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"abstract": "A 69-year-old man without a family history of breast cancer presented to his primary care physician with a 1-year history of clear, unilateral nipple discharge (ND) without an associated palpable breast mass. His laboratory findings were significant for hyperprolactinaemia at 28 ng/mL. Diagnostic work up including mammography, ultrasound and core needle biopsy ultimately revealed a ductal carcinoma in situ and a rare papillary variant of invasive ductal carcinoma. The patient was referred to a multidisciplinary oncology team and underwent a right total mastectomy followed by adjuvant hormonal therapy. The patient made a good postoperative recovery and remains without evidence of recurrence 6 months from surgery. Male breast cancer is rare, but its incidence is increasing. Male breast cancer presenting as ND without a palpable mass is uncommon. Early recognition of breast symptoms in men can lead to earlier diagnoses and improved outcomes.",
"affiliations": "Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, New York, USA.;Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, New York, USA.;Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, New York, USA.;Department of Internal Medicine, SUNY Upstate Medical University, Syracuse, New York, USA [email protected].",
"authors": "Ramakrishna|Karan N|KN|;Durland|Justin|J|;Ramos|Christopher|C|;Dhamoon|Amit Singh|AS|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236223",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "breast cancer; cancer intervention",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D018931:Antineoplastic Agents, Hormonal; D062005:Biopsy, Large-Core Needle; D018567:Breast Neoplasms, Male; D002285:Carcinoma, Intraductal, Noninfiltrating; D002291:Carcinoma, Papillary; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D008408:Mastectomy; D009378:Neoplasms, Multiple Primary; D000071936:Nipple Discharge; D013629:Tamoxifen",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33257364",
"pubdate": "2020-11-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unilateral nipple discharge in a man without a palpable mass diagnosed as breast cancer.",
"title_normalized": "unilateral nipple discharge in a man without a palpable mass diagnosed as breast cancer"
}
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"literaturereference": "Ramakrishna KN, Durland J, Ramos C, Dhamoon AS.. Unilateral nipple discharge in a man without a palpable mass diagnosed as breast cancer. BMJ Case Reports. 2020;13(11):e236223",
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{
"abstract": "Infections that affect the intervertebral discs and vertebrae are known as spondylodiscitis. Such infections are commonly caused by pyogenic organisms, particularly Staphylococcus aureus, and hematogenous spread is the most common route. Non-pyogenic infections include Mycobacterium tuberculosis and Brucellosis. Mycotic infections are becoming more common, in line with the growing number of immunodeficiency disorders. Cryptococcus is included among these mycotic infections. We present a case of such an infection in a non-immunocompromised patient with a known history of treatment with antitubercular therapy. A 52-year-old man came to our hospital with a backache of one-month duration and progressive neurological deficits of the lower limbs of one-week duration. His imaging studies were suggestive of spondylodiscitis at the D10-11 and D11-12 levels with a left paraspinal abscess. The patient underwent anterolateral decompression, biopsy, and instrumented posterior spinal fusion. The pus grew Cryptococcus, and histopathology confirmed Cryptococcal spondylodiscitis. The patient was treated with parenteral amphotericin B and fluconazole. A mycotic infection must be considered in the differential diagnosis of infectious spondylodiscitis.",
"affiliations": "Department of Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India.;Department of Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India.;Department of Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India.;Department of Microbiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India.;Department of Pathology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India.;Department of Infectious Diseases, Kasturba Medical College, Manipal, Karnataka, India.",
"authors": "Bhat|Shyamasunder N|SN|;Kundangar|Raghuraj|R|;Ampar|Nishanth|N|;Banerjee|Barnini|B|;Udupa|Chethana Babu K|CBK|;Saravu|Kavitha|K|",
"chemical_list": null,
"country": "Saudi Arabia",
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"doi": "10.1016/j.jtumed.2021.01.007",
"fulltext": "\n==== Front\nJ Taibah Univ Med Sci\nJ Taibah Univ Med Sci\nJournal of Taibah University Medical Sciences\n1658-3612\nTaibah University\n\nS1658-3612(21)00030-5\n10.1016/j.jtumed.2021.01.007\nCase Report\nCryptococcal spondylodiscitis in a non-HIV patient with CD4 lymphocytopenia\nBhat Shyamasunder N. MS [email protected]\na∗\nKundangar Raghuraj MS a\nAmpar Nishanth MS a\nBanerjee Barnini MD b\nUdupa Chethana Babu K. MD c\nSaravu Kavitha MD d\na Department of Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India\nb Department of Microbiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India\nc Department of Pathology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India\nd Department of Infectious Diseases, Kasturba Medical College, Manipal, Karnataka, India\n∗ Corresponding address: Department of Orthopaedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka 576104, India. [email protected]\n06 2 2021\n6 2021\n06 2 2021\n16 3 470475\n3 11 2020\n1 1 2021\n14 1 2021\n© 2021 The Authors\n2021\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/).\nInfections that affect the intervertebral discs and vertebrae are known as spondylodiscitis. Such infections are commonly caused by pyogenic organisms, particularly Staphylococcus aureus, and hematogenous spread is the most common route. Non-pyogenic infections include Mycobacterium tuberculosis and Brucellosis. Mycotic infections are becoming more common, in line with the growing number of immunodeficiency disorders. Cryptococcus is included among these mycotic infections. We present a case of such an infection in a non-immunocompromised patient with a known history of treatment with antitubercular therapy. A 52-year-old man came to our hospital with a backache of one-month duration and progressive neurological deficits of the lower limbs of one-week duration. His imaging studies were suggestive of spondylodiscitis at the D10–11 and D11–12 levels with a left paraspinal abscess. The patient underwent anterolateral decompression, biopsy, and instrumented posterior spinal fusion. The pus grew Cryptococcus, and histopathology confirmed Cryptococcal spondylodiscitis. The patient was treated with parenteral amphotericin B and fluconazole. A mycotic infection must be considered in the differential diagnosis of infectious spondylodiscitis.\n\nالملخص\n\nتُعرف العدوى التي تؤثر على الأقراص الفقرية وفقراتها باسم التهاب الفقار وأقراصها. تحدث هذه العدوى عادة عن طريق المكروبات المقيحة، ولا سيما من قبل المكورات العنقودية، والطريق الأكثر شيوعا لانتشارها هو انتشار الدم. وتشمل العدوى غير المقيحة المتفطرة السلية وداء البروسيلات. وتزداد العدوى الفطرية شيوعا مع تزايد عدد اضطرابات نقص المناعة. ومن ضمن العدوى الفطرية عدوى المستخفية. نقدم حالة من هذه العدوى في مريض لا يعاني من نقص المناعة مع تاريخ معروف من العلاج بمضاد السل. حضر رجل يبلغ من العمر ٥٢ عاما إلى مستشفانا يعاني من ألم في الظهر لمدة شهر، وعجز عصبي تدريجي في الأطراف السفلية لمدة أسبوع واحد. وكانت دراساته التصويرية موحية بالتهاب الفقار وأقراصها في مستوى الفقرات الظهرية ١٠-١١ و١١-١٢ مع خراج مجاور للفقرات أيسر. خضع المريض لتخفيف الضغط من الجهة الأمامية الوحشية، والخزعة والاندماج الفقري الخلفي بالأدوات الجراحية. نمت المستخفية من القيح، وأكدت الهيستوباتولوجيا التهاب الفقار وأقراصها بالمستخفية. وعولج المريض بـالأمفوترسين-ب وفلاكونازول عن طريق الوريد. يجب النظر في العدوى الفطرية في التشخيص التفريقي لالتهاب الفقار وأقراصها.\n\nالكلمات المفتاحية\n\nالتهاب الفقار وأقراصها بالمستخفية\nقلة اللمفاويات\nالتدبير\nغير المصابين بفيروس نقص المناعة البشرية\nالتهاب الفقار وأقراصها\nKeywords\n\nCryptococcal spondylodiscitis\nLymphocytopenia\nManagement\nNon-HIV\nSpondylodiscitis\n==== Body\nIntroduction\n\nSpinal infections are known to have existed since ancient times. Human skeletons from the Iron Age have shown changes suggesting tuberculosis. The French physician Lannelongue described the first case of pyogenic vertebral osteomyelitis in 1879.1 The first series of pyogenic vertebral infections was published in the literature by Kulowski in 1936.1 Despite advances in surgical and imaging techniques and the discovery of antibiotics, which have given patients hope, morbidity remains significant.1\n\nSpinal infections are classified as pyogenic, granulomatous (tuberculous, brucella, fungal), and parasitic.1 Pyogenic spondylodiscitis can cause significant morbidity and severe long-term sequelae. Skaf et al.2 conducted a literature review to understand the diagnosis, treatment, and prognosis. Appropriate management involves aggressive medical treatment and, sometimes, surgical intervention. Full recovery is expected if diagnosed early and treated appropriately. Hence, clinicians should know the clinical features to improve outcomes.2\n\nThe incidence of spondylodiscitis is on the rise, due to an increase in the susceptible population and available useful diagnostic tools. A high index of suspicion is needed for correct diagnosis to ensure better prognosis. A microbiological diagnosis is required to choose appropriate antibiotics. Surgery may be necessary to alleviate pain, correct deformities, alleviate neural compression, and restore function.1\n\nCryptococcal infection, if disseminated, has higher morbidity and mortality. Typical patients are immunosuppressed due to retroviral infection or immunosuppressive drugs given to solid organ transplant patients. Almutawa et al.3 described a case of disseminated cryptococcal disease in a non-retroviral, nontransplant patient with a good clinical outcome.\n\nHematogenous multifocal bony lesions have been reported in 5–10% of all cryptococcal infections.4, 5, 6 In a case report of disseminated cryptococcal infection, C. neoformans was detected in pleuritic fluid and the resected rib.7 Vertebral lesions need to be monitored by Magnetic Resonance Imaging (MRI), as it has high sensitivity in identifying spinal infections and helps in visualizing abscesses (paravertebral or epidural). No clear guidelines exist concerning the antifungal of choice or duration of treatment for these patients. However, if the CD4 cell count is below 100 cells/μL, prophylaxis has been suggested.7\n\nCase report\n\nA 52-year-old male came to us with back pain of one-month duration, with insidious onset and radiation to the lower limbs. During the previous week, there had been progressive weakness of the lower limbs and an inability to walk. There were no bladder/bowel disturbances. The patient had lost about 3 kgs of weight over 2 months, but there were no other constitutional symptoms. He gave a history of being started with antitubercular drugs a week earlier based on radiographs.\n\nOn examination, the patient had normal vital signs (afebrile, pulse rate 86/min, and blood pressure 140/90 mmHg). There was no spinal deformity. Tenderness was present on the lower thoracic spinous processes. The higher mental functions and upper limb neurology were normal. He had a complete loss of motor power in the lower limbs with preservation of perianal sensation (American Spinal Injury Association grade B). There were mild hypertonia in the lower limbs, a flicker of contractions, exaggerated deep tendon reflexes, and extensor plantar response (Babinski sign) bilaterally.\n\nThe radiographs he brought with him showed destruction of the left pedicle of the D11 vertebra (Winking Owl sign) (Figures 1A and B).Figure 1 A. Frontal radiograph showing destruction of the left pedicle of the D11 vertebra (Winking Owl sign). B. Lateral radiograph showing collapse of the body of D11 vertebra (Arrow).\n\nFigure 1\n\nA contrast MRI reported D10, D11, and D12 vertebral diffuse spondylitis with D10-11 and D11-12 discitis, a D11 vertebral body intra-osseous abscess with epidural extension causing significant cord compression and focal cord oedema, and prevertebral extension with left psoas and left paraspinal intramuscular abscesses (Figure 2A–D).Figure 2 A. Magnetic Resonance T1-weighted sagittal image. B. T1-weighted axial image. C. T2-weighted sagittal image. D. T2-weighted axial image. Arrows show the lesion site.\n\nFigure 2\n\nThe patient was anaemic (haemoglobin 12.4 g/dl) and had leucocytosis (total leucocyte count 12000/cmm), an elevated erythrocyte sedimentation rate (ESR - 65 mm/h), and raised C-Reactive Protein (CRP - 15 mg/l). Blood glucose, renal function tests (blood urea 40 mg/dL, serum creatinine 1.2 mg/dL), and liver function tests were normal. He was negative for HIV 1 and 2 antibodies by ELISA & Western Blot tests. The Brucella Serum Agglutination Test was negative. The blood culture did not grow any organisms.\n\nTherefore, a clinico-radiologically tubercular infection was suspected, and surgical management was indicated for further confirmation and neurological decompression. The patient underwent anterolateral decompression at D11–D12, biopsy, and posterior fusion with fixation using a pedicle screw construct. Intraoperatively, we found pus and granulation tissue, which were sent for aerobic culture and antibiogram. Molecular diagnostic studies such as the Polymerase Chain Reaction (PCR) and GeneXpert test were negative for M. tuberculosis. His postoperative images are shown in Figure 3A and B.Figure 3 A. Postoperative anteroposterior radiograph. B. Lateral radiograph. Posterior instrumented fusion was done.\n\nFigure 3\n\nThe pus culture grew gram-positive round budding yeast cells on sabouraud dextrose agar and 5% sheep blood agar, identified as Cryptococcus neoformans by MALDI-TOF (bioMerieux, Inc., Durham, NC). The mycobacterial culture by the MGIT 960 method showed no growth after 6 weeks of incubation.\n\nThe histopathological report showed granulation tissue along with numerous granulomas of different sizes, consisting of plump endothelial cells, foreign body giant cells, and a few Langhan's type of giant cells. Numerous round to oval organisms were seen with thick mucinous capsules morphologically resembling Cryptococcus neoformans (Figure 4A). Special staining with Mucicarmine and PAS was positive for Cryptococcus (Capsule stained bright red) (Figure 4B).Figure 4 A. H&E, 400X Multiple foreign body giant cells reaction. B. Mucicarmine stain, 400X demonstrating the mucopolysaccharide capsule of Cryptococcus neoformans (Arrow).\n\nFigure 4\n\nThe patient's CD4 were low twice (265 cells/μL and 233 cells/μL during the same admission). He was initiated on a combination of intravenous amphotericin deoxycholate 1 mg/kg and fluconazole 800 mg/day for a period of 2 weeks. Renal function was serially monitored (Table 1). He was clinically stable, but the lower limb weakness persisted. He was discharged on oral fluconazole 400 mg/day and warfarin (as thromboprophylaxis) and was advised to follow up after 1 month. At the time of discharge, the blood urea was 25 mg/dL, and serum creatinine was 1.3 mg/dL. However, the patient was brought to the hospital 3 weeks after discharge with a history of fever for 2 days, altered sensorium, and decreased urine output for 1 day. At presentation, he was drowsy; however, there was no neck stiffness. The total leucocyte counts were 17,100/cmm. Procalcitonin was elevated (152.7 μg/L). Blood urea was 80 mg/dL, and serum creatinine was 2.9 mg/dL. The Prothrombin Time (PT) was 77.6 s, and the Activated Partial Thromboplastin Time (APTT) was 86.6 s. The platelet count was 3,59,000/μL. These parameters suggested septic shock with acute kidney injury requiring haemodialysis and coagulopathy. The focus of the infection was not apparent. The surgical site had healed externally. The patient was started on intravenous vancomycin and meropenem and switched to intravenous fluconazole. A cerebrospinal fluid (CSF) analysis could not be done in view of coagulopathy. The patient succumbed to the illness after a short stay of 2 days. The serum cryptococcal antigen was positive, and the blood culture was sterile. However, our lab could not do cryptococcal antigen titres.Table 1 Serial renal function tests.\n\nTable 1Investigation\tAdmission\tOn treatment with amphotericin\tReadmission\t\nDay 1\tDay 4\tDay 9\tDay 14\t\nUrea (mg/dL)\t40\t37\t35\t27\t33\t80\t\nCreatinine (mg/dL)\t1.0\t0.8\t1.0\t1.1\t1.3\t2.9\t\n\nDiscussion\n\nCentral nervous system cryptococcosis in non-retroviral infected patients usually affects those on immunosuppressive therapy and those who are immunocompetent. The disease can be caused by Cryptococcus neoformans and Cryptococcus gattii; conventional risk factors are patients with HIV, transplant recipients, malignancy, chronic steroid use, and intravenous drug abuse.8 Wagemakers9 reported a case of chronic relapsing cryptococcal meningitis in a patient with a low naïve CD4 cell count and low mannose-binding lectin.\n\nOur patient was HIV negative but had CD4 lymphocytopenia. CD4 lymphocytopenia can occur transiently during various infections such as tuberculosis, bacteria sepsis, and measles. Idiopathic CD4 lymphocytopenia is a diagnosis of exclusion. The diagnosis requires that the CD4 count is < 300 cells/μL i.e. less than 20% of total lymphocytes on two occasions.10 In addition, there should not be other immunological abnormalities and infections that can cause lymphocytopenia. Our patient could have had idiopathic CD4 lymphocytopenia. No other infection was apparent. Idiopathic CD4 lymphocytopenia is a known predisposing condition for cryptococcal infection. However, he was not evaluated for other immunodeficiency conditions such as common variable immunodeficiency. Moreover, he had no history of recurrent infections. An infectious aetiology of idiopathic CD4 lymphocytopenia has not been identified so far.\n\nPatients with CD4 lymphopenia are at risk of opportunistic and non-opportunistic infections, typically when CD4 is less than 200 cells/μL. The most common infections in one series were cryptococcal infections (26.6%) and mycobacterial infections (17%).11 These pathogens can produce focal infections in any organs, including the musculoskeletal compartment, or produce disseminated disease depending on the degree of immunosuppression.\n\nTable 2, adapted from Skaf et al.,2 states the indications for surgery in a case of spondylodiscitis. The indications for surgery in this case were progressive neurological deficits due to mass effect and to obtain material for bacteriological and histopathological confirmation from the site of the lesion.Table 2 Indications for surgery in pyogenic spontaneous spondylodiscitis.2\n\nTable 21\tNo response to conservative therapy\t\n2\tProgressive/significant or neurological involvement\t\n3\tPara spinal abscess causing mass effect or septic embolus\t\n4\tSignificant skeletal involvement (two adjacent vertebral bodies, or > 50% vertebral body height loss\t\n5\tProgressive deformity ± incapacitating backache\t\n\nTreatment of disseminated cryptococcal diseases is challenging. In view of the poor bone concentration of fluconazole, amphotericin is a pivotal drug for treatment of cryptococcal spondylodiscitis.12 The duration of amphotericin administration was shorter, as the patient was unwilling to take the parenteral treatment for longer. For the induction phase, we could not give flucytosine, due to non-availability. There was also an inadvertent drug–drug interaction between fluconazole and warfarin, which could partially explain the patient's coagulopathy on readmission. Although he presented with septic shock, the aetiology, whether disseminated cryptococcal disease or bacterial infection, was not clear. In view of the suboptimal antifungal therapy and presence of fever and altered sensorium, the progression of cryptococcal disease including meningitis is a strong possibility. However, high procalcitonin pointed to a bacterial infection with sepsis.\n\nIn conclusion, cases of infective spondylodiscitis must be rigorously evaluated microbiologically for accurate diagnosis. We report this case to raise the awareness of clinicians concerning the possibility of Cryptococci as potential aetiological agents for spondylodiscitis and to highlight the therapeutic challenge. In the presence of a fungal aetiology, underlying immunosuppressive conditions such as idiopathic CD4 lymphocytopenia must be investigated. The successful treatment of CNS cryptococcal disease and cryptococcal spondylodiscitis requires the administration of a combination of antifungal drugs with careful monitoring for side effects and drug interactions.\n\nSource of funding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConflict of interest\n\nThe authors have no conflict of interest to declare.\n\nEthical approval\n\nThe manuscript has been prepared in accordance with CARE criteria (2013). The patient had subsequently succumbed to the disease, and we learnt that the case was interesting and reportable. We could not trace the patient's family; hence, consent was not obtained. We used only clinical details and anonymized X-Ray and MRI images. For case reports, obtaining Institutional Ethics Committee permission is currently optional in our institution. Permission from the medical superintendent of the hospital was obtained to retrieve the medical records of the patient. However, the case report was approved by the Departmental Review Committee, Department of Orthopaedics for submission to the Journal of Taibah University Medical Sciences (KMC/Ortho/0901/2020 dated Sep 1, 2020).\n\nAuthors' contributions\n\nSNB, RSK, NA, BB, CU, and KS: Involved in patient care including diagnosis and treatment. SNB: Conception and design, acquisition of case details and interpretation. SNB, BB, KS: Drafting the article or revising it critically for important intellectual content. SNB, RSK, NA, BB, CU, KS: Final approval of the version published. All the authors agree to be accountable for the article and to ensure that all questions regarding the accuracy or integrity of the article are investigated and resolved. All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.\n\nPeer review under responsibility of Taibah University.\n==== Refs\nReferences\n\n1 Gouliouris T. Aliyu S.H. Brown N.M. Spondylodiscitis: update on diagnosis and management J Antimicrob Chemother 65 Suppl. 3 2010 11 24 10.1093/jac/dkq303\n2 Skaf G.S. Domloj N.T. Fehlings M.G. Bouclaousa C.H. Sabbagha A.S. Kanafanic Z.A. Pyogenic spondylodiscitis: an overview J Infect Publ Health 3 1 2010 5 16 10.1016/j.jiph.2010.01.001\n3 Almutawa F. Leto D. Chagla Z. Case report disseminated cryptococcal disease in non-HIV , nontransplant patient Case Rep Infect Dis 2016 2016 1 4\n4 Liu P.Y.F. Cryptococcal osteomyelitis: case report and review Diagn Microbiol Infect Dis 30 1 1998 33 35 10.1016/S0732-8893(97)00190-9 9488829\n5 Behrman R.E. Masci J.R. Nicholas P. Cryptococcal skeletal infections: case report and review Rev Infect Dis 12 2 1990 181 190 10.1093/clinids/12.2.181 2184491\n6 Corr P. Musculoskeletal fungal infections Semin Muscoskel Radiol 15 5 2011 506 510 10.1055/s-0031-1293496\n7 Legarth R.A. Christensen M. Calum H. Katzenstein T.L. Helweg-Larsen J. Cryptococcal rib osteomyelitis as primary and only symptom of idiopathic CD4 penia Med Mycol Case Rep 4 1 2014 16 18 10.1016/j.mmcr.2014.02.002 24624326\n8 Beardsley J. Sorrell T.C. Chen S.C.-A. Central nervous system cryptococcal infections in non-HIV infected patients J Fungi 5 3 2019 71 10.3390/jof5030071\n9 Wagemakers A. Ang C.W. Hagen F. Bot J.C.J. Bomers M.K. Visser M.C. Case report: chronic relapsing cryptococcal meningitis in a patient with low mannose-binding lectin and a low naïve CD4 cell count BMC Infect Dis 19 1 2019 1 4 10.1186/s12879-019-4515-0 30606108\n10 Zonios D.I. Falloon J. Bennett J.E. Shaw P.A. Chaitt D. Baseler M.W. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors Blood 112 2 2008 287 294 10.1182/blood-2014-05-577916 Blood 2014;124(3):463-463 18456875\n11 Ahmad D.S. Esmadi M. Steinmann W.C. Idiopathic CD4 Lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases Avicenna J Med 3 2 2013 37 47 10.4103/2231-0770.114121 23930241\n12 Felton T. Troke P.F. Hope W.W. Tissue penetration of antifungal agents Clin Microbiol Rev 27 1 2014 68 88 10.1128/CMR.00046-13 24396137\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1658-3612",
"issue": "16(3)",
"journal": "Journal of Taibah University Medical Sciences",
"keywords": "Cryptococcal spondylodiscitis; Lymphocytopenia; Management; Non-HIV; Spondylodiscitis",
"medline_ta": "J Taibah Univ Med Sci",
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"publication_types": "D002363:Case Reports",
"references": "9488829;22081285;24396137;20701886;27957359;24624326;31382367;18456875;2184491;23930241;31615425;20876624",
"title": "Cryptococcal spondylodiscitis in a non-HIV patient with CD4 lymphocytopenia.",
"title_normalized": "cryptococcal spondylodiscitis in a non hiv patient with cd4 lymphocytopenia"
}
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{
"abstract": "We aimed to assess the efficacy of vinorelbine plus granulocyte colony-stimulating factor (G-CSF) for chemo-mobilization of CD34(+) hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m(2) was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 μg/kg body weight (BW) was given twice daily subcutaneously from day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and be performed for a maximum of 3 consecutive days until at least 4 × 10(6) CD34(+) cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization because of neutropenic fever and renal failure (n = 1), severe bone pain (n = 1), and abdominal pain with constipation (n = 1). In 211 (95%) patients, the leukaphereses were started as planned at day 8, whereas in 8 (3%) patients the procedure was postponed to day 9 and in 2 (1%) patients to day 10. In the great majority of patients (77%), the predefined amount of HPC could be collected with 1 leukapheresis. Forty-four (20%) patients needed a second leukapheresis, whereas only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34(+) cells collected was 6.56 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW at the first day of leukapheresis and 7.65 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of 3 leukaphereses. Patient age (P = .02) and prior exposition to lenalidomide (P < .001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients.",
"affiliations": "Department of Oncology, University Hospital Zurich, Zurich, Switzerland. Electronic address: [email protected].;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.;Biostatistics Unit, Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland.;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.;Medical Oncology and Hematology, Triemli City Hospital, Zurich, Switzerland.;Department of Hematology, University Hospital Zurich, Zurich, Switzerland.;Department of Hematology, University Hospital Zurich, Zurich, Switzerland.;Center of Oncology, Hematology and Transfusion Medicine, Cantonal Hospital Aarau, Aarau, Switzerland.;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.",
"authors": "Samaras|Panagiotis|P|;Pfrommer|Sarah|S|;Seifert|Burkhardt|B|;Petrausch|Ulf|U|;Mischo|Axel|A|;Schmidt|Adrian|A|;Schanz|Urs|U|;Nair|Gayathri|G|;Bargetzi|Mario|M|;Taverna|Christian|C|;Stupp|Roger|R|;Stenner-Liewen|Frank|F|;Renner|Christoph|C|",
"chemical_list": "D018952:Antigens, CD34; D000972:Antineoplastic Agents, Phytogenic; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D013792:Thalidomide; D014747:Vinblastine; D000077269:Lenalidomide; D000069585:Filgrastim; D000077235:Vinorelbine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "21(1)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Chemo-mobilization; Hematopoietic progenitor cell mobilization; Lenalidomide; Multiple myeloma; Vinorelbine",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D018952:Antigens, CD34; D000972:Antineoplastic Agents, Phytogenic; D002452:Cell Count; D004359:Drug Therapy, Combination; D005260:Female; D000069585:Filgrastim; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D000077269:Lenalidomide; D007937:Leukapheresis; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011994:Recombinant Proteins; D012189:Retrospective Studies; D012307:Risk Factors; D013792:Thalidomide; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
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"pubdate": "2015-01",
"publication_types": "D016428:Journal Article",
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"abstract": "Indwelling pleural catheters [IPC] have an important role in the management of malignant pleural effusions. We report the development of a significant air leak following IPC insertion with resultant extensive subcutaneous emphysema. The air leak developed, presumably, as a result of visceral pleural disruption, which occurred at the time of vacuum drainage of pleural fluid after IPC placement and not due to lung injury during insertion. The patient required insertion of a large bore intercostal drain connected to low-pressure negative suction. He was eventually discharged home with the aid of an ambulatory system. Although commonly seen in the surgical setting, we believe emergency and respiratory physicians should be aware of the risk of such a complication, and the challenges in its management.",
"affiliations": "Department of Respiratory Medicine, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Road, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom.;Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Road, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom.;Department of Respiratory Medicine, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Road, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom.;Department of Respiratory Medicine, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Road, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom.",
"authors": "Bhatnagar|Malvika|M|;Slight|Robert|R|;Prasad|Arun Brahmanya|AB|;Stanton|Andrew Ewing|AE|",
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"doi": "10.1016/j.rmcr.2020.101257",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30471-8\n10.1016/j.rmcr.2020.101257\n101257\nCase Report\nProlonged air leak after IPC insertion: An unusual complication\nBhatnagar Malvika [email protected]∗ Slight Robert [email protected] Prasad Arun Brahmanya [email protected] Stanton Andrew Ewing [email protected] a Department of Respiratory Medicine, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Road, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom\nb Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Freeman Road, High Heaton, Newcastle Upon Tyne, NE7 7DN, United Kingdom\nc Department of Respiratory Medicine, Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Trust, Queen Victoria Road, Newcastle Upon Tyne, NE1 4LP, United Kingdom\nd Newcastle University, Newcastle Upon Tyne, NE1 7RU, United Kingdom\n∗ Corresponding author. [email protected]\n16 10 2020 \n2020 \n16 10 2020 \n31 10125713 7 2020 10 10 2020 11 10 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Indwelling pleural catheters [IPC] have an important role in the management of malignant pleural effusions. We report the development of a significant air leak following IPC insertion with resultant extensive subcutaneous emphysema. The air leak developed, presumably, as a result of visceral pleural disruption, which occurred at the time of vacuum drainage of pleural fluid after IPC placement and not due to lung injury during insertion. The patient required insertion of a large bore intercostal drain connected to low-pressure negative suction. He was eventually discharged home with the aid of an ambulatory system. Although commonly seen in the surgical setting, we believe emergency and respiratory physicians should be aware of the risk of such a complication, and the challenges in its management.\n\nKeywords\nIndwelling pleural catheterAir leakVisceral pleural disruptionNegative suction\n==== Body\n1 Introduction\nIndwelling Pleural Catheters [IPCs] are an important tool in the management of recurrent malignant pleural effusions [MPEs] [1]. They are particularly well established in the management of patients with a “trapped lung” wherein the lung is unable to expand completely following pleural fluid drainage due to either a thickened restrictive visceral pleural covering [1], or endobronchial obstruction.\n\nThough relatively safe, IPCs can be associated with complications such as pleural infection, catheter blockage, and catheter tract metastases [2]. It is not uncommon to see a small pneumothorax on X-ray following IPC insertion as air can enter the pleural space during the procedure. Rarely, subcutaneous emphysema can occur post procedure, though this is mostly reported in patients undergoing video-assisted thoracoscopic surgery [VATS] or medical thoracoscopy [2,5].\n\nWe report a case of extensive surgical emphysema following IPC insertion in a patient with a trapped lung who did not have a prior thoracoscopic procedure. Though an infrequent occurrence, we believe this case lends some important learning points.\n\n2 Case presentation\nA 67-year old gentleman was referred to our pleural service for management of a large left-sided malignant effusion due to poorly differentiated adenocarcinoma of the lung [with PDL1 positivity measured at 60–70%]. Despite treatment with pembrolizumab, he developed a large symptomatic pleural effusion. An initial therapeutic aspiration of 700 mL of thick haemorrhagic fluid was performed with minimal symptomatic improvement and the post aspiration chest X-ray showed no pneumothorax. Accordingly, he was offered insertion of an IPC, to which he consented. Thoracic ultrasound confirmed a large free flowing effusion with maximum fluid depth of 9.2 cm at the point of pleural entry for the IPC. The IPC was inserted without any immediate complications, and 1.9 L of haemorrhagic pleural fluid was drained using two 1-Litre vacuum drainage bottles, immediately after inserting the IPC. A post procedure chest X-ray showed some reduction in the effusion but not complete resolution. There was no pneumothorax visualized, and he was discharged home that day (Fig. 1).Fig. 1 Comparison of chest X-rays before and after IPC insertion; X-ray on left shows a large left sided pleural effusion [A] with tracheal deviation to the right [B]; X-ray on the right is after IPC insertion, showing left sided pleural catheter in situ [C] and improved aeration of left lung [D]. No pneumothorax or subcutaneous emphysema seen.\n\nFig. 1\n\nApproximately 36 hours later, he presented to the emergency department with voice change, facial and neck swelling, and breathlessness. He was found to have subcutaneous emphysema involving his neck and face; however, he was saturating in excess of 94% on room air with no evidence of hypotension. A repeat chest X-ray demonstrated a moderate left-sided pneumothorax as well as extensive subcutaneous emphysema (Fig. 2). Although no domiciliary drainage from the IPC had been performed since insertion, the admitting team was able to flush and aspirate through the IPC with no leak evident at the drain exit site or through the incision above entry to pleural space. There was no evidence of dislodgement of the cuff or IPC displacement. The IPC was, thus, connected to an underwater seal, and a negative suction of −2.5 cmH2O was applied. A persistent leak was noted, and the negative suction was increased to −10 cmH2O.Fig. 2 Chest X-Ray done on presentation to the emergency department, showing left pneumothorax [A] with extensive subcutaneous emphysema [B] in the chest wall and extending to the neck bilaterally.\n\nFig. 2\n\nUnfortunately, about 12 hours later, the subcutaneous emphysema progressed involving the eyelids and the patient was more breathless. A repeat chest X-ray demonstrated significant pneumothorax. A large bore 26 Fr intercostal drain was thus inserted on the left side.\n\n3 Investigations\nA CT scan of the chest showed a moderate left sided pneumothorax, with both the drains being well sited and no evidence of any bronchopleural fistula (Fig. 3). The left lower lobe tumor appeared unchanged and progression of pleural thickening was noted.Fig. 3 CT Thorax; Mediastinal window [top] shows left pleural thickening [A]. Lung window [bottom] shows left sided pneumothorax [B] and pleural thickening [A]. Also seen are the two intercostal drains in the pleural space [C, D] and extensive subcutaneous emphysema [E] bilaterally along with pneumomediastinum [F].\n\nFig. 3\n\n4 Differential diagnosis\nThe mechanism of development of such significant surgical emphysema in this patient was initially unclear to the admitting team. One potential reason for surgical emphysema post IPC insertion is poor placement with a fenestration sitting in the extrapleural space. However, this is unlikely in the absence of significant obesity assuming the subcutaneous tract of the IPC is not excessively long. Dislodgement may be another possibility, but this was not the case in our patient as the IPC was well sited and functional. Another important consideration is a bronchopleural fistula, which can develop if there has been lung injury during the procedure, particularly if the dilator is inserted too deeply in the context of a shallow effusion. This was felt unlikely, however, as at the time of thoracic ultrasound prior to IPC insertion, the effusion was almost 10 cm deep from the parietal pleura. Additionally, there was no air drained after the procedure and no pneumothorax was noted on the X-ray after IPC insertion. Finally, with no bronchopleural fistula seen on the CT scan, this explanation was thought to be unlikely.