny WF Burchmore M Shak S Stewart SJ Press M Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer J Clin Oncol 2002 20 719 726 10.1200/JCO.20.3.719 11821453\n4. Cobleigh MA Vogel CL Tripathy D Robert NJ Scholl S Fehrenbacher L Wolter JM Paton V Shak S Lieberman G Slamon DJ Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease J Clin Oncol 1999 17 2639 2648 10561337\n5. Slamon DJ Leyland-Jones B Shak S Fuchs H Paton V Bajamonde A Fleming T Eiermann W Wolter J Pegram M Baselga J Norton L Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N Engl J Med 2001 344 783 792 10.1056/NEJM200103153441101 11248153\n6. Baselga J Carbonell X Castañeda-Soto NJ Clemens M Green M Harvey V Morales S Barton C Ghahramani P Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule J Clin Oncol 2005 23 2162 2171 10.1200/JCO.2005.01.014 15800309\n7. Leyland-Jones B Gelmon K Ayoub JP Arnold A Verma S Dias R Ghahramani P Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel J Clin Oncol 2003 21 3965 3971 10.1200/JCO.2003.12.109 14507946\n8. Bullock K Blackwell K Clinical efficacy of taxane-trastuzumab combination regimens for HER-2-positive metastatic breast cancer Oncologist 2008 13 515 525 10.1634/theoncologist.2007-0204 18515736\n9. Redana S Donadio M Nolè F Jacomuzzi ME Beano A Martinello R Sapino A Viale G Aglietta M Montemurro F Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison BMC Cancer 2010 10 28 10.1186/1471-2407-10-28 20122160\n10. Kuznetsov G Towle MJ Cheng H Kawamura T TenDyke K Liu D Kishi Y Yu MJ Littlefield BA Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389 Cancer Res 2004 64 5760 5766 10.1158/0008-5472.CAN-04-1169 15313917\n11. Towle MJ Salvato KA Budrow J Wels BF Kuznetsov G Aalfs KK Welsh S Zheng W Seletsky BM Palme MH Habgood GJ Singer LA Dipietro LV Wang Y Chen JJ Quincy DA Davis A Yoshimatsu K Kishi Y Yu MJ Littlefield BA In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B Cancer Res 2001 61 1013 1021 11221827\n12. Mukohara T Nagai S Mukai H Namiki M Minami H Eribulin mesylate in patients with refractory cancers: a Phase I study Investig New Drugs 2012 30 1926 1933 10.1007/s10637-011-9741-2 21887501\n13. Aogi K Iwata H Masuda N Mukai H Yoshida M Rai Y Taguchi K Sasaki Y Takashima S A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer Ann Oncol 2012 23 1441 1448 10.1093/annonc/mdr444 21989327\n14. Vahdat LT Pruitt B Fabian CJ Rivera RR Smith DA Tan-Chiu E Wright J Tan AR Dacosta NA Chuang E Smith J O’Shaughnessy J Shuster DE Meneses NL Chandrawansa K Fang F Cole PE Ashworth S Blum JL Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane J Clin Oncol 2009 27 2954 2961 10.1200/JCO.2008.17.7618 19349550\n15. Cortes J Vahdat L Blum JL Twelves C Campone M Roché H Bachelot T Awada A Paridaens R Goncalves A Shuster DE Wanders J Fang F Gurnani R Richmond E Cole PE Ashworth S Allison MA Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine J Clin Oncol 2010 28 3922 3928 10.1200/JCO.2009.25.8467 20679609\n16. Cortes J O’Shaughnessy J Loesch D Blum JL Vahdat LT Petrakova K Chollet P Manikas A Diéras V Delozier T Vladimirov V Cardoso F Koh H Bougnoux P Dutcus CE Seegobin S Mir D Meneses N Wanders J Twelves C Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study Lancet 2011 377 914 923 10.1016/S0140-6736(11)60070-6 21376385\n17. Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L Kaplan R Lacombe D Verweij J New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774\n18. Markman M Management of toxicities associated with the administration of taxanes Expert Opin Drug Saf 2003 2 141 146 10.1517/14740338.2.2.141 12904114\n19. Seidman A Hudis C Pierri MK Shak S Paton V Ashby M Murphy M Stewart SJ Keefe D Cardiac dysfunction in the trastuzumab clinical trials experience J Clin Oncol 2002 20 1215 1221 10.1200/JCO.20.5.1215 11870163\n20. Tokuda Y Watanabe T Omuro Y Ando M Katsumata N Okumura A Ohta M Fujii H Sasaki Y Niwa T Tajima T Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer Br J Cancer 1999 81 1419 1425 10.1038/sj.bjc.6690343 10604742\n21. Wilks S Puhalla S O’Shaughnessy J Schwartzberg L Berrak E Song J Cox D Vahdat L Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer Clin Breast Cancer 2014 25024001\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D005663:Furans; D006801:Humans; D007659:Ketones; D008875:Middle Aged; D018719:Receptor, ErbB-2; D013318:Stroke Volume; D000068878:Trastuzumab; D016896:Treatment Outcome",
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"title": "Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer.",
"title_normalized": "phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer"
}
|
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},
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{
"abstract": "Renal transplant recipients are on long-term potent immunosuppressive therapy, which makes them highly vulnerable to opportunistic fungal infections. Dematiaceous, or dark-pigmented saprophytic fungi, are being increasingly seen as opportunistic pathogens of mycoses in immunosuppressed patients. One of these is Aureobasidium pullulans, which is a black yeast-like dematiaceous fungus found ubiquitously in the environment that can cause various opportunistic human infections. Most infections occur by traumatic inoculation, such as keratitis and cutaneous lesions; disseminated mycoses are very rare and occur only in severely immunocompromised patients. We report a case of disseminated fungal infection due to A. pullulans in a pediatric patient who underwent renal transplant. The use of voriconazole and vacuum-assisted closure along with surgical drainage most likely contributed to the patient's positive outcome.",
"affiliations": "Pediatric Nephrology Department, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.;Urology Department, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.;Pediatric Nephrology Department, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.;Pediatric Infectious Disease Department, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.;Pediatric Infectious Disease Department, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.;Microbiology Department, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.;Pediatric Nephrology Department, Faculty of Medicine, LIV Hospital, Istinye University, Istanbul, Turkey.",
"authors": "Nalcacioglu|Hulya|H|0000-0002-0686-9714;Yakupoglu|Y Kamil|YK|;Genc|Gurkan|G|;Belet|Nursen|N|;Sensoy|Sema Gulnar|SG|;Birinci|Asuman|A|;Ozkaya|Ozan|O|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13152",
"fulltext": null,
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"issn_linking": "1397-3142",
"issue": "22(3)",
"journal": "Pediatric transplantation",
"keywords": "\nAureobasidium pullulans\n; fungal infection; pediatrics; renal transplant; vacuum-assisted closure therapy",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D001203:Ascomycota; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D009181:Mycoses; D009894:Opportunistic Infections",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13152",
"pmc": null,
"pmid": "29388304",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Disseminated fungal infection by Aureobasidium pullulans in a renal transplant recipient.",
"title_normalized": "disseminated fungal infection by aureobasidium pullulans in a renal transplant recipient"
}
|
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{
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],
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"literaturereference": "NALCACIOGLU H, YAKUPOGLU Y, GENC G, BELET N, SENSOY S, BIRINCI A. DISSEMINATED FUNGAL INFECTION BY AUREOBASIDIUM PULLULANS IN A RENAL TRANSPLANT RECIPIENT. PEDIATRIC TRANSPLANTATION. 2018?22:.",
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{
"abstract": "BACKGROUND\nNeurological complications of COVID-19, including delirium, are emerging in the adult population but have not been well described in pediatrics.\n\n\nMETHODS\nWe report the cases of 2 adolescent males, ages 16 and 17, who presented with delirium secondary to an acute COVID-19 infection in the fall of 2020 at Children's Wisconsin in Milwaukee, Wisconsin. The foundation of our treatment strategy was the triad of alpha-2 agonists (clonidine, dexmedetomidine, guanfacine), antipsychotic agents (quetiapine, haloperidol, olanzapine), and melatonin. Discharge planning required involvement from inpatient psychiatry, case management, social work, and the family. Both patients showed improvement after several weeks.\n\n\nCONCLUSIONS\nWe believe these are the first reported cases of COVID-19-associated delirium in children outside of multisystem inflammatory syndrome in children (MIS-C).\n\n\nCONCLUSIONS\nPediatric COVID-19 delirium is a new manifestation of the COVID-19 disease. Treatment guidelines are emerging and lessons regarding therapies and discharge considerations are described in these 2 unique cases.",
"affiliations": "Medical College of Wisconsin, Department of Pediatrics, Section of Hospital Medicine, Milwaukee, Wisconsin, [email protected].;Medical College of Wisconsin, Department of Pediatrics, Section of Hospital Medicine, Milwaukee, Wisconsin.;Medical College of Wisconsin, Department of Pediatrics, Section of Hospital Medicine, Milwaukee, Wisconsin.;Advocate Aurora Health, Milwaukee, Wisconsin.;Medical College of Wisconsin, Pediatric Residency Program, Milwaukee, Wisconsin.;Medical College of Wisconsin, Pediatric Residency Program, Milwaukee, Wisconsin.;Medical College of Wisconsin, Department of Psychiatry, Milwaukee, Wisconsin.;Medical College of Wisconsin, Department of Psychiatry, Milwaukee, Wisconsin.;Medical College of Wisconsin, Department of Pediatrics, Section of Infectious Diseases, Milwaukee, Wisconsin.",
"authors": "Bauer|Sarah Corey|SC|;Moral|Francesca|F|;Preloger|Erin|E|;Spindler|Alexandrea|A|;Roman|Marisa|M|;Logan|Ashley|A|;Sandage|Scott J|SJ|;Manak|Colleen|C|;Mitchell|Michelle|M|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D014150:Antipsychotic Agents; D008550:Melatonin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-1861",
"issue": "120(2)",
"journal": "WMJ : official publication of the State Medical Society of Wisconsin",
"keywords": null,
"medline_ta": "WMJ",
"mesh_terms": "D000293:Adolescent; D058647:Adrenergic alpha-2 Receptor Agonists; D014150:Antipsychotic Agents; D000086382:COVID-19; D003693:Delirium; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008550:Melatonin; D000086402:SARS-CoV-2; D014922:Wisconsin",
"nlm_unique_id": "9716054",
"other_id": null,
"pages": "131-136",
"pmc": null,
"pmid": "34255953",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pediatric COVID-19 Delirium: Case Report of 2 Adolescents.",
"title_normalized": "pediatric covid 19 delirium case report of 2 adolescents"
}
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{
"abstract": "The purpose of this study was to examine outcomes, toxicity, and dosimetric characteristics of patients treated with reirradiation for head and neck cancers.\n\n\n\nFifty patients underwent ≥2 courses of radiation therapy (RT) postoperatively or definitively with or without chemotherapy. Composite dose volume histograms (DVHs) for selected anatomic structures were correlated with grade ≥3 late toxicity.\n\n\n\nMedian initial and retreatment radiation dose was 64 and 60 Gy, respectively. Median overall survival (OS), progression-free survival (PFS), and 1-year PFS rates were 18 months, 11 months, and 45%, respectively, with 13 months median follow-up. Thirty-four percent of patients experienced grade ≥3 late toxicity with 1 death from carotid blowout. The DVH corresponding to the carotid blowout fell above the third quartile compared with other patients.\n\n\n\nOur analysis is the first to systematically evaluate the dose to the carotid artery using composite dosimetry in head and neck reirradiation patients, and demonstrates a promising technique for evaluating the dose to other normal tissue structures. © 2015 Wiley Periodicals, Inc. Head Neck 38: E961-E969, 2016.",
"affiliations": "Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.",
"authors": "Garg|Shivank|S|;Kilburn|Jeremy M|JM|;Lucas|John T|JT|;Randolph|David|D|;Urbanic|James J|JJ|;Hinson|William H|WH|;Kearns|William T|WT|;Porosnicu|Mercedes|M|;Greven|Kathryn|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hed.24136",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "38 Suppl 1()",
"journal": "Head & neck",
"keywords": "blowout; carotid arteries; dosimetry; head and neck; reirradiation",
"medline_ta": "Head Neck",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D006258:Head and Neck Neoplasms; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016609:Neoplasms, Second Primary; D011879:Radiotherapy Dosage; D000069475:Re-Irradiation; D012189:Retrospective Studies",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E961-9",
"pmc": null,
"pmid": "25993910",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reirradiation for second primary or recurrent cancers of the head and neck: Dosimetric and outcome analysis.",
"title_normalized": "reirradiation for second primary or recurrent cancers of the head and neck dosimetric and outcome analysis"
}
|