\n\nA more remote possibility, perhaps, could be rupture of a pleural metastatic deposit or a pleural bleb (though there was no evidence of this on a previous CT scan) that coincided with the time of IPC insertion; but the likelihood of two such events occurring so close together would seem unlikely. Lastly, the final and most probable causality is that a visceral pleural tear would have occurred at the time of vacuum-assisted drainage of pleural fluid immediately after IPC insertion, subsequently leading to the development of pneumothorax and air leak. Although this was not evident on immediate post procedure CXR, it seems most likely that this simply was not large enough to be immediately evident. The patient gave no history to suggest significant extreme changes in intrathoracic pressure (e.g. straining at stool) to precipitate the event otherwise, but there is the possibility this could have aggravated the situation.\n\n5 Treatment and follow-up\nOver the next 5 days, the patient showed good clinical improvement and there was significant reduction in the surgical emphysema. Unfortunately, following an episode of acute delirium, both drains were dislodged a week after insertion. Therefore, a second 26 Fr intercostal drain was inserted, which was, again connected to an underwater seal and negative suction of −2.5 cmH2O. The patient continued to show clinical improvement along with reduction in the air leak, though this did not completely resolve. Therefore, an ambulatory system was connected to the drain, and after ensuring that there was no clinical or radiological worsening of the pneumothorax, the patient was discharged home with the drain in situ. At subsequent follow-up visits, the air leak was found to be reducing along with radiological improvement in the pneumothorax. Eventually, the drain and bag were removed, 2 weeks post discharge, and he resumed follow-up with the respiratory physicians, with an X-ray at that point showing complete re-expansion of the lung and no residual pneumothorax.\n\n6 Discussion\nWith the expanding role of IPCs in MPE management, medical professionals working in emergency and acute medical services are likely to encounter patients with IPCs and should be aware of associated complications. Our case demonstrates an unusual albeit important complication that occurred following IPC insertion. The likely explanation for the development of extensive subcutaneous emphysema and air leak was thought to be due to a tear in the visceral pleura caused at the time of vacuum drainage of pleural fluid after IPC insertion.\n\nIt is known that under normal conditions, the pressure in the pleural space is negative, in the range of −3 to −8 cmH2O. This negative pressure allows for a balance between chest wall expansion and elastic recoil [3]. When fluid occupies the pleural space i.e. in a pleural effusion, the pressure in the pleural space becomes positive. In a normal lung, when thoracocentesis is performed, the pressure in the pleural space falls in a linear fashion as the fluid is removed, allowing complete expansion of the lung. However, in a partially trapped lung, such as in our patient, though the initial pleural pressure is positive and falls in a linear manner when draining the pleural fluid, there comes a point when there is a steep drop in the pleural pressure due to inability of the lung to expand further [4]. A vacuum device attached to a drain in the pleural space would continue to cause further reduction in pleural pressure. It is postulated that this reduction in pressure could cause tears in the lung cortex or visceral pleura (akin to having a painful foot callus that cracks), thereby resulting in an air leak. We drained a large volume at the time of IPC insertion because the prior therapeutic aspiration of 700 mLs of pleural fluid had no impact on symptoms, and hence, a larger drainage was clinically appropriate. Our patient tolerated this larger volume thoracocentesis at the time of insertion. A recently published retrospective study concluded that symptom-limited thoracocentesis of large volumes of pleural fluid using suction is generally safe, though about 4% of patients developed a pneumothorax post drainage, with MPE related to lung and breast cancer being at greater risk of having this complication [5].\n\nThis phenomenon has been reported after VATS and medical thoracoscopy [6], presumably due to the frequency of suction being applied to lung with visceral pleural thickening. Regardless of the underlying cause, air leaks can be challenging to manage. The BTS Guidelines for pneumothorax recommend use of negative suction for a persistent air leak in the context of spontaneous pneumothorax, but the value of routine use of suction is a source of debate [7]. This is applicable for post thoracic surgery patients as well, who may have developed an early postoperative air leak. Ongoing management is essentially conservative with adequate tube drainage of the pleural space to keep up with the air leak and to allow the lung time to heal, rather than any further thoracic surgical intervention [8]. In the context of presumed visceral pleural tear, suction should be avoided where possible but in our case, with such significant symptomatic subcutaneous emphysema, judicious use of this was needed.\n\nIn summary, this case highlights uncommon yet important sequelae of IPC insertion for acute, emergency and also respiratory physicians not undertaking thoracoscopy.\n\n7 Learning points\nThe important learning points from this case are as follows:1. Though rare, IPCs can be associated with the development of an air leak in the context of a trapped lung. The likely mechanism for this is a visceral pleural tear occurring as a consequence of vacuum drainage of pleural fluid.\n\n2. If a patient with an IPC presents with subcutaneous emphysema, it is important to ensure that the drain is patent and not dislodged, and to check the site for leak. A chest CT may be helpful in determining if a fenestration is present in the extrapleural space.\n\n3. Negative suction may potentially cause worsening of an air leak especially if the underlying pathophysiological mechanism is suspected to be a visceral pleural tear.\n\n\n\nCRediT author statement\nMalvika Bhatnagar: Conceptualization, Writing – Original Draft, Writing – Review and Editing.\n\nRobert Slight: Writing – Review and Editing.\n\nArun Brahmanya Prasad: Writing – Review and Editing.\n\nAndrew Ewing Stanton: Conceptualization, Writing – Review and Editing, Supervision.\n\nDeclaration of competing interest\nNone.\n==== Refs\nReferences\n1 Bibby A. Dorn P. Psallidas I. Porcel J. Janssen J. Froudarakis M. ERS/EACTS statement on the management of malignant pleural effusions Eur. Respir. J. 52 1 2018 1800349 30054348 \n2 Bhatnagar R. Maskell N. Indwelling pleural catheters Respiration 88 1 2014 74 85 24853298 \n3 Lai-Fook S. Pleural mechanics and fluid exchange Physiol. Rev. 84 2 2004 385 410 15044678 \n4 Pereyra M. Ferreiro L. Valdés L. Unexpandable lung Arch. Bronconeumol. 49 2 2013 63 69 22749682 \n5 Sagar A. Landaeta M. Adrianza A. Aldana G. Pozo L. Armas-Villalba A. Complications following symptom limited thoracentesis using suction Eur. Respir. J. 2020 1902356 32499336 \n6 Nicholson T. Probyn B. Scott S. Daneshvar C. Marchbank A. The risk of surgical emphysema post VATS pleural biopsy and IPC Thoracic surgery 2019 \n7 MacDuff A. Arnold A. Harvey J. Management of spontaneous pneumothorax: British Thoracic Society pleural disease guideline 2010 Thorax 65 2010 ii18 ii31 20696690 \n8 Marshall M.B. Deeb M.E. Bleier J.I. Kucharczuk J.C. Friedberg J.S. Kaiser L.R. Suction vs water seal after pulmonary resection: a randomized prospective study Chest 121 2002 831 835 11888968\n\n",
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"abstract": "Infections caused by Chromobacterium violaceum are extremely rare but can be relatively fatal in septicemia. We report a case of a 76 year old female who presented with pustules in the skin and later developed into septicemia. She succumbed to the illness despite escalating the antibiotic therapy to meropenem. To the best of our knowledge this is the 16th case report from India.",
"affiliations": "Department of Microbiology, Believers Church Medical College Hospital, Thiruvalla, India.;Department of Medicine, Believers Church Medical College Hospital, Thiruvalla, India.;Department of Critical Care, Believers Church Medical College Hospital, Thiruvalla, India.;Department of Critical Care, Believers Church Medical College Hospital, Thiruvalla, India.;Department of Medicine, Believers Church Medical College Hospital, Thiruvalla, India.;Department of Medicine, Believers Church Medical College Hospital, Thiruvalla, India.;Department of Microbiology, Believers Church Medical College Hospital, Thiruvalla, India.",
"authors": "Sachu|Arun|A|;Antony|Sunil|S|;Mathew|Philip|P|;Sunny|Sanjo|S|;Koshy|Jency|J|;Kumar|Vijaya|V|;Mathew|Renu|R|",
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"fulltext": "\n==== Front\nIran J Microbiol\nIran J Microbiol\nIJM\nIJM\nIranian Journal of Microbiology\n2008-3289 2008-4447 Tehran University of Medical Sciences \n\n10.18502/ijm.v12i4.3941\nijm-12-364\nCase Report\nChromobacterium violaceum causing deadly sepsis\nSachu Arun 1* Antony Sunil 2 Mathew Philip 3 Sunny Sanjo 3 Koshy Jency 2 Kumar Vijaya 2 Mathew Renu 1 1 Department of Microbiology, Believers Church Medical College Hospital, Thiruvalla, India\n2 Department of Medicine, Believers Church Medical College Hospital, Thiruvalla, India\n3 Department of Critical Care, Believers Church Medical College Hospital, Thiruvalla, India\n* Corresponding author: Arun Sachu, Department of Microbiology, Believers Church Medical College Hospital, Thiruvalla, India. Tel: +97-45051455, Email: [email protected]\n8 2020 \n12 4 364 367\n10 2019 6 2020 Copyright© 2020 Iranian Society of Microbiology & Tehran University of Medical Sciences2020This 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 work is properly cited.Infections caused by Chromobacterium violaceum are extremely rare but can be relatively fatal in septicemia. We report a case of a 76 year old female who presented with pustules in the skin and later developed into septicemia. She succumbed to the illness despite escalating the antibiotic therapy to meropenem. To the best of our knowledge this is the 16th case report from India.\n\nChromobacterium violaceumSepticemia\n==== Body\nINTRODUCTION\nChromobacterium violaceum is a Gram negative bacillus that is not a part of normal human flora. It usually inhabits soil and stagnant water in tropical and subtropical regions (1). Chromobacterium violaceum produces a non diffusible pigment called violacein, which is soluble in ethanol and insoluble in water and choloroform (2). The first case of human infection by Chromobacterium violaceum was described in 1927 in Malaysia and since then about 200 cases have been described around the world (3). In India only a few cases have been reported with various clinical presentations at different locations (4, 5). Infection caused by Chromobacterium violaceum has an extremely high fatality rate especially when associated with septicemia. The mortality rate due to this organism ranges from 57% in the United States to 80% in India (6, 7). The objective of this case report is to generate knowledge regarding this rare but fatal organism and their antibiogram for successful management in the future.\n\nCASE REPORT\nA 76 year old female who was a diagnosed case of Myelodysplastic syndrome, Autoimmune Hemolytic anaemia, Type 2 Diabetes Mellitus got admitted in our hospital. She presented with intermittent high grade fever. There was no history of altered sensorium, vomiting, chest pain, dysuria, altered bowel and bladder habits. This patient had numerous admissions in our hospital in the last 2 years due to recurrent episodes of urinary tract infection with different bacteria. She was also treated for typhoid fever 5 months back. Patient gave a history of washing her clothes in nearby lake suggesting a possible exposure to contaminated water.\n\nClinical examination.\nPatient was conscious and oriented. Vitals were stable. There were scattered and discrete papulo-pustular lesions over the body, the largest of which was on the right forearm measuring 5 × 6 cm. Other systemic examination was unremarkable. The treating team suspected a Gram positive skin and soft tissue infection and the patient was empirically started on amoxicillin-clavulanic acid and clindamycin.\n\nBlood Investigations revealed anaemia, leukocytosis and thrombocytopenia.\n\nIncision and drainage was done for the largest lesion on the right forearm and the pus collected was sent for culture. Blood was collected with complete aseptic precautions into aerobic blood culture bottles (Bact T/ ALERT/ 3D; Biomerieux, Marcy L Etoile, France).\n\nBoth Blood cultures became positive after 12 and 15 hrs of incubation respectively. Gram stain from the broth revealed Gram negative bacilli. Blood culture broth was inoculated into Blood and MacConkeys agar.\n\nThe condition of the patient deteriorated within 48 hrs and she developed hypotension. She was shifted to the intensive care unit, antibiotics escalated to meropenem and was initiated on ionotropic supports. There was a significant reduction in total leucocyte count and platelet count (Table 1). She developed acute kidney injury, her general condition continued to worsen, and succumbed to her illness the following day.\n\nTable 1. Laboratory Investigations\n\nLab parameters (Normal Range)\tDay 1\tDay 3\t\nHaemoglobin g/dl (11–15)\t8.7\t7.5\t\nTotal Leucocyte count/μL (4800–10000)\t15480\t8500\t\nPlatelet count Lakh/μL (1.5–4.5)\t86000\t42000\t\nSerum Creatinine mg/dl (0.5–1.2)\t1.79\t2.98\t\nBlood Urea mg/dl (17–49)\t71.2\tNA\t\nC-Reactive protein mg/L (0–10)\t190.9\tNA\t\nNA-Not Applicable.\n\nAfter overnight incubation blood agar showed beta-haemolytic round colonies with blackish pigmentation. MacConkey agar showed non lactose fermenting colonies with blackish pigmentation (Fig. 1). Pus culture also showed similar colonies. Routine biochemical reaction was put up and further identification was done by VITEK-2 (Biomerieux, France). Organism was catalase and oxidase positive and indole negative. Urea was not hydrolysed, citrate was not utilized. Glucose was fermented with the production of acid. It was motile but did not ferment mannitol. Triple sugar iron revealed alkali/acid reaction without production of hydrogen sulphide.\n\nFig. 1. Pigmented colonies of Chromobacterium violaceum\n\nOrganism was identified as Chromobacterium violaceum by VITEK-2 with 99% probability. It was found to be sensitive to amikacin, gentamicin, ciprofloxacin, levofloxacin and meropenem (Fig. 2.) but was resistant to ampicillin, amoxi-clav and cephalosporins. The results were interpreted according to Clinical and Laboratory Standards Institute (CLSI) guidelines for other non-Enterobacteriaceae. The isolation of the same organism from two blood cultures and pus revealed the pathogenic role of the organism.\n\nFig. 2. Antimicrobial susceptibility pattern of Chromobacterium violaceum on Muller Hinton agar\n\nDISCUSSION\nChromobacterium violaceum, a tropical pathogen, was described for the first time in 1872 by Schroeter. It is motile, Gram negative, facultative anaerobic bacillus and took its name from the purple pigment – violacein (8). The fact that there are only few reports of human infections with this organism is a surprise, given the ease with which this organism is isolated from the soil and stagnant water bodies in the tropics and subtropics (9). Mostly human infection is seen in paediatric and young adults (3). Neonatal septicemia caused by Chromobacterium violaceum was described by Tiwari et al. (10).\n\nThe most common mode of transmission is the exposure of wounds and traumatic lesions to soil and stagnant water containing the organism (11, 12). Our case presented with pustules in the skin and then developed into septicemia. So the mode of transmission is probably due to exposure of the wound to soil and stagnant water. Infection can also occur due to ingestion of contaminated water but our patient had no history of diarrhoea and hence can be ruled out (13). Other unusual routes of exposure include scuba diving or near drowning and rarely following surgical procedures (7). Our case was a 76 year old woman, which to our knowledge is the oldest case of Chromobacterium violaceum causing sepsis.\n\nC. violaceum septicemia is usually associated with chronic granulomatous disease (CGD), neutrophil dysfunction and G6PD deficiency (12). Our patient being immunosuppressive probably would have progressed to sepsis, eventually leading to her death. Diagnosis of C. violaceum requires high index of clinical suspicion and isolation of the organism from clinical specimen. A Multiplex PCR for detection of C. violaceum was described by Scholz et al. but it is not yet commercially available (14). Diagnosis is very difficult in case of non pigmented strains. Pathogenecity is not related to pigmentation (15). C. violaceum is generally considered to be of low virulence but septicemia can be deadly. The virulent strains of C. violaceum have elevated levels of superoxide dismutase and catalase which may protect the bacteria from phagocytic attack in humans, in turn leading to fatal infections (16). Data on antimicrobial susceptibility pattern of this organism is scanty because infections are quite rare. Mostly they are resistant to pencillins and cephalosporins (12). C. violaceum infections can be managed with ciprofloxacin, amikacin, gentamicin and meropenem.\n\nCONCLUSION\nChromobacterium violaceum is an uncommon microorganism that can cause fatal sepsis. There are no set guidelines for the management of this infection. Chromobacterium violaceum should be considered as a differential diagnosis especially when sepsis is preceded by a skin infection and the susceptibility pattern should be kept in mind while instituting empirical antibiotic therapy. Eventhough many of the published cases in literature are of young adults, our case shows that this organism can cause sepsis even in elderly people.\n==== Refs\nREFERENCES\n1. Ma T Shi W Cheng J Zhang JK Hu LF Ye Y \nChromobacterium violaceum in China: Three case reports and literature reviews\n. Afr J Microbiol Res \n2011 ;5 :3096 –3102\n.\n2. Ray P Sharma J Marak RS Singhi S Taneja N Garg RK \nChromobacterium violaceum septicaemia from North India\n. Indian J Med Res \n2004 ;120 :523 –526\n.15654137 \n3. Khadanga S Karuna T Dugar D Satapathy SP. \nChromobacterium violaceum- induced sepsis and multiorgan dysfunction, resembling melioidosis in an elderly diabetic patient: A case report with review of literature\n. J Lab Physicians \n2017 ;9 :325 –328\n.28966500 \n4. Saboo AR Vijaykumar R Save SU Bavdekar SB. \nA rare nonfatal presentation of disseminated Chromobacterium violaceum sepsis\n. J Microbiol Immunol Infect \n2015 ;48 :574 –577\n.23380618 \n5. Subithal B Jeyamurugan T Gomatheswari SN Hariprasad G. \nRare cause of sepsis – Chromobacterium violaceum - a case report\n. Int J Curr Microbiol Appl Sci \n2017 ; 6 : 1772 –1775\n.\n6. Lee J Kim JS Nahm CH Choi JW Kim J Pai SH \nTwo cases of Chromobacterium violaceum infection after injury in a subtropical region\n. J Clin Microbiol \n1999 ;37 :2068 –2070\n.10325383 \n7. Karthik R Pancharatnam P Balaji V. \nFatal Chromobacterium violaceum septicemia in a south Indian adult\n. J Infect Dev Ctries \n2012 ;6 :751 –755\n.23103899 \n8. Schattenberg HJ Harris WH. \nChromobacterium violaceum, Var. Manilae as a pathogenic microörganism\n. J Bacteriol \n1942 ; 44 : 509 –521\n.16560589 \n9. Jędruszczak A Węgrzyn-Bąk M Budzyńska-Nosal R Maciejewski M Marczewski K. \nSepsis caused by Chromobacterium violaceum – probably the first case in Europe, or Macbeth read anew\n. Ann Agric Environ Med \n2019 ;26 :508 –510\n.31559812 \n10. Tiwari S Pattanaik S Beriha SS. \nNonpigmented strain of Chromobacterium violaceum causing neonatal septicemia: A rare case report\n. Indian J Pathol Microbiol \n2017 ;60 :427 –429\n.28937390 \n11. Batista JH da Silva Neto JF. \nChromobacterium violaceum pathogenicity: updates and insights from genome sequencing of novel Chromobacterium species”\n. Front Microbiol \n2017 ; 8 :2213 .29176969 \n12. Yang CH Li YH. \nChromobacterium violaceum infection: a clinical review of an important but neglected infection\n. J Chin Med Assoc \n2011 ;74 :435 –441\n.22036134 \n13. Manjunath M. \nFatal septicaemia due to Chromobacterium violaceum\n. West Indian Med J \n2007 ;56 :380 –381\n.18198747 \n14. Scholz HC Witte A Tomaso H Al Dahouk S Neubauer H. \nDetection of Chromobacterium violaceum by multiplex PCR targeting the prgI, spaO, invG and sipB genes\n. Syst Appl Microbiol \n2006 ;29 :45 –48\n.16423655 \n15. Díaz Pérez JA García J Rodriguez Villamizar LA. \nSepsis by Chromobacterium violaceum: first case report from Colombia\n. Braz J Infect Dis \n2007 ;11 :441 –442\n.17874003 \n16. Vishnu Kaniyarakkal V Orvankundil S Lalitha SK Thazhethekandi T Thottathil J. \nChromobacterium violaceum septicaemia and urinary tract infection: case reports from a tertiary care hospital in South India\n. Case Rep Infect Dis \n2016 ;2016 : 6795743 .27747113\n\n",
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"abstract": "Intravenous immunoglobulin (IVIg) therapy has multiple mechanisms of immunomodulatory action. We wished therefore to assess its efficacy in a spectrum of patients with refractory uveitis. Retrospective review of clinical charts was conducted to document response to IVIg treatment in consecutive patients with treatment-refractory uveitis. Main outcome measures were control of intraocular inflammation, visual acuity, progression of the disease, and complications. Four (two male) patients, with a mean age at the beginning of the treatment of 47 years (range: 39-64), were included in the study. Indication for treatment was patients with active non-infectious uveitis refractory to steroids and immunomodulatory therapy. All patients received a course of 0.5 g/kg per day of IVIg for three consecutive days, repeating this course at a mean of 11 week (range: 2-39 weeks) intervals when indicated clinically. The median duration of the IVIg therapy was 7 months (range: 3-14 months). In three patients treatment resulted in stabilisation and prevention of progression of the disease, and additionally in two patients it facilitated a decrease in prednisolone dose. Treatment failed to induce long-term remission in one patient with recurrence of macular oedema. IVIg was well tolerated with neither immediate nor longer-term adverse events observed. In three out of four cases IVIg was an effective adjunctive therapy and well tolerated for the management of treatment-refractory uveitis.",
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{
"abstract": "A case of a 32-year-old woman with type 1 diabetes diagnosed 1.5 year before presention. The patient was referred to the diabetology department due to decompensation of diabetes and excessive hypodermic atrophy of both thighs. Early symptoms of lipoatrophy appeared after 1.5-2 months of insulin glargine use, in spite of frequently changed hypodermic needles and injection sites on both thighs. Simultaneously, deterioration of diabetes compensation was observed (hyperglycaemia between meals and in the morning), which was corrected by the patient with extra injections of a short acting analogue. Additional examinations confirmed type 1 diabetes (C-peptide <0.01 ng/ml) with concomitant hypothyroidism in the course oh Hashimoto disease. After change of insulin (Insulatard twice daily, Novo Rapid with meals) and injection site (administration to hypodermic tissues of arms and abdomen was started), diabetes compensation was achieved. At follow-up visit after 12 months, diabetes was still under control - HbA1c 6.8%. Moreover, progress of lipoatrophy is not observed.",
"affiliations": "Oddział Diabetologiczny Miedziowego Centrum Zdrowia w Lubinie. [email protected]",
"authors": "Dziura|Maria|M|;Wasikowa|Renata|R|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D061386:Insulin, Regular, Human; D000068880:Isophane Insulin, Human; D000069036:Insulin Glargine; D007336:Insulin, Isophane; D061267:Insulin Aspart",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2083-8441",
"issue": "14(1)",
"journal": "Pediatric endocrinology, diabetes, and metabolism",
"keywords": null,
"medline_ta": "Pediatr Endocrinol Diabetes Metab",
"mesh_terms": "D000328:Adult; D003922:Diabetes Mellitus, Type 1; D050031:Hashimoto Disease; D006801:Humans; D007004:Hypoglycemic Agents; D007037:Hypothyroidism; D007328:Insulin; D061267:Insulin Aspart; D000069036:Insulin Glargine; D007336:Insulin, Isophane; D049528:Insulin, Long-Acting; D061386:Insulin, Regular, Human; D000068880:Isophane Insulin, Human; D008060:Lipodystrophy; D008297:Male",
"nlm_unique_id": "101518750",
"other_id": null,
"pages": "61-3",
"pmc": null,
"pmid": "18577350",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Lipoatrophy after use of long acting insulin glargine analogue in a 32-year-old patient with type 1 diabetes.",
"title_normalized": "lipoatrophy after use of long acting insulin glargine analogue in a 32 year old patient with type 1 diabetes"
}
|
[
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"companynumb": "PL-SA-2020SA020070",
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{
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"activesubstancename": "INSULIN GLARGINE"
},
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"drugindication": "TYPE 1 DIABETES MELLITUS",
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"medicinalproduct": "INSULIN GLARGINE"
}
],
"patientagegroup": "5",
"patientonsetage": "32",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Hyperglycaemia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Extra dose administered",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Insulin C-peptide increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diabetic metabolic decompensation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypoglycaemia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood iron decreased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood thyroid stimulating hormone increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lipoatrophy",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DZIURA M., WASIKOWA R.. LIPOATROPHY AFTER USE OF LONG ACTING INSULIN GLARGINE ANALOGUE IN A 32-YEAR-OLD PATIENT WITH TYPE 1 DIABETES. PEDIATRIC ENDOCRINOLOGY, DIABETES AND METABOLISM. 2008?14:1:61-63",
"literaturereference_normalized": "lipoatrophy after use of long acting insulin glargine analogue in a 32 year old patient with type 1 diabetes",
"qualification": "3",
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},
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"receiptdate": "20200302",
"receivedate": "20200130",
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},
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"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "Neoadjuvant chemotherapy (NAC) using the combination of anthracycline and taxanes is the standard regimen for patients with primary breast cancer. Among the taxanes, conventional paclitaxel (PTX) and docetaxel have usually been adopted in the neoadjuvant or adjuvant setting. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a solvent-free formulation that can be delivered to cancer cells at higher doses than conventional PTX. This study is a retrospective observational study in a single institution. We evaluated the efficacy and safety of nab-PTX followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) in the neoadjuvant setting. In this study, 50 patients with primary breast cancer received nab-PTX (q3w, 260 mg/m2 ± trastuzumab 6 mg/kg) followed by FEC (q3w, 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) prior to surgery. The efficacy was evaluated using the clinical response rate (CRR), pathological complete response (pCR) rate, and Ki67 labeling index. Safety was evaluated using the frequency of treatment-related adverse events and relative dose intensity (RDI). All patients received at least one course of chemotherapy. The CRR and pCR rate were 88.0% and 40.0%, respectively. The mean Ki67 labeling index was significantly decreased from 47.7% to 24.6% after NAC. The safety profiles were comparable with previously reported regimens, and high RDIs were obtained (97.2% for nab-PTX and 95.5% for FEC). This study illustrated the efficacy and tolerability of a neoadjuvant regimen of nab-PTX followed by FEC.",
"affiliations": "Department of Breast Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan.;Department of Breast Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan.;Department of Breast Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan.;Department of Breast Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan.;Department of Breast Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan.",
"authors": "Shizuku|Masato|M|;Shibata|Masahiro|M|;Shimizu|Yoshimi|Y|;Takeuchi|Dai|D|;Mizuno|Yutaka|Y|",
"chemical_list": "D000068196:Albumin-Bound Paclitaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D000068878:Trastuzumab; D017239:Paclitaxel; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.18999/nagjms.82.3.457",
"fulltext": "\n==== Front\nNagoya J Med Sci\nNagoya J Med Sci\nNagoya Journal of Medical Science\n0027-7622 2186-3326 Nagoya University \n\n10.18999/nagjms.82.3.457\nOriginal Paper\nClinical outcomes of neoadjuvant chemotherapy for patients with breast cancer: Tri-weekly nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide: a retrospective observational study\nShizuku Masato 12 Shibata Masahiro 13 Shimizu Yoshimi 1 Takeuchi Dai 13 Mizuno Yutaka 1 \n1 Department of Breast Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan\n\n2 Department of Transplantation Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan\n\n3 Department of Breast and Endocrine Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan\nCorresponding Author: Masahiro Shibata, MD, PhD\n\nDepartment of Breast and Endocrine Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan\n\nTel: +81-52-744-2251, Fax: +81-52-744-2252, E-mail: [email protected]\n\n\n8 2020 \n82 3 457 467\n10 1 2020 3 2 2020 This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).ABSTRACT\nNeoadjuvant chemotherapy (NAC) using the combination of anthracycline and taxanes is the standard regimen for patients with primary breast cancer. Among the taxanes, conventional paclitaxel (PTX) and docetaxel have usually been adopted in the neoadjuvant or adjuvant setting. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a solvent-free formulation that can be delivered to cancer cells at higher doses than conventional PTX. This study is a retrospective observational study in a single institution. We evaluated the efficacy and safety of nab-PTX followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) in the neoadjuvant setting. In this study, 50 patients with primary breast cancer received nab-PTX (q3w, 260 mg/m2 ± trastuzumab 6 mg/kg) followed by FEC (q3w, 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) prior to surgery. The efficacy was evaluated using the clinical response rate (CRR), pathological complete response (pCR) rate, and Ki67 labeling index. Safety was evaluated using the frequency of treatment-related adverse events and relative dose intensity (RDI). All patients received at least one course of chemotherapy. The CRR and pCR rate were 88.0% and 40.0%, respectively. The mean Ki67 labeling index was significantly decreased from 47.7% to 24.6% after NAC. The safety profiles were comparable with previously reported regimens, and high RDIs were obtained (97.2% for nab-PTX and 95.5% for FEC). This study illustrated the efficacy and tolerability of a neoadjuvant regimen of nab-PTX followed by FEC.\n\nKey Words\nbreast cancernab-PTXFECneoadjuvant chemotherapy\n==== Body\nINTRODUCTION\nNeoadjuvant chemotherapy (NAC) including anthracycline and taxanes has been widely used for patients with primary breast cancer, especially those who have locally advanced disease. It has been reported that the response to NAC can predict patient prognosis; namely, patients who achieve pathological complete responses (pCRs) have favorable prognoses.1,2 Although several neoadjuvant and adjuvant chemotherapy regimens, such as anthracyclines, taxanes, capecitabine, and gemcitabine, have been evaluated to date,3,4 which regimen is the most effective and safe remains controversial.\n\nNanoparticle albumin-bound paclitaxel (nab-PTX) is a unique non-solvent-containing protein formulation. It can obviate the need for prophylactic anti-histamine and steroid treatment because of its much lower risk of hypersensitivity compared with conventional paclitaxel (PTX), although it is prone to cause peripheral neuropathy.5 Nab-PTX allows the accumulation of a higher dose of PTX into cancer cells than conventional PTX, which possibly induces stronger cytotoxic effects.6,7 In a phase 3 trial of patients with metastatic breast cancer, nab-PTX exhibited superior antitumor activity and improved progression-free survival compared with conventional PTX.8 These results suggest the superiority of nab-PTX over conventional PTX for neoadjuvant chemotherapy. In the neoadjuvant setting, previous studies reported that pCR was achieved in 5.7%–38% of patients who received nab-PTX–containing regimens.9-11 In patients with human epidermal growth factor receptor 2 (HER2) positivity, the pCR rate was increased up to 49% following the treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) followed by nab-PTX plus trastuzumab.12 Despite these promising effects of nab-PTX–containing NAC regimens, conventional PTX or docetaxel is more likely to be adopted in clinics. Indeed, the guideline of the National Comprehensive Cancer Network does not strongly recommend nab-PTX in NAC, and it is considered an option.13\n\nIn this study, we aimed to clarify the efficacy and tolerability of a NAC regimen consisting of nab-PTX and FEC in patients with primary breast cancer.\n\nPATIENTS AND METHODS\nPatient population\nWe performed a retrospective observational study in a single institution. Patients who visited Yokkaichi Municipal Hospital from August 2013 to December 2017 with previously untreated breast cancer were enrolled. All patients were pathologically confirmed to have invasive carcinoma via core needle biopsy or vacuum-assisted biopsy, and they had measurable disease. The patients’ Eastern Cooperative Oncology Group performance status scores were 0 or 1. Estrogen receptor (ER) positivity, progesterone receptor positivity, the HER2 status, and the Ki67 labeling index were evaluated using biopsied tissues. The breast tumor size of each patient was measured via contrast-enhanced magnetic resonance imaging (MRI) before and after NAC. All patients were proven to not have distant metastatic sites using computed tomography prior to chemotherapy. The postoperative pathological classification was evaluated by one pathologist according to the Union for International Cancer Control staging system for breast cancer (7th edition).\n\nTreatment\nFigure 1 presents the treatment schedule. Four cycles of nab-PTX (q3w, 260 mg/m2) followed by four cycles of FEC (q3w, 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) were administered prior to surgery. For patients with HER2 positivity, trastuzumab (8 mg/kg in the first cycle and 6 mg/kg in the remaining cycles) was added to nab-PTX. Pre-medication, such as antiemetic drugs and granulocyte colony-stimulation factor, was administered per each physician’s discretion. The dose of each chemotherapy agent was reduced in the event of febrile neutropenia, grade 3–4 thrombocytopenia, or grade 3–4 non-hematological toxicities (excluding nausea, vomiting, and fatigue). After the completion of NAC, all patients underwent MRI to evaluate the change of tumor size. The operative procedure (i.e., total or partial mastectomy) was decided in consideration of the result of MRI and the patient’s preference. Axillary lymph node dissection was performed when the nodes were pathologically found to be metastatic before NAC; otherwise, sentinel node biopsy was conducted. Postoperative radiation therapy was performed for patients who opted for breast-conserving surgery. Post-surgical endocrine therapy was administered to patients with ER-positive lesions for a minimum of 5 years. For patients with HER2-positive cancer, trastuzumab was administered for 1 year after surgery.\n\nFig. 1 A flowchart shows the treatment strategy.\n\nFour cycles of nanoparticle albumin-bound paclitaxel (nab-PTX) followed by four cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) were administrated prior to surgery. Contra-enhanced magnetic resonance imaging (MRI) was performed before and after chemotherapy.\n\nClinicopathological response and toxicity assessment\nThe clinical response rate (CRR) was assessed via MRI to evaluate the change of the primary tumor size before breast surgery based on Response Evaluation Criteria In Solid Tumors version 1.1.14 The pathological response to chemotherapy was assessed by one pathologist as follows: pCR was defined as necrosis and/or the replacement of cancer cells by granulation and/or fibrosis at both primary and lymph node sites. The presence of residual duct components was defined as quasi-pCR. The Ki67 labeling index was evaluated using biopsied tissues resected before and after NAC. In patients with pCR, the Ki67 labeling index was calculated as 0%. Adverse events for laboratory and non-laboratory toxicities were summarized for each chemotherapeutic regimen using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0.15 If adverse events did not improve during the drug holiday, chemotherapy was discontinued.\n\nThe relative dose intensity (RDI) represents the ratio of the amount of actually administered dose (actual dose intensity) to the planned dose (planned dose intensity) for a scheduled period. Indeed, the RDI (%) was defined as follows: (actual dose intensity/planned dose intensity) × 100.16\n\nStatistical methods\nAll statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). This modified version of the R commander comprises additional statistical functions frequently used in biostatistics.17 To compare means between two groups, the Mann-Whitney U-test was employed according to the data distribution. P < 0.05 was considered statistically significant.