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"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK, CYCLIC (EITHER EVERY 3 WEEKS OR WEEKLY)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "LARYNGEAL CANCER STAGE IV",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Arterial rupture",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GARG, S.. REIRRADIATION FOR SECOND PRIMARY OR RECURRENT CANCERS OF THE HEAD AND NECK: DOSIMETRIC AND OUTCOME ANALYSIS. HEAD AND NECK. 2016?38 (SUPPLE 1):E961-E969",
"literaturereference_normalized": "reirradiation for second primary or recurrent cancers of the head and neck dosimetric and outcome analysis",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180320",
"receivedate": "20180320",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14661357,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Primary lung neoplasms are rare in children. The most common primary lung malignancies in children are pleuropulmonary blastoma and carcinoid tumour. Synovial sarcoma (SS) accounts for approximately 1% of all childhood malignancies. In absolute terms, the SS of the lungs and pleura are extremely rare and pose a diagnostic difficulty. Soft tissue sarcomas usually have a high potential for metastases, however, metastasis to the brain is rare, even in widely disseminated disease, and it has been described only in 3 case reports previously. Primary pleuropulmonary SS with brain metastases is even rarer. Here we present a case of an 11-year-old boy who presented with respiratory complaints, viz. fever and cough for 20 days. Initial impression was lung abscess, however, on histopathological, immunohistochemical and molecular study, the disorder was diagnosed as synovial sarcoma. After a week from the first consult, the child developed neurological symptoms, viz., an episode of convulsion and gradually worsening power of the lower limb. Computed tomography scan and Magnetic Resonance Spectroscopy was suggestive of brain metastases. Given the rarity of primary lung neoplasms in children, clinical detection remains a challenge. Delayed diagnoses are common as respiratory symptoms may be attributed to inflammatory or infective processes. Primary pleuropulmonary synovial sarcoma is a rare tumour and it is not known to commonly metastasise to the brain. Though rare, primary pleuropulmonary SS should be considered an important differential among peadiatric primary lung neoplasms due to its potential for curability if detected early, and more aggressive metastatic pattern, e.g. brain metastases making early detection imperative.",
"affiliations": "Gujarat Cancer and Research Institute, Ahmedabad, India 380016. [email protected].",
"authors": "Chirmade|Pushpak Chandrakant|PC|;Parikh|Sonia|S|;Anand|Asha|A|;Panchal|Harsha|H|;Patel|Apurva|A|;Shah|Sandip|S|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "Poland",
"delete": false,
"doi": "10.5603/ARM.2017.0034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2451-4934",
"issue": "85(4)",
"journal": "Advances in respiratory medicine",
"keywords": "SS18 rearrangement; TLE positive; brain metastases; peadiatric sarcoma; primary pleuropulmonary synovial sarcoma",
"medline_ta": "Adv Respir Med",
"mesh_terms": "D014408:Biomarkers, Tumor; D001932:Brain Neoplasms; D002648:Child; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D010994:Pleura; D010997:Pleural Neoplasms; D013584:Sarcoma, Synovial",
"nlm_unique_id": "101697329",
"other_id": null,
"pages": "206-210",
"pmc": null,
"pmid": "28871588",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary pleuropulmonary synovial sarcoma with brain metastases in a paediatric patient: an unusual presentation.",
"title_normalized": "primary pleuropulmonary synovial sarcoma with brain metastases in a paediatric patient an unusual presentation"
}
|
[
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-152287",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "METASTASES TO CENTRAL NERVOUS SYSTEM",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IFOSFAMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "203263",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "METASTASES TO CENTRAL NERVOUS SYSTEM",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXORUBICIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "FOR 3 DAYS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SYNOVIAL SARCOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugseparatedosagenumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "IFOSFAMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "203263",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "FOR 2 DAYS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SYNOVIAL SARCOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXORUBICIN"
}
],
"patientagegroup": null,
"patientonsetage": "11",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Therapeutic response decreased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHIRMADE PC, PARIKH S, ANAND A, PANCHAL H, PATEL A, SHAH S. PRIMARY PLEUROPULMONARY SYNOVIAL SARCOMA WITH BRAIN METASTASES IN A PAEDIATRIC PATIENT: AN UNUSUAL PRESENTATION. ADV RESPIR MED. 2017;85:206-210",
"literaturereference_normalized": "primary pleuropulmonary synovial sarcoma with brain metastases in a paediatric patient an unusual presentation",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20171013",
"receivedate": "20171013",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14084091,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
}
] |
{
"abstract": "We report a 66-year-old man with a history of congestive heart failure, atrial fibrillation on warfarin therapy and chronic kidney disease that presented with acute dyspnoea. He had multiple palpable purpuric lesions on his bilateral lower extremities. Laboratory findings supported acute anaemia with no obvious bleeding source, supratherapeutic international normalised ratio and acute on chronic kidney injury. Oesophogastroduodenoscopy and colonoscopy initially suggested ischaemic colitis. The patient's legs were treated symptomatically with topical steroids. He later developed acute large volume bloody diarrhoea that made him haemodynamically unstable. Punch biopsy of the skin was consistent with leucocytoclastic vasculitis and direct immunofluorescence demonstrated immunoglobulin A and C3 deposits consistent with Henoch-Schonlein purpura. The patient was treated with oral steroids. Bleeding stabilised and rash resolved. Steroids were successfully tapered. The patient was discharged on haemodialysis but ultimately this was able to be discontinued.",
"affiliations": "Internal Medicine, University of Tennessee at Chattanooga, College of Health Education and Professional Studies, Chattanooga, Tennessee, USA.;College of Medicine, University of Tennessee at Chattanooga, College of Health Education and Professional Studies, Chattanooga, Tennessee, USA.;Internal Medicine, University of Tennessee at Chattanooga, College of Health Education and Professional Studies, Chattanooga, Tennessee, USA.",
"authors": "Maxfield|Luke|L|;Peck|Aurora|A|;Youngblood|Laura Bond|LB|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007070:Immunoglobulin A; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-224816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "acute renal failure; dermatology; ulcer; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000893:Anti-Inflammatory Agents; D005076:Exanthema; D006801:Humans; D011695:IgA Vasculitis; D007070:Immunoglobulin A; D035002:Lower Extremity; D008297:Male; D009102:Multiple Organ Failure; D011241:Prednisone",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30093466",
"pubdate": "2018-08-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24424188;16490741;22959234;19750891;22985708;26258874;15086888;12528079;11961015;25340125;23833668;24637207;20388738",
"title": "Adult Henolch-Schonlein purpura: multiorgan failure in the setting of a purpuric rash.",
"title_normalized": "adult henolch schonlein purpura multiorgan failure in the setting of a purpuric rash"
}
|
[
{
"companynumb": "US-CIPLA LTD.-2018US23750",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "090935",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTICOAGULANT THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "WARFARIN"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Henoch-Schonlein purpura",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anticoagulation drug level above therapeutic",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MAXFIELD L, PECK A, YOUNGBLOOD LB. ADULT HENOLCH-SCHONLEIN PURPURA: MULTIORGAN FAILURE IN THE SETTING OF A PURPURIC RASH. BMJ CASE REPORTS. 2018",
"literaturereference_normalized": "adult henolch schonlein purpura multiorgan failure in the setting of a purpuric rash",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190107",
"receivedate": "20181224",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15755022,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "BACKGROUND\nTo the best of the authors' knowledge, the renal side effects of crizotinib have not been investigated previously.\n\n\nMETHODS\nThe estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based prediction equation during the first 12 weeks of crizotinib therapy and after crizotinib but before the introduction of any further systemic therapy.\n\n\nRESULTS\nA total of 38 patients with stage IV anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer who were treated with crizotinib were identified. The mean eGFR decreased by 23.9% compared with baseline (P < .0001; 95% confidence interval, 21.3%-26.6%), with the majority of the decrease occurring within the first 2 weeks of therapy. Clinical history and blood urea nitrogen/creatinine ratios did not suggest prerenal causes. The objective response rate among evaluable patients (n = 27) was 41%. Tumor shrinkage was not correlated with changes in eGFR (correlation coefficient, -0.052; P = .798). Among the 16 patients for whom data after treatment with crizotinib were available, recovery to within 84% of the baseline eGFR occurred in all patients. After adjusting for the number of scans with intravenous contrast and the use of known nephrotoxic drugs, the issue of whether a patient was on or off crizotinib treatment was found to be significantly associated with changes in eGFR (P < .0001).\n\n\nCONCLUSIONS\nAs assessed by the Chronic Kidney Disease Epidemiology Collaboration prediction equation, eGFR is reduced by treatment with crizotinib, but the majority of patients will recover their eGFR after the cessation of therapy. The early onset, size of the change, minimal cumulative effect, and rapid reversibility raise the possibility that this may be a pharmacological and/or tubular creatinine secretion effect rather than a direct nephrotoxic effect. Increased vigilance with regard to the concomitant use of renally cleared medications or nephrotoxic agents should be considered for patients receiving crizotinib and, when eGFR is reduced, additional renal investigations should be undertaken.",
"affiliations": "Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.",
"authors": "Brosnan|Evelyn M|EM|;Weickhardt|Andrew J|AJ|;Lu|Xian|X|;Maxon|Delee A|DA|;Barón|Anna E|AE|;Chonchol|Michel|M|;Camidge|D Ross|DR|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.28478",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "120(5)",
"journal": "Cancer",
"keywords": "anaplastic lymphoma kinase (ALK) gene rearrangements; crizotinib; glomerular filtration rate (GFR); kidney injury; non-small cell lung cancer; renal function",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D057286:Electronic Health Records; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "664-74",
"pmc": null,
"pmid": "24258622",
"pubdate": "2014-03-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "4005491;23169500;17483355;21737852;22473102;22312131;22879434;22954507;22488744;15212162;8678060;22088989;19744017;23154552;22223530;20186162;3617154;7168798;8517692;18089725;7079556;1360044;9371351;20979469",
"title": "Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.",
"title_normalized": "drug induced reduction in estimated glomerular filtration rate in patients with alk positive non small cell lung cancer treated with the alk inhibitor crizotinib"
}
|
[
{
"companynumb": "US-PFIZER INC-2015154856",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CRIZOTINIB"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "202570",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "250 MG, 2X/DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "250",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CRIZOTINIB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": "58",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Glomerular filtration rate decreased",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal failure",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BROSNAN EM. DRUG-INDUCED REDUCTION IN ESTIMATED GLOMERULAR FILTRATION RATE IN PATIENTS WITH ALK-POSITIVE NON-SMALL CELL LUNG CANCER TREATED WITH THE ALK INHIBITOR CRIZOTINIB.. CANCER. 2014;120 (5):664-674",
"literaturereference_normalized": "drug induced reduction in estimated glomerular filtration rate in patients with alk positive non small cell lung cancer treated with the alk inhibitor crizotinib",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150506",