\n\nEthical Consideration\nThis study was conducted in accordance with the Declaration of Helsinki and approved by Yokkaichi Municipal Hospital’s institutional review board (No.2013-34). Prior to NAC, all patients provided written informed consent for the administration of nab-PTX and FEC for individual treatment and the use of their clinical data for retrospective analysis in the future.\n\nRESULTS\nPatient characteristics\nFifty patients were evaluated in this study. Their baseline characteristics are summarized in Table 1. The median age was 53.3 years (range, 31–72 years). The mean tumor size was 2.9 ± 1.2 cm (T1, 13 patients; T2, 32 patients; and T3, five patients), and 22 patients (44.0%) were clinical nodal stage N1 or N2. The Union for International Cancer Control stage distribution was as follows: stage I, 11 patients; stage IIA, 17 patients; stage IIB, 19 patients; and stage IIIA, three patients. The ER, progesterone receptor, and HER2 statuses at the primary tumor sites were as follows: ER-positive, n = 13; ER-negative, n = 37; progesterone receptor-positive, n = 10; progesterone receptor-negative, n = 40; HER2-positive, n = 19; and HER2-negative, n = 31. When the ER and HER2 statuses were combined, two patients were ER+/HER2−, 11 patients were ER+/HER2+, nine patients were ER−/HER2+, and 28 patients were ER−/HER2−. Regarding surgery, 30 and 20 patients underwent total and partial mastectomy, respectively. Twenty patients underwent axially lymph node dissection.\n\nTable 1 Patient characteristics\n\n\tValue\t\nAge (median, range), years\t53.3 (31–72)\t\nPerformance status\t\t\n0\t50 (100 %)\t\n1\t0 (0 %)\t\n\t\t\nClinical tumor stage\t\t\nT1\t13 (26.0 %)\t\nT2\t32 (64.0 %)\t\nT3\t5 (10.0 %)\t\n\t\t\nClinical nodal stage\t\t\nN0\t28 (56.0 %)\t\nN1\t21 (42.0 %)\t\nN2\t1 (2.0 %)\t\n\t\t\nClinical stage\t\t\nI\t11 (22.0 %)\t\nIIA\t17 (34.0 %)\t\nIIB\t19 (38.0 %)\t\nIIIA\t3 (6.0 %)\t\n\t\t\nER status\t\t\nPositive\t13 (26.0 %)\t\nNegative\t37 (74.0 %)\t\n\t\t\nPgR status\t\t\nPositive\t10 (20.0 %)\t\nNegative\t40 (80.0 %)\t\n\t\t\nHER2 status\t\t\nPositive\t19 (38.0 %)\t\nNegative\t31 (62.0 %)\t\n\t\t\nSubtype\t\t\nER+/HER2−\t2 (4.0 %)\t\nER+/HER2+\t11 (22.0 %)\t\nER−/HER2+\t9 (18.0 %)\t\nER−/HER2−\t28 (56.0 %)\t\n\t\t\nSurgery\t\t\nTotal mastectomy\t30 (60.0 %)\t\nPartial mastectomy\t20 (40.0 %)\t\nAxially lymph node dissection\t20 (40.0 %)\t\nER: estrogen receptor, HER2: human epidermal growth factor receptor 2, PgR: progesterone receptor.\n\nClinical and pathological assessments\nThe clinical and pathological responses after NAC are summarized in Table 2. The CRR, which includes complete and partial responses, was 88.0%. Specifically, 26 patients (52.0%) achieved complete responses, and 18 patients (36.0%) achieved partial responses. Conversely, three patients (6.0%) had stable disease, and one patient (2.0%) had progressive disease. The therapeutic response could not be evaluated in two patients (4.0%) because they underwent surgery at another hospital.\n\nTable 2 Clinical and pathological responses\n\nVariable\tn (%)\t\nClinical response\t\t\nCR\t26 /50 (52.0 %)\t\nPR\t18 /50 (36.0 %)\t\nSD\t3 /50 (6.0 %)\t\nPD\t1 /50 (2.0 %)\t\nUnknown\t2 /50 (4.0 %)\t\n\t\t\nPathological response\t\t\nOverall pCR\t20 /50 (40.0 %)\t\nSubtype, pCR\t\t\nER+/HER2−\t0 /2 (0.0 %)\t\nER+/HER2+\t4 /11 (36.4 %)\t\nER−/HER2+\t3 /9 (33.3 %)\t\nER−/HER2−\t13 /28 (46.4 %)\t\n\t\t\nOverall quasi-pCR\t24 /50 (48.0 %)\t\nSubtype, quasi-pCR\t\t\nER+/HER2−\t1 /2 (50.0 %)\t\nER+/HER2+\t5 /11 (45.5 %)\t\nER−/HER2+\t4 /9 (44.4 %)\t\nER−/HER2−\t14 /28 (50.0 %)\t\nCR: complete response, ER: estrogen receptor, HER2: human epidermal growth factor receptor 2, pCR: pathological complete response, PD: progressive disease, PgR: progesterone receptor, PR: partial response, SD: stable disease.\n\nRegarding the pathological response after NAC, 20 patients (40.0%) achieved pCR as follows: ER+/HER2−, n = 0; ER+/HER2+, n = 4 (36.4%); ER−/HER2+, n = 3 (33.3%); and ER−/HER2−, n = 13 (48.0%). In total, 24 patients (48.0%) achieved quasi-pCR as follows: ER+/HER2−, n = 1 (50.0%); ER+/HER2+, n = 5 (45.5%); ER−/HER2+, n = 4 (44.4%); and ER−/HER2−, n = 14 (50.0%) (Table 2).\n\nWhen the mean changes of the Ki67 labeling index in evaluable patients were compared between pre-NAC and post-surgery, the value was significantly decreased from 47.7 to 24.6% after NAC (P < 0.001) (Fig. 2).\n\nFig. 2 Box plots showing change of the Ki67 labeling index between before and after neoadjuvant chemotherapy (NAC).\n\nThe mean Ki67 labeling index was significantly decreased from 47.7% to 24.6%.\n\nToxicities and RDI\nThe incidence of treatment-related adverse events for each chemotherapeutic regimen is listed in Table 3. Comparing the adverse events between these two chemotherapies, arthralgia, peripheral neuropathy, and rash were likely to occur during nab-PTX, whereas stomatitis, fatigue, and nausea were likely to occur during FEC. Grade 3 adverse events during nab-PTX included neutropenia in two patients (4.0%), liver dysfunction in one patient (2.0%), and rash in three patients (6.0%). Grade 3 adverse events during FEC included neutropenia in three patients (6.0%), anemia in two patients (4.0%), and stomatitis, fatigue, and nausea in one patient each (2.0%). No patients experienced grade 4 adverse events during either regimen. The mean RDI of nab-PTX was 97.2% (range, 80.0−100%), and that of FEC was 95.5% (range, 80.0−100%) (Fig. 3).\n\nTable 3 Adverse events of each chemotherapeutic regimen\n\nnab-PTX followed by FEC (n = 50)\t\nAdverse events\tnab-PTX\tFEC\t\n\tAll Grade\n\nn (%)\tGrade 3\n\nn (%)\tAll Grade\n\nn (%)\tGrade 3\n\nn (%)\t\nNeutropenia\t3 (6.0)\t2 (4.0)\t6 (12.0)\t3 (6.0)\t\nAnemia\t0\t0\t2 (4.0)\t2 (4.0)\t\nHepatopathy\t5 (10.0)\t1 (2.0)\t0\t0\t\nStomatitis\t2 (4.0)\t0\t12 (24.0)\t1 (2.0)\t\nFatigue\t4 (8.0)\t0\t21 (42.0)\t1 (2.0)\t\nConstipation\t3 (6.0)\t0\t8 (16.0)\t0\t\nNausea\t1 (2.0)\t0\t13 (26.0)\t1 (2.0)\t\nArthralgia\t26 (52.0)\t0\t1 (2.0)\t0\t\nPeripheral neuropathy\t48 (96.0)\t0\t24 (48.0)\t0\t\nRash\t11 (22.0)\t3 (6.0)\t2 (4.0)\t0\t\nAnaphylactic shock\t0\t0\t0\t0\t\nKeratitis\t0\t0\t1 (2.0)\t0\t\nFever\t4 (8.0)\t0\t1 (2.0)\t0\t\nHand foot syndrome\t1 (2.0)\t0\t2 (4.0)\t0\t\nDiarrhea\t0\t0\t3 (6.0)\t0\t\nEdema\t1 (2.0)\t0\t2 (4.0)\t0\t\nBlurred vision\t1 (2.0)\t0\t1 (2.0)\t0\t\nMyalgia\t1 (2.0)\t0\t0\t0\t\nFEC: 5-fluorouracil, epirubicin, and cyclophosphamide, nab-PTX: nanoparticle albumin-bound paclitaxel.\n\nFig. 3 Histogram of the relative dose intensity (RDI) for each chemotherapeutic regimen.\n\nThe mean RDI for nanoparticle albumin-bound paclitaxel (nab-PTX) was 97.2%, whereas that for 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) was 95.5%.\n\nDISCUSSION\nThis study demonstrated the clinical outcomes of nab-PTX followed by FEC in the neoadjuvant setting for patients with breast cancer. This regimen provided comparable clinical and pathological effects as the conventional PTX-containing regimens. In addition, this regimen was associated with a significant decrease in the Ki67 labeling index, acceptable safety, and high RDIs.\n\nTaxanes have been widely used for decades in the treatment of breast, lung, and advanced ovarian cancers.18,19 In breast cancer, taxanes have been recognized as key drugs for neoadjuvant and adjuvant chemotherapy, and the pCR rates of PTX- and docetaxel-containing regimens are 30%–40% and 20%–30%, respectively.11,20-22 Recently, nab-PTX has been developed and administered to patients with breast cancer. Because nab-PTX facilitates the accumulation of a higher PTX dose into cancer cells, it has been expected to exert more feasible effects, and several studies have demonstrated its superiority over conventional PTX for patients with breast cancer.8,11 Moreover, some studies reported nab-PTX–including regimens in NAC, and the pCR rates were 22.2 and 30.3% when FEC and EC were combined with nab-PTX, respectively.23,24 In another study, the pCR rate of nab-PTX and cyclophosphamide followed by FEC was 37.3%.25 In this study, the combination of nab-PTX followed by FEC offered CRR and pCR rate of 88.0% and 40.0%, respectively, which are considered equal or superior to the outcomes of conventional taxanes or nab-PTX combined with anthracycline.\n\nInterestingly, this study also found that this regimen significantly decreased the Ki67 labeling index. Ki67, a nuclear protein associated with cellular proliferation, is a well-established marker for predicting the outcomes of patients with breast cancer receiving NAC.26 A recent retrospective study reported that patients who developed metastases exhibited higher Ki67 labeling indices after NAC than those who did not develop metastases.27 Our results suggest that nab-PTX followed by FEC can attenuate cellular proliferation, which possibly leads to better prognoses.\n\nPrevious studies reported that nab-PTX is more likely to cause peripheral neuropathy instead of less allergy-related events compared with conventional PTX.24,28 Indeed, peripheral neuropathy during nab-PTX was observed in almost all patients in this study. However, no patients experienced grade 3/4 peripheral neuropathy. As previously reported, despite the high frequency of peripheral neuropathy, nab-PTX hardly causes severe neuropathy.8 Conversely, FEC frequently cause adverse events, such as fatigue, nausea, stomatitis, and neutropenia.29,30 Notably, extremely high RDIs were recorded for both regimens (97.2% for nab-PTX and 95.5% for FEC). Although RDIs exceeding 85% are considered important for maintaining therapeutic effects during breast cancer chemotherapy,31 the FEC regimen tends to lead to low RDIs because of the high frequency of the subjective adverse events (e.g., fatigue and nausea).32 When patients experience these subjective symptoms, they are likely to feel anxiety and refuse further chemotherapy. Administration of taxanes prior to FEC is believed to contribute to maintaining higher RDIs.\n\nThis study is a retrospective observational study conducted in a single center without a pre-planned design of patient management and data analysis. The limitations include the small sample size and lack of a randomized controlled design. In addition, long-term outcomes were not evaluated. Because of an observational study, patient selection bias possibly led to increased RDIs without any dropout cases. These points should be reminded to interpret the results.\n\nIn conclusion, the neoadjuvant regimen of nab-PTX followed by FEC provides feasible clinical benefits, acceptable safety, and good tolerability. On the basis of this study, further clinical trials comparing the efficacy and safety of nab-PTX and conventional PTX followed by FEC regimen are warranted.\n\nACKNOWLEDGEMENT\nWe thank all the patients who participated in our study, as well as their families. We thank Joe Barber Jr., PhD, from Liwen Bianji, Edanz Editing China, for editing the English text of a draft of this manuscript.\n\nDISCLOSURE\nAll authors declare that we have no conflicts of interest.\n\nAbbreviations\nCRRclinical response rate\n\nERestrogen receptor\n\nFEC5-fluorouracil, epirubicin, and cyclophosphamide\n\nHER2human epidermal growth factor receptor 2\n\nMRImagnetic resonance imaging\n\nnab-PTXnanoparticle albumin-bound paclitaxel\n\nNACneoadjuvant chemotherapy\n\npCRpathological complete response\n\nPTXpaclitaxel\n\nRDIrelative dose intensity\n==== Refs\nREFERENCES\n1. Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol. 2008;26(5):814–819. doi: 10.1200/jco.2007.15.3510 .\n2. Kitajima K, Miyoshi Y, Yamano T, Odawara S, Higuchi T, Yamakado K. 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Phase I and pharmacokinetic study of ABI-007, a cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002;8(5):1038–1044.\n6. Gardner ER, Dahut WL, Scripture CD, et al. Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. Clin Cancer Res. 2008;14(13):4200–4205. doi: 10.1158/1078-0432.ccr-07-4592 .\n7. Madappa N Kundranda JN. Albumin-bound paclitaxel in solid tumors: clinical development and future directions. Drug Des Devel Ther. 2015;9:3767–3777.\n8. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794–7803. doi: 10.1200/jco.2005.04.937 .\n9. Robidoux A, Buzdar AU, Quinaux E, et al. A phase II neoadjuvant trial of sequential nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide in locally advanced breast cancer. Clin Breast Cancer. 2010;10(1):81–86. doi: 10.3816/CBC.2010.n.011 .\n10. Shimada H, Ueda S, Saeki T, et al. Neoadjuvant triweekly nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide for Stage II/III HER2-negative breast cancer: evaluation of efficacy and safety. Jpn J Clin Oncol. 2015;45(7):642–649. doi: 10.1093/jjco/hyv055 .\n11. Untch M, Jackisch C, Schneeweiss A. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016;17(7):E270-E270.\n12. Tanaka S, Iwamoto M, Kimura K, et al. Phase II study of neoadjuvant anthracycline-based regimens combined with nanoparticle albumin-bound paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive operable breast cancer. Clin Breast Cancer. 2015;15(3):191–196. doi: 10.1016/j.clbc.2014.12.003 .\n13. Network NCC. Clinical Practice Guidelines in Oncology. Breast Cancer Version 3. 2019. https://www.nccn.org/professionals/physician_gls/default.aspx. Published September 6, 2019. Accessed February 4, 2020.\n14. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026 .\n15. Cancer Therapy Evaluation Program (CTEP). Common terminology criteria for adverse events (CTCAE) v4.0. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed February 4, 2020.\n16. Morita S, Kikumori T, Tsunoda N, et al. Feasibility of dose-dense epirubicin and cyclophosphamide with subcutaneous pegfilgrastim 3.6 mg support: a single-center prospective study in Japan. Int J Clin Oncol. 2018;23(1):195–200. doi: 10.1007/s10147-017-1177-z .\n17. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–458. doi: 10.1038/bmt.2012.244 .\n18. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med. 1995;332(15):1004–1014. doi: 10.1056/nejm199504133321507 .\n19. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents .6. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus-Brevifolia. J Am Chem Soc. 1971;93(9):2325–2327. doi: 10.1021/ja00738a045 .\n20. Loibl S, de la Pena L, Nekljudova V, et al. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+primary breast cancer: a randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). 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Breast Cancer. 2017;24(4):615–623. doi: 10.1007/s12282-016-0748-6 .\n24. Kojima Y, Kawamoto H, Nishikawa T, et al. Feasibility study of weekly nanoparticle albumin-bound paclitaxel (150 mg/m(2)) followed by fluorouracil, epirubicin, and cyclophosphamide therapy as neoadjuvant chemotherapy for HER2-negative breast cancer. Clin Breast Cancer. 2018;18(5):374–379. doi: 10.1016/j.clbc.2018.01.002 .\n25. Shigematsu H, Kadoya T, Masumoto N, et al. The efficacy and safety of preoperative chemotherapy with triweekly abraxane and cyclophosphamide followed by 5-fluorouracil, epirubicin, and cyclophosphamide therapy for resectable breast cancer: a multicenter clinical trial. Clin Breast Cancer. 2015;15(2):110–116. doi: 10.1016/j.clbc.2014.09.010 .\n26. Cheang MCU, Chia SK, Voduc D, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736–750. doi: 10.1093/jnci/djp082 .\n27. Tokuda E, Horimoto Y, Arakawa A, et al. Differences in Ki67 expressions between pre- and post-neoadjuvant chemotherapy specimens might predict early recurrence of breast cancer. Hum Pathol. 2017;63:40–45. doi: 10.1016/j.humpath.2017.02.005 .\n28. Untch M, Jackisch C, Schneeweiss A, et al. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016;17(3):345–356. doi: 10.1016/s1470-2045(15)00542-2 .\n29. Earl HM, Hiller L, Dunn JA, et al. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16(6):656–666. doi: 10.1016/s1470-2045(15)70137-3 .\n30. Foldi J, Mougalian S, Silber A, et al. Single-arm, neoadjuvant, phase II trial of pertuzumab and trastuzumab administered concomitantly with weekly paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide (FEC) for stage I-III HER2-positive breast cancer. Breast Cancer Res Treat. 2018;169(2):333–340. doi: 10.1007/s10549-017-4653-2 .\n31. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332(14):901–906. doi: 10.1056/nejm199504063321401 \n32. Raza S, Welch S, Younus J. Relative dose intensity delivered to patients with early breast cancer: Canadian experience. Curr Oncol. 2009;16(6):393–397. doi. 10.3747/co.v16i6.311 .\n\n",
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"issue": "82(3)",
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"keywords": "FEC; breast cancer; nab-PTX; neoadjuvant chemotherapy",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000068196:Albumin-Bound Paclitaxel; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D010865:Pilot Projects; D012189:Retrospective Studies; D000068878:Trastuzumab",
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"title": "Clinical outcomes of neoadjuvant chemotherapy for patients with breast cancer: Tri-weekly nanoparticle albumin-bound paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide: a retrospective observational study.",
"title_normalized": "clinical outcomes of neoadjuvant chemotherapy for patients with breast cancer tri weekly nanoparticle albumin bound paclitaxel followed by 5 fluorouracil epirubicin and cyclophosphamide a retrospective observational study"
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"literaturereference": "SHIZUKU M, SHIBATA M, SHIMIZU Y, TAKEUCHI D, MIZUNO Y. CLINICAL OUTCOMES OF NEOADJUVANT CHEMOTHERAPY FOR PATIENTS WITH BREAST CANCER: TRI-WEEKLY NANOPARTICLE ALBUMIN-BOUND PACLITAXEL FOLLOWED BY 5-FLUOROURACIL, EPIRUBICIN, AND CYCLOPHOSPHAMIDE: A RETROSPECTIVE OBSERVATIONAL STUDY. NAGOYA J MED SCI. 2020 AUG?82(3):457-467.",
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"abstract": "Pulmonary infarction is an infrequent complication of pulmonary embolism due to the dual blood supply of the lung. Autopsy studies have reported cavitation to occur in only 4-5% of all pulmonary infarctions with an even smaller proportion of these cases becoming secondarily infected. Patients with infected cavitating pulmonary infarction classically present with fever, positive sputum culture, and leukocytosis days to weeks following acute pulmonary embolism. We describe a rare case of acute pulmonary embolism with pulmonary infarction leading to cavitation and subsequent abscess formation requiring left lower lobe resection.",
"affiliations": "San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234, United States.;Wright-Patterson Medical Center, 4881 Sugar Maple Drive, Wright-Patterson AFB, OH 45433, United States.",
"authors": "Koroscil|Matthew T|MT|;Hauser|Timothy R|TR|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30181-210.1016/j.rmcr.2016.12.001ArticleAcute pulmonary embolism leading to cavitation and large pulmonary abscess: A rare complication of pulmonary infarction Koroscil Matthew T. [email protected]∗Hauser Timothy R. M.D.ba San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234, United Statesb Wright-Patterson Medical Center, 4881 Sugar Maple Drive, Wright-Patterson AFB, OH 45433, United States∗ Corresponding author. [email protected] 12 2016 2017 18 12 2016 20 72 74 20 11 2016 10 12 2016 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pulmonary infarction is an infrequent complication of pulmonary embolism due to the dual blood supply of the lung. Autopsy studies have reported cavitation to occur in only 4–5% of all pulmonary infarctions with an even smaller proportion of these cases becoming secondarily infected. Patients with infected cavitating pulmonary infarction classically present with fever, positive sputum culture, and leukocytosis days to weeks following acute pulmonary embolism. We describe a rare case of acute pulmonary embolism with pulmonary infarction leading to cavitation and subsequent abscess formation requiring left lower lobe resection.\n==== Body\n1 Introduction\nAcute pulmonary embolism (PE) leads to pulmonary infarction in only 10% of cases because of the dual blood supply of the lungs [1]. Pulmonary infarction causes cavitation in 4–7% of cases [2]. Infarct size larger than 4 cm is a strong risk factor for aseptic necrosis leading to pulmonary cavitation [3]. Infected pulmonary cavitation can lead to pulmonary abscess in a small subset of patients and these patients classically present with fever, leukocytosis, and positive sputum; however it is uncommon to have all 3. We present a rare cause of acute PE leading to cavitation and subsequent pulmonary abscess which required left lower lobe resection.\n\n2 Case Presentation\nA previously healthy 62-year-old male presented to the emergency department with complaints of chest pain and dyspnea. CT pulmonary angiogram (CTPA) revealed acute pulmonary emboli within the left lower lobe segmental and subsegmental pulmonary arteries. Imaging also showed a left basilar peripheral groundglass and consolidative opacity likely representing pulmonary infarction (Fig. 1). Intravenous heparin and warfarin therapy were initiated and the patient's hospital course was otherwise unremarkable. Because the patient's venous thromboembolism was unprovoked, he was discharged with a plan for indefinite anticoagulation. The patient returned for a routine outpatient follow-up 3 weeks later with severe cough, generalized malaise, and fatigue. Initial laboratory analysis was unremarkable. A chest radiograph showed interval development of a left lower lobe consolidation with an air-fluid level and pleural effusion (Fig. 2). CTPA demonstrated a large cavitary lesion of the left lower lobe and a loculated pleural fluid collection (Fig. 3). A pulmonary embolus was still evident in the segmental pulmonary artery of the posterior-basilar segment of the left lower lobe. Cardiothoracic surgery was concerned that immediate surgical resection may contaminate the surgical field so intravenous antibiotics and percutaneous drainage of the lung abscess were recommended. The patient was started on intravenous vancomycin and piperacillin/tazobactam and a percutaneous drain was inserted by interventional radiology after 36 hours of antibiotics. The patient clinically decompensated with these treatment modalities, so the patient underwent a left thoracotomy and lysis of adhesions with resection of the left lower lobe. On surgical pathology, the entire left lower lobe was an abscess cavity with copious amounts of purulent material. The procedure was tolerated well and the patient was transitioned to oral antibiotics. Cultures obtained from the percutaneous drain and surgical pathology showed no growth of any organisms.\n\n3 Discussion\nThis case radiographically and chronologically highlights the transition of an acute PE with pulmonary infarction to an infected pulmonary cavity with an abscess. This patient's pulmonary infarction size was larger than 4 cm which is a well-known risk factor for pulmonary cavitation. Other risk factors for pulmonary infarction with cavitation include older age, heart failure, and chronic lung disease [2]. Infected pulmonary infarctions lead to cavitation faster than bland infarctions with aseptic necrosis. The mean time to cavitation for an infected pulmonary infarction is 18 days, which is the approximate time interval experienced by our patient [1]. Gram negative organisms are most commonly isolated but positive cultures do not occur in all patients. Our patient was on broad spectrum antibiotics for over 36 hours prior to percutaneous drainage of the left lower lobe abscess which likely affected the culture results. There is a paucity of data on the surgical treatment of infected pulmonary infarction. Some authors have advocated early surgical resection due to of high rates of medical failure which is theorized to be due to the lack of blood supply within the cavity and risk of continued infection [4]. Older case series report high mortality rates for both infected and bland pulmonary cavitation. It is likely that the reported mortality rates are significantly lower in the modern era of medicine due to earlier diagnosis and improved therapies for venous thromboembolism. Clinicians should consider infected cavitating pulmonary infarction in patients with recent PE and symptoms of bacterial pneumonia.\n\nThe views expressed are those of the authors and do not reflect the official views or policy of the Department of Defense or its Components.\n\nFig. 1 Initial CTPA demonstrating a left basilar peripheral opacity, likely representing pulmonary infarction, as well as a contralateral pleural effusion.\n\nFig. 1Fig. 2 Chest radiograph showing the interval development of a left lower lobe consolidation with an air-fluid level and pleural effusion.\n\nFig. 2Fig. 3 Repeat CTPA demonstrating a large cavitary lesion of the left lower lobe with a loculated pleural fluid collection and evidence of a pulmonary embolus in the segmental pulmonary artery of the posterior-basilar segment of the left lower lobe.\n\nFig. 3\n==== Refs\nReferences\n1 Rajagopala Srinivas Devaraj Uma D’Souza George Infected Cavitating Pulmonary Infarction Respir. Care 56 5 2011 707 709 21276286 \n2 Libby L.S. King T.E. LaForce F.M. Schwarz M.I. Pulmonary cavitation following pulmonary infarction Medicine (Baltimore) 64 5 1985 342 348 4033411 \n3 Wilson A.G. Joseph A.E. Butland R.J. The Radiology of aseptic cavitation in pulmonary infarction Clin. Radiol. 37 1986 327 333 3731699 \n4 Butler Michael D. Biscardi Frank H. Schain Denise C. Humphries John E. Blow Osbert Spotnitz William D. Pulmonary resection for treatment of cavitary pulmonary infarction Ann. Thorac. Surg. 63 1997 849 850 9066420\n\n",
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"title": "Acute pulmonary embolism leading to cavitation and large pulmonary abscess: A rare complication of pulmonary infarction.",
"title_normalized": "acute pulmonary embolism leading to cavitation and large pulmonary abscess a rare complication of pulmonary infarction"
}
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{
"abstract": "Aortobronchial fistulae (ABF) are uncommon but potentially fatal anomalies. Patients may initially present with small volume hemoptysis, which can rapidly lead to massive hemoptysis and death if not diagnosed and intervened upon early. Diagnosis by imaging and bronchoscopy is not always conclusive; thus, a high index of suspicion is necessary to diagnose this life-threatening condition. Herein, we describe a case of a young man who had a late presentation of ABF 21 years following heart transplantation. This case illustrates the diagnostic and clinical challenge of ABF as a late sequela of cardiac transplantation and highlights the rarity of this anomaly.",
"affiliations": "Divisions of Cardiology and Heart Transplant, Loma Linda University Medical Center, Loma Linda, CA. Electronic address: [email protected].;Divisions of Cardiology and Heart Transplant, Loma Linda University Medical Center, Loma Linda, CA.;Divisions of Cardiology and Heart Transplant, Loma Linda University Medical Center, Loma Linda, CA.;Divisions of Cardiology and Heart Transplant, Loma Linda University Medical Center, Loma Linda, CA.",
"authors": "Doctorian|Tanya|T|;Narasimha|Deepika|D|;Sakr|Antoine|A|;Stoletniy|Liset|L|",
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"mesh_terms": "D000328:Adult; D001018:Aortic Diseases; D001983:Bronchial Fistula; D016027:Heart Transplantation; D006469:Hemoptysis; D006801:Humans; D008297:Male; D013997:Time Factors",
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"title": "Aortobronchial Fistula Causing Recurrent Hemoptysis 21 Years Post-Heart Transplant.",
"title_normalized": "aortobronchial fistula causing recurrent hemoptysis 21 years post heart transplant"
}
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{
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{
"abstract": "Sequencing of Cytomegalovirus (CMV) genes to investigate antiviral resistance is a growing area of interest as treatment for CMV infection becomes more widely available and used. Using conventional sequencing methods, we identified a deletion in UL54 gene, del524, which conferred resistance to ganciclovir in a renal transplant recipient, in the absence of a co-existing resistance-conferring mutation in UL97 gene. This case report reinforces that both UL97 and UL54 genes should be sequenced when exploring CMV antiviral resistance as mutations have been identified in both genes independently of each other.",
"affiliations": "Department of Virology, Royal Free London NHS Foundation Trust, Royal Free Hospital, Pond Street, London, NW3 2QG, United Kingdom. Electronic address: [email protected].;Department of Nephrology, Royal Free London NHS Foundation Trust, Royal Free Hospital, Pond Street, London, NW3 2QG, United Kingdom.;Department of Virology, Royal Free London NHS Foundation Trust, Royal Free Hospital, Pond Street, London, NW3 2QG, United Kingdom.;Department of Virology, Royal Free London NHS Foundation Trust, Royal Free Hospital, Pond Street, London, NW3 2QG, United Kingdom.",
"authors": "Green|Cameron B|CB|;O'Riordan|Aisling|A|;Griffiths|Paul|P|;Haque|Tanzina|T|",
"chemical_list": "C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D015774:Ganciclovir",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "80()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Anti-viral resistance; Cytomegalovirus; Del524; Renal transplantation; UL54; UL97",
"medline_ta": "J Clin Virol",
"mesh_terms": "D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004259:DNA-Directed DNA Polymerase; D024882:Drug Resistance, Viral; D005260:Female; D015774:Ganciclovir; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor); D017384:Sequence Deletion; D014764:Viral Proteins",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "24-6",
"pmc": null,
"pmid": "27131599",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A deletion at CMV UL54 codon 524 without co-existing resistance-associated mutation at UL97 confers resistance to ganciclovir: A case report.",
"title_normalized": "a deletion at cmv ul54 codon 524 without co existing resistance associated mutation at ul97 confers resistance to ganciclovir a case report"
}
|
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{
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"reactionmeddraversionpt": "19.0",
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}
],
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"literaturereference": "GREEN CB, O^RIORDAN A, GRIFFITHS P, HAQUE T. A DELETION AT CMV UL54 CODON 524 WITHOUT CO-EXISTING RESISTANCE-ASSOCIATED MUTATION AT UL97 CONFERS RESISTANCE TO GANCICLOVIR: A CASE REPORT. J-CLIN-VIROL 2016;80:24-26.",
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},
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{
"abstract": "Alkaline phosphatase is an enzyme present in all tissues of the human body. Several isoforms of this enzyme have been described with different catalytic nature, stability and antigenic structure. Rises in the activity of alkaline phosphatase are recognised in various states including bone diseases, liver disease, pregnancy, hyperthyroidism and malignant processes. The Regan isoenzyme, a rare variant of placental alkaline phosphatase, has been identified circulating in association with various tumours. The reported case describes a rising Regan isoform of alkaline phosphatase concentrations that led to a new diagnosis of occult renal cell carcinoma and persistently elevated activity postoperatively signposting persistent or recurrent disease.",
"affiliations": "Department of Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK [email protected].;Department of Clinical Biochemistry, South Tees Hospitals NHS Foundation Trust, James Cook University Hospital, Middlesbrough, UK.;Department of Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne, UK.;Department of Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.",
"authors": "Bukowczan|J|J|;Pattman|S|S|;Jenkinson|F|F|;Quinton|R|R|",
"chemical_list": "D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D007527:Isoenzymes; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental",
"country": "England",
"delete": false,
"doi": "10.1177/0004563214526169",
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"issn_linking": "0004-5632",
"issue": "51(Pt 5)",
"journal": "Annals of clinical biochemistry",
"keywords": "Isoenzymes; amylase; cancer",
"medline_ta": "Ann Clin Biochem",
"mesh_terms": "D000368:Aged; D000469:Alkaline Phosphatase; D014408:Biomarkers, Tumor; D002292:Carcinoma, Renal Cell; D017115:Catheter Ablation; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007527:Isoenzymes; D007680:Kidney Neoplasms",
"nlm_unique_id": "0324055",
"other_id": null,
"pages": "611-4",
"pmc": null,
"pmid": "24615345",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Regan isoenzyme of alkaline phosphatase as a tumour marker for renal cell carcinoma.",
"title_normalized": "regan isoenzyme of alkaline phosphatase as a tumour marker for renal cell carcinoma"
}
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"medicinalproduct": "ATORVASTATIN"
},
{
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"drugtreatmentdurationunit": null,
"medicinalproduct": "BUDESONIDE W/FORMOTEROL"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
},
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"drugindication": "VITAMIN D DEFICIENCY",
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"medicinalproduct": "CHOLECALCIFEROL"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
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"drugauthorizationnumb": "016608",
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"drugindication": "DROP ATTACKS",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CARBAMAZEPINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
"drugadministrationroute": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PARACETAMOL"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TIOTROPIUM"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugenddate": null,
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"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TIOTROPIUM"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"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": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SALBUTAMOL"
}
],
"patientagegroup": null,
"patientonsetage": "71",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Renal cell carcinoma",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Blood alkaline phosphatase increased",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PATTMAN S, JENKINSON F, QUINTON R, BUKOWCZAN J.. REGAN ISOENZYME OF ALKALINE PHOSPHATASE AS A TUMOUR MARKER FOR RENAL CELL CARCINOMA.. ANNALS OF CLINICAL BIOCHEMISTRY. 2014;51 (5):611-614",
"literaturereference_normalized": "regan isoenzyme of alkaline phosphatase as a tumour marker for renal cell carcinoma",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20140911",
"receivedate": "20140911",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10447002,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150326"
}
] |
{
"abstract": "Hypersensitivity reactions (HRs) to macrolides are rare.\n\n\n\nThe aim of this study was to evaluate the diagnostic value of in vivo tests in the diagnosis of HRs to macrolides and also to assess cross-reactivity between 4 different macrolides (clarithromycin, dirithromycin, spiramycin, and azithromycin) belonging to 3 different groups.\n\n\n\nTwenty-five patients with a history of immediate or delayed-type HRs to at least 1 macrolide and 20 healthy control subjects underwent skin testing for both the culprit and alternative macrolides. Then, all subjects underwent single-blind drug provocation tests (SBDPTs) with these drugs.\n\n\n\nTwenty-one patients (84%) described an early reaction, whereas the remaining 4 (16%) had delayed-type reactions. Skin prick test results with culprit macrolides were positive in only 2 patients who had experienced anaphylaxis. These 2 and another 4 patients with anaphylaxis history and 6 patients with negative skin test results who did not give consent were not challenged. A total of 13 patients with negative skin test results were challenged with the culprit drugs and all of them experienced HRs during the SBDPTs. Skin test results with alternative drugs were positive in only 2 patients with negative SBDPT results. Conversely, 5 patients with negative skin test results reacted to SBDPTs with alternative macrolides. In healthy control subjects, the skin test results were positive in 3 patients (1 positivity with clarithromycin, 2 positivity with spiramycin) whereas all DPT results were negative.\n\n\n\nOur results suggested that DPT is the only reliable method to predict macrolide hypersensitivity as well as to detect cross-reactivity between macrolides.",
"affiliations": "Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address: [email protected].;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Ünal|Derya|D|;Demir|Semra|S|;Gelincik|Aslı|A|;Olgaç|Müge|M|;Coşkun|Raif|R|;Çolakoğlu|Bahattin|B|;Büyüköztürk|Suna|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2017.06.036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "6(2)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Anaphylaxis; Drug provocation tests; Drug skin tests; Hypersensitivity; Macrolides",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007159:Immunologic Tests; D018942:Macrolides; D008875:Middle Aged; D016037:Single-Blind Method",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "521-527",
"pmc": null,
"pmid": "28923488",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Diagnostic Value of Oral Challenge Testing in the Diagnosis of Macrolide Hypersensitivity.",
"title_normalized": "diagnostic value of oral challenge testing in the diagnosis of macrolide hypersensitivity"
}
|
[
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-171960",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "65174",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"drugstartdateformat": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CLARITHROMYCIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "AZITHROMYCIN ANHYDROUS."