"receivedate": "20150506",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11094690,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Left bundle branch block (LBBB) during exercise can be associated with chest pain. Though this association is mostly correlated with an underlying coronary artery disease, painful LBBB has been described in patients with normal coronary arteries. We report a case of exercise-induced LBBB with typical angina pectoris related to antimalarial prophylaxis with chloroquine in a 66-year old woman with normal coronary arteries, which was reversed after treatment discontinuation. The effect of chloroquine on the electrophysiological properties of nodal cardiac tissue is responsible for this rate-dependent LBBB. Precautions for future antimalarial prophylaxis are also discussed.",
"affiliations": "Hôpital d'instruction des armées Laveran, service de cardiologie, Marseille.;Hôpital d'instruction des armées Laveran, service de cardiologie, Marseille.;Hôpital d'instruction des armées Laveran, service de cardiologie, Marseille.;Hôpital d'instruction des armées Laveran, service de cardiologie, Marseille.;Hôpital d'instruction des armées Laveran, service de cardiologie, Marseille.;Hôpital d'instruction des armées Laveran, service de cardiologie, Marseille.",
"authors": "Fourcade|L|L|;Camus|O|O|;Roche|N|N|;Chenilleau|M C|MC|;Gil|J M|JM|;Massoure|P L|PL|",
"chemical_list": "D000962:Antimalarials; D002738:Chloroquine",
"country": "France",
"delete": false,
"doi": "10.1684/mst.2014.0338",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2261-3684",
"issue": "24(3)",
"journal": "Medecine et sante tropicales",
"keywords": "Left bundle branch block; chest pain; chloroquine; exercise",
"medline_ta": "Med Sante Trop",
"mesh_terms": "D000368:Aged; D000962:Antimalarials; D002037:Bundle-Branch Block; D018890:Chemoprevention; D002637:Chest Pain; D002738:Chloroquine; D015444:Exercise; D005260:Female; D006801:Humans; D008288:Malaria",
"nlm_unique_id": "101581406",
"other_id": null,
"pages": "320-2",
"pmc": null,
"pmid": "24919211",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Exercise-induced left bundle branch block with chest pain related to antimalarial prophylaxis with chloroquine.",
"title_normalized": "exercise induced left bundle branch block with chest pain related to antimalarial prophylaxis with chloroquine"
}
|
[
{
"companynumb": "FR-WATSON-2016-12287",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CHLOROQUINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "087979",
"drugbatchnumb": "UNCONFIRMED",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNK",
"drugdosagetext": "100 MG, DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MALARIA PROPHYLAXIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugrecurrence": null,
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"drugstructuredosageunit": "003",
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"medicinalproduct": "CHLOROQUINE."
}
],
"patientagegroup": null,
"patientonsetage": "66",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Bundle branch block left",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Angina pectoris",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FOURCADE L, CAMUS O, ROCHE N, CHENILLEAU MC, GIL JM, MASSOURE PL. [EXERCISE-INDUCED LEFT BUNDLE BRANCH BLOCK WITH CHEST PAIN RELATED TO ANTIMALARIAL PROPHYLAXIS WITH CHLOROQUINE]. MED SANTE TROP. 2014;24:320-322.",
"literaturereference_normalized": "exercise induced left bundle branch block with chest pain related to antimalarial prophylaxis with chloroquine",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20160627",
"receivedate": "20160614",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12465638,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160815"
},
{
"companynumb": "FR-SA-2016SA115360",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "CHLOROQUINE"
},
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"drugauthorizationnumb": "006002",
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"drugindication": "MALARIA PROPHYLAXIS",
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"medicinalproduct": "CHLOROQUINE."
}
],
"patientagegroup": "6",
"patientonsetage": "66",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Bundle branch block left",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Angina pectoris",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Chest pain",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FOURCADE L, CAMUS O, ROCHE N, CHENILLEAU M-C, GIL J-M, MASSOURE P-L. EXERCISE-INDUCED LEFT BUNDLE BRANCH BLOCK WITH CHEST PAIN RELATED TO ANTIMALARIAL PROPHYLAXIS WITH CHLOROQUINE. MED SANTE TROP. 2014;24(3):320-2. DOI: 10.1684/MST.2014.0338",
"literaturereference_normalized": "exercise induced left bundle branch block with chest pain related to antimalarial prophylaxis with chloroquine",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20160624",
"receivedate": "20160624",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160815"
}
] |
{
"abstract": "Status epilepticus (SE) is a common indication for neurocritical care and can be refractory to standard measures. Refractory SE (RSE) is associated with high morbidity and mortality. Unconventional therapies may be utilized in certain cases, including therapeutic hypothermia (TH), bumetanide, and the ketogenic diet. However, the literature describing the use of such therapies in RSE is limited. Details of a case of TH for RSE in an infant with malignant migrating partial seizures of infancy were obtained from the medical record. A 4-month-old child developed SE that was refractory to treatment with concurrent midazolam, phenobarbital, fosphenytoin, topiramate, levetiracetam, folinic acid, and pyridoxal-5-phosphate. This led to progressive implementation of three unconventional therapies: TH, bumetanide, and the ketogentic diet. Electrographic seizures ceased for the entirety of a 43-hour period of TH with a target rectal temperature of 33.0°C–34.0°C. No adverse effects of hypothermia were noted other than a single episode of asymptomatic hypokalemia. Seizures recurred 10 hours after rewarming was begun and did not abate with reinstitution of hypothermia. No effect was seen with administration of bumetanide. Seizures were controlled long-term within 48 hours of institution of the ketogenic diet. TH and the ketogenic diet may be effective for treating RSE in children.",
"affiliations": null,
"authors": "Shein|Steven L|SL|;Reynolds|Thomas Q|TQ|;Gedela|Satyanarayana|S|;Kochanek|Patrick M|PM|;Bell|Michael J|MJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/ther.2012.0013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2153-7658",
"issue": "2(3)",
"journal": "Therapeutic hypothermia and temperature management",
"keywords": null,
"medline_ta": "Ther Hypothermia Temp Manag",
"mesh_terms": null,
"nlm_unique_id": "101543518",
"other_id": null,
"pages": "144-9",
"pmc": null,
"pmid": "23667778",
"pubdate": "2012-09",
"publication_types": "D016428:Journal Article",
"references": "12181015;11879350;15030906;10082808;19406757;18355392;2919138;10488906;10618152;17101884;21569025;2924747;20060761;8780085;7555952;16843675;19469847;6705545;4978766;5457637;9521266;15996395;20164112;7698098;12771566;22528274;18602345;17918265;14999046;16454774;8298996;7925795;18486818;18415032;21463287;11442146",
"title": "Therapeutic hypothermia for refractory status epilepticus in a child with malignant migrating partial seizures of infancy and SCN1A mutation: a case report.",
"title_normalized": "therapeutic hypothermia for refractory status epilepticus in a child with malignant migrating partial seizures of infancy and scn1a mutation a case report"
}
|
[
{
"companynumb": "US-JNJFOC-20140709882",
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"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "PER KG.H",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "STATUS EPILEPTICUS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugseparatedosagenumb": "1",
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"medicinalproduct": "LEVETIRACETAM."
},
{
"actiondrug": "5",
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"activesubstancename": "TOPIRAMATE"
},
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"drugindication": "STATUS EPILEPTICUS",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "TOPIRAMATE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM\\MIDAZOLAM HYDROCHLORIDE"
},
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"medicinalproduct": "MIDAZOLAM"
},
{
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"activesubstance": {
"activesubstancename": "FOSPHENYTOIN\\FOSPHENYTOIN SODIUM"
},
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"medicinalproduct": "FOSPHENYTOIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "PER KG.H",
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"medicinalproduct": "PHENOBARBITAL."
},
{
"actiondrug": "5",
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"activesubstancename": "PYRIDOXAL PHOSPHATE"
},
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"drugauthorizationnumb": null,
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"drugdosagetext": "PER KG.H",
"drugenddate": null,
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"drugindication": "STATUS EPILEPTICUS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
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"drugstructuredosagenumb": "70",
"drugstructuredosageunit": "007",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PYRIDOXAL PHOSPHATE"
}
],
"patientagegroup": "2",
"patientonsetage": "4",
"patientonsetageunit": "802",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Product use issue",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug level below therapeutic",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHEIN SL, REYNOLDS TQ, GEDELA S, KOCHANEK PM, BELL MJ. THERAPEUTIC HYPOTHERMIA FOR REFRACTORY STATUS EPILEPTICUS IN A CHILD WITH MALIGNANT MIGRATING PARTIAL SEIZURES OF INFANCY AND SCN1A MUTATION: A CASE REPORT. THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT 2012 03-NOV-2012;2 (3):144-9.",
"literaturereference_normalized": "therapeutic hypothermia for refractory status epilepticus in a child with malignant migrating partial seizures of infancy and scn1a mutation a case report",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150525",
"receivedate": "20150321",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10947110,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno-occlusive disease, is a rare disorder in solid organ transplant patients, and is an uncommon complication after liver transplantation. Severe SOS with hepatic failure causes considerable mortality. Tacrolimus has been reported to be an offending agent, which potentially plays a role in the pathophysiological process of SOS. SOS due to tacrolimus has been reported in lung and pancreatic transplantations, but has never been described in a liver transplant recipient. Herein, we present a case of SOS after liver transplantation, which was possibly related to tacrolimus. A 27-year-old man developed typical symptoms of SOS with painful hepatomegaly, ascites and jaundice after liver transplantation, which regressed following withdrawal of tacrolimus. By excluding other possible predisposing factors, we concluded that tacrolimus was the most likely cause of SOS.",
"affiliations": "Tian Shen, Xiao-Wen Feng, Lei Geng, Shu-Sen Zheng, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.;Tian Shen, Xiao-Wen Feng, Lei Geng, Shu-Sen Zheng, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.;Tian Shen, Xiao-Wen Feng, Lei Geng, Shu-Sen Zheng, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.;Tian Shen, Xiao-Wen Feng, Lei Geng, Shu-Sen Zheng, Division of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.",
"authors": "Shen|Tian|T|;Feng|Xiao-Wen|XW|;Geng|Lei|L|;Zheng|Shu-Sen|SS|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i20.6422",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(20)",
"journal": "World journal of gastroenterology",
"keywords": "Liver transplantation; Predisposing factor; Sinusoidal obstruction syndrome; Tacrolimus; Veno-occlusive disease",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D016572:Cyclosporine; D057915:Drug Substitution; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D011237:Predictive Value of Tests; D012307:Risk Factors; D016559:Tacrolimus; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "6422-6",
"pmc": null,
"pmid": "26034381",
"pubdate": "2015-05-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "8143956;24102514;9725784;17663504;22136416;16707401;16393276;21351239;22483502;10534334;22796578;25068424;23602212;16038116",
"title": "Reversible sinusoidal obstruction syndrome associated with tacrolimus following liver transplantation.",
"title_normalized": "reversible sinusoidal obstruction syndrome associated with tacrolimus following liver transplantation"
}
|
[
{
"companynumb": "TW-ALKEM LABORATORIES LIMITED-TW-ALKEM-2021-04296",
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"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
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"drugauthorizationnumb": "203740",
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"medicinalproduct": "TACROLIMUS."