}
],
"patientagegroup": null,
"patientonsetage": "28",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Urticaria",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaphylactic reaction",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic product cross-reactivity",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus generalised",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "UNAL D, DEMIR S, GELINCIK A, OLGAC M, COSKUN R, COLAKOGLU B, ET AL. DIAGNOSTIC VALUE OF ORAL CHALLENGE TESTING IN THE DIAGNOSIS OF MACROLIDE HYPERSENSITIVITY. J ALLERGY CLIN IMMUNOL PRACT. 2018?MARCH/APRIL6(2):521-527",
"literaturereference_normalized": "diagnostic value of oral challenge testing in the diagnosis of macrolide hypersensitivity",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20180508",
"receivedate": "20180508",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14858064,
"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"
},
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-171880",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "65174",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "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": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CLARITHROMYCIN."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pruritus",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fixed eruption",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug eruption",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "UNAL D, DEMIR S, GELINCIK A, OLGAC M, COSKUN R, COLAKOGLU B, ET AL. . DIAGNOSTIC VALUE OF ORAL CHALLENGE TESTING IN THE DIAGNOSIS OF MACROLIDE HYPERSENSITIVITY. J ALLERGY CLIN IMMUNOL PRACT. 2018?MARCH/APRIL6(2):521-527",
"literaturereference_normalized": "diagnostic value of oral challenge testing in the diagnosis of macrolide hypersensitivity",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20180508",
"receivedate": "20180508",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14857198,
"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": "Allogeneic bone marrow transplantation or peripheral blood stem cell transplantation (PBSCT) are the only curative therapies for patients with sickle cell disease (SCD). Once the patients have successfully undergone transplantation and engrafted, the hallmark of hemolytic anemia resolves, and normal hemoglobin levels are achieved. Some transplant protocols exclude patients with open wounds, including leg ulcers, because of infection risks associated with transplantation and long-term immunosuppression required to prevent graft-versus-host disease. Recalcitrant and recurrent leg ulcers are a serious complication of SCD and a determinant of morbidity. Here, we report the case of a 37-year-old man with sickle cell anemia and a chronic leg ulcer, who underwent PBSCT, engrafted successfully, and then had complete healing of his ulcer 16 months posttransplant.",
"affiliations": "1 National Institutes of Health, Bethesda, MD, USA.;1 National Institutes of Health, Bethesda, MD, USA.;4 National Heart, Lung, and Blood Institute and National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.;4 National Heart, Lung, and Blood Institute and National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.",
"authors": "Connor|Joseph L|JL|;Minniti|Caterina P|CP|;Tisdale|John F|JF|;Hsieh|Matthew M|MM|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1177/1534734616685636",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1534-7346",
"issue": "16(1)",
"journal": "The international journal of lower extremity wounds",
"keywords": "immunosuppression; leg ulcer; nonmyeloablative; sickle cell; sirolimus; stem cell transplant",
"medline_ta": "Int J Low Extrem Wounds",
"mesh_terms": "D000328:Adult; D000755:Anemia, Sickle Cell; D019072:Antibiotic Prophylaxis; D006801:Humans; D007166:Immunosuppressive Agents; D007871:Leg Ulcer; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation; D020379:Risk Adjustment; D020123:Sirolimus; D016896:Treatment Outcome; D014945:Wound Healing; D014946:Wound Infection",
"nlm_unique_id": "101128359",
"other_id": null,
"pages": "56-59",
"pmc": null,
"pmid": "28682672",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12196058;12919093;15239621;18458272;18477043;21196716;21630312;24050921;25058217;25459186;26293989;26537664;4818436;8982148",
"title": "Sickle Cell Anemia and Comorbid Leg Ulcer Treated With Curative Peripheral Blood Stem Cell Transplantation.",
"title_normalized": "sickle cell anemia and comorbid leg ulcer treated with curative peripheral blood stem cell transplantation"
}
|
[
{
"companynumb": "US-DRREDDYS-USA/USA/18/0099581",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": null,
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"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
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"drugdosageform": null,
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"drugindication": "PROPHYLAXIS",
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"medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "201578",
"drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "DAY 1",
"drugenddate": null,
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"drugindication": "IMMUNOSUPPRESSION",
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"medicinalproduct": "SIROLIMUS."
},
{
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"activesubstancename": "SIROLIMUS"
},
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"drugcharacterization": "1",
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"drugdosagetext": "TAPERED TO 5NG/ML",
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"medicinalproduct": "SIROLIMUS."
},
{
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},
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"medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM"
},
{
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},
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"drugauthorizationnumb": "201578",
"drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugintervaldosagedefinition": null,
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"medicinalproduct": "SIROLIMUS."
},
{
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"medicinalproduct": "ALEMTUZUMAB"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NYSTATIN"
},
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"medicinalproduct": "NYSTATIN."
},
{
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"activesubstancename": "ACYCLOVIR"
},
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"drugindication": "PROPHYLAXIS",
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"medicinalproduct": "ACYCLOVIR."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
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"medicinalproduct": "ACYCLOVIR."
}
],
"patientagegroup": null,
"patientonsetage": "37",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Lymphadenopathy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pain in extremity",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Mouth ulceration",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Otitis media",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oedema peripheral",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pain",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin ulcer",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CONNOR J, MINNITI C, TISDALE J, HSIEH M. SICKLE CELL ANEMIA AND COMORBID LEG ULCER TREATED WITH CURATIVE PERIPHERAL BLOOD STEM CELL TRANSPLANTATION. INT J LOW EXTREM WOUNDS. 2017?16(1):56-9.",
"literaturereference_normalized": "sickle cell anemia and comorbid leg ulcer treated with curative peripheral blood stem cell transplantation",
"qualification": "1",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "US",
"receiptdate": "20180531",
"receivedate": "20180531",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14958307,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "Herpes simplex virus type 1 or 2 (HSV 1/2)-related infections in neonates are rare but associated with high morbidity and mortality, especially if specific treatment is delayed. Due to immaturity of the immunological system, premature infants are particularly at risk. In addition, symptoms of neonatal HSV infections may imitate prematurity-related problems, such as sepsis. So, a thorough patient's history and appropriate diagnostic measures are important to confirm the diagnosis. We present 2 premature infants with systemic HSV infections and discuss diagnostic and therapeutic management. Both were treated with intravenous acyclovir followed by enteral aciclovir suppressive therapy.",
"affiliations": "Abteilung für Neonatologie und Pädiatrische Intensivmedizin, Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Deutschland.;Universitätsklinik und Poliklinik für Geburtshilfe und Pränatalmedizin, Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Deutschland.;Abteilung für Neonatologie und Pädiatrische Intensivmedizin, Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Deutschland.",
"authors": "Haase|Roland|R|;Seliger|Gregor|G|0000-0001-6201-9303;Baier|Jan|J|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1345-9835",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0948-2393",
"issue": "225(5)",
"journal": "Zeitschrift fur Geburtshilfe und Neonatologie",
"keywords": null,
"medline_ta": "Z Geburtshilfe Neonatol",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D005260:Female; D006561:Herpes Simplex; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious",
"nlm_unique_id": "9508901",
"other_id": null,
"pages": "441-444",
"pmc": null,
"pmid": "33530114",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Herpes Simplex Virus Infection in Two Premature Infants - Diagnostic and Therapeutic Management.",
"title_normalized": "herpes simplex virus infection in two premature infants diagnostic and therapeutic management"
}
|
[
{
"companynumb": "DE-LUPIN PHARMACEUTICALS INC.-2022-00223",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "210209",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Prophylaxis",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstartdate": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "HYDROCORTISONE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "15 MILLIGRAM/KILOGRAM, BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Prophylaxis",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "15",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACYCLOVIR"
}
],
"patientagegroup": "1",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": ".63",
"reaction": [
{
"reactionmeddrapt": "Herpes simplex",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Haase R, Seliger G, Baier J. Herpes simplex virus infection in two premature infants - diagnostic and therapeutic management. Zeitschrift fur Geburtshilfe und Neonatologie. 2021;225(5):441-444",
"literaturereference_normalized": "herpes simplex virus infection in two premature infants diagnostic and therapeutic management",
"qualification": "1",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20220116",
"receivedate": "20220116",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20338692,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
}
] |
{
"abstract": "Investigations have highlighted the lack of evidence regarding the likelihood of congenital malformations following exposure to antipsychotic drugs during pregnancy. To gain further knowledge regarding their safety, we evaluated signals of congenital malformations with antipsychotics using VigiBase(®), the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database.\n\n\n\nA case/non-case study was conducted in VigiBase(®) between 1967 and 2014. Signals of disproportionate reporting (SDRs) were detected using the proportional reporting ratio (PRR), which defines SDRs as drug-report associations with a PRR ≥2, Chi square ≥4, and number of cases ≥3. SDR detection for antipsychotics was performed for congenital malformations after removing all reports related to drug competitors and reports of movement disorders from the database.\n\n\n\nAfter removing reports related to drug competitors (antiepileptics, antidepressants, antivirals) and movement disorders, three signals were revealed: 'palate disorders congenital' (PRR 2.1, 95 % CI 1.6-2.9, Chi square = 30; n = 41), 'oesophageal disorders congenital' (PRR 2.5, 95 % CI 1.3-4.7, Chi square = 11; n = 10) and 'anorectal disorders congenital' (PRR 3.0, 95 % CI 1.6-5.6, Chi square = 13; n = 11). Among antipsychotics, phenothiazines with a piperazine side-chain, risperidone and aripiprazole appeared to be more suspect.\n\n\n\nConfirming a first signal from spontaneous reporting data, three SDRs for antipsychotics and gastrointestinal congenital abnormalities were unmasked in VigiBase(®). This signal should be further explored by ad hoc pharmacoepidemiologic studies in order to assess whether it is relevant for prescription and public health.",
"affiliations": "INSERM, U1219-Pharmacoepidemiology, Université de Bordeaux, 33000, Bordeaux, France. [email protected].;INSERM, U1219-Pharmacoepidemiology, Université de Bordeaux, 33000, Bordeaux, France.;INSERM, U1219-Pharmacoepidemiology, Université de Bordeaux, 33000, Bordeaux, France.;INSERM, U1219-Pharmacoepidemiology, Université de Bordeaux, 33000, Bordeaux, France.;INSERM, U1219-Pharmacoepidemiology, Université de Bordeaux, 33000, Bordeaux, France.",
"authors": "Montastruc|François|F|;Salvo|Francesco|F|;Arnaud|Mickaël|M|;Bégaud|Bernard|B|;Pariente|Antoine|A|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-016-0413-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "39(7)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D014150:Antipsychotic Agents; D015982:Bias; D016022:Case-Control Studies; D062313:Databases, Pharmaceutical; D004065:Digestive System Abnormalities; D006801:Humans; D060735:Pharmacovigilance",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "689-96",
"pmc": null,
"pmid": "26961536",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "25488315;168764;24698193;19176788;23389622;14695418;25932852;26715499;19358225;23764684;6109278;20305605;15966965;23673817;20059452;23852139;21658092;7468292;879206;18787227;22967190;21266628;15816786;5755906;2951947;22483705;23124892;21077702;26441156;15106251;21254289;8011183;19230751;10945372;15317031;17328645;841482;15222664;4428425;23921799;25083265;18480684;17671284;17110152;22474072",
"title": "Signal of Gastrointestinal Congenital Malformations with Antipsychotics After Minimising Competition Bias: A Disproportionality Analysis Using Data from Vigibase(®).",
"title_normalized": "signal of gastrointestinal congenital malformations with antipsychotics after minimising competition bias a disproportionality analysis using data from vigibase"
}
|
[
{
"companynumb": "FR-JNJFOC-20160626337",
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"occurcountry": "FR",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "TROPATEPINE"
},
"drugadditional": "3",
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"drugcharacterization": "1",
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "TROPATEPINE"
},
{
"actiondrug": "5",
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"activesubstancename": "PYRIDOXINE"
},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "PYRIDOXINE"
},
{
"actiondrug": "5",
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"activesubstancename": "DOXYLAMINE"
},
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"medicinalproduct": "DOXYLAMINE"
},
{
"actiondrug": "5",
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"activesubstancename": "ACETAMINOPHEN"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PARACETAMOL"
},
{
"actiondrug": "5",
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"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "RISPERIDONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPICILLIN"
},
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"medicinalproduct": "AMPICILLIN"
},
{
"actiondrug": "5",
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"activesubstancename": "HALOPERIDOL"
},
"drugadditional": "3",
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"medicinalproduct": "HALOPERIDOL."
},
{
"actiondrug": "5",
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"activesubstancename": "FENFLURAMINE"
},
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"medicinalproduct": "FENFLURAMINE"
},
{
"actiondrug": "5",
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"activesubstancename": "LEVOTHYROXINE"
},
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"abstract": "•Progestins can produce clinical benefit in a subset of women with metastatic endometrial cancer.•Corticosteroid-related effects of megestrol can cause morbidity over the long term.•Norethindrone is a progestin without corticosteroid side effects.•A switch from megestrol to norethindrone decreased toxicity with continued benefit.•A clinical trial of norethindrone for this population of patients would be welcome.",
"affiliations": "Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.;Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA.;Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.",
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"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(17)30107-810.1016/j.gore.2017.09.015Case SeriesNorethindrone substituted for megestrol in the treatment of metastatic endometrial carcinoma: Three cases Read William L. [email protected]⁎Trivedi Sumita bWilliams Felicia aa Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USAb Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA⁎ Corresponding author. [email protected] 10 2017 11 2017 02 10 2017 22 75 77 29 6 2017 27 9 2017 28 9 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Megestrol is an effective palliative treatment for endometrial carcinoma. Some persons with progestin-responsive cancer continue on hormonal therapy for months or even years. In persons who respond to megestrol, long term use can cause weight gain and other side effects via activity of the drug at the corticosteroid receptor. Norethindrone is a progestin which has been used clinically for decades and which is without corticosteroid activity. We report three women with metastatic endometrial cancer responding to megestrol for whom a switch to norethindrone decreased weight gain with continued cancer control. A clinical trial of first line norethindrone for metastatic endometrial cancer could benefit people with this disease.\n\nHighlights\n• Progestins can produce clinical benefit in a subset of women with metastatic endometrial cancer.\n\n• Corticosteroid-related effects of megestrol can cause morbidity over the long term.\n\n• Norethindrone is a progestin without corticosteroid side effects.\n\n• A switch from megestrol to norethindrone decreased toxicity with continued benefit.\n\n• A clinical trial of norethindrone for this population of patients would be welcome.\n==== Body\n1 Introduction\nIt has long been recognized that progestin therapy can provide palliative benefit to a subset of women with advanced endometrial cancer. In their 2000 review of hormonal therapy for advanced endometrial cancer, Elit and Hirte concluded that for a population unselected by hormone receptor status, “progestin therapy provides a response rate of 10–20% and survival of less than one year in women with advanced or metastatic disease” (Elit & Hirte, 2000). Reviewed studies include one with hydroxyprogesterone, and ten others with either medroxyprogesterone or megestrol. No agent proved to be superior over the others. Subsequent phase 2 studies for this population attempted to improve on megestrol by adding tamoxifen (Fiorica et al., 2004) and subsequently tamoxifen and temsirolimus (Fleming et al., 2014). Reported outcomes for combinations were similar to those obtained with megestrol alone.\n\nWomen with hormone receptor positive endometrial carcinoma are more likely to benefit from progestin treatment. A study by Thigpen et al. compared high and low dose medroxyprogesterone and found the response rate for progesterone receptor negative tumors was 14% for low dose and 2% for high dose versus 48% and 28% for progesterone receptor positive tumors (Thigpen et al., 1999). For responding patients, progression free survival of a year or more is not uncommon. In their study of megestrol and tamoxifen, Fiorca et al. described three study participants with progression free survival of four years or more.\n\nAlthough they are the only drugs that have been studied for palliative hormonal treatment of endometrial cancer, long term megestrol and medroxyprogesterone are less than ideal for this population. Patients treated for prolonged periods can suffer morbidity from the cumulative corticosteroid activity of these drugs. Both megestrol and medroxyprogesterone have activity at the glucocorticoid receptor and side effects are the same as those associated with corticosteroids (Koubovec et al., 2005, Mann et al., 1997). These include thrombophlebitis, pulmonary embolism, diabetes, osteoporosis and most importantly, weight gain. These side effects are especially problematic for persons with advanced endometrial cancer. Many persons with endometrial cancer are already obese, as this is a risk factor for developing the cancer. Persons with metastatic malignancies are already hypercoagulable.\n\nDue to problematic weight gain in some of our patients with proven disease control on megestrol, we tried substituting norethindrone for megestrol. Norethindrone is a synthetic progestin with some androgenic and estrogen/antiestrogen activity but no affinity for the glucocorticoid receptor (Koubovec et al., 2005). Norethindrone has been used for decades as an oral contraceptive, to treat endometrial hyperplasia, and as add-back hormonal replacement for women on ovarian suppression with GHRH agonists (Chandra et al., 2016, Chwalisz et al., 2012, Schindler et al., 2008). We were not able to find reports of its use to treat advanced endometrial adenocarcinoma. Here we describe the clinical course of three patients with advanced endometrial adenocarcinoma who responded to megestrol and were then successfully switched to norethindrone.\n\n2 Case 1\nA 62 year old presented with vaginal discharge and pain. She underwent hysterectomy, with pathology describing a grade 3 endometrioid adenocarcinoma with squamous differentiation. She then underwent adjuvant therapy with 6 cycles of chemotherapy, whole abdominal radiation and vaginal brachytherapy.\n\nSurveillance imaging of the chest 19 months after completing chemotherapy commented on questionable new subcentimeter nodules. Repeat imaging was not done until 1 year later, at which time interval growth of these nodules and new nodules were noted. The largest was still only 5 mm. Thoracoscopic biopsy of a right upper lobe nodule confirmed metastatic endometrioid adenocarcinoma with squamous differentiation. Malignant cells expressed estrogen receptor.\n\nBecause of the indolent growth of these nodules together with estrogen receptor positivity it was decided to try megestrol. In January 2012 she began megestrol at 80 mg twice daily. Initial repeat imaging at 2 months showed the larger nodules to have cavitated and they subsequently slowly regressed (Fig. 1).Fig. 1 Representative lung metastases are seen to first cavitate and then regress completely during endocrine therapy.\n\nFig. 1\n\nBy February 2013 she had gained 20 kg and was struggling with lymphedema. We decided to try switching from megestrol to norethindrone 0.35 mg daily, with a plan to switch back if her disease began to progress. By April 2014 she had lost 13 kg with improved control of her lymphedema, and without progression of her lung nodules on surveillance CT imaging. Seventy-five months after starting progestin for metastatic endometrial cancer and 62 months after switching to norethindrone she has no evidence of progression and no side effects.\n\n3 Case 2\nA 62 year old nonsmoking woman was diagnosed with squamous carcinoma of the lung in 2004. This was metastatic to multiple lung sites on presentation and over the ensuing 4 years she received four courses of palliative chemotherapy. In 2008 because of her lack of symptoms and very slow progression of her lung lesions, treatment stopped and she was followed with serial imaging only.\n\nIn February 2009 she developed vaginal bleeding and was found to have a uterine mass. Pathology described a grade 2 endometrioid adenocarcinoma with extensive squamous metaplasia. Hormone receptors were not checked. In the belief that this was a second primary cancer she underwent surgery followed by internal and external radiation. In December 2011 surveillance imaging found her to have a pelvic mass which on biopsy was called metastatic adenocarcinoma and she was referred.\n\nIn January 2011 she began megestrol at 400 mg daily, with initial CT at 2 months calling slight growth in pelvic masses. She continued on megestrol and by June 2012 CT imaging showed response in the pelvis. Surprisingly she also had a marked response in the lung lesions which in retrospect must have been metastases from her endometrial carcinoma presenting 5 years before the primary tumor. In June 2013 her tumors seen on CT continued to regress but she had become wheelchair bound because of decreased strength and weight gain. She additionally developed new diabetes. She was switched to norethindrone 5 mg daily. She experienced subjective improvement and her tumor masses continued to regress.(Fig. 2) In October 2015, 48 months after starting progestin treatment and 28 months after switching to norethindrone, imaging described questionable increase in one lung mass as well as a new pelvic nodule, with stability at other sites. She was switched back to megestrol 80 twice daily. CT scan done December 2015 described stability of these lesions. Recurrent pneumonia and increasing debility precluded further imaging, and she died of complications of urinary tract infection in March 2016.Fig. 2 Large metastatic lesions in the lung are seen to regress almost completely during megestrol followed by norethindrone therapy.\n\nFig. 2\n\n4 Case 3\nA 54 year old woman presented in 2007 with uterine adenocarcinoma and underwent surgery followed by radiation. In November 2010 she developed a cough with hemoptysis and was found to have multiple lung nodules, which on biopsy proved to be metastatic adenocarcinoma with squamous differentiation, positive for estrogen receptor. She was treated with carboplatin and paclitaxel. Her treatment was complicated by a cerebrovascular accident and hemiplegia. She completed her chemotherapy in April 2011 with an excellent response.\n\nIn November 2014 a residual abnormality on chest CT was seen to have grown from 1 to 2 cm. This was not treated, and by May 2015 this nodule had grown to 3 cm. She began megestrol at 80 mg bid and repeat imaging August 2015 showed the mass to have regressed. By February 2016 the lung nodule continued to regress, but the patient had become wheelchair bound because of her residual hemiplegia and 16 kg weight gain. She was switched to norethindrone 5 mg, but discontinuation of megestrol was complicated by acute adrenal insufficiency necessitating restart and slow taper of megestrol over one month. Adrenal insufficiency is another corticosteroid-like side effect of megestrol which has been previously described (Dev et al., 2007) On norethindrone, she lost 4 kg over the ensuing year. At the time of this writing she has been on progestin for 2 years and norethindrone for 15 months, with stability of her lung nodule and her weight.\n\n5 Discussion\nThese three women with advanced endometrial adenocarcinoma responded to hormonal treatment with megestrol but suffered corticosteroid-type side effects after months on treatment. They were switched off megestrol to norethindrone, with resolution of side effects and continued disease control for many months. It is interesting that all three had endometrioid adenocarcinoma with squamous differentiation. In their phase II study, Fiorca et al. noted this histologic variant to respond to hormonal treatment (Fiorica et al., 2004). Also interesting is that after the switch to norethindrone, all three of the described women had or have a hematocrit slightly higher than normal (between 41 and 45). An elevation of hematocrit in women taking norethindrone has been previously described (Derham & Buchan, 1989). The mechanism behind this is not known but could be due to action of this drug at the androgen receptor.\n\nThis report should not be taken to mean that norethindrone is equivalent to megestrol in the treatment of metastatic endometrial cancer. All of our patients start on megestrol first as it is the standard of care for palliative treatment of endometrial cancer which might be progestin responsive, and all continue on megestrol long enough to establish response or stability of their disease. Patients are switched from megestrol to norethindrone only if they struggle with weight gain, which is not universal. The above cases describe our successful efforts to mitigate megestrol-related side effects while maintaining effective progestin treatment. We chose norethindrone because of its favorable side effect profile and its decades-long track record of safe use as a contraceptive and in the treatment of benign uterine conditions.\n\nThese case indicate a need for data supporting the use of norethindrone in the first line. Patients could avoid megestrol-related side effects altogether. Women with metastatic well-differentiated endometrial cancer would be well served by a clinical trial investigating the efficacy and side effect profile of norethindrone or another progestin without activity at the corticosteroid receptor.\n\nConflict of interest statement\nNone of the three authors on this report have any relevant conflicts of interest.\n==== Refs\nReferences\nChandra V. Kim J.J. Benbrook D.M. Dwivedi A. Rai R. Therapeutic options for management of endometrial hyperplasia J. Gynecol. Oncol. 27 1 2016 e8 Epub 2015/10/16 https://doi.org/10.3802/jgo.2016.27.e8 (PubMed PMID: 26463434 ; PubMed Central PMCID: PMCPMC4695458) 26463434 \nChwalisz K. Surrey E. Stanczyk F.Z. The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis Reprod. Sci. 19 6 2012 563 571 Epub 2012/03/30 https://doi.org/10.1177/1933719112438061 (PubMed PMID: 22457429 ) 22457429 \nDerham R.J. Buchan P.C. Haemorheological consequences of oestrogen and progestogen therapy Eur. J. Obstet. Gynecol. Reprod. Biol. 32 2 1989 109 114 (Epub 1989/08/01. PubMed PMID: 2673883) 2673883 \nDev R. Del Fabbro E. Bruera E. Association between megestrol acetate treatment and symptomatic adrenal insufficiency with hypogonadism in male patients with cancer Cancer 110 6 2007 1173 1177 17647248 \nElit L. Hirte H. Novel strategies for systemic treatment of endometrial cancer Expert Opin. Investig. Drugs 9 12 2000 2831 2853 \nFiorica J.V. Brunetto V.L. Hanjani P. Lentz S.S. Mannel R. Andersen W. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study Gynecol. Oncol. 92 1 2004 10 14 Epub 2004/01/31. PubMed PMID: 14751131 14751131 \nFleming G.F. Filiaci V.L. Marzullo B. Zaino R.J. Davidson S.A. Pearl M. Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study Gynecol. Oncol. 132 3 2014 585 592 Epub 2014/01/25 https://doi.org/10.1016/j.ygyno.2014.01.015 (PubMed PMID: 24456823 ; PubMed Central PMCID: PMCPMC4063288) 24456823 \nKoubovec D. Ronacher K. Stubsrud E. Louw A. Hapgood J.P. Synthetic progestins used in HRT have different glucocorticoid agonist properties Mol. Cell. Endocrinol. 242 1–2 2005 23 32 Epub 2005/08/30 https://doi.org/10.1016/j.mce.2005.07.001 (PubMed PMID: 16125839 ) 16125839 \nMann M. Koller E. Murgo A. Malozowski S. Bacsanyi J. Leinung M. Glucocorticoidlike activity of megestrol: a summary of food and drug administration experience and a review of the literature Arch. Intern. Med. 157 15 1997 1651 1656 9250225 \nSchindler A.E. Campagnoli C. Druckmann R. Huber J. Pasqualini J.R. Schweppe K.W. Classification and pharmacology of progestins Maturitas 61 1–2 2008 171 180 (Epub 2009/05/13. PubMed PMID: 19434889 ) 19434889 \nThigpen J.T. Brady M.F. Alvarez R.D. Adelson M.D. Homesley H.D. Manetta A. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group J. Clin. Oncol. 17 6 1999 1736 1744 Epub 1999/11/24 https://doi.org/10.1200/jco.1999.17.6.1736 (PubMed PMID: 10561210 ) 10561210\n\n",
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"abstract": "Tumor necrosis factor inhibitors have been implicated in many pulmonary complications. Before starting these class of drugs latent infection as tuberculosis and preexisting lung disease should be excluded. These agents have been linked to pulmonary nodules, pneumonitis, fibrosis, autoimmune reactions and infection. We report a case of adalimumab induced organizing pneumonia in an old gentleman who was started on the drug for his uncontrolled Psoriasis.",
"affiliations": "Staten Island University Hospital, 522A seaview avenue, Staten Island, United States.;Staten Island University Hospital, 522A seaview avenue, Staten Island, United States.;Staten Island University Hospital, 522A seaview avenue, Staten Island, United States.",
"authors": "Aqsa|Anum|A|;Sharma|Dikshya|D|;Chalhoub|Michel|M|",
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"country": "England",
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"doi": "10.1016/j.rmcr.2020.101012",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30399-510.1016/j.rmcr.2020.101012101012Case ReportAdalimumab induced interstitial lung disease Aqsa Anum [email protected]∗Sharma Dikshya Chalhoub Michel Staten Island University Hospital, 522A seaview avenue, Staten Island, United States∗ Corresponding author. [email protected] 2 2020 2020 01 2 2020 29 1010129 12 2019 27 1 2020 31 1 2020 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tumor necrosis factor inhibitors have been implicated in many pulmonary complications. Before starting these class of drugs latent infection as tuberculosis and preexisting lung disease should be excluded. These agents have been linked to pulmonary nodules, pneumonitis, fibrosis, autoimmune reactions and infection. We report a case of adalimumab induced organizing pneumonia in an old gentleman who was started on the drug for his uncontrolled Psoriasis.\n==== Body\n1 Introduction\nTumor necrosis factor inhibitors are used for a number of inflammatory conditions. They have been implicated, however, in serious pulmonary complications. These include granulomatous disease, pneumonitis, fibrosis, autoimmune reactions, and infections. We report a case of adalimumab-induced organizing pneumonia in a gentleman who was started on the drug for uncontrolled psoriasis.\n\n2 Case report\nA 71-year-old male presented to pulmonary clinic for a 3-week history of dyspnea on exertion. Review of systems was positive for subjective fever, chills, and night sweats. He reported no recent travel, sick contacts, weight loss, occupational exposure, or smoking history. He had a medical history of uncontrolled psoriasis for several years. Five weeks before presentation, he was started on tumor necrosis factor inhibitor, Adalimumab, by his dermatologist, for uncontrolled psoriasis. One week ago, he was prescribed a course of Levofloxacin by his primary care doctor without any improvement of his symptoms.\n\nOn his physical examination, the patient appeared in no distress. His vitals were stable with a pulse oximetry reading of 94% on room air. He had bilateral rhonchi on chest auscultation. He had no positive JVD, no pedal edema, and no palpable neck or axillary lymphadenopathy. He had healed rashes of psoriasis on the extensor surface of both arms.\n\nPulmonary function tests were notable for a restrictive defect with decreased DLCO. High resolution CT chest (Fig. 1) revealed bilateral opacities predominantly on the periphery. Bronchoscopy for BAL reveled increased cellularity. A transbronchial biopsy of the left lower lobe was positive for subpleural well-formed Masson bodies plugging the airway suggesting organizing pneumonia.Fig. 1 HRCT scan chest showing extensive peripheral opacities.\n\nFig. 1\n\nAdalimumab was discontinued and the patient was started on 40 mg of oral prednisone once daily. His symptoms improved dramatically. Repeat CT chest (Fig. 2) in a month showed significant resolution of opacities.Fig. 2 CT scan chest showing resolution of opacities following Adalimumab discontinuation and 4 weeks course of steroid therapy.\n\nFig. 2\n\n3 Discussion\nCytokines are proteins secreted by T cells and macrophages that help regulate immune responses along with cellular proliferation and differentiation. Tumor necrosis factor-alpha (TNF-a) is a pro inflammatory cytokine, also known as Cachectin. Its inhibitors are used as immunosuppressant modulating drugs. After their discovery in 1991, as effective drugs for rheumatoid arthritis, use of TNF inhibitors has been on the rise. They are now being increasingly used in many inflammatory and autoimmune disorder like rheumatoid arthritis, spondylarthritis, systemic sclerosis, inflammatory bowel disease, systemic lupus erythematosus (SLE) with encouraging outcomes. However, high vigilance is required during administration of anti-TNF drugs as they have been linked to both infectious and noninfectious side effects. Many anti-TNF-induced pulmonary complications have been identified. These include exacerbations of underlying lung disease, development of accelerated lung nodules, interstitial lung disease (ILD), unmasking of latent infections, granulomatous lung disease, SLE-like reactions and vasculitis [1,2].\n\nThe exact mechanism of pulmonary toxicity, however, remains unclear. Inhibition of inflammatory cells by anti-TNF drugs leads to unopposed activity of inflammatory cells resulting in characteristic changes of interstitial pneumonitis. Old age, delayed onset of symptoms, co-administration of other immunosuppressant, and, especially, prior diagnosis of ILD are associated with poor prognosis.\n\nAnti-TNF-induced diffuse interstitial lung disease (ILD) is an emerging entity with a prevalence of 0.5–3% [3]. A spectrum of ILDs has been associated with this class of drugs. Perez-Alvarez et al. review article mentioned 122 cases of anti-TNF induced lung injury; three of which were secondary to adalimumab [4]. Adalimumab, a monoclonal antibody, is the least tied to lung toxicity, among anti-TNF drugs. Bibliography review showed ten case reports of adalimumab-induced ILD. Of these ten cases, two involved patients with psoriasis [[5], [6], [7], [8], [9], [10], [11]].\n\nPatients with adalimumab-induced ILD mostly present with difficulty breathing, dry cough, fever, malaise, and shortness of breath, as seen in the presented case. Symptoms are dose-dependent and worsen with cumulative doses. Mean time to symptom onset after drug initiation is about 26 weeks. Imaging modalities like high resolution computed tomography (HRCT) disclose ground glass opacities (83%), honeycomb appearance (22%), and reticulonodular opacities (38%) [4]. Pulmonary function tests reveal restrictive ventilatory pattern and reduced diffusion capacity of lungs. Bronchoscopy with bronchoalveolar lavage and lung biopsy are mostly reserved to rule out other possible causes. Conditions including heart failure, infections, idiopathic interstitial pneumonia, and exacerbation of pre-existing ILD must be ruled out.\n\nDrug-disease association is usually made on the basis of prior reports of similar complications with anti-TNF agents, former absence of symptoms, rapid onset and progressive nature of disease after drug initiation, negative infectious disease workup, pathological confirmation, exclusion of other possible causes and improvement of symptoms after drug discontinuation. The disease course varies from either complete resolution, in about 65% of cases, to failed treatment with rapid progression to death.\n\nThe mainstay of treatment is discontinuation of adalimumab. Adjunctive measures also include treatment with steroids and addition of immunosuppressants in steroid-unresponsive cases or patients with fulminant disease. Symptom improvement along with radiological improvement is seen within one to two weeks of adalimumab cessation. Despite the side effects, preexisting lung diseases is not an absolute contraindication to the use of TNF inhibitors. However, patients must be forewarned of the side effects of the drug as it can significantly affect their quality of life. Higher degree of clinical suspicion is required to make the diagnosis of adalimumab-induced ILD as it reversible.\n\nDeclaration of competing interest\nWe know of no conflicts of interest associated with this publication.\n==== Refs\nReferences\n1 Thavarajah K. Wu P. Rhew E.J. Yeldandi A.K. Kamp D.W. Pulmonary complications of tumor necrosis factor-targeted therapy Respir. Med. 103 5 2009 661 669 19201589 \n2 Ramos-Casals M. Brito-Zeron P. Munoz S. Soria N. Galiana D. Bertolaccini L. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases Medicine (Baltim.) 86 4 2007 242 251 \n3 Dixon W.G. Hyrich K.L. Watson K.D. Lunt M. Symmons D.P. Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register Ann. Rheum. Dis. 69 6 2010 1086 1091 20444754 \n4 Perez-Alvarez R. Perez-de-Lis M. Diaz-Lagares C. Pego-Reigosa J.M. Retamozo S. Bove A. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases Semin. Arthritis Rheum. 41 2 2011 256 264 21277618 \n5 Komiya K. Ishii H. Fujita N. Oka H. Iwata A. Sonoda H. Adalimumab-induced interstitial pneumonia with an improvement of pre-existing rheumatoid arthritis-associated lung involvement Intern. Med. 50 7 2011 749 751 21467710 \n6 Dias O.M. Pereira D.A. Baldi B.G. Costa A.N. Athanazio R.A. Kairalla R.A. Adalimumab-induced acute interstitial lung disease in a patient with rheumatoid arthritis J. Bras. Pneumol. 40 1 2014 77 81 24626274 \n7 Alaee S. Jones Q. Case of drug-induced interstitial lung disease secondary to adalimumab BMJ Case Rep. 2018 2018 \n8 Casanova M.J. Chaparro M. Valenzuela C. Cisneros C. Gisbert J.P. Adalimumab-induced interstitial pneumonia in a patient with Crohn's disease World J. Gastroenterol. 21 7 2015 2260 2262 25717268 \n9 Yamazaki H. Isogai S. Sakurai T. Nagasaka K. A case of adalimumab-associated interstitial pneumonia with rheumatoid arthritis Mod. Rheumatol. 20 5 2010 518 521 20467775 \n10 Reid J.D. Bressler B. English J. A case of adalimumab-induced pneumonitis in a 45-year-old man with Crohn's disease Canc. Res. J. 18 5 2011 262 264 \n11 Phang K.F. Teng G.G. Teo L.L.S. Seet J.E. Teoh C.M. Teo F.S.W. A 67-year-old man with psoriatic arthritis and new-onset dyspnea Chest 154 5 2018 e127 e134 30409366\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "29()",