},
{
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"activesubstancename": "MYCOPHENOLATE SODIUM"
},
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},
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},
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"medicinalproduct": "PREDNISOLONE."
},
{
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"activesubstancename": "BASILIXIMAB"
},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Vascular pseudoaneurysm",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Venoocclusive liver disease",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHEN T, FENG XW, GENG L, ZHENG SS. REVERSIBLE SINUSOIDAL OBSTRUCTION SYNDROME ASSOCIATED WITH TACROLIMUS FOLLOWING LIVER TRANSPLANTATION. WORLD J GASTROENTEROL. 2015?21(20):6422?6426",
"literaturereference_normalized": "reversible sinusoidal obstruction syndrome associated with tacrolimus following liver transplantation",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20210713",
"receivedate": "20210713",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "Legalization efforts in many states have heightened awareness of the medicinal uses of cannabis, and oncology nurses are more frequently caring for patients who have used or are using cannabis. Significant epidemiologic data on the prevalence of cannabis use in patients with cancer are not yet available, and not much is known about the effects of cannabis on cancer treatment.\n\n\n\nThis article describes the effects cannabis may have on the lungs, reviews indications for cannabis use in patients with cancer, and explores an atypical case of progressive pulmonary toxicity in a young patient with a history of Hodgkin lymphoma and cannabis use.\n\n\n\nA review of the literature on cannabis-associated lung injury was conducted, with 32 articles selected for full review.\n\n\n\nAs cannabis use in cancer care continues to gain support, further research evaluating cannabis use in patients treated with bleomycin is warranted. In addition, the pros and cons of cannabis use must be fully evaluated and discussed with the patient with cancer prior to recommending its use.",
"affiliations": "PIH Health Hospital.;Idaho State University.",
"authors": "Merkle|Sarah|S|;Tavernier|Susan S|SS|",
"chemical_list": "D000970:Antineoplastic Agents; D064086:Medical Marijuana; D001761:Bleomycin",
"country": "United States",
"delete": false,
"doi": "10.1188/18.CJON.438-443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-1095",
"issue": "22(4)",
"journal": "Clinical journal of oncology nursing",
"keywords": "bleomycin; cannabis; lung injury; marijuana; pulmonary toxicity; vaping; vaporization",
"medline_ta": "Clin J Oncol Nurs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001761:Bleomycin; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008171:Lung Diseases; D008297:Male; D064086:Medical Marijuana; D008875:Middle Aged; D009369:Neoplasms; D014481:United States",
"nlm_unique_id": "9705336",
"other_id": null,
"pages": "438-443",
"pmc": null,
"pmid": "30035790",
"pubdate": "2018-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cannabis Use and Bleomycin: An Overview and Case Study of Pulmonary Toxicity.",
"title_normalized": "cannabis use and bleomycin an overview and case study of pulmonary toxicity"
}
|
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},
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},
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"medicinalproduct": "DACARBAZINE."
}
],
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"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Acute respiratory failure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Acute respiratory distress syndrome",
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},
{
"reactionmeddrapt": "Pneumonitis",
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"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Pulmonary fibrosis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Pneumothorax",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
}
],
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},
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},
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},
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},
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"transmissiondate": "20191004"
},
{
"companynumb": "US-FRESENIUS KABI-FK201907470",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
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"drugindication": "HODGKIN^S DISEASE STAGE IV",
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"medicinalproduct": "BLEOMYCIN"
},
{
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},
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"medicinalproduct": "DACARBAZINE."
},
{
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"activesubstancename": "DOXORUBICIN"
},
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"medicinalproduct": "DOXORUBICIN"
},
{
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},
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}
],
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"reaction": [
{
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"reactionoutcome": "5"
}
],
"summary": null
},
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"literaturereference_normalized": "cannabis use and bleomycin an overview and case study of pulmonary toxicity",
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},
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},
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},
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},
{
"companynumb": "PHHY2019US160028",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
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"medicinalproduct": "METHYLPREDNISOLONE."
},
{
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},
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"drugdosagetext": "125 MG, BID",
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"drugindication": "PULMONARY TOXICITY",
"drugintervaldosagedefinition": "804",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Pneumothorax",
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},
{
"reactionmeddrapt": "Acute respiratory failure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pulmonary fibrosis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pneumonitis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
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}
],
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},
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"literaturereference": "MERKLE S, TAVERNIER SS. CANNABIS USE AND BLEOMYCIN AN OVERVIEW AND CASE STUDY OF PULMONARY TOXICITY. CLINICAL JOURNAL OF ONCOLOGY NURSING. 2018?22(4):438-43",
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},
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},
"serious": 1,
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"transmissiondate": "20191004"
}
] |
{
"abstract": "Cystic fibrosis (CF) is a progressive genetic disorder caused by mutations in a gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein leading to persistent and difficult to treat lower airway infections. Multi-drug resistant Pseudomonas aeruginosa is becoming increasingly more common as a cause of pulmonary exacerbations, and newer agents such as ceftolozane/tazobactam (C/T) are being sought for treatment. There is currently little published data regarding its use in cystic fibrosis, particularly in the setting of reduced renal clearance. This report details the case of a 63-year-old female with cystic fibrosis and chronic kidney disease stage III (estimated creatinine clearance of 25-30 ml/min, Cockroft-Gault) who was successfully treated for a pulmonary exacerbation with C/T 3 g (2000 mg/1000 mg) infused intravenously every 8 h when the P. aeruginosa minimum inhibitory concentration (MIC) was elevated at 8 mcg/mL. Serum samples were collected to determine concentrations by a validated high-performance liquid chromatography assay. The steady state 1-hr post-infusion peak (Cmax) and trough (Cmin) concentrations for ceftolozane were 145.04 mcg/mL and 82.08 mcg/mL, and 15.93 mcg/mL and 3.20 mcg/mL for tazobactam, respectively. The patient's symptoms resolved and her lung function returned to baseline. She completed 14 days of therapy and tolerated the infusion well without any infusion-related or adverse events.",
"affiliations": "Ascension Sacred Heart Hospital, Pensacola, FL, United States.;Ascension Sacred Heart Hospital, Pensacola, FL, United States.;Adult Cystic Fibrosis Center, Pensacola Lung Group, Pensacola, FL, United States.;Adult Cystic Fibrosis Center, Pensacola Lung Group, Pensacola, FL, United States.",
"authors": "Romano|Meredith Tate|MT|;Premraj|Sasha|S|;Bray|John M|JM|;Murillo|Luis C|LC|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00830",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30138-4\n10.1016/j.idcr.2020.e00830\ne00830\nArticle\nCeftolozane/tazobactam for pulmonary exacerbation in a 63-year-old cystic fibrosis patient with renal insufficiency and an elevated MIC to Pseudomonas aeruginosa\nRomano Meredith Tate [email protected]⁎ Premraj Sasha a Bray John M. b Murillo Luis C. b a Ascension Sacred Heart Hospital, Pensacola, FL, United States\nb Adult Cystic Fibrosis Center, Pensacola Lung Group, Pensacola, FL, United States\n⁎ Corresponding author at: Inpatient Pharmacy Department, Ascension Sacred Heart Pensacola, 5151 N. 9th Avenue, Pensacola, FL, 32504, United States. [email protected]\n18 5 2020 \n2020 \n18 5 2020 \n21 e008307 4 2020 7 5 2020 14 5 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Ceftolozane/tazobactam was successfully used in an adult CF patient with CKD and an elevated MIC for P. aeruginosa in culture.\n\n• Therapeutic drug monitoring can be useful to validate dosing, particularly with newer antimicrobials that do not have well established dosing in cystic fibrosis.\n\n• Higher serum concentrations and PK/PD targets may help to preserve susceptibility of Pseudomonas aeruginosa, but more studies are needed.\n\n\n\nCystic fibrosis (CF) is a progressive genetic disorder caused by mutations in a gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein leading to persistent and difficult to treat lower airway infections. Multi-drug resistant Pseudomonas aeruginosa is becoming increasingly more common as a cause of pulmonary exacerbations, and newer agents such as ceftolozane/tazobactam (C/T) are being sought for treatment. There is currently little published data regarding its use in cystic fibrosis, particularly in the setting of reduced renal clearance. This report details the case of a 63-year-old female with cystic fibrosis and chronic kidney disease stage III (estimated creatinine clearance of 25−30 ml/min, Cockroft-Gault) who was successfully treated for a pulmonary exacerbation with C/T 3 g (2000 mg/1000 mg) infused intravenously every 8 h when the P. aeruginosa minimum inhibitory concentration (MIC) was elevated at 8 mcg/mL. Serum samples were collected to determine concentrations by a validated high-performance liquid chromatography assay. The steady state 1-hr post-infusion peak (Cmax) and trough (Cmin) concentrations for ceftolozane were 145.04 mcg/mL and 82.08 mcg/mL, and 15.93 mcg/mL and 3.20 mcg/mL for tazobactam, respectively. The patient’s symptoms resolved and her lung function returned to baseline. She completed 14 days of therapy and tolerated the infusion well without any infusion-related or adverse events.