"journal": "Respiratory medicine case reports",
"keywords": null,
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101012",
"pmc": null,
"pmid": "32055438",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "24626274;20444754;21277618;19201589;30409366;21467710;21969926;17632266;20467775;25717268;29764848",
"title": "Adalimumab induced interstitial lung disease.",
"title_normalized": "adalimumab induced interstitial lung disease"
}
|
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{
"abstract": "Few studies have compared the programmatic effectiveness of the recommended strategies of antenatal highly active antiretroviral therapy (HAART) and zidovudine for prevention of mother-to-child transmission. We prospectively followed infants (93% formula fed) whose mothers who took either HAART (258 infants) or zidovudine (170 infants) during pregnancy in the Botswana national program. Overall, 10 infants (2.5%) acquired HIV--9 infants in the zidovudine group (5.5%, 95% confidence interval: 2.6% to 10.2%) and 1 infant in the HAART group (0.4%, 95% confidence interval: 0.0% to 2.2%). Maternal HAART was associated with decreased prevention of mother-to-child transmission (P = 0.001) and improved HIV-free survival (P = 0.040) compared with zidovudine (with or without single-dose nevirapine) in a programmatic setting.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA. [email protected]",
"authors": "Dryden-Peterson|Scott|S|;Jayeoba|Oluwemimo|O|;Hughes|Michael D|MD|;Jibril|Haruna|H|;Keapoletswe|Koona|K|;Tlale|Josephine|J|;Modise|Taolo A|TA|;Asmelash|Aida|A|;Moyo|Sikhulile|S|;van Widenfelt|Erik|E|;Makhema|Joseph|J|;Essex|Max|M|;Shapiro|Roger L|RL|;Lockman|Shahin|S|",
"chemical_list": "D019380:Anti-HIV Agents; D015215:Zidovudine",
"country": "United States",
"delete": false,
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"issue": "58(3)",
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"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D001902:Botswana; D005260:Female; D015658:HIV Infections; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011446:Prospective Studies; D015215:Zidovudine",
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"other_id": null,
"pages": "353-7",
"pmc": null,
"pmid": "21792062",
"pubdate": "2011-11-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11018164;17620755;19864957;15668871;16905785;8965861;7912084;20517161;18162933;17713983;11981365;18753864;21237718;1361750;20554983",
"title": "Highly active antiretroviral therapy versus zidovudine for prevention of mother-to-child transmission in a programmatic setting, Botswana.",
"title_normalized": "highly active antiretroviral therapy versus zidovudine for prevention of mother to child transmission in a programmatic setting botswana"
}
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{
"abstract": "Myeloma is a haematological malignancy which typically follows a relapsing-remitting course. While treatment can control the myeloma and improve quality of life for given periods of time, remissions generally become progressively shorter with subsequent relapses, and patients ultimately enter a final refractory phase. To help control symptoms and enhance quality of life, some patients use complementary therapies as an adjunct to their conventional therapy. Here, we describe a myeloma patient who started a daily dietary supplement of curcumin when approaching her third relapse. In the absence of further antimyeloma treatment, the patient plateaued and has remained stable for the last 5 years with good quality of life.",
"affiliations": "Department of Haematology, Barts Health NHS Trust, London, UK.;Myeloma UK, Edinburgh, UK.;Department of Haematology, Barts Health NHS Trust, London, UK.",
"authors": "Zaidi|Abbas|A|;Lai|Maggie|M|;Cavenagh|Jamie|J|",
"chemical_list": "D003474:Curcumin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218148",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2016-21814810.1136/bcr-2016-218148ArticleUnexpected Outcome (Positive or Negative) Including Adverse Drug Reactions161215061525Female51-70 yearsWhiteUnited KingdomCase ReportLong-term stabilisation of myeloma with curcumin Zaidi Abbas 1Lai Maggie 2Cavenagh Jamie 1\n1 Department of Haematology, Barts Health NHS Trust, London, UK\n2 Myeloma UK, Edinburgh, UKCorrespondence to Dr Abbas Zaidi, [email protected] 16 4 2017 16 4 2017 2017 bcr201621814819 2 2017 2017 BMJ Publishing Group Ltd2017This is an Open Access article 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. See: http://creativecommons.org/licenses/by-nc/4.0/Myeloma is a haematological malignancy which typically follows a relapsing-remitting course. While treatment can control the myeloma and improve quality of life for given periods of time, remissions generally become progressively shorter with subsequent relapses, and patients ultimately enter a final refractory phase. To help control symptoms and enhance quality of life, some patients use complementary therapies as an adjunct to their conventional therapy. Here, we describe a myeloma patient who started a daily dietary supplement of curcumin when approaching her third relapse. In the absence of further antimyeloma treatment, the patient plateaued and has remained stable for the last 5 years with good quality of life.\n\nspecial-featureunlockedspecial-featurepress-release\n==== Body\nBackground\nMyeloma is a B-cell malignancy that is characterised by the monoclonal expansion and accumulation of abnormal plasma cells within the bone marrow. Clinical manifestations include bone pain, renal impairment, recurrent infections and anaemia.1 Over the past decade, advances in the understanding of the disease, together with the development of several novel treatments, have led to significant improvements in overall survival.2\n\nDespite this, myeloma remains incurable, with a median overall survival of 5.2 years from diagnosis.3 The course of the disease is typically one of recurrent remission and relapse. However, patients progressively acquire resistance to treatment and subsequent remissions become shorter and shorter. Eventually, either they run out of treatment options or become refractory to them.\n\nIn an effort to improve long-term outcomes, some myeloma patients seek to use dietary supplements, mostly for palliative purposes. While they may help to improve quality of life, there is little evidence they can increase survival.4 Among them, curcumin, the active constituent of turmeric, has gained popularity as a complementary therapy in several cancers.\n\nHere, we present a case of a heavily pretreated relapsing myeloma patient who, in the absence of further treatment options at the time, started daily curcumin and has since remained stable for the past 5 years.\n\nCase presentation\nA woman aged 57 years was initially diagnosed with monoclonal gammopathy of undetermined significance (MGUS) in 2007 following an incidental finding of M-protein (18 g/L) during investigation for hypertension.\n\nWithin 15 months, the patient had rapidly progressed to ISS stage 3 myeloma with M-protein 49 g/L, urinary protein 1.3 g/24-hour, Bence-Jones protein 1.0 g/24-hour, Hb 9.7 g/dL and increasing back pain. She initially declined antimyeloma treatment but 6 months later, following vertebral collapse at T5 and T12, started cyclophosphamide, thalidomide and dexamethasone (CTD) treatment. However, after a week, the patient was admitted with idiosyncratic syndrome including hyponatraemia, a fall in albumin and worsening of blood counts. She received red cell transfusion and her electrolyte abnormalities were carefully corrected.\n\nAlthough there was evidence of a response to CTD (M-protein 34 g/L), bortezomib and dexamethasone treatment was initiated as an alternative, but this was discontinued after three cycles due to progressive disease (M-protein 49 g/L). The patient was then treated with lenalidomide and dexamethasone with the aim of reducing disease burden prior to high-dose therapy and autologous stem cell transplantation. Treatment was frequently interrupted and dose adjusted to account for neutropenia and despite a minor response after six cycles (starting M-protein 47 g/L, finishing M-protein 34 g/L), in October 2009, she proceeded with stem cell mobilisation. However, neither cyclophosphamide nor plerixafor/GCSF priming were successful. A bone marrow biopsy revealed 50% myeloma cells and a course of CTD was restarted with cautious titration of thalidomide.\n\nThe patient achieved a partial response with CTD retreatment over the course of 17 cycles (M-protein 13 g/L) with no further episodes of idiosyncratic syndrome. However, attempts to harvest stem cells in February 2011 and again there months later, both failed. By then, her M-protein had risen to 24 g/L and the patient was too neutropenic to be considered for a clinical trial.\n\nAt this point, the patient began a daily regime of oral curcumin complexed with bioperine (to aid absorption), as a single dose of 8 g each evening on an empty stomach. A few months later, she also embarked on a once-weekly course of hyperbaric oxygen therapy (90 min at 2 ATA) which she has maintained ever since. Her paraprotein levels gradually declined to a nadir of 13 g/L, her blood counts steadily improved and there was no evidence of further progressive lytic bone disease.\n\nOutcome and follow-up\nThe patient continues to take oral curcumin 8 g daily without further antimyeloma treatment. Over the last 60 months, her myeloma has remained stable with minimal fluctuation in paraprotein level, her blood counts lie within the normal range and she has maintained good quality of life throughout this period. Repeat bone imaging in 2014 identified multiple lucencies <1 cm in the right hip and degenerative changes in both hips, but these were attributed to osteoarthritis rather than the myeloma. Recent cytogenetic analysis revealed she had no abnormal cytogenetics by fluorescent in situ hybridisation.\n\nDiscussion\nA small but significant number of myeloma patients consume dietary supplements in conjunction with conventional treatment primarily to help cope with the side effects of treatment, manage symptoms and enhance general well-being. Few, if any, use dietary supplementation as an alternative to standard antimyeloma therapy. Here, we describe a case in which curcumin has maintained long-term disease control in a multiply-relapsed myeloma patient. To the best of our knowledge, this is the first report in which curcumin has demonstrated an objective response in progressive disease in the absence of conventional treatment.\n\nCurcumin is a polyphenol derived from the perennial herb Curcuma longa (turmeric) and has, for centuries, been used as a traditional Indian medicine. Several reports published over the two decades have claimed various health benefits of curcumin and this has led to its increasing popularity as a dietary supplement to prevent or treat a number of different diseases.5\n6\n\nThe biological activity of curcumin is indeed remarkable. It is a highly pleiotropic molecule which possesses natural antioxidant, anti-inflammatory, antiseptic and analgesic properties.7 More recently, it has demonstrated antiproliferative effects in a wide variety of tumour cells including myeloma cells and exerts its antiproliferative effects through multiple cellular targets that regulate cell growth and survival.\n\nIn vitro, curcumin prevents myeloma cell proliferation through inhibition of IL-6-induced STAT-3 phosphorylation and through modulation of the expression of NF-kB-associated proteins such as IkB〈,Bcl-2, Bcl-xL, cyclin D1 and IL-68 and apoptosis-related molecules including p53 and Bax.9 In other studies, curcumin was shown to circumvent resistance to dexamethasone, doxorubicin and melphalan as well as potentiate the effects of bortezomib, thalidomide10 and lenalidomide.11 Furthermore, curcumin-induced cell death was not influenced by myeloma molecular heterogeneity.12\n\nThe antimyeloma effects of curcumin in the clinical setting however are less clear. Only one phase I/II study has evaluated curcumin treatment in myeloma patients. These patients were either asymptomatic, relapsed or had plateau phase disease. Treatment with curcumin downregulated the expression of NFkB, COX-2 and STAT3 in peripheral blood mononuclear cells, but no objective responses were observed in any subgroup of patients.13 This may be as a result of small sample size in this study, follow-up was limited to 3 months and clinical responses may have been observed with longer follow-up. However, downregulation of NFkB, COX-2 and STAT3 expression may not correlate with the clinical activity of curcumin and there may be further mechanisms of action that remain unclear, possibly through the modulation of another target. We would not be able to identify any patient-specific mechanisms of activity in this case study, as the patient has been taking curcumin for some time now and baseline bone marrow or peripheral blood samples are not available. However, in the setting of a clinical trial, it may be possible to use next-generation sequencing to help identify a mutation that may be a potential target for curcumin.\n\nAnother study examined its effects in preventing the progression of MGUS and smouldering myeloma to myeloma.14\n15 The results showed that curcumin exerted a trace of biological activity with modest decreases in free light chain and paraprotein levels and a reduction in a marker of bone resorption with curcumin treatment, suggesting the therapeutic potential of curcumin in MGUS and smouldering myeloma. However, more studies are needed to address this further.\n\nWhether such effects are observed in patients with active disease remains to be seen. The fact that our patient, who had advanced stage disease and was effectively salvaged while exclusively on curcumin, suggests a potential antimyeloma effect of curcumin. She continues to take daily curcumin and remains in a very satisfactory condition with good quality of life. This case provides further evidence of the potential benefit for curcumin in myeloma. We would recommend further evaluation of curcumin in myeloma patients in the context of a clinical trial.\nLearning points\nMyeloma is a relapsing-remitting cancer for which there is currently no cure.\n\nCurcumin, a polyphenol derived from turmeric, has been used for many years in some\n\nherbal remedies.\n\nWe report a case of a myeloma patient with advanced myeloma who, in the absence of conventional treatment, plateaued and has remained stable for many years with daily curcumin.\n\nDietary supplements, such as curcumin, may be beneficial for some myeloma patients.\n\n\n\nTwitter: Follow Maggie Lai @MyelomaUK\n\nContributors: AZ and JC involved in treating the described patient initially discussed and planned writing this case. The planning was made with ML of Myeloma UK. Each performed a review of the literature and a summary of the case was provided by AZ and JC to ML who wrote the initial draft. The final paper was edited by AZ and reviewed and edited by JC.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Smith D , Yong K \nMultiple myeloma . BMJ \n2013 ;346 :f3863 \n10.1136/bmj.f3863 23803862 \n2 Kumar SK , Rajkumar SV , Dispenzieri A , et al \nImproved survival in multiple myeloma and the impact of novel therapies . Blood \n2008 ;111 :2516 –20 . 10.1182/blood-2007-10-116129 17975015 \n3 Kumar SK , Dispenzieri A , Lacy MQ , et al \nContinued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients . Leukaemia \n2014 ;28 :1122 –8 . 10.1038/leu.2013.313 \n4 Smith PJ , Clavarino A , Long J , et al \nWhy do some cancer patients receiving chemotherapy choose to take complementary and alternative medicines and what are the risks? \nAsia Pac J Clin Oncol \n2014 ;10 :1 –10 . 10.1111/ajco.12115 \n5 Aggarwal BB , Harikumar KB \nPotential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases . Int J Biochem Cell Biol \n2009 ;41 :40 –59 . 10.1016/j.biocel.2008.06.010 18662800 \n6 Gupta SC , Patchva S , Aggarwal BB \nTherapeutic roles of curcumin: lessons learned from clinical trials . AAPS J \n2013 ;15 :195 –218 . 10.1208/s12248-012-9432-8 23143785 \n7 Aggarwal BB , Sung B \nPharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets . Trends Pharmacol Sci \n2009 ;30 :85 –94 . 10.1016/j.tips.2008.11.002 19110321 \n8 Bharti AC , Donato N , Singh S , et al \nCurcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and Ikappa B alpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis . Blood \n2003 ;101 :1053 –62 . 10.1182/blood-2002-05-1320 12393461 \n9 Li W , Wang Y , Song Y , et al \nA preliminary study of the effect of curcumin on the expression of p53 protein in a human multiple myeloma cell line . Oncol Lett \n2015 ;9 :1719 –24 . 10.3892/ol.2015.2946 25789029 \n10 Sung B , Kunnumakkara AB , Sethi G , et al \nCurcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model . Mol Cancer Ther \n2009 ;8 :959 –70 . 10.1158/1535-7163.MCT-08-0905 19372569 \n11 Wong R , Golombick T , Diamond TH , et al \nCurcumin enhances the cytotoxic and chemo-sensitising effects of lenalidomide in human multiple myeloma cells . J Hematol Malig \n2013 ;3 :1 –7 .\n12 Gomez-Bougie P , Halliez M , Maïga S , et al \nCurcumin induces cell death of the main molecular myeloma subtype, particularly the poor prognosis subgroups . Cancer Biol Ther \n2015 ;16 :60 –5 . 10.4161/15384047.2014.986997 25517601 \n13 Vadhan-Raj S , Weber D , Wang M , et al \nCurcumin downregulates NF-B and related genes in patients with multiple myeloma: results of a phase I/II study . Blood \n2007 ;110 :1177 .\n14 Golombick T , Diamond TH , Badmaev V , et al \nThe potential role of curcumin in patients with monoclonal gammopathy of undefined significance—its effect on paraproteinemia and the urinary N-telopeptide of type I collagen bone turnover marker . Clin Cancer Res \n2009 ;15 :5917 –22 . 10.1158/1078-0432.CCR-08-2217 19737963 \n15 Golombick T , Diamond TH , Manoharan A , et al \nMonoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled cross-over 4 g study and an open-label 8 g extensions study . Am J Hematol \n2012 ;87 :455 –60 . 10.1002/ajh.23159 22473809\n\n",
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{
"abstract": "Imatinib is a crucial therapeutic strategy against chronic myeloid leukemia. Though superficial edema is a common adverse effect of imatinib, massive fluid retention is rarely reported. Here, we report the case of an adolescent who had tolerated imatinib for a long time, and then presented with massive pleural/pericardial effusion during an episode of Campylobacter jejuni bacteremia. A stepwise and comprehensive survey excluded all other plausible causes of disease. The Naranjo scale was used to assess the probability of an adverse effect of medication, and the score turned out to be 9, indicating severe fluid retention to be a definite reaction to imatinib. Drug discontinuation, antibiotic administration, and invasive procedures improved this condition. After this episode, the patient could tolerate imatinib again, illustrating the transient and reversible nature of this reaction. Since prolonged imatinib usage is crucial for chronic myeloid leukemia control, alertness to drug-related adverse effects is recommended, even if the subject has previously shown a good tolerance to the drug due to various physical conditions, especially physiological stressors, like infection or inflammation.",
"affiliations": "Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan.;Department of Pediatrics, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan.;Department of Pediatrics, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan.;Department of Pediatrics, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan.;Department of Pediatrics, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan.;Department of Pediatrics, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan.;Department of Pharmacy, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan.;Department of Pediatrics, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan. Electronic address: [email protected].",
"authors": "Su|Po-Yu|PY|;Tan|Boon Fatt|BF|;Fu|Chun-Min|CM|;Chen|Chi-Nien|CN|;Chou|An-Kuo|AK|;Kung|Po-Jung|PJ|;Liao|Ling-Chun|LC|;Li|Meng-Ju|MJ|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D000069439:Dasatinib",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2021.10.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "28(1)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Chronic myeloid leukemia; Fluid retention; Imatinib mesylate; Pericardial effusion",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D016470:Bacteremia; D002167:Campylobacter; D000069439:Dasatinib; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010490:Pericardial Effusion",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "103-107",
"pmc": null,
"pmid": "34649758",
"pubdate": "2022-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Concurrence of imatinib-induced massive pleural/pericardial effusion and Campylobacter bacteremia in an adolescent with chronic myeloid leukemia.",
"title_normalized": "concurrence of imatinib induced massive pleural pericardial effusion and campylobacter bacteremia in an adolescent with chronic myeloid leukemia"
}
|
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{
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},
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},
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"drugdosagetext": "400 MILLIGRAM, QD",
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"medicinalproduct": "IMATINIB MESYLATE"
}
],
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"patientonsetage": "17",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Pleural effusion",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pericardial effusion",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Campylobacter infection",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Bacteraemia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Influenza",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myocarditis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Su PY, Tan BF, Fu CM, Chen CN, Chou AK, Kung PJ, et al. Concurrence of imatinib-induced massive pleural/pericardial effusion and Campylobacter bacteremia in an adolescent with chronic myeloid leukemia. Journal of Infection and Chemotherapy. 2021;28(1):103-107",
"literaturereference_normalized": "concurrence of imatinib induced massive pleural pericardial effusion and campylobacter bacteremia in an adolescent with chronic myeloid leukemia",
"qualification": "3",
"reportercountry": "TW"
},
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"receivedate": "20211217",
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"receivertype": "6"
},
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"safetyreportid": 20200618,
"safetyreportversion": 2,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220424"
},
{
"companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-321046",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
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{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
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"drugdosagetext": "400 MILLIGRAM, DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Chronic myeloid leukaemia",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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},
{
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},
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"drugtreatmentduration": "3",
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"medicinalproduct": "IMATINIB"
},
{
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"activesubstancename": "IMATINIB"
},
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"medicinalproduct": "IMATINIB"
},
{
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"activesubstancename": "IMATINIB"
},
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"drugauthorizationnumb": "078340",
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"drugcharacterization": "1",
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"drugdosagetext": "200 MILLIGRAM, DAILY",
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosageunit": "003",
"drugtreatmentduration": "4",
"drugtreatmentdurationunit": "804",
"medicinalproduct": "IMATINIB"
}
],
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"patientonsetage": "19",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Pericardial effusion",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Campylobacter infection",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Influenza",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myocarditis infectious",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cytopenia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Su PY, Tan BF, Fu CM, Chen CN, Chou AK, Kung PJ, et al. Concurrence of imatinib-induced massive pleural/pericardial effusion and Campylobacter bacteremia in an adolescent with chronic myeloid leukemia. J Infect Chemother. 2022;28(1):103-107",
"literaturereference_normalized": "concurrence of imatinib induced massive pleural pericardial effusion and campylobacter bacteremia in an adolescent with chronic myeloid leukemia",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20211220",
"receivedate": "20211220",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20205698,
"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": "OBJECTIVE\nTakotsubo cardiomyopathy, also called apical ballooning syndrome, is characterized by regional left ventricular systolic dysfunction that resembles myocardial infarction in its initial presentation; however, it lacks angiographic evidence of coronary artery disease. We evaluated the incidence of takotsubo cardiomyopathy following liver transplant at a diverse urban transplant program.\n\n\nMETHODS\nThis is a retrospective review of patients transplanted at a single center between 2017 and 2019. Here we report 2 cases of takotsubo cardiomyopathy that developed after liver transplantation.\n\n\nRESULTS\nA 65-year-old woman diagnosed with alcoholic cirrhosis underwent a brain-dead donor liver transplant. The postoperative course was complicated by stroke, pulmonary hypertension, and a left internal jugular thrombus. Six months following transplant, the patient developed takotsubo cardiomyopathy with congestive hepatopathy and died of heart failure complications despite maximal medical care. The second case was a 65-year-old woman with alcoholic cirrhosis admitted for a living donor liver transplant. The postoperative period involved recurrent seizures and elevated troponins with markedly reduced ejection fraction, which were appropriately managed. The patient recovered well with supportive care and was discharged to a rehabilitation facility shortly after.\n\n\nCONCLUSIONS\nWe present a series of patients with takotsubo cardiomyopathy after liver transplantation. The diagnosis depends on the clinical presentation and findings on electrocardiography, echocardiography, and cardiac enzymes. Our patients met the Mayo Clinic diagnostic criteria and were appropriately managed according to guidelines. Our report highlights the possibility of pulmonary hypertension contributing to the development of takotsubo cardiomyopathy. Additional studies are needed to establish a definite correlation.",
"affiliations": "Internal Medicine, Henry Ford Hospital, Detroit, Michigan, United States. Electronic address: [email protected].;Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan, United States.;General Surgery, Henry Ford Hospital, Detroit, Michigan, United States.;Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan, United States.;Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan, United States.",
"authors": "Shamaa|Omar|O|;Jafri|Syed-Mohammed|SM|;Shamaa|M Tayseer|MT|;Brown|Kimberly|K|;Venkat|Deepak|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.07.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "239-243",
"pmc": null,
"pmid": "32980136",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Takotsubo Cardiomyopathy Following Liver Transplantation: A Report of 2 Cases.",
"title_normalized": "takotsubo cardiomyopathy following liver transplantation a report of 2 cases"
}
|
[
{
"companynumb": "US-MYLANLABS-2021M1017647",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "HIGH?DOSE",
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"drugindication": "JUGULAR VEIN THROMBOSIS",
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"medicinalproduct": "HEPARIN"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "209932",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "UNK",
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"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "MAGNESIUM SULFATE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SELEXIPAG"
},
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"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "PULMONARY HYPERTENSION",
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"medicinalproduct": "UPTRAVI"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "APIXABAN"
},
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"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "5 MILLIGRAM, BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "JUGULAR VEIN THROMBOSIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ELIQUIS"
}
],
"patientagegroup": null,
"patientonsetage": "65",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHAMAA O, JAFRI S?M, SHAMAA MT, BROWN K, VENKAT D. TAKOTSUBO CARDIOMYOPATHY FOLLOWING LIVER TRANSPLANTATION: A REPORT OF 2 CASES. TRANSPLANT?PROC 2021?53(1):239?243.",
"literaturereference_normalized": "takotsubo cardiomyopathy following liver transplantation a report of 2 cases",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210325",
"receivedate": "20210325",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19056734,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210420"
}
] |
{
"abstract": "Dapsone may be used for Pneumocystis jirovecii pneumonia (PJP) prophylaxis in hematology patients receiving immunosuppressive therapy or after hematopoietic stem cell transplant (HSCT) in the setting of trimethoprim-sulfamethoxazole (TMP-SMX) adverse drug reaction (ADR) history. Dapsone-induced hematological toxicities such as oxidative hemolysis may limit use in these patients and modern assessments of dapsone allergy cross-reactivity in non-HIV patients with a sulfonamide allergy are largely absent. The aim of this single-centre, retrospective study was to describe dapsone usage in hematology patients requiring PJP prophylaxis, including HSCT recipients, over a 12-month period in terms of indications, incidence of dapsone-attributed oxidative hemolysis, and immune cross-reactivity in those previously labeled with a sulfonamide allergy, as well as describing potential opportunities for first-line TMP-SMX PJP prophylaxis reintroduction. Of 24 patients meeting the study inclusion criteria, 12 (50%) were receiving dapsone PJP prophylaxis post-HSCT. No cases of breakthrough PJP infection were noted. Sixteen patients (67%) were initiated on dapsone to avoid the perceived risk of further myelosuppression with TMP-SMX and five patients (21%) because of prior delayed immune-mediated allergy to TMP-SMX. None experienced rash with dapsone therapy. Six patients (25%) were successfully rechallenged on TMP-SMX, including one patient with prior TMP-SMX-associated rash. Four (17%) patients had confirmed oxidative hemolysis, all resulting in dapsone cessation. Dapsone PJP prophylaxis in hematology patients was effective and safe, with nonlife threatening dapsone-related hemolysis noted in a small number. An absence of sulfonamide allergy cross-reactivity was noted, suggesting greater TMP-SMX rechallenges or desensitization could be considered in those receiving dapsone.",
"affiliations": "Pharmacy Department, Austin Health, Heidelberg, Victoria, Australia.;Pharmacy Department, Austin Health, Heidelberg, Victoria, Australia.;Clinical Haematology Department, Austin Health, Heidelberg, Victoria, Australia.;Infectious Diseases Department and Centre for Antibiotic Allergy and Research, Austin Health, Heidelberg, Victoria, Australia.",
"authors": "Urbancic|Karen F|KF|http://orcid.org/0000-0002-9275-578X;Pisasale|Daisy|D|;Wight|Joel|J|;Trubiano|Jason A|JA|http://orcid.org/0000-0002-5111-6367",
"chemical_list": "D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D003622:Dapsone",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12968",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Pneumocystis jirovecii pneumonia; adverse drug reactions; dapsone; hematopoietic stem cell transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000743:Anemia, Hemolytic; D000890:Anti-Infective Agents; D019072:Antibiotic Prophylaxis; D003622:Dapsone; D005260:Female; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006461:Hemolysis; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012189:Retrospective Studies; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12968",
"pmc": null,
"pmid": "30030892",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dapsone safety in hematology patients: Pathways to optimizing Pneumocystis jirovecii pneumonia prophylaxis in hematology malignancy and transplant recipients.",
"title_normalized": "dapsone safety in hematology patients pathways to optimizing pneumocystis jirovecii pneumonia prophylaxis in hematology malignancy and transplant recipients"
}
|
[
{
"companynumb": "AU-MYLANLABS-2018M1096081",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DAPSONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "100 MILLIGRAM, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTIFUNGAL PROPHYLAXIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
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"medicinalproduct": "DAPSONE."
},
{
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"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
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"drugindication": "ANTIFUNGAL PROPHYLAXIS",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Haemolysis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Type IV hypersensitivity reaction",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "URBANCIC KF, PISASALE D, WIGHT J, TRUBIANO JA. DAPSONE SAFETY IN HEMATOLOGY PATIENTS: PATHWAYS TO OPTIMIZING PNEUMOCYSTIS JIROVECII PNEUMONIA PROPHYLAXIS IN HEMATOLOGY MALIGNANCY AND TRANSPLANT RECIPIENTS. TRANSPL-INFECT-DIS 2018?20(6):E12968.",
"literaturereference_normalized": "dapsone safety in hematology patients pathways to optimizing pneumocystis jirovecii pneumonia prophylaxis in hematology malignancy and transplant recipients",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20190102",
"receivedate": "20190102",
"receiver": {
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},
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},
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}
] |
{
"abstract": "The purpose of this study is to report a case of cystoid macular edema (CME) as a rare first manifestation of ocular sarcoidosis after cataract surgery. A 60-year-old male developed a CME following uneventful phacoemulsification cataract extraction on his left eye. It resolved with conventional medical therapy. One year later the patient was diagnosed with bilateral CME. Oral corticosteroid therapy produced a significant regression. His medical and ocular histories were unremarkable and all tests for etiological diagnosis were negative. There were inflammation recurrences in his left eye, which were also treated with steroids. Optical coherence tomography showed complete resolution of foveal thickening without improvement in vision. Four years later, the patient presented with CME in both eyes. The laboratory tests included high angiotensin-converting enzyme levels and a gallium scan which were also consistent with sarcoidosis. Azathioprine was needed for management of ocular involvement, but it was withheld due to side-effects. At the present time, the CME is controlled with low-dose corticoids. Ocular involvement in sarcoidosis occurs in 20-50 % of patients. CME is not often the initial manifestation of the disease, but ocular sarcoidosis may present with a wide variety of ocular symptoms in all parts of the eye. Therefore, sarcoidosis should be kept in mind when evaluating a patient with ocular inflammation.",
"affiliations": "Department of Ophthalmology, Universtiy Hospital of Salamanca, Salamanca, Spain, [email protected].",
"authors": "Cabrillo-Estevez|Lucia|L|;de Juan-Marcos|Lourdes|L|;Kyriakou|Danai|D|;Hernández-Galilea|Emiliano|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-013-9888-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "34(4)",
"journal": "International ophthalmology",
"keywords": null,
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D005128:Eye Diseases; D006801:Humans; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D018918:Phacoemulsification; D012507:Sarcoidosis",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "961-5",
"pmc": null,
"pmid": "24322273",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22605949;19585358;21287227;20970226;14504590;21374555;18297240;18021432;10611110;2625091;9098308;21343403;22595776",
"title": "Cistoid macular edema as first manifestation of sarcoidosis.",
"title_normalized": "cistoid macular edema as first manifestation of sarcoidosis"
}
|
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],
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Cystoid macular oedema",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "18.0",
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},
{
"reactionmeddrapt": "Pyrexia",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Dizziness",
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}
],
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},
"primarysource": {
"literaturereference": "CABRILLO-ESTEVEZ L, JUAN-MARCOS LD, KYRIAKOU D, HERNANDEZ-GALILEA E.. CISTOID MACULAR EDEMA AS FIRST MANIFESTATION OF SARCOIDOSIS.. INT OPHTHALMOL. 2014;34 (4):961-5",
"literaturereference_normalized": "cistoid macular edema as first manifestation of sarcoidosis",
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},
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},
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"sendertype": "2"
},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150528"
},
{
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},
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"drugindication": "CYSTOID MACULAR OEDEMA",
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"drugindication": "CYSTOID MACULAR OEDEMA",
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"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": null,
"patientonsetage": "60",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dizziness",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CABRILLO-ESTEVEZ L,DE JUAN-MARCOS L,KYRIAKOU D,HERNANDEZ-GALILEA E. CISTOID MACULAR EDEMA AS FIRST MANIFESTATION OF SARCOIDOSIS. INTERNATIONAL OPHTHALMOLOGY 2014 AUG;34:4:961-965.",
"literaturereference_normalized": "cistoid macular edema as first manifestation of sarcoidosis",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "ES",
"receiptdate": "20141023",
"receivedate": "20141023",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150529"
}
] |
{
"abstract": "Hypertriglyceridemia-induced acute pancreatitis (HGAP) is the third most common etiology of acute pancreatitis. HGAP can be attributed to genetic disturbances in triglyceride metabolism or multiple secondary causes. Here, we presented three cases for HGAP and explored different therapeutic approaches for treating HGAP. A case series of three patients who presented with HGAP and underwent different therapeutic approaches was conducted. The first patient was a 37-year-old male who presented with nonsevere HGAP; he was treated with conservative therapy with insulin and heparin infusion, which resulted in clinical and laboratory improvement. The second patient was a 64-year-old male with human immunodeficiency virus on multiple highly active antiretroviral therapy. He presented with severe HGAP and multiorgan failure. After initiation of therapeutic plasma exchange, his HGAP resolved. The third patient was a 28-year-old male who presented with recurrent episodes of HGAP; his conservative therapy failed and was eventually escalated to therapeutic plasma exchange (TPE). HGAP can be attributed to genetic disturbances of lipid or secondary etiologies. A nonsevere form of HGAP can be managed with conventional therapy including insulin and heparin; however, severe HGAP may require TPE.",
"affiliations": "Department of Internal Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana.;Department of Internal Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana.;Department of Internal Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana.;Department of Radiology, Ochsner Clinic Foundation, New Orleans, Louisiana.;Department of Internal Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana.;Department of Pulmonary and Critical Care, Ochsner Clinic Foundation, New Orleans, Louisiana.",
"authors": "Joury|Abdulaziz|A|https://orcid.org/0000-0002-6936-8888;Alshehri|Mona|M|;Mahendra|Arjun|A|;Anteet|Mahmoud|M|;Yousef|Mohammad A|MA|;Khan|Abdul M|AM|",
"chemical_list": "D007328:Insulin; D008055:Lipids; D014280:Triglycerides; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "35(2)",
"journal": "Journal of clinical apheresis",
"keywords": "hypertriglyceridemia; pancreatitis; therapeutic plasma exchange",
"medline_ta": "J Clin Apher",
"mesh_terms": "D000328:Adult; D048909:Diabetes Complications; D006493:Heparin; D006801:Humans; D006949:Hyperlipidemias; D015228:Hypertriglyceridemia; D007328:Insulin; D008055:Lipids; D008297:Male; D008875:Middle Aged; D009765:Obesity; D010195:Pancreatitis; D010951:Plasma Exchange; D010956:Plasmapheresis; D014280:Triglycerides",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "131-137",
"pmc": null,
"pmid": "31724761",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Therapeutic approaches in hypertriglyceridemia-induced acute pancreatitis: A literature review of available therapies and case series.",
"title_normalized": "therapeutic approaches in hypertriglyceridemia induced acute pancreatitis a literature review of available therapies and case series"
}
|
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"abstract": "BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.",
"affiliations": "Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA. [email protected].;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Bristol-Myers Squibb, San Francisco, CA, USA.;Bluebird Bio, Cambridge, MA, USA.;Bristol-Myers Squibb, San Francisco, CA, USA.;Bristol-Myers Squibb, Seattle, WA, USA.;University Cancer Center of Toulouse Institut National de la Santé, Toulouse, France.;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].",
"authors": "Samur|Mehmet Kemal|MK|0000-0002-9978-5682;Fulciniti|Mariateresa|M|0000-0002-1432-9742;Aktas Samur|Anil|A|0000-0002-0183-0562;Bazarbachi|Abdul Hamid|AH|0000-0003-0243-4040;Tai|Yu-Tzu|YT|0000-0001-6199-3569;Prabhala|Rao|R|;Alonso|Alejandro|A|;Sperling|Adam S|AS|;Campbell|Timothy|T|;Petrocca|Fabio|F|;Hege|Kristen|K|;Kaiser|Shari|S|;Loiseau|Hervé Avet|HA|;Anderson|Kenneth C|KC|0000-0002-6418-0886;Munshi|Nikhil C|NC|0000-0002-7344-9795",
"chemical_list": "D053301:B-Cell Maturation Antigen",
"country": "England",
"delete": false,
"doi": "10.1038/s41467-021-21177-5",
"fulltext": "\n==== Front\nNat Commun\nNat Commun\nNature Communications\n2041-1723 Nature Publishing Group UK London \n\n21177\n10.1038/s41467-021-21177-5\nArticle\nBiallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma\nhttp://orcid.org/0000-0002-9978-5682Samur Mehmet Kemal [email protected] 123 http://orcid.org/0000-0002-1432-9742Fulciniti Mariateresa 3 http://orcid.org/0000-0002-0183-0562Aktas Samur Anil 12 http://orcid.org/0000-0003-0243-4040Bazarbachi Abdul Hamid 34 http://orcid.org/0000-0001-6199-3569Tai Yu-Tzu 3 Prabhala Rao 35 Alonso Alejandro 3 Sperling Adam S. 3 Campbell Timothy 6 Petrocca Fabio 7 Hege Kristen 6 Kaiser Shari 8 Loiseau Hervé Avet 9 http://orcid.org/0000-0002-6418-0886Anderson Kenneth C. 3 http://orcid.org/0000-0002-7344-9795Munshi Nikhil C. [email protected] 35 1 grid.65499.370000 0001 2106 9910Department of Data Science, Dana Farber Cancer Institute, Boston, MA USA \n2 grid.38142.3c000000041936754XDepartment of Biostatistics, Harvard T. H. Chan School of Public Health Boston, Boston, MA USA \n3 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA USA \n4 grid.251993.50000000121791997Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, New York, NY USA \n5 grid.410370.10000 0004 4657 1992VA Boston Healthcare System, Boston, MA USA \n6 grid.419971.3Bristol-Myers Squibb, San Francisco, CA USA \n7 grid.434678.a0000 0004 0455 430XBluebird Bio, Cambridge, MA USA \n8 grid.419971.3Bristol-Myers Squibb, Seattle, WA USA \n9 University Cancer Center of Toulouse Institut National de la Santé, Toulouse, France \n8 2 2021 \n8 2 2021 \n2021 \n12 86816 10 2020 14 1 2021 © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.\n\nRelapse following BCMA targeted CAR T-cell therapy is frequently observed in patients with multiple myeloma (MM). Here, by single cell transcriptome profiling on serially collected bone marrow samples, the authors report biallelic loss of BCMA as the mechanism of resistance underlying both relapse and lack of response to a second CAR T infusion in a patient with MM.\n\nSubject terms\nCancer genomicsCancer microenvironmentCancer immunotherapyCancer therapeutic resistanceMyelomahttps://doi.org/10.13039/100000054U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)P01 CA155258P50 CA100707Munshi Nikhil C. U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)https://doi.org/10.13039/100000738U.S. Department of Veterans Affairs (Department of Veterans Affairs)5I01BX001584Munshi Nikhil C. Celgene Corporation and Paula and Roger Riney Foundation.issue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\nChimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has provided frequent, deep, and durable responses in relapsed, refractory multiple myeloma (MM), with initial Phase I/II studies reporting 73–100% overall response and 31–69% complete response1–3. However, progression-free survival in some studies have been <12 months, indicating myeloma recurrence despite the persistence of CAR T cells in a number of cases1,2. Importantly, among the small number of patients retreated with the same CAR T cell product at the time of progression, responses have been infrequent4,5. This highlights development of acquired resistance mechanisms6,7, which may preclude effectiveness of the second CAR T infusion, and may also explain relapse following the initial CAR T-cell therapy.\n\nIn this work, by performing single-cell transcriptome profiling on serially collected bone marrow (BM) samples, we show biallelic loss of BCMA as one of the resistance mechanisms to anti-BCMA CAR T-cell therapy with Idecabtagene Vicleucel in a patient with initial response but relapse with resistance to retreatment with the same CAR T-cell product. Furthermore, our results also highlight that MM cells may develop alternative paths to survive without BCMA.\n\nResults\nWe evaluated samples from an individual patient who was diagnosed with IgG lambda MM with hypodiploidy and a complex karyotype with t(8;12) (q24;q14), clonal t(11;14) (q13;q32), and clonal deletion 13. The patient was treated with four lines of therapy including proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody before CAR T-cell therapy, with limited response. The patient was enrolled in a Phase I trial (CRB-401 ClinicalTrials.gov number, NCT02658929) of anti-BCMA CAR T-cell therapy with Idecabtagene Vicleucel (ide-cel) and received 150 × 106 CAR+ T cells at day 0 following lymphodepletion with fludarabine (30 mg/m2 per day) and cyclophosphamide (300 mg/m2 per day) on days −5, −4, and −3, as reported in ref. 1. The patient developed grade 1 cytokine release syndrome and achieved partial response by 3 months. The patient relapsed 9 months after the first CAR T infusion and was treated a second time with identical lymphodepletion and using the same CAR T-cell product as the first infusion but at a higher dose of 450 × 106 CAR+ T cells with no response (Fig. 1A, B).Fig. 1 Response to CAR T cell treatment and microenvironment changes.\nA M spike and lambda free light chain evaluations for the patient. The y axis on left shows the M spike values (blue) and on the right it shows the lambda free light chain values (green). Time points (x axis) marked with red labels also shows the longitudinal sample collection for single-cell RNA sequencing. B Expansion of CAR T cells (y axis) measured with qPCR after first (blue) and second (red) infusions from day 0 to day 60 (x axis). C Timeline of the eight samples collected for single-cell RNA sequencing. D Thirteen single-cell clusters from eight longitudinal bone marrow samples. Annotation of cell clusters are marked in the bottom part with color codes. Cell embedings are shown by using UMAP1 and UMAP2. E Ide-cel expression in single cells. Only limited number of cells are CAR+ at 2 weeks after the first infusion. None of the other time points show CAR+ cells. F Re-clustered T cells divided by time points from study screening to 1 month after second infusion and T-cell annotations for CD4+ and CD8+ cells are shown with color codes. G Percentage of particular T-cell types (y axis) at each time point (x axis) evaluated with single-cell RNA seqeuecning for T-cell clusters (top figure legend). Percentages are reflecting the % of particular cluster at given time point within all T cell populations. H Gene-set enrichment FDR values for differentially expressed genes for two samples collected two weeks after first (blue) and second (green) infusions. I Percentage of T cells (y axis) expressing immune checkpoint inhibitors at each time point (x axis).\n\n\n\nChanges in BM microenvironment post-CAR T-cell therapy\nTo delineate changes in BM cellular components as a potential mechanism underlying lack of response to CAR T-cell reinfusion, we performed single-cell transcriptome profiling on serially collected BM samples (Fig. 1C). Clustering analysis from 37,658 cells from 8 time points, before the first CAR T cell infusion to 1 month after the second infusion, identified 13 clusters consisting of hematopoietic cells and MM cells (Fig. 1D and Supplementary Fig. 1). The BM sample before the first infusion was depleted of CD138+ cells by cell selection. A small number of MM cells were observed at 2 weeks after the first infusion of the CAR T-cell therapy. Thereafter, MM cells became undetectable and remained undetectable until eight months after the first infusion, when biochemical as well as cytological relapse occurred (Fig. 2A and Supplementary Fig. 1B). We observed a predicted suppression of B-cell count at study entry as an effect of the MM cell growth, with B-cell recovery at 1 month coinciding with anti-MM response (3% of all cells) and reaching 18% at 8 months after first infusion (Supplementary Fig. 1B), and again suppressed to 3% at relapse. We detected CAR+ T cells in the BM only at 2 weeks after first infusion, when maximal CAR+ T-cell expansion was observed in blood using reverse-transcription PCR (RT-PCR)-based detection (Fig. 1B, E). We did not detect infused CAR T cells in the BM with single-cell transcriptome profiling after the second CAR T infusion, but a limited expansion was confirmed in the blood using RT-PCR (Fig. 1E). The 6-log expansion of CAR+ T cells in the blood after the first infusion is consistent with observed expansion in the KarMMA study, where 5.5 log expansion was observed in the responding patients with a median peak CAR+ T-cell expansion at day 112. A lower expansion (2-log) with the second infusion may represent environmental influences or MM-intrinsic factors.Fig. 2 Tumor-intrinsic changes.\nA Cell embedings for plasma/multiple myeloma (MM) cells (green colors) and B cells (cream colors) are shown from screening to 2 weeks after second infusion (x axis). B cells are first detected at 1 month after first infusion and increased frequency until relapse. MM cells are detected at the 8 months after first infusion sample and remain same for further time points. B Soluble BCMA (sBCMA) level (y axis) at the study screening, after first infusion, relapse, and after second infusion (x axis) are shown. Time points makerd with * indicates the time points scRNAseq data also available. Screening refers to screening before first infusion (S1). Day 14 and Months 3 are refering to two weeks after first infusion (S2) and 3 months after first infusion (S4). Retreatment Screening is the relapse after first infusion (S6) and Retreatment Day 14 (S7) is 2 weeks after second infusion. C Expression levels of CD138, CCND1, XBP1, and RB1 in multiple myeloma (MM) cells and B cells. Normalized expression level scales are shown with legends. D Copy number predictions for each single cell (columns) from single-cell RNA sequencing data for chromosomal arms (rows). Deletions are shown with blue and gains are shown with red color for MM cells (left) and B cells (right). E Copy number estimates for CD138+ cells after second CAR T-cell infusion using whole exome sequencing. The top panel displays total copy number log-ratio where diploid state is shown with purple line and the second panel displays allele-specific log odds ratio data for allele-specific copy number calls with chromosomes alternating in blue and gray. Third panel shows the corresponding integer (black line for total copy number, red line for minor copy number) copy number calls. The bottom panel shows the predicted clonality of each events. Dark blue colors show regions with colonal copy number alterations and light blue color shows subclonal copy number events. F Percentage (x axis) of single multiple myeloma/plasma cells with various copy number deletions (del) or gains (y axis). Copy number events for each cell predicted using single-cell RNA sequencing. G Somatic mutaitons detected at relapse after second infusion with whole exome sequencing. Nonsense mutation which creates early stop codon in BCMA (top panel) and missense TP53 mutation (bottom panel) are shown in their amino acid locations. Protein domains are shown with color codes in each genes. H Clonal evolution of MM cells from diagnosis to relapse after second CAR T-cell infusion. I Co-occurrences of deletion 17p (del17p) and deletion 16p (del16p) on large-scale MM cohort. Clonal (red color), subclonal (yellow) deletions are shown for newly diagnosed MM patients (columns) and only patients with del16p and/or del17p are shown.\n\n\n\nRe-clustering of the T-cell cluster showed an increased proportion of CD4+ helper and T-regulatory cells (Treg) 2 weeks after first infusion (Fig. 1F, G and Supplementary Fig. 2), and these two clusters had high expression of proliferation-related genes (Fig. 1H and Supplementary Data 1 and 2). However, Treg proportion remained similar at the second infusion, ruling out its impact on lack of expansion of CAR+ T cells. To detect any unusual endogenous T-cell activity that may potentially affect CAR T-cell function, we investigated inhibitory markers CD274 (PD-L1), PDCD1 (PD-1), LAG3, TIGIT at early and late time points including after second infusion. As can be seen (Fig. 1I and Supplementary Table 1), at no time point the proportion of the cells expressing these checkpoint inhibitors is higher then the base line. Moreover, the absence of change in these markers on endogenous T cells does not mean that the CAR+ T cells do not express these markers. However, in absence of detectable CAR T cells there is no direct way to look at expressed inhibitory markers on CAR T cells. Therefore, future studies will require investigation of resistance associated with presence of checkpoint inhibitors.\n\nRole of tumor intrinsic factors in resistance\nAs we did not delineate a role of the BM milieu mediating suppression of CAR T-cell expansion and function following second infusion, we next explored tumor intrinsic factors. We evaluated soluble BCMA (sBCMA) level (produced predominantly by MM cells) in serum at different time points, and observed high levels before the first CAR T cell infusion, which dropped significantly to a very low level coincident with the clinical response; however, sBCMA remained low even at the time of relapse with increased burden of MM, indicating a lack of BCMA production by MM cells (Fig. 2B). We therefore investigated genomic changes in MM cells at the time of relapse. This patient had clonal t(11;14) translocation (96% of all cells) and clonal deletion 13 (94% of all cells) at the time of diagnosis. A similar clonal composition was observed by fluorescence in situ hybridization (FISH) analysis at study enrollment, when 4% of the cells also showed deletion 17p. Our single-cell transcriptomic analysis of BM samples identified three samples (at the time of relapse and post second CAR T-cell infusion) with significant numbers of MM cells, evidenced by expression of CD138 and XBP1 (markers of plasma cells), CCND1 (upregulated in this patient with t(11;14)), and lack of RB1 (downregulated in this patient with del13) (Fig. 2C). Imputation of copy number alterations from single-cell transcriptomic data showed that the majority of MM cells had a deletion of 16p, including the BCMA locus located on 16p13.13. (Fig. 2D). We further validated these findings using deep whole exome sequencing (WES) of purified CD138+ cells collected 2 weeks after the second CAR T infusion. Of note, copy number alterations detected by WES almost completely overlapped with CNAs predicted by single-cell RNA sequencing (scRNAseq), including deletion 16p (Fig. 2E). Before the first CAR T-cell infusion, 4% of BM MM cells showed deletion 17p, whereas after the second infusion both WES and scRNAseq prediction showed that del17p and del16p were clonal, and longitudinal scRNAseq analysis indicated that del17p and del16p co-occurred in the same clone (Fig. 2D, F). Interestingly, WES also identified a high subclonal (~70%) nonsense mutation (p.Q38*) in BCMA that creates an early stop codon in the BCMA gene (Fig. 2G and Supplementary Fig. 3). This biallelic BCMA loss, acquired with one copy deletion and a second copy loss-of-function mutation, provides the molecular basis for lack of BCMA expression in MM cells at the time of relapse.\n\nDiscussion\nThis case represents initial response followed by development of an acquired resistant phenotype as represented by both relapse and then lack of response to second CAR T infusion (Fig. 2H). BCMA represents an important component of plasma cell function, and thus its loss is not frequently observed. However, this case highlights a possibility that myeloma cells may be able to acuire alternative growth mechanisms to survive without BCMA expression and related signaling intermediates. Studies have shown that MM usually shows substantial inter and intra-tumor heterogeneity, which is closely related to progression, resistance to therapy, and recurrences8–12. Loss of several other targets for different treatments, such as CRBN with immunomodulatory agents or BCL-2 with venetoclax, has been associated with resistance to these treatments13,14. A single antigen targeting CAR T-cell treatment may also be affected by the loss of target as a result of tumor evolution and selection. Targeted antigen-negative relapse is one of the main reasons for resistance to CD19-directed CAR T-cell therapy and accounts for ~9–25% of cases of relapse in other hematological cancers3,4,6,7. In addition to antigen loss, immune-mediated rejection of the murine construct may play a role in resistance15. We did observe low level anti-drug antibodies (ADAs) at 6 months post first infusion, which persisted during the retreatment. ADA could have potential impact on CAR T cell expansion following second infusion. However, lack of BCMA expression was likely the predominant factor responsible for lack of response to second infusion. The extent of the role of ADA in this setting will need to be ascertained in a larger cohort of patients in the future. Previously, a large study evaluating CD19-targeted CAR T-cell therapy in B-cell malignincies showed that addition of fludarabine to cyclophosphamide-based lymphodepletion before the first infusion and an increased dose in the second infusion compared to the first infusion would increase the response rate16, both of which were followed in the currect study.\n\nHere we describe emergence of a clone with loss of BCMA target leading to acquired resistance to retreatment. However, as it is equally important and previously shown in other hematological cancers, there are other possible factors such as microenvironmental changes and immune-mediated rejection of the murine construct that may contribute to resistance to CAR T-cell therapies. Here we only report one mechanism with limited power; however, future studies with larger sample size will be able to determine the dominant resistance factors and expected frequency of each mechanism in MM. We also observed a clonal TP53 missense mutation (p.P278T) (Fig. 2G) using WES, suggesting that both TP53 and BCMA had deletion in one allele and mutation in the second allele. We analyzed our data from 300 newly diagnosed MM patients and using a conservative estimate observed del16p in 6% patients (44% were subclonal deletions) and, interestingly, it co-occured with del17p in 77% of the del16p patients (sixfold encrichmnet, hypergeometric test p-value = 3.38e − 11, Fig. 2I). Importantly, we also observed that 36% of patients with del17p also carried del16p. These results support our previous observation regarding similar relative timing for both deletion events8,17, and may highlight the need to carefully examine for BCMA gene alterations in patients being retreated with subsequent BCMA targeting therapy at relapse from initial BCMA CAR T-cell treatment. The co-occurrence of 16p deletion in patients with del 17p also underscores the need to further evaluate the role of BCMA targted therapies in high-risk del17p MM. It would also be important to further investigate, with more sensitive methods, the presence and frequency of very low subclonality del16p. In general, WES data from 1300 newly diagnosed MM patients failed to detect any missense or nonsense mutations in BCMA18. This suggests that pressure of specific BCMA-targeted treatment can select for a very low level of biallelic deletion (BCMA and TP53) in these patients (Fig. 2H). As BCMA has a functional role in MM, such BCMA-independent growth on one hand may indicate a more aggressive phenotype, but it may also suggest a new vulnerability that can be targeted by alternative therapies. Anecdotal instances of post-CAR T-cell sensitivity to various therapies have been reported and the index patient in this report has remained alive 3 years from CAR T-cell therapy.\n\nThis case represents molecular characteristics of MM. It identifies significant genomic evolution that may represent clonal selection and/or induction of new changes under the pressure of therapy. Our results suggest that BCMA-negative cell populations may get selected under strong treatments like CAR T-cell therapies. Although the platform we have used was not sensitive enough to detect the presence of low-level resistant cells at an early stage, our results still support a possible role for sensitive and deep sequencing of BCMA locus before CAR T-cell reinfusion or consideration of sequential BCMA-targeted therapies, to identify the outgrowth of a rare MM cell with BCMA loss. Recently, CAR T-cell therapy approach simultaneously targeting dual antigens BCMA and GPRC5D was shown as one approach to prevent BCMA escape-driven relapse19. The presence of subclonal changes may also provide clinically important information supporting dual antigen-targeted CAR T cell or other combination or maintenance therapies.\n\nMethods\nPatient samples\nAll eight samples for scRNAseq (CD138− sample before the first infusion (S1) and BM mononuclear cells from S2 to S8) and CD138+ sample for WES have been collected from an individual patients’ posterior superior iliac spine area, who was enrolled in a phase I clinical study (CRB-401 ClinicalTrials.gov number, NCT02658929) of bb2121 involving patients with relapsed or refractory MM was initiated. The primary outcome results of this clinical trial have been published1. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice. The protocol was approved by Dana Farber/Harvard Cancer Center Institutional Review Board, and samples and data were obtained after a written informed consent was signed by the patient.\n\nSingle-cell RNA sequencing\nFor all eight samples, single-cell library constructions were performed using Chromium Single Cell 3′ Reagent kits v2. Each sample was processed individually according to 10× genomics protocols. Poly-A selected transcripts were reverse transcribed and full-length cDNA along with cell barcode identifiers were PCR amplified. The constructed libraries then sequenced with Illumina platform using paired-end sequencing. On average each sample sequenced with 118 M reads (range 87 M–141 M) (Suplementary Table 1). The Cell Ranger Suite (v3.1.0) from 10× genomics with GRCh38 reference genome was used to perform sample de-multiplexing, barcode processing and unique molecular identifier counting. Cellranger mkfastq and count funtions were used to quantify the expression values for captured single cells. The filtered gene-barcode matrix from Cellranger output then used for downstream analysis with Seurat (v3.1.5)20,21 to filter out Gel Bead-In Emulsions do not actually contain cells. Estimated number of cells per sample before additional filtering with Seurat20,21 was 5864 (range 4868–7801) and mean reads per cell was 20,682 (range 14,730–28,924). Additional quality control measurements can be found in Supplementary Tables 2 and 3.\n\nFiltered counts then transferred to R and Seurat for downstream analysis. Only cells with at least 200 detected features and only feateres that are detected in 3 or more cells were kept for downstream analysis. After these additional filtering steps with Seurat, 4707 cells (range 3075–6818) per sample with 3695 reads per cell were used (Supplemantary Table 1 and Supplementary Fig. 4). Integration of multiple single-cell datasets was performed using anchored Analysis with SCTransform20,21 workflow and using 5000 integration features. First 20 dimensions for the Principle Componenet Analysis were used for clustering and Uniform Manifold Approximation and Projection analysis. Single-cell visualizations and downstream marker detections then performed as explained in Seurat website. Resolution was set to 0.3 for the clustering analysis. Known cell-type annotations were perfomed using SingleR(v1.4.0)22, as well as known gene surface markers for T, NK, B, plasma cells, monocytes, and erythyrocytes (CD3D, CD3E, CD3G, CD4, CD8A, CD5, NCAM1, CCL5, KLRC1, KLRD1, KLRC2, CD79A, CD79B, CCND1, SLAMF7, XBP1, POU2AF1, CD38, IRF4, CD14, FCGR3A, CD68, PECAM1, HBB) (Supplementary Fig. 1). T-cell subgroups also identified using T-cell subgroup-specific markers (CD4, CD8A, CCR4, CCR6, FOXP3, IL2RA, CCR7, IL7R, CD8A, CD8B, FASLG, IFNG, NKG7, GZMB, GZMH) (Supplemantary Fig. 2). Cytotoxic CD8+ T-cell makers were collected from Zavidij et al.23. Copy number analysis for the scRNAseq was done using CONICSmat(v0.1)24 and plasma cells were compared with B cells as reference set. Only the chromosomal arms that passed Bayesian information criteria > 0 and adjusted p-value < 1e−5 were considered significantly altered. Differentially expressed genes were detected using FindAllMarkers and FindMarkers function in the Seurat21 package. Gene-set enrichment analysis was done using molecular signature database (MSigDb) provided by Broad Institute25,26.\n\nWhole exome sequencing\nWES data for tumor sample generated from CD138+ cells collected after the second infusion. Peripheral blood mononuclear cells were used as germline control. WES libraries generated using Twist Bioscience Human Core Exome Kit and sequenced as 75 bp paired-end reads with Illumina Novoseq platform. The average sequence coverage for targeted regions was 110× for tumor sample and 602× for germline DNA. We aligned paired-end reads using BWA-mem (v0.7.17-r1188)27 to GRCh38. We followed GATK (v4.0.11) best practice to mark duplicated reads with MarkDuplicates function and base quality score recalibration with ApplyBQSR28. Mutect229 was used to call mutations. Only mutation calls with at least 10× coverage for tumor and germline samples and passed FilterMutectCalls function were annoted using Variant Effect Predictor from Ensembl (v100). Allele-specific copy number calls as well as ploidy and purity of the sample were analyzed using FACETS (v0.6.1) (Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing)30.\n\nFISH analysis\nCD138+ sorted BM plasma cells were analyzed by FISH using commercially available probes specific for 8q24.1, del13, 17p13.1, gain11, gain1q22, t(4;14), t(11;14), t(14;16), t(14;20) by Mayo Clinic Laboratories. All probes were set up separately and for each probe, plasma cells (if possible) are scored and the result for each probe is reported.\n\nOther statistical analysis\nAll other analyses were completed in the R programming language. Data preparation and processing were done using ggplot2, cowplot, and dplyr packages. R maftools was used for downstream analysis for the Single Nucleotide Variant (SNV) and small insertion deletion data. Protein domains were combined with SNV calls using ProteinPaint to generate lollipop plots.\n\nDetecting CAR+ cells with qPCR\nCopies of vector transgene per microgram genomic DNA was determined by quantitative PCR (qPCR) as previously described1. Briefly, CD3+ cells were isolated to high purity from whole blood. Genomic DNA from the purified CD3+ cell pellet was extracted and DNA concentration was determined. Purified CD3+ DNA (100 ng) was included in the qPCR reaction for specific quantification of the bb2121 transgene (Psi-gag) and a reference housekeeping gene (RNaseP). Detection and quantification of the Psi-Gag sequence and RNaseP were achieved using target-specific oligonucleotide primers and dual-labeled oligonucleotide hydrolysis probes1. The amplified targets were detected in real time by Stratagene Mx3005P instrument using TaqMan® Universal PCR Master Mix, no UNG (Thermo Fisher Scientific), and quantified using a standard curve. Quantified copies of vector transgene per reaction is reported as copies per standardized input DNA (100 ng). Primer probe sequences are shown in Supplementary Table 4.\n\nReporting summary\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\nSupplementary Information\n\n Descriptions of Additional Supplementary Files\n\n Supplementary Data 1\n\n Supplementary Data 2\n\n Reporting Summary\n\n Peer review information\nNature Communications thanks the anonymous reviewers for their contribution to the peer review of this work.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nThe online version contains supplementary material available at 10.1038/s41467-021-21177-5.\n\nAcknowledgements\nThis study has been supported by NIH grants P01 CA155258 and P50 CA100707, Celgene Corporation and VA Healthcare System Grant 5I01BX001584, and Paula and Roger Riney Foundation grant.\n\nAuthor contributions\nM.K.S. and N.M. designed and conduct the study. M.K.S., M.F., A.A.S., A.H.B., Y.T., R.P., A.A., A.S., T.C., F.P., K.H., S.K., H.A.L., K.C.M., and N.M. collected the data. M.K.S., A.A.S., A.H.B., R.P., and N.M. analyzed the data. All authors discussed the data and wrote the manuscript.\n\nData availability\nThe single-cell RNA sequencing data generated in this study have been deposited in the GEO database under accession code GSE164551. In addition, the single-cell RNA sequencing dataset, BAM file for BCMA locus, SNP counts for allelic copy number, and meta data for single cells after clustering with Seurat are also available in the Harvard Dataverse database under accession code doi:10.7910/DVN/1RKYQ8 [10.7910/DVN/1RKYQ8]. The remaining data are available within the Article, Supplementary Information, or available from the authors upon request.\n\nCompeting interests\nK.C.A. has received consulting fees from Bristol-Myers Squibb, Celgene, Gilead, Janssen, Precision Biosciences, Sanofi-Aventis, Takeda, and Tolero, and on the board of directors and stock options Oncopep. N.C.M. is a consultant for BMS, Janssen, Oncopep, Amgen, Karyopharm, Legened, Abbvie, Takeda, and GSK, and on the board of directors and stock options Oncopep. T.C., K.H., and S.K. are employed by Bristol-Myers Squibb. F.P. is employed by Bluebird Bio. Other authors declare no competing interests.\n==== Refs\nReferences\n1. Raje N Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma N. Engl. J. Med. 2019 380 1726 1737 10.1056/NEJMoa1817226 31042825 \n2. Munshi NC Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa results J. Clin. Oncol. 2020 38 8503 8503 10.1200/JCO.2020.38.15_suppl.8503 \n3. Shah N Chari A Scott E Mezzi K Usmani SZ B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches Leukemia 2020 34 985 1005 10.1038/s41375-020-0734-z 32055000 \n4. D’Agostino M Raje N Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do better? Leukemia 2020 34 21 34 10.1038/s41375-019-0669-4 31780814 \n5. Li C Clinical responses and pharmacokinetics of fully human BCMA targeting CAR T-cell therapy in relapsed/refractory multiple myeloma J. Clin. Oncol. 2019 37 8013 8013 10.1200/JCO.2019.37.15_suppl.8013 \n6. Cheng J Understanding the mechanisms of resistance to CAR T-cell therapy in malignancies Front. Oncol. 2019 9 1237 10.3389/fonc.2019.01237 31824840 \n7. Shah NN Fry TJ Mechanisms of resistance to CAR T cell therapy Nat. Rev. Clin. Oncol. 2019 16 372 385 30837712 \n8. Aktas Samur A Deciphering the chronology of copy number alterations in multiple myeloma Blood Cancer J. 2019 9 39 10.1038/s41408-019-0199-3 30914633 \n9. Robiou du Pont S Genomics of multiple myeloma J. Clin. Oncol. 2017 35 963 967 10.1200/JCO.2016.70.6705 28297630 \n10. Neuse, C. J. et al. Genome instability in multiple myeloma. Leukemia34, 2887–2897 (2020).\n11. Samur, M. K. et al. Genome-wide somatic alterations in multiple myeloma reveal a superior outcome group. J. Clin. Oncol. 38, JCO2000461 (2020).\n12. Rasche L Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing Nat. Commun. 2017 8 268 10.1038/s41467-017-00296-y 28814763 \n13. Gooding, S. et al. Multiple cereblon genetic changes associate with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood, 10.1182/blood.2020007081 (2020).\n14. Cleynen A Variable BCL2/BCL2L1 ratio in multiple myeloma with t(11;14) Blood 2018 132 2778 2780 10.1182/blood-2018-09-876433 30429160 \n15. Shah NN Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial Nat. Med 2020 26 1569 1575 10.1038/s41591-020-1081-3 33020647 \n16. Gauthier, J. et al. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies. Blood, 10.1182/blood.2020006770 (2020).\n17. Maura F Genomic landscape and chronological reconstruction of driver events in multiple myeloma Nat. Commun. 2019 10 3835 10.1038/s41467-019-11680-1 31444325 \n18. Walker BA Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma Blood 2018 132 587 597 10.1182/blood-2018-03-840132 29884741 \n19. de Larrea CF Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape-driven relapse in multiple myeloma Blood Cancer Discov. 2020 1 146 154 10.1158/2643-3230.BCD-20-0020 33089218 \n20. Hafemeister C Satija R Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression Genome Biol. 2019 20 296 10.1186/s13059-019-1874-1 31870423 \n21. Stuart T Comprehensive integration of single-cell data Cell 2019 177 1888 1902 e1821 10.1016/j.cell.2019.05.031 31178118 \n22. Aran D Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage Nat. Immunol. 2019 20 163 172 10.1038/s41590-018-0276-y 30643263 \n23. Zavidij O Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma Nat. Cancer 2020 1 493 506 10.1038/s43018-020-0053-3 33409501 \n24. Muller S Cho A Liu SJ Lim DA Diaz A CONICS integrates scRNA-seq with DNA sequencing to map gene expression to tumor sub-clones Bioinformatics 2018 34 3217 3219 10.1093/bioinformatics/bty316 29897414 \n25. Subramanian A Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles Proc. Natl Acad. Sci. USA 2005 102 15545 15550 10.1073/pnas.0506580102 16199517 \n26. Liberzon A Molecular signatures database (MSigDB) 3.0 Bioinformatics 2011 27 1739 1740 10.1093/bioinformatics/btr260 21546393 \n27. Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Preprint at arXiv, 1303.3997 (2013).\n28. Poplin, R. et al. Scaling accurate genetic variant discovery to tens of thousands of samples. Preprint at bioRxiv, 10.1101/201178 (2018).\n29. Benjamin, D. et al. Calling somatic SNVs and indels with Mutect2. Preprint at bioRxiv, 10.1101/861054 (2019).\n30. Shen R Seshan VE FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing Nucleic Acids Res. 2016 44 e131 10.1093/nar/gkw520 27270079\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2041-1723",