\n\nKeywords\nCeftolozane/tazobactamCystic fibrosisTherapeutic drug monitoring\n==== Body\nIntroduction\nCystic fibrosis (CF) is a progressive genetic disorder caused by mutations in a gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein. Altered protein function leads to persistent and difficult to treat lower airway infections [1,2]. In 2018, the mean age of those living with cystic fibrosis was 22.2 years. The median age at death was 30.8 years but this is predicted to increase to 47.4 years for those born in 2018 [3]. The number of adults with cystic fibrosis continues to increase as treatment advances with adults representing more than 50 % of the CF population in 2018 compared to 31.1 % in 1988 [3]. Despite the encouraging trends, the number of patients greater than 60 years of age living with cystic fibrosis remains rare and subsequently these patients are poorly represented in the available literature.\n\nWith advancing age, the prevalence of individuals with CF who are colonized with P. aeruginosa also increases. Last year, approximately 45 % of CF patients had respiratory cultures positive for P. aeruginosa and 16.9 % of those strains causing acute infection displayed multi-drug resistance (MDR) [3]. The presence of P. aeruginosa in respiratory cultures has been shown to be a major predictor of mortality and morbidity and is becoming progressively difficult to treat as cumulative lifetime antibiotics increase and drug resistance develops [4]. This has led to various treatment approaches including combination therapy; modified dosing strategies such as extended and continuous infusion beta-lactams to optimize pharmacokinetic/pharmacodynamic (PK/PD) parameters; as well as the development of novel antipseudomonal agents such as ceftolozane/tazobactam (C/T). C/T is effective against many gram-negative bacilli, including MDR P. aeruginosa. Ceftolozane, by itself, is one of the most active antipseudomonals, while the addition of tazobactam extends the coverage to include extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae [5,6]. Manufacturer’s labeling recommends that C/T be dosed at 3 g (2000 mg/1000 mg) every 8 h intravenously over 60 min in patients with creatinine clearance (CrCl) > 50 mL/min with bacterial pneumonia, with an adjustment to 1.5 mg every 8 h for CrCl 30−50 ml/min and 750 mg every 8 h for CrCl 15−29 ml/min. The manufacturer does not provide dosage adjustments for CrCl <15 mL/min in a patient not receiving dialysis [7].\n\nWhile the use of C/T has been well established for urinary tract infections, nosocomial pneumonia, and complicated intraabdominal infections [[8], [9], [10]], there is limited information regarding its use for acute pulmonary exacerbations in cystic fibrosis. Further, it is well known that patients with CF demonstrate altered pharmacokinetic properties from the non-CF population. Studies have reported enhanced renal and non-renal elimination, delayed absorption, and increased volume of distribution to a variety of antibiotics leading to the use of higher doses and more frequent administration times than that recommended by the manufacturer [11,12]. One small study (n = 20) and several case reports have utilized therapeutic drug monitoring to attempt to describe how C/T pharmacokinetics are altered in cystic fibrosis [6,13,14]. Another case report described the use of C/T in a 35-year-old female with CKD and a P. aeruginosa isolate demonstrating a low minimum inhibitory concentration (MIC) [15]. To our knowledge, there is no published data regarding the use and characterization of the pharmacokinetics of C/T in an older cystic fibrosis patient with renal insufficiency and an elevated P. aeruginosa MIC.\n\nThis report will review the successful use of C/T for a pulmonary exacerbation due to P. aeruginosa in the case of a 63-year-old female with cystic fibrosis and chronic kidney disease. Serum concentrations of C/T were collected and utilized to determine the most appropriate dose for this patient given her CrCl and in vitro susceptibility data showing an elevated MIC.\n\nCase presentation\nA 63-year-old female with cystic fibrosis presented with increased productive cough, persistent wheezing, decreased appetite, general malaise, and a significant acute decline in lung function with an FEV1 of 0.8 L (35 % of predicted from her baseline of 45–50 % of predicted). She was diagnosed with an acute pulmonary exacerbation and it was decided to begin intravenous antibiotics. Drug allergies and intolerances include trimethoprim/sulfamethoxazole (hyperkalemia), ceftazidime (shortness of breath), ticarcillin-clavulanate (hives), and levofloxacin (muscle cramps, light-headedness). Past medical history includes cystic fibrosis-related diabetes mellitus, hypothyroidism, anemia, and chronic kidney disease stage III (estimated CrCl of 25−30 ml/min, Cockroft-Gault). She is colonized with methicillin-susceptible Staphylococcus aureus (MSSA) and MDR P. aeruginosa. Intravenous meropenem 2 g every 8 h infused over 3 h [[16], [17], [18]] and oral ciprofloxacin 500 mg twice daily were initiated empirically based on previous treatment success. However, after the second dose of meropenem the patient reported significant shortness of breath and tachycardia thought to be related to the meropenem infusion and as a result meropenem was discontinued.\n\nWith few options left, it was decided to initiate C/T 3 g every 8 h infused intravenously over 60 min in order to maximize exposure and ensure optimal time above the MIC. The dose of the C/T was not reduced because susceptibility of the organism was shown to be intermediate with an MIC of 8 mcg/mL on the most recent culture. Additional susceptibility data are presented in Table 1.Table 1 Pseudomonas aeruginosa Culture and Susceptibility Data [19] a.\n\nTable 1\tMost recent culture prior to exacerbation\t2 months post-exacerbation\t3 months post-exacerbation\t\nAmikacin\tS (8)\tS\tS\t\nAztreonam\t–\tR (>16)\tR (>16)\t\nCefepime\tR (≥64)\tR (>16)\tR (>16)\t\nCeftazidime\tR (≥64)\tR (>16)\tR (>16)\t\nCeftazidime/Avibactam\tS (8)\tS (4)\tS (4)\t\nCeftolozane/Tazobactam\tI (8)\tS (4)\tS (≤2)\t\nCiprofloxacin\tS (1)\tS\t–\t\nColistin\t–\t–\tS (≤0.25)\t\nGentamicin\tS (4)\tS\tS\t\nLevofloxacin\tI (4)\tR (8)\t–\t\nMeropenem\tR (≥16)\tR (>8)\tR (>8)\t\nPiperacillin/Tazobactam\t–\tR (>128)\tR (>128)\t\nPolymyxin B\t–\t–\tS (0.5)\t\nTobramycin\tS (≤1)\tS\tS\t\na Susceptibility data based on CLSI Performance Standards for Antimicrobial Susceptibility Testing, 28th edition, 2018.\n\n\n\nTwo steady-state serum samples were collected, a 1-hr post-infusion peak and a trough, to perform patient-specific pharmacokinetics. The samples were sent to the Center for Anti-Infective Research and Development at Hartford Hospital where concentrations were determined by a validated high-performance liquid chromatography assay [20]. Steady state 1-hr post-infusion peak (Cmax) and trough (Cmin) serum concentrations for ceftolozane were 145.04 mcg/mL and 82.08 mcg/mL, and 15.93 mcg/mL and 3.20 mcg/mL for tazobactam, respectively.\n\nAfter completing 14 days of therapy with intravenous C/T and oral ciprofloxacin, the patient’s symptoms resolved and lung function returned to baseline. She tolerated the infusions well without any reports of adverse events.\n\nDiscussion\nThis case demonstrates the usefulness of therapeutic drug monitoring (TDM) in this population and how it can be used to validate dosing, particularly with newer antimicrobials that do not have well established dosing in cystic fibrosis. Like other beta-lactams, C/T exhibits time-dependent activity, meaning it is more bactericidal the longer it is present at the site of action with an unbound concentration greater than the targeted pathogen’s MIC (fT > MIC).21 PK/PD studies have also consistently shown that beta-lactams exhibit maximum killing at concentrations 3–4 times the MIC, though effectiveness of beta-lactams ultimately depends on the duration the concentration is above the MIC more than the magnitude of the concentration (Huttner et al). Currently, standard dosing regimens of beta-lactams target approximately 50 % fT > MIC based on murine infection models from the 1980s to the 2000s [21]. Cephalosporins exhibit a fT > MIC of 30–40 %. C/T, on the other hand, has a fT > MIC similar to carbapenems, as in vitro models demonstrate a 24%–31% fT > MIC to achieve a 24 -h static effect against P. aeruginosa [6].\n\nSome studies have suggested improved clinical outcomes with more aggressive PK/PD beta-lactam targets of 100 % fT > MIC and minimum trough concentrations up to 5–6 times the MIC, primarily in critically ill patients with sepsis and lower respiratory tract infections [21,22]. TDM of beta-lactam antibiotics historically has not been considered routine clinical practice since beta-lactams do not have a narrow therapeutic index. Due to the association of low antibiotic serum concentrations and increasing resistance to beta-lactams, in addition to the increasing prevalence of multi-drug resistant organisms, TDM has increased in clinical relevance to ensure target concentrations are being achieved [21]. Patients most likely to benefit from TDM include patients with altered PK, such as the critically ill, obese, elderly, and those with CF [21].\n\nMost centers utilizing TDM target beta-lactam concentrations of 100 % fT > MIC, while some target 100 % fT>4xMIC, and a few target 50 % fT>4xMIC or 70 % fT>4x MIC [21]. For this patient, the target utilized was 100 % fT>4xMIC, or a trough of 32 mcg/mL. The specific dose of C/T 3 g every 8 h was chosen based on previous Monte Carlo simulations published by Monogue, et al. which predict a 60–70 % probability of a target attainment of 100 % fT > MIC for an MIC of 8 for this dose in adult CF patients with a mean CrCl of 117.7 mL/min. For the same dose, the reduced CrCl in this patient would increase the probability of target attainment under the assumption that CrCl is the most significant predictor of ceftolozane clearance [13]. Of note, the patient had previously tolerated non-renally-adjusted doses of other beta-lactams, including meropenem.\n\nThe serum samples tested were used to estimate unbound serum concentrations. The estimated unbound Cmax and Cmin were 116 mcg/mL and 66 mcg/mL, respectively, based on 20 % protein binding for ceftolozane. The estimated unbound Cmax and Cmin were 11 mcg/mL and 2 mcg/mL, respectively, based on 30 % protein binding for tazobactam [7]. This confirmed unbound drug concentrations of ceftolozane greater than 4 times the MIC for the entire dosing interval. As expected, the calculated half-life of ceftolozane was 7 h, which is significantly longer than that observed in adult CF patients with normal renal function (2.9 h) and healthy adults without CF (2.7 h) [13].\n\nThis patient tolerated the C/T infusion well without any infusion-related or adverse reactions despite having a documented allergy to ceftazidime in the medical chart. Ceftazidime and ceftolozane share similar side chains and potential for cross-reactivity is unknown. It is possible the previous reaction to ceftazidime was an infusion- or disease-related reaction rather than hypersensitivity\n\nIn the future, it may be reasonable to use a reduced dose of C/T 1.5 g every 8 h and still expect to achieve a target of 100 % fT>4xMIC in this patient, however given that she tolerated the high concentrations well, it would also be reasonable to utilize the same dose of C/T 3 g every 8 h in the event of future exacerbations. Of further note, subsequent respiratory culture and susceptibility data collected 2- and 3-months post-exacerbation shows P. aeruginosa isolates with reduced MICs to C/T (Table 1). Development of resistance has previously been shown in vitro with C/T even when 100 % fT > MIC is achieved [6]. This supports the hypothesis that higher serum concentrations and PK/PD targets may help to preserve susceptibility, but further studies are needed.