"issue": "12(1)",
"journal": "Nature communications",
"keywords": null,
"medline_ta": "Nat Commun",
"mesh_terms": "D000483:Alleles; D053301:B-Cell Maturation Antigen; D001853:Bone Marrow; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016219:Immunotherapy, Adoptive; D009101:Multiple Myeloma; D059016:Tumor Microenvironment",
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"pubdate": "2021-02-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
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"title": "Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.",
"title_normalized": "biallelic loss of bcma as a resistance mechanism to car t cell therapy in a patient with multiple myeloma"
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"abstract": "Collapsing glomerulopathy (CG) is a well-recognized distinct morphological pattern of proliferative parenchymal injury leading to rapid graft failure. We conducted a single-center retrospective study to evaluate the prevalence, clinicopathological features, and prognosis of CG in renal transplant recepient. We analyzed 2518 renal allograft biopsies performed from 2007 to 2015 and correlated their clinicopathological features. The prevalence of CG was 0.83% (21 out of 2518) of allograft biopsies with a higher prevalence of 1.4% during the period from 2012 to 2015. Out of 21 patients, 18 (85.71%) patients had undergone live donor and 3 (14.28%) patients had undergone deceased donor renal transplant. Hypertension was observed in 3 (14.28%) patients. The mean duration of diagnosis for CG was 1.85 ± 1.91 years. Urinalysis revealed microhematuria in 5 (23.8%) patients. The mean 24 h urinary protein excretion was 4.77 ± 5.3 g and serum creatinine was 2.12 ± 1.5 mg/dl. The predominant native kidney diseases in recipients were chronic glomerulonephritis of unknown etiology in 12 (57.14%) patients and hypertensive nephropathy in 3 (14.28%) patients. CG was associated with rejection in 9 (42.85%), calcineurin-inhibitor toxicity in 2 (9.5%), and BK virus nephropathy in 1 patient. All patients received standard triple immunosuppression. Eleven (52.38%) patients developed graft failure over a mean period of 2.2 ± 1.7 years and 6 (28.57%) patients recovered with stable graft function. CG can coexist with viral infection, drug toxicity, rejection, microvascular injury, etc. CG usually presents with moderate to severe proteinuria and may lead to rapid graft dysfunction and subsequent graft failure in most of the patients.",
"affiliations": "Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.;Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.;Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.;Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.;Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.;Department of Nephrology and Transplantation Medicine, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.;Department of Regenerative Medicine and Cell Therapy, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.",
"authors": "Kanodia|K V|KV|;Vanikar|A V|AV|;Nigam|L K|LK|;Patel|R D|RD|;Suthar|K S|KS|;Patel|H V|HV|;Trivedi|H L|HL|",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-27-34210.4103/ijn.IJN_287_16Original ArticleCollapsing Glomerulopathy- A Troublemaker for the Renal Allograft: Lessons Learnt Kanodia K. V. 1Vanikar A. V. 12Nigam L. K. 1Patel R. D. 1Suthar K. S. 1Patel H. V. 3Trivedi H. L. 231 Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India2 Department of Regenerative Medicine and Cell Therapy, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India3 Department of Nephrology and Transplantation Medicine, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, IndiaAddress for correspondence: Dr. K. V. Kanodia, Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre, Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India. E-mail: [email protected] 2017 27 5 342 346 Copyright: © 2017 Indian Journal of Nephrology2017This 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.Collapsing glomerulopathy (CG) is a well-recognized distinct morphological pattern of proliferative parenchymal injury leading to rapid graft failure. We conducted a single-center retrospective study to evaluate the prevalence, clinicopathological features, and prognosis of CG in renal transplant recepient. We analyzed 2518 renal allograft biopsies performed from 2007 to 2015 and correlated their clinicopathological features. The prevalence of CG was 0.83% (21 out of 2518) of allograft biopsies with a higher prevalence of 1.4% during the period from 2012 to 2015. Out of 21 patients, 18 (85.71%) patients had undergone live donor and 3 (14.28%) patients had undergone deceased donor renal transplant. Hypertension was observed in 3 (14.28%) patients. The mean duration of diagnosis for CG was 1.85 ± 1.91 years. Urinalysis revealed microhematuria in 5 (23.8%) patients. The mean 24 h urinary protein excretion was 4.77 ± 5.3 g and serum creatinine was 2.12 ± 1.5 mg/dl. The predominant native kidney diseases in recipients were chronic glomerulonephritis of unknown etiology in 12 (57.14%) patients and hypertensive nephropathy in 3 (14.28%) patients. CG was associated with rejection in 9 (42.85%), calcineurin-inhibitor toxicity in 2 (9.5%), and BK virus nephropathy in 1 patient. All patients received standard triple immunosuppression. Eleven (52.38%) patients developed graft failure over a mean period of 2.2 ± 1.7 years and 6 (28.57%) patients recovered with stable graft function. CG can coexist with viral infection, drug toxicity, rejection, microvascular injury, etc. CG usually presents with moderate to severe proteinuria and may lead to rapid graft dysfunction and subsequent graft failure in most of the patients.\n\nKeywords\nCollapsing glomerulopathyend-stage renal diseasehypertensionpodocyteproteinuria\n==== Body\nIntroduction\nCollapsing glomerulopathy (CG) was first described by Weiss et al. as a distinct variant of focal segmental glomerulosclerosis (FSGS) with progressive renal failure and pathological changes characterized by segmental or global capillary collapse, visceral epithelial cell hypertrophy and hyperplasia with hyaline droplets, and extensive tubulointerstitial inflammation.[1] Clinically, CG is characterized by nephrotic syndrome (NS) with poor response to therapy, rapidly progressing to end-stage renal disease.[23] CG was known to be associated with human immunodeficiency virus (HIV) infection. However, Detwiler et al. reported CG for the first time in 1994 in patients who were HIV negative.[4] CG in a renal allograft can present as recurrent or as a de novo disease. We conducted this single-center retrospective study to evaluate the prevalence, clinicopathological features, and prognosis of CG in renal transplant.\n\nMaterials and Methods\nWe analyzed renal allograft biopsies performed in our center from 2007 to 2015. All biopsies were performed by nephrologists under ultrasound guidance using 16-gauge renal biopsy needle and subjected to light microscopy. All the slides were examined by three pathologists and were reported according to Banff classification. Immunofluorescence (IF) studies were undertaken in a subset of patients where de novo or recurrent disease was suspected clinically. Electron microscopy was not performed due to its nonavailability. For light microscopy, 3 μm thick paraffin sections were stained for hematoxylin and eosin, periodic acid–Schiff, Jone's methenamine silver, and Gomori's trichrome stains. Cryostat frozen sections were subjected to IF studies using antihuman IgG, IgA, IgM, C3, C1q, and fibrinogen antisera (MP Biomedical, France). C4d antibodies were tested by immunohistochemistry using polyclonal antihuman C4d antisera (BioGenex, CA, USA). Tests for antinuclear antibody, anti-double-stranded deoxyribonucleic acid, anti-neutrophil cytoplasmic antibodies (by enzyme-linked immunosorbent assays [ELISA]), and complement components (C3 and C4) were recorded in pertinent cases. ELISA for HIV and hepatitis B and C virus was also carried out.\n\nDemographics included evaluation for donor and recipient age, gender, human leukocyte antigen match, original disease causing renal failure, disease duration, hypertension, serum creatinine (SCr) (mg/dl), 24 h urinary protein loss (g/24 h), and urinalysis. Hypertension was defined as blood pressure >140/90 mmHg and/or ongoing antihypertensive medication. NS was defined as edema, nephrotic-range proteinuria (>40 mg/m²/h on timed sample, spot albumin to creatinine ratio >2 mg/mg), and hypoalbuminemia (<2.5 g/dl). Adequacy of graft biopsies was defined according to Banff criteria. A biopsy with ten viable glomeruli and two arteries in a sample was considered to be adequate.[5] CG was defined morphologically if at least one glomerulus revealed segmental or global collapse of the glomerular capillary tuft with hyperplasia and hypertrophy of visceral epithelial cells. A total number of glomeruli with percentage of globally/segmentally collapsed capillary tufts were reported. Associated involvement of tubulointerstitial compartment in the form of active interstitial inflammation/fibrosis, tubular atrophy, and microcystic dilatation was reported as percentage of cortical area involved. Tubular atrophy was graded as ct1, ct2, and ct3 if ≤25%, 26%–50%, and >50% of the cortex revealed atrophy, respectively. Similarly, interstitial fibrosis was graded as ci1, ci2, and ci3 if ≤25%, 26%–50%, and >50% of the cortex showed fibrosis, respectively.\n\nAll the patients received the standard triple drug immunosuppression according to KDIGO clinical practice guidelines.[6]\n\nStatistical analysis was performed and continuous data were expressed as mean ± standard deviation, non-continuous data were expressed in percentage and numerical values.\n\nResults\nTwenty-one (0.83%) biopsies showed features of CG out of 2518 renal allograft biopsies performed from 2007 to 2015. However, a higher prevalence of CG, 1.4% was observed during the period from 2012 to 2015. Out of these 21 patients, 18 (85.71%) patients had undergone live donor and 3 (14.28%) patients had undergone deceased donor renal transplant. Males were predominantly affected (male:female 20:1). The mean age of patients was 35 ± 3.65 years. CG was recorded at a mean interval of 1.85 ± 1.91 years posttransplant. Hypertension was noted in 3 (14.28%) patients. Urinalysis revealed microscopic hematuria in 5 (23.8%) patients. The mean 24 h urinary protein excretion was 4.77 ± 5.3 g, and mean SCr was 2.12 ± 1.5 mg/dl [Table 1]. All the patients were serologically nonreactive for HIV, hepatitis B surface antigen, and hepatitis C virus. The predominant native kidney diseases leading to chronic renal failure were chronic kidney disease (CKD) of unknown origin in 12 (57.14%), hypertensive nephropathy in 3 (14.28%) followed by 1 patient each of diabetic nephropathy, sarcoidosis, pauci-immune crescentic glomerulonephritis (GN), C3 glomerulopathy, solitary kidney with CGN, and IgA nephropathy [Table 2]. All the renal biopsies were adequate for interpretation with mean number of glomeruli being 12.43 ± 5.39. The mean number of glomeruli that revealed global/segmental capillary collapse was 3.81 ± 4.29 [Table 3]. Associated focal global sclerosis was observed in 3.25 ± 1.04 glomeruli. Tubular microcystic dilatation was noted in 6 (28.57%) biopsies. Tubular atrophy was graded as ct1 in 15 (71.43%), ct2 in 3 (14.28%), and ct3 in 3 (14.28%) biopsies and interstitial fibrosis as ci1 in 14 (66.67%) biopsies, ci2 in 6 (28.57%), and ci3 in 1 (4.76%) [Table 4]. Vascular changes were noted in 9 (42.8%) patients. Out of nine, five had mild arteriosclerosis, two had nodular subintimal hyalinosis, and two had mucoid intimal proliferation with fibrinoid necrosis of vessel wall suggestive of thrombotic microangiopathy (TMA).\n\nTable 1 Demographic and laboratory parameters (n=21)\n\nTable 2 Native renal diseases of recipients\n\nTable 3 Histological features of renal allograft biopsies\n\nTable 4 Morphological diagnosis of renal allograft biopsies\n\nCG alone was reported in 7 (33.3%) patients [Figure 1a], and CG associated with rejection was noted in 9 (42.85%) patients [Figure 1b]. Out of these 9 patients, acute T-cell rejection (TCR) + antibody-mediated rejection (AMR) was observed in 4 (19%), AMR in 4 (19%), and acute TCR in 1 (4.76%) case. AMR was noted in the form of glomerulitis, peritubular capillaritis along with linear C4d deposits across the peritubular capillary membranes, whereas TCR was reported according to tubulitis, intimal arteritis, and interstitial infiltration. CG with acute TMA was reported in 2 (9.5%) patients. Two (9.5%) patients with CG associated with calcineurin inhibitor (CNI) toxicity revealed nodular subintimal hyalinosis with stripped pattern of interstitial fibrosis, and tubular atrophy. One patient also had associated BK virus (BKV) nephropathy.\n\nFigure 1 (a) Glomerular collapse with hyperplasia/hypertrophy of podocytes (periodic acid–Schiff, ×400). (b) Collapsing glomerulopathy and acute antibody-mediated rejection (antihuman C4d antisera, ×200)\n\nIF study was performed in five (23.8%) cases, of which one case showed coarse granular deposits of complement C3 of +3 intensity, along the capillary wall consistent with diagnosis of recurrent C3 glomerulopathy. The second case revealed granular deposits of IgG, IgM and C3 of +2 intensity across the capillary walls and segmental mesangial region, consistent with de novo immune complex glomerulopathy (primary disease was pauci-immune GN). The third case showed granular capillary wall staining of +2 intensity with antihuman IgG antiserum only, and the remaining two cases showed the absence of any immune deposits (native renal primary disease was CKD of unknown origin in these three cases).\n\nAll the patients continued to follow the standard triple drug immunosuppression i.e., prednisolone 20 mg/day, Tacrolimus 3.5 mg/day and Mycophenolate sodium 360 mg four times a day. Even in cases with CNI toxicity the patients were kept on triple immunosuppression with standard dose. About sixteen patients underwent plasmapheresis. Plasmapheresis was performed on Cobe Spectra version 7 (Gambro China), on alternate days by exchanging 80-90% total plasma volume per session (approx 1.5 lts). Replacement of the removed plasma was done with 40% colloids (20% albumin) and 60% crystalloids (normal saline). Post plasmapheresis all the patients were given i.v. Immunoglobulin (10 gm/day) for 5 days. Sirolimus could not be offered as all the patients had significant proteinuria. We did not use Rituximab in any of our patients. However, over a mean follow-up period of 2.5 ± 1.52 years, four (19.04%) patients were lost for follow-up and six (28.57%) patients had stable graft function with mean SCr of 1.89 ± 0.82 mg/dl and urinary protein leak of <+1 by dipstick method. Eleven (52.38%) patients developed graft failure over a mean period of 2.2 ± 1.7 years.\n\nDiscussion\nCG is now a well-recognized distinct morphological pattern of proliferative parenchymal injury with a poor response to empirical therapy.[7] CG in renal allografts has been reported in literature in the form of few case reports and small studies [Table 5].[891011] In the present study, the overall prevalence of CG in renal transplant was 0.83%. However, we report a higher prevalence of 1.4% in the last 4 years, which shows an increasing awareness of disease in recent years. Similarly, Meehan et al. have also reported an overall prevalence of de novo CG of 0.6%. However, the prevalence in the same study over the period of 1993–1997 was 3.2%.[9]\n\nTable 5 Review of literature: De novo/recurrent collapsing glomerulopathy\n\nThe predominant native kidney disease was CKD of unknown etiology (57.14%) leading to end stage renal disease, so CG could be de novo/recurrent. The majority of patients presented as end stage renal disease, so we did not have biopsy-proven evidence of native disease of FSGS.\n\nCG was diagnosed over a mean period of 1.85 ± 1.91 years posttransplant. Other reports showed that CG in allograft can occur anytime from 6 to 98 months after transplantation.[9101112] The range of proteinuria in our study was 1.3–6.7 g/24 h and SCr was 1.4–4.6 mg/dl. Swaminathan et al. have also reported high-range proteinuria and high SCr levels in patients with CG versus patients with noncollapsing FSGS in kidney transplant.[12]\n\nMeehan et al. have reported the role of CNI induced hyaline arteriosclerosis and ischemic changes in the development of CG.[9] We have also observed associated CNI toxicity in two patients. One patient out of the two had acute TMA, suggesting role of microvascular injury secondary to CNI toxicity. Other authors have also reported similar findings in their studies suggesting the role of ischemia in the pathogenesis of CG.[9111213] Nadasdy et al. have observed zonal distribution of glomerular collapse in three allograft nephrectomies with obliterative vascular changes and also mentioned that CG in transplant is not same as CG in native kidneys, rather it represents pattern of renal injury.[14]\n\nHIV and parvovirus B19 are known to be associated with CG.[15] We observed SV40 antigen positivity in one patient with CG, suggesting that other viral pathogens may be associated in the genesis of CG. Other authors have also observed the role of BKV in FSGS.[1617]\n\nShah et al. have mentioned APOL1 polymorphism (G1 and G2) as risk factors for the development of FSGS and chronic kidney disease. They observed two renal allograft failures in recipients who received kidneys from deceased donors having APOL1 polymorphism.[18]\n\nGraft dysfunction may be due to associated acute rejection and immune complex glomerulopathy in CG. We observed 9 (45%) cases of CG with rejection, 8 with acute TCR and AMR, and 1 with chronic TCR. Three patients had immune complex deposits, and recurrence of C3 glomerulopathy was observed in 1 case. Other authors also reported similar results.[91011] Plasmapheresis has been attempted to treat / de novo recurrent focal and segmental glomerulosclerosis with little benefit.[1011] Thus, prognosis of CG remains dismal. Most of the studies have reported that patients with CG eventually develop graft failure over a variable time period.[91011] We also have observed that 11 (52.38%) out of 21 patients in our study developed graft failure over a period of 2.2 ± 1.7 years.\n\nAs such there is no evidence based therapy for CG for renal allograft patients. Current regimens comprises of high dose steroids and other immunosuprresants, along with plasmapharesis but success of these regimens is limited.[19]\n\nConclusions\nCG usually presents with moderate to marked proteinuria with rapid graft dysfunction leading to graft failure in most of the transplant patients. CG in renal allograft can coexist with viral infection, drug toxicity, rejection and microvascular injury, etc.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Weiss MA Daquioag E Margolin EG Pollak VE Nephrotic syndrome, progressive irreversible renal failure, and glomerular “collapse”: A new clinicopathologic entity? Am J Kidney Dis 1986 7 20 8 3510532 \n2 Albaqumi M Soos TJ Barisoni L Nelson PJ Collapsing glomerulopathy J Am Soc Nephrol 2006 17 2854 63 16914539 \n3 Schwimmer JA Markowitz GS Valeri A Appel GB Collapsing glomerulopathy Semin Nephrol 2003 23 209 18 12704581 \n4 Detwiler RK Falk RJ Hogan SL Jennette JC Collapsing glomerulopathy: A clinically and pathologically distinct variant of focal segmental glomerulosclerosis Kidney Int 1994 45 1416 24 8072254 \n5 Racusen LC Solez K Colvin RB Bonsib SM Castro MC Cavallo T The Banff 97 working classification of renal allograft pathology Kidney Int 1999 55 713 23 9987096 \n6 Kasiske BL Zeier MG Chapman JR Craig JC Ekberg H Garvey CA KDIGO clinical practice guideline for the care of kidney transplant recipients: A summary Kidney Int 2010 77 299 311 19847156 \n7 Albaqumi M Barison L Current views on collapsing glomerulopathy J Am Soc Nephrol 2008 19 1276 81 18287560 \n8 Kanodia KV Vanikar AV Patel RD Shah PR Nagpal M Firoz A De novo collapsing glomerulopathy in a renal allograft recipient Saudi J Kidney Dis Transpl 2008 19 793 5 18711298 \n9 Meehan SM Pascual M Williams WW Tolkoff-Rubin N Delmonico FL Cosimi AB De novo collapsing glomerulopathy in renal allografts Transplantation 1998 65 1192 7 9603167 \n10 Gupta R Sharma A Agarwal SK Dinda AK Collapsing glomerulopathy in renal allograft biopsies: A study of nine cases Indian J Nephrol 2011 21 10 3 21655163 \n11 Stokes MB Davis CL Alpers CE Collapsing glomerulopathy in renal allografts: A morphological pattern with diverse clinicopathologic associations Am J Kidney Dis 1999 33 658 66 10196006 \n12 Swaminathan S Lager DJ Qian X Stegall MD Larson TS Griffin MD Collapsing and non-collapsing focal segmental glomerulosclerosis in kidney transplants Nephrol Dial Transplant 2006 21 2607 14 16705026 \n13 Mubarak M Collapsing focal segmental glomerulosclerosis: Current concepts World J Nephrol 2012 1 35 42 24175240 \n14 Nadasdy T Allen C Zand MS Zonal distribution of glomerular collapse in renal allografts: Possible role of vascular changes Hum Pathol 2002 33 437 41 12055680 \n15 Tanawattanacharoen S Falk RJ Jennette JC Kopp JB Parvovirus B19 DNA in kidney tissue of patients with focal segmental glomerulosclerosis Am J Kidney Dis 2000 35 1166 74 10845832 \n16 Li RM Branton MH Tanawattanacharoen S Falk RA Jennette JC Kopp JB Molecular identification of SV40 infection in human subjects and possible association with kidney disease J Am Soc Nephrol 2002 13 2320 30 12191976 \n17 Hirsch HH Knowles W Dickenmann M Passweg J Klimkait T Mihatsch MJ Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients N Engl J Med 2002 347 488 96 12181403 \n18 Shah PB Cooper JE Lucia MS Boils C Larsen CP Wiseman AC APOL1 polymorphisms in a deceased donor and early presentation of collapsing glomerulopathy and focal segmental glomerulosclerosis in two recipients Am J Transplant 2016 16 1923 7 26849829 \n19 Mubarak M Collapsing glomerulopathy in transplanted kidneys: Only a tip of the iceberg? J Transplant Technol Res 2011 1 105e\n\n",
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"reactionoutcome": "6"
}
],
"summary": null
},
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"literaturereference": "KANODIA KV, VANIKAR AV, NIGAM LK, PATEL RD, SUTHAR KS, PATEL HV ET AL.. COLLAPSING GLOMERULOPATHY- A TROUBLEMAKER FOR THE RENAL ALLOGRAFT: LESSONS LEARNT. INDIAN JOURNAL OF NEPHROLOGY. 2017;27:342-6",
"literaturereference_normalized": "collapsing glomerulopathy a troublemaker for the renal allograft lessons learnt",
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},
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"seriousnesslifethreatening": null,
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"transmissiondate": "20180321"
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{
"abstract": "Thromboembolism is a known complication of pacemaker implantation. However, published literature describes only a few cases, in which the events occurred in absence of antithrombotic prophylaxis, not routinely employed for its prevention in current clinical practice. We report a case of pacemaker lead-associated thrombosis in a patient taking continuative oral anticoagulant therapy with edoxaban tosylate (edoxaban). No data in present literature supports the use of anticoagulant prophylaxis for pacemaker lead thrombosis. In our report ongoing treatment with edoxaban proved ineffective for thrombosis prevention. We also discuss the role of three-dimensional transthoracic echocardiography for diagnostic assessment of thrombosis in a fragile patient.",
"affiliations": "Internal Medicine 3, University Hospital of Padova, Via Giustiniani 2, 35128, Padua, Italy. [email protected].;Cardiology Clinic, University Hospital of Padova, Padua, Italy.;Internal Medicine 3, University Hospital of Padova, Via Giustiniani 2, 35128, Padua, Italy.;Internal Medicine 3, University Hospital of Padova, Via Giustiniani 2, 35128, Padua, Italy.",
"authors": "Di Vincenzo|Angelo|A|;Rizzo|Alessandro|A|;Russo|Lucia|L|;Mioni|Roberto|R|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-018-1733-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "46(4)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Anticoagulation; Edoxaban; Pacemaker; Thrombosis",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D004452:Echocardiography; D065427:Factor Xa Inhibitors; D006801:Humans; D010138:Pacemaker, Artificial; D011725:Pyridines; D013844:Thiazoles; D013927:Thrombosis",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "549-550",
"pmc": null,
"pmid": "30182222",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10965084;11888964;29231094;7702196",
"title": "Pacemaker-associated thrombosis in ongoing therapy with edoxaban tosylate.",
"title_normalized": "pacemaker associated thrombosis in ongoing therapy with edoxaban tosylate"
}
|
[
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"companynumb": "IT-DSJP-DSE-2018-140365",
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"activesubstancename": "INSULIN NOS"
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{
"reactionmeddrapt": "Thrombosis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DI VINCENZO A? RIZZO A? RUSSO L? MIONI R?. PACEMAKER?ASSOCIATED THROMBOSIS IN ONGOING THERAPY WITH EDOXABAN TOSYLATE.. JOURNAL OF THROMBOSIS + THROMBOLYSIS. 2018",
"literaturereference_normalized": "pacemaker associated thrombosis in ongoing therapy with edoxaban tosylate",
"qualification": "1",
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},
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},
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"transmissiondate": "20181010"
}
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{
"abstract": "BACKGROUND\nC1q is an essential part of the classical pathway of complement activation. Genetic deficiencies, caused by homozygous mutations in one of the C1q genes, are rare and are strongly associated with development of systemic lupus erythematosus (SLE). Here we describe a C1q-deficient patient with a compound heterozygous mutation.\n\n\nMETHODS\nSerum was analysed with enzyme-linked immunosorbent assay (ELISA) and Western blot for the presence of C1q, and DNA and RNA sequencing was performed to identify the mutations and confirm that these were located on different chromosomes.\n\n\nRESULTS\nThe medical history of the patient includes SLE diagnosis at age 11 years with cerebral involvement at age 13, various infections, osteonecrosis and hemophagocytic syndrome. Using ELISA and Western blot, we confirmed the absence of C1q in the serum of the patient. Using DNA sequencing, two mutations in the C1QC gene were identified: c.100G > A p.(Gly34Arg) and c.205C > T p.(Arg69X). With RNA sequencing we confirmed that the mutations are located on different chromosomes.\n\n\nCONCLUSIONS\nThe patient described in this case report has a compound heterozygous mutation in C1QC resulting in C1q deficiency.",
"affiliations": "1 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.;1 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.;2 Sanquin Diagnostic Services, Amsterdam, the Netherlands.;2 Sanquin Diagnostic Services, Amsterdam, the Netherlands.;2 Sanquin Diagnostic Services, Amsterdam, the Netherlands.;3 Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Rheumatology and Immunology, Amsterdam, the Netherlands.;4 Spaarnegasthuis, Hoofddorp, the Netherlands.;5 Radboud University Medical Center, Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Nijmegen, the Netherlands.;4 Spaarnegasthuis, Hoofddorp, the Netherlands.;1 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.;1 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.;1 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.",
"authors": "Lubbers|R|R|https://orcid.org/0000-0002-8661-4833;Beaart-van de Voorde|L J J|LJJ|;van Leeuwen|K|K|;de Boer|M|M|;Gelderman|K A|KA|;van den Berg|M J|MJ|;Ketel|A G|AG|;Simon|A|A|;de Ree|J|J|;Huizinga|T W J|TWJ|;Steup-Beekman|G M|GM|;Trouw|L A|LA|",
"chemical_list": "D015922:Complement C1q",
"country": "England",
"delete": false,
"doi": "10.1177/0961203319865029",