\n\nConclusion\nThe use of 3 g (2000/1000 mg) of intravenous C/T infused over 60 min in a 63-year-old CF patient with renal dysfunction and P. aeruginosa with a high MIC to C/T was safe and effective in achieving concentrations well over PK/PD targets used for cephalosporins in centers routinely performing beta-lactam TDM.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public,\n\ncommercial, or not-for-profit sectors.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nCRediT authorship contribution statement\nMeredith Tate Romano: Conceptualization, Writing - original draft, Writing - review & editing, Visualization, Supervision, Project administration. Sasha Premraj: Conceptualization, Writing - original draft, Writing - review & editing. John M. Bray: Writing - review & editing, Supervision. Luis C. Murillo: Writing - review & editing, Supervision.\n\nDeclaration of Competing Interest\nNo conflicts of interest to disclose.\n\nAcknowledgements\nDavid Nicolau, PharmD, FCCP, FIDSA; Kylie Lucas, PharmD, BCPS.\n==== Refs\nReferences\n1 Rowe S.M. Miller S. Sorscher E.J. Cystic fibrosis: mechanisms of disease N Engl J Med 352 2005 1992 2001 15888700 \n2 Gibson R.L. Burns J.L. Ramsey B.W. Pathophysiology and management of pulmonary infections in cystic fibrosis Am J Respir Crit Care Med 168 2003 918 951 14555458 \n3 CFFP Registry 2018 patient registry data report 2019 \n4 Emerson J. Rosenfeld M. McNamara S. Ramsey B. Gibson R.L. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis Pediatr Pulmonol 34 August (2) 2002 91 100 12112774 \n5 Horcajada J.P. Montero M. Oliver A. Sorlí L. Luque S. Gómez-Zorrilla S. Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections Clin Microbiol Rev 32 August (4) 2019 pii: e00031-19. \n6 Davis E. Ham J. Hucks J. Gould A. Foster R. Justo J.A. Use of continuous infusion ceftolozane-tazobactam with therapeutic drug monitoring in a patient with cystic fibrosis Am J Health Syst Pharm 76 April (80) 2019 501 504 31361864 \n7 Ceftolozane/tazobactam (Zerbaxa). Wolters Kluwer Clinical Drug Information, Inc. (Lexi-Drugs). Wolters Kluwer Clinical Drug Information, Inc.; Accessed 26 January 2019.\n8 Kollef M.H. Nováček M. Kivistik Ü Réa-Neto Á Shime N. Martin-Loeches I. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial Lancet Infect Dis September (25) 2019 pii: S1473-3099(19)30403-30407 \n9 Wagenlehner F.M. Umeh O. Steenbergen J. Yuan G. Darouiche R.O. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI) Lancet 385 May (9981) 2015 1949 1956 25931244 \n10 Lucasti C. Hershberger E. Miller B. Yankelev S. Steenbergen J. Friedland I. Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections Antimicrob Agents Chemother 58 September (9) 2014 5350 5357 24982069 \n11 Prandota J. Clinical pharmacology of antibiotics and other drugs in cystic fibrosis Drugs 35 May (5) 1988 542 578 3293970 \n12 Rey E. Tréluyer J.M. Pons G. Drug disposition in cystic fibrosis Clin Pharmacokinet 35 October (4) 1998 313 329 9812180 \n13 Monogue M.L. Pettit R.S. Muhlebach M. Cies J.J. Nicolau D.P. Kuti J.L. Population pharmacokinetics and safety of ceftolozane-tazobactam in adult cystic fibrosis patients admitted with acute pulmonary exacerbation Antimicrob Agents Chemother 60 October (11) 2016 6578 6584 27550351 \n14 Vickery S.B. McClain D. Wargo K.A. Successful use of ceftolozane-tazobactam to treat a pulmonary exacerbation of cystic fibrosis caused by multidrug-resistant Pseudomonas aeruginosa Pharmacotherapy 36 October (10) 2016 e154 e159 27522066 \n15 Stokem K. Zuckerman J.B. Nicolau D.P. Use of ceftolozane-tazobactam in a cystic fibrosis patient with multidrug-resistant pseudomonas infection and renal insufficiency Respir Med Case Rep 23 October (28) 2017 8 9 29159032 \n16 Kuti J.L. Moss K.M. Nicolau D.P. Knauft R.F. Empiric treatment of multidrug-resistant burkhlderia cepacia lung exacerbation in a patient with cystic fibrosis: application of pharmacodynamic concepts to meropenem therapy Pharmacotherapy 24 11 2004 1641 1645 15537567 \n17 Kuti J.L. Nightingale C.H. Knauft R.K. Nicolau D.P. Pharmacokinetic properties and stability of continuous-infusion meropenem in adults with cystic fibrosis Clin Ther 26 4 2004 493 501 15189746 \n18 Thompson R.Z. Martin C.A. Burgess D.R. Rutter W.C. Burgess D.S. Optimizing beta-lactam pharmacodynamics against Pseudomonas aeruginosa in adult cystic fibrosis patients J Cyst Fibros 15 2016 660 663 27132188 \n19 CLSI Performance standards for antimicrobial susceptibility testing CLSI supplement M100 28th ed. 2018 Clinical and Laboratory Standards Institute Wayne, PA \n20 Sutherland C.A. Nicolau D.P. Development of an HPLC method for the determination of ceftolozane/tazobactam in biological and aqueous matrixes J. Chromatogr. Sci. 54 6 2016 1037 1040 27048639 \n21 Huttner A. Harbarth S. Hope W.W. Lipman J. Roberts J.A. Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother 70 December (12) 2015 3178 3183 26188037 \n22 Wong G. Taccone F. Villois P. Scheetz M.H. Rhodes N.J. Briscoe S. β-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill J Antimicrob Chemother 75 February (2) 2020 429 433 31665353\n\n",
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"title": "Ceftolozane/tazobactam for pulmonary exacerbation in a 63-year-old cystic fibrosis patient with renal insufficiency and an elevated MIC to Pseudomonas aeruginosa.",
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{
"abstract": "A 64-year-old man presented for evaluation of proximally pronounced weakness of the arms with preserved facial and lower extremity strength. Symptoms slowly developed over the last two years, and the patient's history was notable for severe Listeria monocytogenes meningitis four years prior to presentation, which was adequately treated with antibiotics. On examination, symptoms clinically reassembled 'man-in-the-barrel' syndrome and localized to the cervicothoracic central cord. Blood analysis was unremarkable, and CSF analysis showed no recurrent or persistent infection. Spinal MRI revealed pockets of sequestered CSF from C3 to C4 and areas of CSF space effacement from C3 to T12. MRI findings were interpreted as cord tethering suggestive of adhesive arachnoiditis. CT myelogram showed insufficient contrast agent migration above T10 and contour irregularities of the conus medullaris, confirming the postulated pathomechanism of cord tethering. Final diagnosis was therefore cervicothoracic central cord damage due to cord tethering in the setting of postinfectious adhesive arachnoiditis following bacterial meningitis. The patient failed a course of pulsed methylprednisolone therapy, and symptoms progressed. Best supportive care was provided. The clinical presentation of adhesive arachnoiditis is variable, and advanced imaging techniques and invasive studies such as CT myelogram may be required to establish the diagnosis. Timely diagnosis is warranted as early surgical or medical therapy can improve symptoms.",
"affiliations": "Department of Neurology, Yale School of Medicine, New Haven, CT.;Department of Neurology, Yale School of Medicine, New Haven, CT.;Department of Neurosurgery, Ludwig-Maximilians-University Munich, Munich, Germany.;Department of Neurology, Yale School of Medicine, New Haven, CT [email protected].",
"authors": "Karschnia|Philipp|P|;Kaulen|Leon|L|;Thon|Niklas|N|;Baehring|Joachim M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000013085",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": null,
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": null,
"nlm_unique_id": "0401060",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34799459",
"pubdate": "2021-11-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Reasoning: A 64-Year-Old Man With History of Meningitis Presenting With Proximal Weakness of the Arms.",
"title_normalized": "clinical reasoning a 64 year old man with history of meningitis presenting with proximal weakness of the arms"
}
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{
"abstract": "Tumor necrosis factor antagonists (TNFs) are effective for moderate-severe Crohn's disease (CD). Approximately one-third of patients have primary-nonresponse to TNFs, which is reported to predict worse response to subsequent TNF therapy. However, this is based on treatment with subcutaneously (SC) administered, fixed-dose TNFs after failure of intravenously (IV) administered, weight-based TNFs. No study has specifically assessed the clinical and endoscopic effectiveness of IV TNFs following primary-nonresponse to SC TNFs. We hypothesize that IV, weight-based TNF dosing offers advantages over SC, fixed-dose TNFs and may be effective despite primary-nonresponse to previous SC fixed-dose TNFs.\n\n\n\nThis retrospective cohort study identified patients with moderate-severe CD with primary-nonresponse to one or more SC TNFs who subsequently received the IV TNF, infliximab for ≥ 12 weeks. We described baseline characteristics, and clinical, endoscopic and biochemical response to therapy.\n\n\n\nKey characteristics of 17 patients are described in Table 1. After ≥ 12 weeks of infliximab, 11 of 15 (73.3%) patients with clinical data reported clinical response and remission. Of 11 patients with endoscopic data, restaging colonoscopy revealed mucosal improvement in seven (63.6%) patients. Of these, five (45.5%) had endoscopic remission and three (27.3%) had mucosal healing. Table 1 Baseline characteristics of CD patients with primary-nonresponse to subcutaneous (SC) tumor necrosis antagonists (TNF), subsequently treated with intravenous (IV) TNF therapy Characteristics N 17 Mean age, years (range) 37.5 (18-67) Mean BMI, kg/m2 (range) 26.6 (17.8-40.6) Mean albumin prior to infliximab, g/dL (range) RR: 3.5-5.2 g/dL 3.57 (2.5-4.2) Female sex [n (%)] 7 (41.2) Tobacco use [n (%)] Never 15 (88.2) Former 1 (5.88) Current 1 (5.88) Age at diagnosis [n (%)] Less than 17 2 (11.8) 17-40 11 (64.7) Over 40 4 (23.5) Mean disease duration, yrs (range) 7.76 (1-24) Disease extent [n (%)] Ileal 2 (11.8) Colonic 5 (29.4) Ileocolonic 10 (64.7) Disease behavior [n (%)] Nonstenosing, nonpenetrating 10 (58.8) Stenosing 3 (17.6) Penetrating 2 (11.8) Stenosing and penetrating 2 (11.8) History of gastrointestinal surgery [n (%)] 4 (23.5) Ileocecal resection (n) 2 Hemicolectomy (n) 2 Prior therapy [n (%)] IV corticosteroids 3 (17.6) Oral corticosteroids 14 (82.4) 5-ASA 12 (70.6) Thiopurine 14 (82.4) Methotrexate 10 (58.8) Prior biologic therapy Adalimumab only 12 (70.6) Certolizumab pegol only 2 (11.8) Adalimumab and certolizumab pegol 2 (11.8) Adalimumab, certolizumab pegol and golimumab 1 (5.88) Dose escalation of prior SC TNF [n (%)] Adalimumab 9 (52.9) Certolizumab pegol 0 (0.0) Golimumab 0 (0.0) During infliximab, concomitant therapy [n (%)] Immunomodulator 13 (76.5) Corticosteroid 5 (29.4) CONCLUSIONS: Patients with moderate-severe CD with prior primary-nonresponse to SC, fixed-dose TNFs, subsequently treated with IV, weight-based TNF have high rates of clinical and endoscopic response and remission. Therefore, despite primary-nonresponse to SC TNFs, patients may benefit from IV TNF therapy and may not require a change to a different class of biologic therapy.",
"affiliations": "Division of Gastroenterology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.;Division of Gastroenterology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.;Division of Gastroenterology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. [email protected].",
"authors": "Clark-Snustad|Kindra Dawn|KD|;Singla|Anand|A|;Lee|Scott David|SD|",
"chemical_list": "D001688:Biological Products; C439524:TNF protein, human; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-019-05490-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "64(7)",
"journal": "Digestive diseases and sciences",
"keywords": "Crohn’s disease; Infliximab; Primary-nonresponse; Tumor necrosis factor antagonist",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D001688:Biological Products; D003424:Crohn Disease; D005260:Female; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014945:Wound Healing; D055815:Young Adult",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "1952-1958",
"pmc": null,
"pmid": "30815825",
"pubdate": "2019-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": "20393175;17634459;26607562;27142671;26992847;29073159;25652884;12047962;17634458;17241859;23066316;16472588;17470824;9321530;27720840;17299059;25861832;26981855",
"title": "Efficacy of Infliximab in Crohn's Disease Patients with Prior Primary-Nonresponse to Tumor Necrosis Factor Antagonists.",
"title_normalized": "efficacy of infliximab in crohn s disease patients with prior primary nonresponse to tumor necrosis factor antagonists"
}
|
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{
"abstract": "To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness.\n\n\n\nErenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures.\n\n\n\nA 48-week, multicenter, longitudinal cohort real-life study was conducted at 15 headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18-65 years. Each patient was treated with erenumab 70 mg, administered monthly. The dose was switched to 140 mg in nonresponders and in responders who had become nonresponders for at least 4 weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45-48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval.\n\n\n\nA total of 242 patients with migraine received at least one dose of erenumab 70 mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48 weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3 migraine-preventive medication classes. From baseline to Weeks 45-48, erenumab treatment reduced MMD by 4.3 ± 5.3 (mean ± SD) in patients with HFEM, and MHD by 12.8 ± 8.9 (mean ± SD) in subjects with CM. VAS and HIT-6 scores were decreased by 1.8 ± 1.9 (mean ± SD) and 12.3 ± 11 (mean ± SD) in HFEM, and by 3.0 ± 2.2 (mean ± SD) and 13.1 ± 11.2 (mean ± SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0-13.0) to 5 (IQR 2.0-8.0) in HFEM and from 20.0 (IQR 15.0-30.0) to 6.0 (IQR 3.8-10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52-19.41; p = 0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03-8.7; p = 0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05-1.20; p = 0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15-0.87; p = 0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64-0.92; p = 0.004).\n\n\n\nLong-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140 mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.",
"affiliations": "Headache and Pain Unit, IRCCS San Raffaele Pisana, Rome, Italy.;Headache and Pain Unit, IRCCS San Raffaele Pisana, Rome, Italy.;IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.;Headache and Pain Unit, IRCCS San Raffaele Pisana, Rome, Italy.;Headache and Pain Unit, IRCCS San Raffaele Pisana, Rome, Italy.;Neurology Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;San Giovanni Addolorata Hospital, Rome, Italy.;Unit of Neurology, Department of Medicine and Surgery, Headache Center, University of Parma, Parma, Italy.;Neurophysiopathology Unit, Headache Center, University Hospital of Rome \"TorVergata\", Rome, Italy.;San Filippo Neri Hospital, Rome, Italy.;Center for Headache and Intracranial Pressure Disorders, Neurology Unit, A.O.U. Mater Domini, Catanzaro, Italy.;Neuroalgology Unit, Headache Center Fondazione IRCCS Istituto Neurologico \"Carlo Besta\", Milan, Italy.;Neurology Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Headache and Neurosonology Unit, Policlinico Universitario Campus Bio-Medico, Rome, Italy.;Headache and Neurosonology Unit, Policlinico Universitario Campus Bio-Medico, Rome, Italy.",
"authors": "Barbanti|Piero|P|;Aurilia|Cinzia|C|0000-0002-2658-2243;Cevoli|Sabina|S|;Egeo|Gabriella|G|;Fofi|Luisa|L|;Messina|Roberta|R|;Salerno|Antonio|A|;Torelli|Paola|P|;Albanese|Maria|M|;Carnevale|Antonio|A|;Bono|Francesco|F|;D'Amico|Domenico|D|;Filippi|Massimo|M|;Altamura|Claudia|C|0000-0002-5934-5535;Vernieri|Fabrizio|F|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/head.14194",
"fulltext": null,
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"issn_linking": "0017-8748",
"issue": "61(9)",
"journal": "Headache",
"keywords": "allodynia; calcitonin gene-related peptide; erenumab; long-term treatment; migraine; sex",
"medline_ta": "Headache",
"mesh_terms": null,
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "1351-1363",
"pmc": null,
"pmid": "34309862",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study.",
"title_normalized": "long term 48 weeks effectiveness safety and tolerability of erenumab in the prevention of high frequency episodic and chronic migraine in a real world results of the early 2 study"
}
|
[
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"literaturereference": "Barbanti P, Aurilia C, Cevoli S, Egeo G, Fofi L, Messina R et al.. Long-term (48 weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study. HEADACHE. 2021;00:1-13. doi:10.1111/head.l4194",
"literaturereference_normalized": "long term 48 weeks effectiveness safety and tolerability of erenumab in the prevention of high frequency episodic and chronic migraine in a real world results of the early 2 study",
"qualification": "3",
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},
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},
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{
"abstract": "A 32-year-old female with stage IV colorectal cancer and metastasis to the liver experienced cardiotoxic reactions after treatment with 5-fluorouracil and its oral prodrug capecitabine even at two-thirds the recommended dose. After careful considerations, the decision was made to attempt capecitabine retrial at a further suboptimal dose with combination chemotherapy where she no longer experienced cardiac events. As a result, the liver tumour shrank and rectal mass stabilised, tumour markers dropped and she underwent surgical resection of both masses. Later there was local recurrence of disease near the previous liver tumour, so the suboptimal capecitabine therapy was restarted without complaint. The patient became a candidate for a NanoKnife procedure, offering a potentially curative therapy. This case report summarises a novel treatment strategy for those patients with advanced colorectal cancer who experience cardiotoxic reactions to fluoropyrimidines, the active agent of gold standard treatment.",
"affiliations": "School of Medicine, University of Miami, Miami, Florida, USA.;Internal Medicine, Jackson Memorial Hospital, Miami, Florida, USA.;Department of Haematology/Oncology, Internal Medicine, Jackson Memorial Hospital, Miami, Florida, USA.;Department of Haematology and Oncology, Internal Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.",
"authors": "Cioffi|Joseph H|JH|;Estes|Derek J|DJ|;Florou|Vaia|V|;Ardalan|Bach|B|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220952",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "cancer intervention; chemotherapy; colon cancer; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D066126:Cardiotoxicity; D015179:Colorectal Neoplasms; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008113:Liver Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29183892",
"pubdate": "2017-11-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12771913;8422644;27798021;15978800;20179805;25186061;24428956;17636329;16418875;2278719;25032886;9250550;28489615;11996484;23582737;15160338",
"title": "Treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5-fluorouracil and capecitabine using suboptimal doses.",
"title_normalized": "treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5 fluorouracil and capecitabine using suboptimal doses"
}
|
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},
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{
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},
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{
"drugrecuraction": "Chest pain"
}
],
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},
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},
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"drugindication": "COLORECTAL CANCER STAGE IV",
"drugintervaldosagedefinition": null,
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"drugrecurrence": [
{
"drugrecuraction": "Chest pain"
}
],
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"medicinalproduct": "5-FLUOROURACIL"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
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"drugcumulativedosagenumb": null,
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"drugdosagetext": "1.5 GRAM DAILY;",
"drugenddate": null,
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"drugintervaldosageunitnumb": null,
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{
"drugrecuraction": "Chest pain"
}
],
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"drugstructuredosagenumb": "1.5",
"drugstructuredosageunit": "002",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CAPECITABINE."
}
],
"patientagegroup": null,
"patientonsetage": "32",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Chest pain",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Palpitations",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Ventricular extrasystoles",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CIOFFI J, ESTES D, FLOROU V, ARDALAN B. TREATMENT OF ADVANCED COLORECTAL CANCER IN A PATIENT WITH CARDIOTOXIC REACTIONS TO 5-FLUOROURACIL AND CAPECITABINE USING SUBOPTIMAL DOSES. BMJ-CASE-REP. 2017?.",
"literaturereference_normalized": "treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5 fluorouracil and capecitabine using suboptimal doses",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180105",
"receivedate": "20180105",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14355370,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
},
{
"companynumb": "US-BAUSCH-BL-2017-036366",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
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"drugdosagetext": "500 MG/M2; CYCLICAL",
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"medicinalproduct": "FOLINIC ACID"
},
{
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"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
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"drugcumulativedosagenumb": null,
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"drugdosagetext": "IRINOTECAN 100 MG/M2; CYCLICAL",
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"drugindication": "ADENOCARCINOMA",
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"medicinalproduct": "IRINOTECAN"
},
{
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},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": "020985",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "5-FU 1600 MG/M2; CYCLICAL",
"drugenddate": null,
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"drugindication": "ADENOCARCINOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "2",
"drugrecurrence": null,
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"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1600",
"drugstructuredosageunit": "009",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUOROURACIL."
}
],
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"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
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"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cardiotoxicity",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CIOFFI J, ESTES D, FLOROU V, ARDALAN B. TREATMENT OF ADVANCED COLORECTAL CANCER IN A PATIENT WITH CARDIOTOXIC REACTIONS TO 5-FLUOROURACIL AND CAPECITABINE USING SUBOPTIMAL DOSES. BMJ CASE REPORTS. 2017;.",
"literaturereference_normalized": "treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5 fluorouracil and capecitabine using suboptimal doses",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20171230",
"receivedate": "20171230",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14339175,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
}
] |
{
"abstract": "Intra-anal warts are frequently recalcitrant to surgical removal, but imiquimod 5% cream is not formulated to use in clinical practice due to the risk of mucosal inflammation. In the present, prospective, open study examining the efficacy and safety of imiquimod 5% cream, the drug was applied to the entire inner surface of the anal canal with a cotton swab under anoscopy three times weekly for 16 weeks. If complete remission was not achieved, the treatment was continued until week 28. Electrocautery was applied once in a poorly responsive case. In total, 21 patients with intra-anal warts, of whom 16 were HIV-positive, were enrolled. Two patients withdrew before week 16, and nine more patients withdrew before week 28. The complete clearance rate was 36.8% (7/19) at week 16 and 70% (7/10) at week 28. Four patients achieved complete clearance at week 16 and maintained clearance at week 28 without further treatment. Three of four patients resistant to previous electrocautery achieved clearance with imiquimod 5% cream treatment. Adverse events occurred in 81% (17/21) of the patients mainly at the application site, but serious or previously unencountered adverse events were not observed. Imiquimod 5% cream applied to intra-anal warts was nearly as efficacious and safe as when applied to external anogenital warts. Since treatment modalities for intra-anal warts are very limited, application of imiquimod 5% cream alone with careful and frequent observation or in combination with electrocautery is a useful option for refractory cases of intra-anal wart.",
"affiliations": "Department of Dermatology, Tokyo Medical University, Tokyo, Japan.;Department of Dermatology, Tokyo Medical University, Tokyo, Japan.;Department of Dermatology, Tokyo Medical University, Tokyo, Japan.;Department of Dermatology, Tokyo Medical University, Tokyo, Japan.",
"authors": "Irisawa|Ryokichi|R|https://orcid.org/0000-0002-9095-3192;Tsuboi|Ryoji|R|;Saito|Masuyoshi|M|;Harada|Kazutoshi|K|https://orcid.org/0000-0002-9059-4097",
"chemical_list": "D000634:Aminoquinolines; D000077271:Imiquimod",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.15759",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "48(4)",
"journal": "The Journal of dermatology",
"keywords": "HIV infection; Japanese subjects; condyloma acuminatum; men who have sex with men; surgical removal",
"medline_ta": "J Dermatol",
"mesh_terms": "D000634:Aminoquinolines; D003218:Condylomata Acuminata; D006801:Humans; D000077271:Imiquimod; D011446:Prospective Studies; D016896:Treatment Outcome; D014860:Warts",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "476-480",
"pmc": null,
"pmid": "33460189",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of intra-anal warts with imiquimod 5% cream: A single-center prospective open study.",
"title_normalized": "treatment of intra anal warts with imiquimod 5 cream a single center prospective open study"
}
|
[
{
"companynumb": "JP-TOLMAR, INC.-21JP025201",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMIQUIMOD"
},
"drugadditional": "3",
"drugadministrationroute": "054",
"drugauthorizationnumb": "091044",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CREAM",
"drugdosagetext": "UNK UNK, 3/WEEK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SKIN PAPILLOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "3",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IMIQUIMOD."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "IRISAWA R, TSUBOI R, SAITO M, HARADA K.. TREATMENT OF INTRA?ANAL WARTS WITH IMIQUIMOD 5% CREAM: A SINGLE?CENTER PROSPECTIVE OPEN STUDY. J DERMATOL. 2021",
"literaturereference_normalized": "treatment of intra anal warts with imiquimod 5 cream a single center prospective open study",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20210208",
"receivedate": "20210208",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18864031,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210420"
}
] |
{
"abstract": "Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.",
"affiliations": "Division of Hematology and Medical Oncology, Perlmutter Cancer Center at NYU Langone Health, New York University School of Medicine & Langone Medical Center, New York, NY, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.;Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.;Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.;Division of Hematology and Oncology, University of Tennessee Medical Center, Knoxville, TN, USA.;Department of Oncology, Karmanos Cancer Institute, Detroit, MI, USA.;McGill University, Montreal, QC, Canada.;McGill University, Montreal, QC, Canada.;Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.;Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.;Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Rush University Medical Center, Chicago, IL, USA.;Division of Hematology, Northwestern University, Chicago, IL, USA.;Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.;Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.;Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.;Division of Hematology/Oncology, University of Arizona Cancer Center, Tucson, AZ, USA.;University of Chicago, Chicago, IL, USA.;Moffitt Cancer Center, Tampa, FL, USA.;New York University School of Medicine, New York, NY, USA.;Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA.",
"authors": "Carreau|Nicole A|NA|;Armand|Philippe|P|0000-0001-6098-1603;Merryman|Reid W|RW|0000-0002-6360-3234;Advani|Ranjana H|RH|;Spinner|Michael A|MA|0000-0002-5013-4651;Herrera|Alex F|AF|0000-0002-9665-7415;Ramchandren|Radhakrishnan|R|;Hamid|Muhammad S|MS|;Assouline|Sarit|S|;Santiago|Raoul|R|;Wagner-Johnston|Nina|N|;Paul|Suman|S|;Svoboda|Jakub|J|;Bair|Steven M|SM|;Barta|Stefan K|SK|;Nathan|Sunita|S|;Karmali|Reem|R|;Torka|Pallawi|P|0000-0002-1681-5883;David|Kevin|K|;Lansigan|Frederick|F|;Persky|Daniel|D|0000-0002-3483-2142;Godfrey|James|J|;Chavez|Julio C|JC|0000-0002-2045-6238;Xia|Yuhe|Y|;Diefenbach|Catherine|C|0000-0003-1116-3246",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.16756",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "191(1)",
"journal": "British journal of haematology",
"keywords": "chemosensitivity; immunotherapy; non-Hodgkin lymphoma",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064591:Allografts; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D016219:Immunotherapy, Adoptive; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D019172:Transplantation Conditioning",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "44-51",
"pmc": null,
"pmid": "32430944",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Checkpoint blockade treatment sensitises relapsed/refractory non-Hodgkin lymphoma to subsequent therapy.",
"title_normalized": "checkpoint blockade treatment sensitises relapsed refractory non hodgkin lymphoma to subsequent therapy"
}
|
[
{
"companynumb": "US-AMGEN-USASP2020175188",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "202714",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN FORMULATION",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-HODGKIN^S LYMPHOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CARFILZOMIB"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute myeloid leukaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Non-Hodgkin^s lymphoma",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Therapy partial responder",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ARMAND, P.. CHECKPOINT BLOCKADE TREATMENT SENSITISES RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA TO SUBSEQUENT THERAPY. BRITISH JOURNAL OF HAEMATOLOGY. 2020?191 (1):44-51",
"literaturereference_normalized": "checkpoint blockade treatment sensitises relapsed refractory non hodgkin lymphoma to subsequent therapy",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201102",
"receivedate": "20201102",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18450619,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210114"
}
] |
{
"abstract": "Fusobacterium nucleatum is part of the commensal flora of the oral cavity, frequently associated with periodontal infections. We describe the case of a 49-year-old woman, on immunsuppressive therapy for multiple sclerosis, who presented with a 3-month history of debilitating back pain. She had a recent episode of periodontitis, and was under regular dental review. Her MRI scan demonstrated findings suggestive of L2-L3 spondylodiscitis. Her CT-guided biopsy yielded negative cultures and the patient failed two courses of empirical antibiotic treatment. With clinical and radiological disease progression, she underwent a percutaneous disc washout and biopsy, which subsequently grew F. nucleatum Treatment with clindamycin and metronidazole was commenced orally for 6 weeks. She improved gradually, and at 1 year follow-up was asymptomatic. The diagnosis of spondylodiscitis caused by F. nucleatum is challenging. The perseverance on identification by surgical biopsy, minimally invasive washout and targeted antibiotics are the mainstay of effective treatment.",
"affiliations": "The Centre for Spinal Studies and Surgery, Queen's Medical Centre Nottingham, University Hospital NHS Trust, Nottingham, UK [email protected].;The Centre for Spinal Studies and Surgery, Queen's Medical Centre Nottingham, University Hospital NHS Trust, Nottingham, UK.;The Centre for Spinal Studies and Surgery, Queen's Medical Centre Nottingham, University Hospital NHS Trust, Nottingham, UK.;The Centre for Spinal Studies and Surgery, Queen's Medical Centre Nottingham, University Hospital NHS Trust, Nottingham, UK.",
"authors": "Pasku|Dritan|D|;Shah|Siddharth|S|;Aly|Ahmed|A|;Quraishi|Nasir A|NA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-239664",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "bone and joint infections; dentistry and oral medicine; multiple sclerosis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015299:Discitis; D005260:Female; D005674:Fusobacterium Infections; D016967:Fusobacterium nucleatum; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis; D010518:Periodontitis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33737279",
"pubdate": "2021-03-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rare, post-periodontitis spondylodiscitis caused by Fusobacterium nucleatum in a patient with multiple sclerosis: challenge of diagnosis and treatment.",
"title_normalized": "rare post periodontitis spondylodiscitis caused by fusobacterium nucleatum in a patient with multiple sclerosis challenge of diagnosis and treatment"
}
|
[
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-294485",
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"patient": {
"drug": [
{
"actiondrug": "5",
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"activesubstancename": "CLINDAMYCIN"
},
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},
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},
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"medicinalproduct": "METRONIDAZOLE."
}
],
"patientagegroup": null,
"patientonsetage": "49",
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Disease progression",
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"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PASKU D, SHAH S, ALY A, QURAISHI NA. RARE, POST?PERIODONTITIS SPONDYLODISCITIS CAUSED BY FUSOBACTERIUM NUCLEATUM IN A PATIENT WITH MULTIPLE SCLEROSIS: CHALLENGE OF DIAGNOSIS AND TREATMENT. BMJ CASE REP. 2021?14:E239664",
"literaturereference_normalized": "rare post periodontitis spondylodiscitis caused by fusobacterium nucleatum in a patient with multiple sclerosis challenge of diagnosis and treatment",
"qualification": "3",
"reportercountry": "GB"
},
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},
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},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210717"
}
] |
{
"abstract": "Surgical treatment of multiple vertebral fractures in patients with glucocorticoid-induced osteoporosis is difficult because of a high rate of secondary fracture postoperatively. A case is described in which initial treatment with teriparatide to improve osteoporosis followed by treatment of kyphosis with correction fusion achieved a favorable outcome.\n\n\n\nSecondary fracture frequently occurs after treatment of vertebral fracture with vertebroplasty and balloon kyphoplasty in patients with glucocorticoid-induced osteoporosis, but effective treatment of multiple vertebral fractures has rarely been reported. Thus, a treatment of kyphosis following multiple vertebral fractures associated with glucocorticoid-induced osteoporosis is required.\n\n\n\nThe patient was a 24-year-old woman diagnosed with glucocorticoid-induced osteoporosis who was under treatment with oral alendronate, vitamin D, and elcatonin injection. Secondary multiple vertebral fractures occurred despite these treatments and low back pain gradually aggravated.\n\n\n\nVertebroplasty or balloon kyphoplasty was not performed in the early phase. Instead, treatment with teriparatide was used for initial improvement of osteoporosis. Kyphosis in the center of the residual thoracolumbar junction was then treated with posterior correction fusion. At 2 years after surgery, the corrected position has been maintained and no new fracture has occurred.\n\n\n\nThere is no established method for treatment of multiple vertebral fractures caused by glucocorticoid-induced osteoporosis. Initial treatment with teriparatide to improve osteoporosis followed by treatment of kyphosis with correction fusion may result in a more favorable outcome.",
"affiliations": "Department of Orthopaedic Surgery, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan. [email protected].;Department of Orthopaedic Surgery, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.;Department of Orthopaedic Surgery, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.;Department of Orthopaedic Surgery, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.;Department of Orthopaedic Surgery, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan.",
"authors": "Uei|Hiroshi|H|http://orcid.org/0000-0001-9631-4861;Tokuhashi|Yasuaki|Y|;Maseda|Masafumi|M|;Nakahashi|Masahiro|M|;Nakayama|Enshi|E|",
"chemical_list": "D005938:Glucocorticoids",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-018-4425-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "29(5)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Glucocorticoid-induced osteoporosis; Kyphosis; Teriparatide; Vertebral compression fracture",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D003131:Combined Modality Therapy; D005260:Female; D050815:Fractures, Compression; D005938:Glucocorticoids; D006801:Humans; D007738:Kyphosis; D010024:Osteoporosis; D058866:Osteoporotic Fractures; D012008:Recurrence; D055502:Secondary Prevention; D016103:Spinal Fractures; D013123:Spinal Fusion; D055815:Young Adult",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "1211-1215",
"pmc": null,
"pmid": "29476202",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24374285;9682041;22991246;15454702;19940397;10555025;24905394;23354115;14613287;26782683;17032871;21240045;16506477;23429686;16574519;23970111;20638627;21732837;18003959;28425086",
"title": "Multiple vertebral fractures associated with glucocorticoid-induced osteoporosis treated with teriparatide followed by kyphosis correction fusion: a case report.",
"title_normalized": "multiple vertebral fractures associated with glucocorticoid induced osteoporosis treated with teriparatide followed by kyphosis correction fusion a case report"
}
|
[
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}
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},
{
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},
{
"reactionmeddrapt": "Osteoporosis",
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}
],
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},
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},
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},
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{
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},
{
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},
{
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"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
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},
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},
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},
{
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"patient": {
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"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
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] |
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