"fulltext": "\n==== Front\nLupusLupusLUPsplupLupus0961-20331477-0962SAGE Publications Sage UK: London, England 10.1177/096120331986502910.1177_0961203319865029Case ReportComplex medical history of a patient with a compound heterozygous mutation in C1QC https://orcid.org/0000-0002-8661-4833Lubbers R 1Beaart-van de Voorde L J J 1van Leeuwen K 2de Boer M 2Gelderman K A 2van den Berg M J 3Ketel A G 4Simon A 5de Ree J 4Huizinga T W J 1Steup-Beekman G M 1Trouw L A 161 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands2 Sanquin Diagnostic Services, Amsterdam, the Netherlands3 Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Rheumatology and Immunology, Amsterdam, the Netherlands4 Spaarnegasthuis, Hoofddorp, the Netherlands5 Radboud University Medical Center, Center for Immunodeficiency and Autoinflammation, Department of Internal Medicine, Nijmegen, the Netherlands6 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the NetherlandsLA Trouw, Leiden University Medical Center, Department of Immunohematology and Blood Transfusion, E3-P, PO Box 9600, 2300 RC Leiden, the Netherlands. Email: [email protected] 7 2019 9 2019 28 10 1255 1260 11 3 2019 28 6 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Introduction\nC1q is an essential part of the classical pathway of complement activation. Genetic deficiencies, caused by homozygous mutations in one of the C1q genes, are rare and are strongly associated with development of systemic lupus erythematosus (SLE). Here we describe a C1q-deficient patient with a compound heterozygous mutation.\n\nMaterial and methods\nSerum was analysed with enzyme-linked immunosorbent assay (ELISA) and Western blot for the presence of C1q, and DNA and RNA sequencing was performed to identify the mutations and confirm that these were located on different chromosomes.\n\nResults\nThe medical history of the patient includes SLE diagnosis at age 11 years with cerebral involvement at age 13, various infections, osteonecrosis and hemophagocytic syndrome. Using ELISA and Western blot, we confirmed the absence of C1q in the serum of the patient. Using DNA sequencing, two mutations in the C1QC gene were identified: c.100G > A p.(Gly34Arg) and c.205C > T p.(Arg69X). With RNA sequencing we confirmed that the mutations are located on different chromosomes.\n\nDiscussion\nThe patient described in this case report has a compound heterozygous mutation in C1QC resulting in C1q deficiency.\n\nC1q deficiencycompound heterozygousFFPmutationSLEZonMwhttps://doi.org10.13039/501100001826Vidi grant no. 91712334\n==== Body\nIntroduction\nThe complement system consists both of soluble and membrane-bound proteins. Activation can occur via three different pathways: the classical pathway (CP), the lectin pathway and the alternative pathway. The CP is activated when C1q is bound to immunoglobulin M (IgM), IgG immunocomplexes or pentraxins.1 Many complement proteins are produced by hepatocytes, but cells of the immune system also produce several complement proteins.2 Importantly, C1q is produced not by hepatocytes but largely by cells of myeloid lineage. C1q has been described to have other functions outside the complement system cascade: in the remodelling of the maternal decidua during pregnancy, during embryonic development, in neurological synapse function and in the coagulation process.3 The C1q protein is a molecule of 480 kDa that has six identical arms. Each arm consists of three combined peptide chains: A, B and C. These peptide chains are generated from three different genes: C1QA, C1QB and C1QC, which have a synchronized transcription.4\n\nC1q deficiency is a rare condition with more than 70 documented cases from at least 45 different families.5 These deficiencies all are the result of homozygous mutations in one of the three C1q genes, except in one case with a compound heterozygous mutation in C1QA.6 Patients with C1q deficiency have various clinical presentations and outcomes.7 Most common is the diagnosis of systemic lupus erythematosus (SLE) in early childhood and recurrent infections.6–8 Other common clinical manifestations are alopecia, Raynaud phenomenon, and involvement of the central nervous system, and Sjögren syndrome and hyper-IgM syndrome have been reported.5–7 Treatment of C1q-deficient patients mainly focuses on the treatment of symptoms. For combating the C1q deficiency itself, intravenous administration of fresh frozen plasma (FFP) is used. In rare cases allogenic hematopoietic stem cell transplantation has been performed.9,10\n\nHere we describe a patient with C1q deficiency based on a compound heterozygous mutation in the C1QC gene. This patient was treated with FFP for more than a decade; over time it has resulted in various adverse reactions ranging from mild to anaphylactic, which led to discontinuation of the FFP therapy.\n\nMaterial and methods\nPatient\nThe patient is a 29-year-old Dutch woman diagnosed with C1q deficiency since early childhood. Blood was obtained from the patient on signing an informed consent in compliance with the Declaration of Helsinki.\n\nSamples\nBlood was collected from the patient to obtain serum as well as peripheral blood mononuclear cells (PBMCs) using Ficoll-Paque density gradient centrifugation.\n\nWestern blot\nWith Western blot the availability of C1q was examined by detection of the three chains of the C1q protein. Serum from the patient and normal human serum (NHS), which was used as a positive control, were applied in reduced and non-reduced sodium dodecyl sulphate conditions. Western blot was performed using previously described methods.11\n\nEnzyme-linked immunosorbent assay (ELISA)\nC1q measurement by an in-house–developed ELISA was performed as previously described.12 In short, plates were coated with mouse anti-human C1q ((2204), Nephrology Department, Leiden University Medical Center (LUMC)) in coating buffer (0.1 M Na2CO3, 0.1 M NaHCO3, pH 9.6), samples were incubated at 37℃ and detection was performed with rabbit anti-human C1q (Dako catalogue no. A0136) for one hour at 37℃ and subsequently a goat anti-rabbit horseradish peroxidase (Dako catalogue no. P0448), also incubated for one hour at 37℃. The substrate was added to the plates using 2,2'-azino-bis-3-ethyl benzthiazoline-6-sulphonic acid, and the signal was measured at an absorbance level of 415 nm using a Biorad iMark Microplate Absorbance Reader.\n\nRNA isolation and complementary DNA (cDNA) preparation\nPBMCs (1 × 106 cells/ml) from the patient were cultured for 72 hours in Roswell Park Memorial Institute (RPMI) (Gibco) culture medium supplemented with +1% penicillin/streptomycin, +1% GlutaMAX and +8% foetal calf serum. PBMCs were cultured either in medium alone or in the presence of dexamethasone (10 µM, Pharmacy LUMC) and interferon (IFN)-γ (200 U/ml, PeproTech), to increase C1QA/B/C expression.13 After 72 hours RNA was isolated from the PBMCs using the mirVana microRNA isolation kit (Life Technologies catalogue no. AM1561) according to the manufacturer’s protocol. The isolated RNA was subsequently treated with DNase I, Amplification Grade (Invitrogen), and cDNA was synthesized using SuperScript III (200 U/µl, Invitrogen).\n\nIon Torrent sequencing\nAn AmpliSeq custom panel (Thermo Fisher Scientific, Waltham, MA, USA) was used to sequence the coding regions of the following genes: C4A, C2, C1S, C1R, DNASE1L3, TREX1, MASP2, C4B, C1QA, C1QB, C1QC, PLG and SERPING1. Library preparation and sequencing was performed according to manufacturer protocols on an S5 system (Thermo Fisher Scientific).\n\nPolymerase chain reaction (PCR)\nTo confirm mutations found by Ion Torrent sequencing and to test whether the mutations found were on different alleles, mutation (allele)-specific PCR was used on the patient’s cDNA. We used the Rapid Cycler technology (BioFire Diagnostics, Salt Lake City, UT, USA) with 50 cycles of five seconds at 95℃, 30 seconds at 65℃ and 60 seconds at 72℃, in 15 μl of PCR buffer containing 2 U of Taq polymerase (Promega Benelux, Leiden, the Netherlands), 2 U of TaqStart antibody (Takara, Mountain View, CA, USA), 50 ng of each primer, 200 μM for each of the deoxyribonucleoside triphosphates, 50 mM KCl, 1.5 mM MgCl2, 0.1% (v/v) Triton X-100, 10 mM Tris, pH 9.0 at 25℃, in 10 μl glass capillaries (BioFire Diagnostics). The C1QC primer sequences for cDNA are shown in Table 1.\nTable 1 C1QC primer sequences\n\nName of Primer\tSequence\t\nC1QC-exon2-fw\tGCCCCTCAGGGGCCAAGCCAACAC\t\nC1QC-exon2-mut-fw\tGGGCCAAGCCAACACAGGCTGCTTCA\t\nC1QC-exon2-wt-fw\tGGGCCAAGCCAACACAGGCTGCTTCG\t\nC1QC-exon3-rev\tGGTAAGCCGGGTTCTCCCTTCTGC\t\nC1QC-exon3-mut-rev\tTCCCTTCTGCCCTTTGGGTCCACA\t\nC1QC-exon3-wt-rev\tTCCCTTCTGCCCTTTGGGTCCACG\t\n\n\nSanger sequencing\nPCR products from genomic DNA and cDNA were sequenced on an automated fluorescent sequencer (ABI 3730; Thermo Fisher Scientific) with the use of Big Dye Terminator (v.1.1) chemistry (Thermo Fisher Scientific). Primers used for sequencing were the same as those used for the PCR. For cDNA numbering, the A of the ATG translation initiation codon was taken as 1. This codon is codon 1. NM_172369.4 was used as a reference sequence.\n\nResults\nPatient medical history\nHere we describe a Dutch woman born from two Caucasian non-consanguineous parents. She has two half brothers who are reported to be healthy. Her C1q deficiency was diagnosed at the age of 5. The patient has encountered many different clinical problems, including infections and neurological, vascular and bone complications. Her case will be presented per disease manifestation and not in chronological order. The use of FFP throughout her medical history will be discussed separately.\n\nInfections\nDuring the first year of her life, the patient suffered from recurring otitis and gingivitis. She was reported to be a non-responder for hepatitis B vaccination. Additionally, at the age of 6 she developed sepsis caused by Streptococcus pneumoniae. She experienced a herpes zoster infection when she was 12 years old. During adulthood, she was hospitalized with hemophagocytic lymphohistiocytosis (confirmed with a bone marrow biopsy) and pancytopenia, which was potentially induced by co-trimoxazole. During this hospitalization various infections were also diagnosed and treated accordingly: Escherichia coli and candidiasis.\n\nSanger sequencing\nFrom the age of 4, clinical symptoms were compatible with SLE-like disease, with butterfly rash. At age 11 years, the diagnosis of SLE was established based on butterfly rash, oral ulcers, thrombocytopenia and positive antibodies (positive antinuclear antibodies, positive anti-Sm and positive anti-SSA). Anti-double-stranded DNA and antiphospholipid antibodies were not present. Furthermore, she experienced recurrent fevers with lymphadenopathy and vasculitis lesions of the hand and feet. Initially, the SLE was treated with hydroxychloroquine and prednisolone, with serious side effects, including weight gain (cushingoid), osteoporosis and bone infarctions. Furthermore, symptoms of fatigue, headache and arthralgia occurred during attempts to taper prednisolone treatment. On the basis of the diagnosis of SLE in combination with the earlier established C1q deficiency, and the side effects and inability to taper prednisolone, treatment with FFP was initiated.\n\nCerebral involvement\nWhen the patient was 14 years old she was hospitalized with a fever, paraesthesia and difficulties with speech. Infectious causes were excluded. Magnetic resonance imaging scans of the brain were normal. Electroencephalogram showed left parieto-occipital irritative abnormalities. Liquor analysis revealed enhanced protein content without elevated cell count. With the working diagnosis of transient ischaemic attack (TIA)/partial epileptic seizure due to cerebral vasculitis, she was treated with prednisolone and carbasalate calcium. Subsequent visits at the age of 24, 25 and 28 at the Leiden University Medical Center multidisciplinary neuropsychiatric SLE (NPSLE) clinic14 for anxiety and difficulty with speech did not reveal signs of active inflammatory NPSLE.\n\nVascular problems\nAt the age of 26 the patient developed a deep venous thrombosis, although no antiphospholipid antibodies were detected (anticardiolipin antibodies IgM/immunoglobulin G (IgG), anti-β2 glycoprotein I IgM/IgG and lupus anticoagulant). When the patient was 27 years old, she experienced a spontaneous abortion at a gestation of 8 weeks.\n\nBone lesions\nAt the age of 9 she developed an avascular necrosis of the humerus which led to a destructed right shoulder. During recent years she developed extensive bone infarctions around the knee. Because of the osteonecrosis, she underwent total hip replacement surgery at the age of 29. Osteoporosis had already been identified during childhood.\n\nTherapy\nInitially, prednisolone and hydroxychloroquine were used to treat the SLE. Because the patient was unable to taper the prednisolone and she was already diagnosed with C1q deficiency, FFP treatment was started at the age of 11 with 15 ml per kg. The FFP infusions were administered one to four times per month and were preceded by clemastine and prednisolone intravenously. CP activity was measured preceding each FFP infusion. When FFP took place each week, the CP activity was 80% to 90%; when the FFP was every two weeks, the CP activity dropped below 50%, which was in line with previous reports.15 Anti-C1q antibodies were detectable, though not increased. There were several adverse reactions to the FFP therapy, ranging from mild urticarial to anaphylactic reaction. Despite these adverse reactions, the patient preferred the FFP therapy because of reduction of fatigue, arthralgia and number of infections. However, because of a serious anaphylactic reaction at the age of 25, FFP treatment was discontinued and her current treatment regimen consists of hydroxychloroquine, azathioprine, low-dose prednisolone, clopidogrel, bisphosphonates and cholecalciferol.\n\nComplete absence of C1q in serum\nWestern blot analyses of serum from the patient and NHS (pool of four healthy adults) were analysed for the presence of C1q. The same amount of serum was applied in native, denaturing or reducing conditions. Only in the NHS lane was C1q detected (Figure 1 (a)–(c)). Therefore, we confirmed the absence of circulating C1q in the patient’s serum. Additionally, her serum was tested for C1q in ELISA format, next to 21 healthy female controls (ages 26–32 years). The C1q levels in the healthy controls had an average of 171 µg/ml C1q, whereas in the patient’s serum the C1q level was below the detection limit of 0.065 µg per ml (Figure 1(d)).\nFigure 1 C1q protein analysis shows no C1q in the patient’s serum. Western blot analysis of serum from the patient and a control (normal human serum). The serum samples were prepared under (a) reducing condition, (b) denaturing and non-reduced condition or (c) non-reducing and non-denaturing conditions. Measurement of C1q with enzyme-linked immunosorbent assay in the serum of healthy female age-matched controls (n = 21) and (d) the patient.\n\n\n\nSequencing\nTo determine what the mutation(s) are in this patient and where they are located, DNA and RNA sequencing was performed. Two previously described mutations were identified in the patient’s C1QC gene: c.100G > A p.(Gly34Arg) and c.205C > T p.(Arg69X). With RNA sequencing we confirmed that both mutations were heterozygous, meaning these mutations are compound heterozygous (Figure 2).\nFigure 2 Compound heterozygous mutation located in the C1QC gene. RNA sequence analysis revealed heterozygous mutations of C1QC highlighted by the red box: c.100G > A p.(Gly34Arg) and c.205C > T p.(Arg69X).\n\n\n\nDiscussion\nC1q deficiency is a rare genetic disorder which is often accompanied by development of SLE. The patient described here was already diagnosed both with C1q deficiency and SLE in early childhood. She has suffered from recurrent infections, which is also a hallmark of C1q deficiency.12 Another part of her medical history involves bone lesions. Interestingly, osteoclasts are able to produce and secrete C1q, which could be suggestive of a direct relation between C1q deficiency and development of bone lesions, although the function of C1q is unknown in this environment.16 However, it is unclear and difficult to determine whether these bone lesions and recurrent infections are a consequence of the C1q deficiency, the SLE, the steroid treatment, or a combination of these factors. C1q is important in the clearance of apoptotic material and immune complexes. In addition to activation of the CP of the complement system, C1q has various functions independent of CP activation.3\n\nPreviously, 15 C1q-deficient patients with NPSLE have been described in literature, with the most frequent presenting symptom being seizures (67%), which is much higher than observed in conventional SLE patients.12 Cerebral vasculitis has also been reported in 27% of C1q-deficient NPSLE patients. The patient described here experienced neurological symptoms in adolescence and was diagnosed as having a TIA/partial epileptic seizure due to cerebral vasculitis. It is known that C1q inhibits IFN production. In patients with C1q deficiency, high IFN levels are observed in serum and cerebrospinal fluid. Recently, it was found that type I IFN stimulates microglia to engulf synaptic material, resulting in synaptic loss in the central nervous system.17,18 This could contribute to neuropsychiatric involvement in C1q deficiency.\n\nThis patient has been treated with FFP for almost 14 years. Shortly after infusion C1q levels reach their maximum and rapidly decline, whereas CP activity is sustained for a longer period of time. Even though the C1q levels and CP activity effects are relatively short lived, the symptomatic relief and substantial improvement in quality of life of the FFP treatment is sustained for several weeks. Empirically it has been established for this patient that two units of FFP every two weeks is most optimal. The FFP therapy has been accompanied by adverse events on infusion, even anaphylactoid reactions, although anti-C1q antibodies were not increased in this patient.\n\nOf the C1q-deficient patients who have been described so far, all except one have been reported to have a homozygous mutation in the C1q genes. Here, we report the second case of C1q deficiency with a compound heterozygous mutation, in this case located in C1QC: c.100G > A p.(Gly34Arg) and c.205C > T p.(Arg69X).\n\nDeclaration of conflicting interests\nThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding\nThe authors received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 Beurskens FJ van Schaarenburg RA Trouw LA \nC1q, antibodies and anti-C1q autoantibodies . Mol Immunol \n2015 ; 68 : 6 –13 .26032012 \n2 Lubbers R van Essen MF van Kooten C Trouw LA \nProduction of complement components by cells of the immune system . Clin Exp Immunol \n2017 ; 188 : 183 –194 .28249350 \n3 Nayak A Ferluga J Tsolaki AG Kishore U \nThe non-classical functions of the classical complement pathway recognition subcomponent C1q . Immunol Lett \n2010 ; 131 : 139 –150 .20381531 \n4 Chen G Tan CS Teh BK Lu J \nMolecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and macrophages . J Biol Chem \n2011 ; 286 : 34941 –34950 .21862594 \n5 Stegert M Bock M Trendelenburg M \nClinical presentation of human C1q deficiency: How much of a lupus? \nMol Immunol \n2015 ; 67 : 3 –11 .25846716 \n6 Schejbel L Skattum L Hagelberg S , et al.\nMolecular basis of hereditary C1q deficiency – revisited: Identification of several novel disease-causing mutations . Genes Immun \n2011 ; 12 : 626 –634 .21654842 \n7 van Schaarenburg RA Schejbel L Truedsson L , et al.\nMarked variability in clinical presentation and outcome of patients with C1q immunodeficiency . J Autoimmun \n2015 ; 62 : 39 –44 .26119135 \n8 Afzali P Isaeian A Sadeghi P , et al.\nComplement deficiency in pediatric-onset systemic lupus erythematosus . J Lab Physicians \n2018 ; 10 : 232 –236 .29692593 \n9 Olsson RF Hagelberg S Schiller B Ringdén O Truedsson L Åhlin A \nAllogeneic hematopoietic stem cell transplantation in the treatment of human C1q deficiency: The Karolinska experience . Transplantation \n2016 ; 100 : 1356 –1362 .26516671 \n10 Ekinci Z Ozturk K \nSystemic lupus erythematosus with C1q deficiency: Treatment with fresh frozen plasma . Lupus \n2018 ; 27 : 134 –138 .29113537 \n11 van Schaarenburg RA Daha NA Schonkeren JJ , et al.\nIdentification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections . Immunobiology \n2015 ; 220 : 422 –427 .25454803 \n12 van Schaarenburg RA Magro-Checa C Bakker JA , et al.\nC1q deficiency and neuropsychiatric systemic lupus erythematosus . Front Immunol \n2016 ; 7 : 647 –647 .28082982 \n13 Moosig F Damm F Knorr-Spahr A , et al.\nReduced expression of C1q-mRNA in monocytes from patients with systemic lupus erythematosus . Clin Exp Immunol \n2006 ; 146 : 409 –416 .17100759 \n14 Zirkzee EJ Steup-Beekman GM van der Mast RC , et al.\nProspective study of clinical phenotypes in neuropsychiatric systemic lupus erythematosus; multidisciplinary approach to diagnosis and therapy . J Rheumatol \n2012 ; 39 : 2118 –2126 .22984275 \n15 Mehta P Norsworthy PJ Hall AE , et al.\nSLE with C1q deficiency treated with fresh frozen plasma: A 10-year experience . Rheumatology (Oxford) \n2010 ; 49 : 823 –824 .19965977 \n16 Teo BH Bobryshev YV Teh BK Wong SH Lu J \nComplement C1q production by osteoclasts and its regulation of osteoclast development . Biochem J \n2012 ; 447 : 229 –237 .22812635 \n17 Bialas AR Presumey J Das A , et al.\nMicroglia-dependent synapse loss in type I interferon-mediated lupus . Nature \n2017 ; 546 : 539 –543 .28614301 \n18 Santer DM Hall BE George TC , et al.\nC1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes . J Immunol \n2010 ; 185 : 4738 –4749 .20844193\n\n",
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"issn_linking": "0961-2033",
"issue": "28(10)",
"journal": "Lupus",
"keywords": "C1q deficiency; FFP; SLE; compound heterozygous; mutation",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D015922:Complement C1q; D005260:Female; D006720:Homozygote; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D009154:Mutation; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Complex medical history of a patient with a compound heterozygous mutation in C1QC.",
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"abstract": "Angioedema is a well-known side effect of angiotensin converting enzyme inhibitors (ACEi). However, ACE inhibitors induced angioedema after cervical surgery is a rare condition. They result in increased levels of circulating bradykinins. Rare cases of angioedema following local trauma in patients using ACE inhibitors have been published. We present such a case. A 54-year-old Caucasian female with a history significant for hypertension, controlled with lisinopril, was admitted for routine cervical spine surgery. She has severe degenerative cervical disc disease and was admitted to the hospital for an elective cervical diskectomy. The patient failed weaning off the ventilator on multiple attempts postoperatively. There were no observed symptoms of an allergic reaction. A CT scan of the neck showed extensive soft tissue edema at the level of the arytenoids. Dexamethasone was given to reduce the edema without successful resolution. On review of her medications, it was found that the patient was resumed on lisinopril following the procedure. It was subsequently discontinued. By the following day the patient had a positive leak around the ET tube cuff and patient was successfully extubated.",
"affiliations": "Wayne State University, Detroit, MI, USA.;Wayne State University, Detroit, MI, USA.",
"authors": "Hannoodi|Faris|F|0000-0003-1835-1899;Sabbagh|Hussam|H|",
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"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2017/4268962Case ReportACE Inhibitor-Induced Angioedema following Cervical Spine Surgery http://orcid.org/0000-0003-1835-1899Hannoodi Faris \n*\nSabbagh Hussam Wayne State University, Detroit, MI, USA*Faris Hannoodi: [email protected] Editor: Assad Movahed\n\n2017 1 3 2017 2017 426896224 10 2016 16 2 2017 Copyright © 2017 Faris Hannoodi and Hussam Sabbagh.2017This 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.Angioedema is a well-known side effect of angiotensin converting enzyme inhibitors (ACEi). However, ACE inhibitors induced angioedema after cervical surgery is a rare condition. They result in increased levels of circulating bradykinins. Rare cases of angioedema following local trauma in patients using ACE inhibitors have been published. We present such a case. A 54-year-old Caucasian female with a history significant for hypertension, controlled with lisinopril, was admitted for routine cervical spine surgery. She has severe degenerative cervical disc disease and was admitted to the hospital for an elective cervical diskectomy. The patient failed weaning off the ventilator on multiple attempts postoperatively. There were no observed symptoms of an allergic reaction. A CT scan of the neck showed extensive soft tissue edema at the level of the arytenoids. Dexamethasone was given to reduce the edema without successful resolution. On review of her medications, it was found that the patient was resumed on lisinopril following the procedure. It was subsequently discontinued. By the following day the patient had a positive leak around the ET tube cuff and patient was successfully extubated.\n==== Body\n1. Introduction\nAngioedema is a well-known side effect of angiotensin converting enzyme inhibitors (ACEi). Angioedema occurs because ACE inhibitors impair bradykinin degradation, leading to increase in bradykinin levels. Bradykinin in turn leads to increased vasodilation and vascular permeability, resulting in angioedema. Mast cells are not involved in this pathway. As a result, histamine is not produced, therefore symptoms of pruritus and urticaria do not present.\n\nACE inhibitor-induced angioedema tends to involve the periorbital region and structures within the oral cavity, oropharynx, and larynx [1, 2]. ACE inhibitor-induced angioedema after cervical surgery is a rare condition. A few cases of angioedema following local trauma in patients using ACE inhibitors have been published [3–7]. We present an interesting case of severe angioedema causing airway obstruction after anterior cervical surgery in a patient using ACE inhibitors.\n\n2. Case Report\nA 54-year-old Caucasian female with a medical history significant for hypertension, hyperlipidemia, cervical disc disease, and depression was admitted for routine cervical spine surgery. She has never smoked and does not drink alcohol. Her medications included lisinopril 10 mg, atorvastatin 40 mg, citalopram 20 mg, and furosemide 20 mg. She has severe degenerative disk disease at C4–C7, with herniated nucleus pulposus. The patient was admitted to hospital for an elective cervical disk arthroplasty with diskectomy at C4 to C7 and fusion at C5–C7.\n\nThe patient failed weaning off the ventilator on multiple attempts postoperatively. There were no observed symptoms of an allergic reaction. Her vital signs and laboratory tests were unremarkable. CT scan of the neck showed extensive edema at the level of the arytenoids, but no retropharyngeal hematoma or abscess were noted (Figure 1). A bronchoscopy confirmed arytenoid edema.\n\nDexamethasone 8 mg was given every 6 hours for 4 days to reduce the edema without successful resolution. On review of her medications, it was found that the patient was on lisinopril following the procedure for the treatment of hypertension. It was subsequently discontinued. The following day, the patient was weaned and successfully extubated.\n\n3. Discussion\nIn our case the surgery most likely resulted in marked bradykinin release in a patient who was already on an ACE inhibitor. The release of bradykinin, in addition to decreased bradykinin catabolism as a result of ACE inhibitor therapy, has precipitated angioedema. The definitive treatment of angioedema is to completely stop the offending medication, in this case lisinopril.\n\nThere are several risk factors that can contribute to ACE inhibitor-induced angioedema, including previous angioedema, age above 65, NSAID use, female sex, smoking, seasonal allergies, certain immunosuppressants (sirolimus and everolimus), underlying C1 inhibitor deficiency or dysfunction, history of ACE inhibitor-induced cough, and surgery [8–10]. The relevant risk factors to our case are female sex and surgery, though no further testing was carried out to look for C1 inhibitor deficiency.\n\nThe areas affected by ACE inhibitor-induced angioedema are the face, mouth, upper airway, and intestine. In the reported cases where angioedema occurred following surgical procedures, the affected areas involved the oral cavity and upper airway [5–7]. This is likely due to local trauma as a result of the cervical spinal surgery. This is consistent with reviewed literature since head and neck surgery appear to increase the incidence of ACE inhibitor-induced angioedema to the oropharynx and upper airway. Of the three surgical cases reported, two required definitive airways to be present to prevent airway compromise, one of which failed intubation and required a tracheotomy [5, 7]. Only one reported case did not require intubation to secure the airway [6].\n\nThe mainstay of management is to secure the airway, discontinue the ACE inhibitor, and give systemic steroids. Other additions can include giving epinephrine and antihistaminics [5]. Persistent symptoms may require synthetic bradykinin B2-receptor antagonist. In the reviewed cases, however, the management was similar to that of our case. The airway was secured and systemic steroids were given. In one case, Benadryl and epinephrine were administered as angioedema was treated as an allergic reaction. In another case systemic steroids were given for a period of 7 days for complete resolution [5–7].\n\n4. Conclusion\nTo sum up, although ACE inhibitor-induced angioedema is rare in the surgical setting, the complications can be life-threatening. ACE inhibitors should be discontinued in ALL patients undergoing neck surgery, regardless of the presence of specific risk factors. There is no sense in taking any risks.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Soft tissue edema demonstrated around the endotracheal tube.\n==== Refs\n1 Agostoni A. Cicardi M. Drug-induced angioedema without urticaria incidence, prevention and management Drug Safety 2001 24 8 599 606 10.2165/00002018-200124080-00004 2-s2.0-0034947385 11480492 \n2 Kuo D. C. Barish R. A. Isolated uvular angioedema associated with ACE inhibitor use Journal of Emergency Medicine 1995 13 3 327 330 10.1016/0736-4679(95)00003-S 2-s2.0-0029048579 7673623 \n3 Brent Simmons B. Folsom M. A. Bryden L. A. Studdiford J. S. Angioedema after local trauma in a patient on angiotensin-converting enzyme inhibitor therapy The Journal of the American Board of Family Medicine 2008 21 6 577 579 10.3122/jabfm.2008.06.080103 18988727 \n4 Homma H. Aoki J. Tanabe K. Life-threatening angioedema after primary percutaneous coronary intervention Internal Medicine 2015 54 8 999 1000 10.2169/internalmedicine.54.4004 25876594 \n5 Ogbureke K. U. E. Cruz C. Johnson J. V. Helfrick J. F. Perioperative angioedema in a patient on long-term angiotensin-coverting enzyme (ACE)-inhibitor therapy) Journal of Oral and Maxillofacial Surgery 1996 54 7 917 920 10.1016/S0278-2391(96)90550-9 2-s2.0-0030484670 8676243 \n6 Marrocco-Trischitta M. M. Melissano G. De Dominicis D. Chiesa R. Angiotensin-converting enzyme inhibitor-induced angioedema following carotid endarterectomy misdiagnosed as cervical hematoma Annals of Vascular Surgery 2006 20 1 145 147 10.1007/s10016-005-6859-8 2-s2.0-29744435342 16374538 \n7 Krnacik M. J. Heggeness M. H. Severe angioedema causing airway obstruction after anterior cervical surgery Spine 1997 22 18 2188 2190 10.1097/00007632-199709150-00019 2-s2.0-0031418243 9322331 \n8 Kostis J. B. Kim H. J. Rusnak J. Incidence and characteristics of angioedema associated with enalapril Archives of Internal Medicine 2005 165 14 1637 1642 10.1001/archinte.165.14.1637 2-s2.0-23744447222 16043683 \n9 Duerr M. Glander P. Diekmann F. Dragun D. Neumayer H.-H. Budde K. Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients Clinical Journal of the American Society of Nephrology 2010 5 4 703 708 10.2215/CJN.07371009 2-s2.0-77950933411 20093343 \n10 Byrd J. B. Touzin K. Sile S. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor-associated angioedema Hypertension 2008 51 1 141 147 10.1161/HYPERTENSIONAHA.107.096552 2-s2.0-37349104226 18025295\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2017()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "4268962",
"pmc": null,
"pmid": "28348897",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "16043683;25876594;9322331;20093343;11480492;7673623;16374538;8676243;18988727;18025295",
"title": "ACE Inhibitor-Induced Angioedema following Cervical Spine Surgery.",
"title_normalized": "ace inhibitor induced angioedema following cervical spine surgery"
}
|
[
{
"companynumb": "US-APOTEX-2017AP011740",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
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"drugauthorizationnumb": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "FUROSEMIDE."
},
{
"actiondrug": "1",
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"activesubstancename": "LISINOPRIL"
},
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"medicinalproduct": "LISINOPRIL."
},
{
"actiondrug": "5",
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"activesubstancename": "ATORVASTATIN"
},
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"medicinalproduct": "ATORVASTATIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
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"drugauthorizationnumb": null,
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"drugdosagetext": "20 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"medicinalproduct": "CITALOPRAM"
}
],
"patientagegroup": null,
"patientonsetage": "56",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Angioedema",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HANNOODI F, SABBAGH H.. ACE INHIBITOR-INDUCED ANGIOEDEMA FOLLOWING CERVICAL SPINE SURGERY. CASE-REP-CARDIOL. 2017;2017:4268962",
"literaturereference_normalized": "ace inhibitor induced angioedema following cervical spine surgery",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170511",
"receivedate": "20170511",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13535236,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "Functional constipation is a common pediatric problem that is often treated through well-established algorithms. Fecal disimpaction is the initial therapeutic step, and severe cases require hospitalization for intensive therapies. We describe a significant unexpected complication of this common clinical situation. An 8-year-old boy with suspected chronic functional constipation was hospitalized for disimpaction by continuous nasogastric administration of polyethylene glycol electrolyte (PEG-E) solution. On the sixth day of disimpaction, the patient abruptly developed fever, tachycardia, and tachypnea. Evaluation included blood culture, which grew Escherichia coli, and treatment with a course of appropriate antibiotics was provided. The safety of PEG-E solutions has been shown in studies of children with constipation, which made this patient's illness surprising. Several potential etiologies of his infection were considered, including bacterial translocation (BT). BT is defined as the passage of live microbes and microbial products from the gastrointestinal tract to extraintestinal sites, such as the bloodstream. It has been shown to occur in a variety of clinical conditions but is of unclear clinical significance. In this case, physical damage to the intestinal mucosa was thought to contribute to the potential occurrence of BT, and prolonged disimpaction was considered as a risk factor. E coli sepsis in a child undergoing inpatient nasogastric fecal disimpaction with PEG-E represents a clinical problem never before reported in the literature and should increase clinicians' indices of suspicion for uncommon complications of common procedures.",
"affiliations": "Naval Medical Center Portsmouth, Department of Pediatrics, 620 John Paul Jones Cir, Portsmouth, VA 23708. [email protected].",
"authors": "Darrow|Cory J|CJ|;Devito|Justin F|JF|",
"chemical_list": "D002400:Cathartics; D011092:Polyethylene Glycols",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2012-2963",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "133(1)",
"journal": "Pediatrics",
"keywords": "Escherichia coli; bacterial translocation; constipation; sepsis",
"medline_ta": "Pediatrics",
"mesh_terms": "D002400:Cathartics; D002648:Child; D002908:Chronic Disease; D003248:Constipation; D004927:Escherichia coli Infections; D006760:Hospitalization; D006801:Humans; D007441:Intubation, Gastrointestinal; D008297:Male; D011092:Polyethylene Glycols; D018805:Sepsis",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e235-9",
"pmc": null,
"pmid": "24366993",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An occurrence of sepsis during inpatient fecal disimpaction.",
"title_normalized": "an occurrence of sepsis during inpatient fecal disimpaction"
}
|
[
{
"companynumb": "JP-BAUSCH-BL-2017-023996",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SENNA LEAF\\SENNOSIDES\\SENNOSIDES A AND B"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugseparatedosagenumb": null,
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"medicinalproduct": "SENNA"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASCORBIC ACID\\POLYETHYLENE GLYCOL 3350\\POTASSIUM CHLORIDE\\SODIUM ASCORBATE\\SODIUM CHLORIDE\\SODIUM SULFATE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021881",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POWDER FOR ORAL SOLUTION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CONSTIPATION",
"drugintervaldosagedefinition": "805",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
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"drugstructuredosagenumb": "300",
"drugstructuredosageunit": "012",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MOVIPREP"
}
],
"patientagegroup": null,
"patientonsetage": "8",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Escherichia bacteraemia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DARROW C, DEVITO J. AN OCCURRENCE OF SEPSIS DURING INPATIENT FECAL DISIMPACTION. PEDIATRICS. 2013;133:E235-E239.",
"literaturereference_normalized": "an occurrence of sepsis during inpatient fecal disimpaction",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20170830",
"receivedate": "20170815",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13870036,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
}
] |
{
"abstract": "Ascariasis lumbricoides infections are common in tropical and sub-tropical countries. As it is one of the common causes for common bile duct obstruction. But in pregnancy is a rare entity. It may present with complications like acute pancreatitis. Here we present a case of 24 year female gravida 2 para 1 at 34 weeks of pregnancy presented with chief complain of pain over epigastric region radiating to back and associated with two episodes of vomiting, non bilious, not mixed with blood. Ultrasonography showed long tubular hyperechoic structure in gallbladder lumen most likely ascariasis and then she was diagnosed as a case of acute pancreatitis with alive ascariasis.",
"affiliations": "Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.;Department of Obstetrics and Gynecology, Kathmandu Model Hospital, Kathmandu, Nepal.",
"authors": "Thakur|S K|SK|;Dangal|G|G|;Karki|A|A|;Pradhan|H|H|;Shrestha|R|R|;Bhattachan|K|K|;Bajracharya|N|N|;Tiwari|K|K|;Bharati|S|S|;Maharjan|O|O|;Maharjan|S|S|",
"chemical_list": null,
"country": "Nepal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1812-2027",
"issue": "18(71)",
"journal": "Kathmandu University medical journal (KUMJ)",
"keywords": null,
"medline_ta": "Kathmandu Univ Med J (KUMJ)",
"mesh_terms": "D000208:Acute Disease; D000818:Animals; D001196:Ascariasis; D017164:Ascaris lumbricoides; D005260:Female; D006801:Humans; D010195:Pancreatitis; D011247:Pregnancy; D014463:Ultrasonography",
"nlm_unique_id": "101215359",
"other_id": null,
"pages": "324-326",
"pmc": null,
"pmid": "34158446",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnancy Complicated by Acute Pancreatitis with Ascariasis.",
"title_normalized": "pregnancy complicated by acute pancreatitis with ascariasis"
}
|
[
{
"companynumb": "NP-LUPIN PHARMACEUTICALS INC.-2021-17033",
"fulfillexpeditecriteria": "2",
"occurcountry": "NP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALBENDAZOLE"
},
"drugadditional": "4",
"drugadministrationroute": "065",
"drugauthorizationnumb": "211636",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Tablet",
"drugdosagetext": "400 MILLIGRAM, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Pancreatitis acute",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "400",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ALBENDAZOLE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALBENDAZOLE"
},
"drugadditional": "4",
"drugadministrationroute": null,
"drugauthorizationnumb": "211636",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Tablet",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Ascariasis",
"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": "ALBENDAZOLE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFIXIME"
},
"drugadditional": "4",
"drugadministrationroute": "048",
"drugauthorizationnumb": "065130",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "200 MILLIGRAM, BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Pancreatitis acute",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": "5",
"drugtreatmentdurationunit": "804",
"medicinalproduct": "CEFIXIME"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFIXIME"
},
"drugadditional": "4",
"drugadministrationroute": null,
"drugauthorizationnumb": "065130",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Ascariasis",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CEFIXIME"
}
],
"patientagegroup": null,
"patientonsetage": "24",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Thakur SK, Dangal G, Karki A, Pradhan H, Shrestha R, Bhattachan K, et al. Pregnancy complicated by acute pancreatitis with ascariasis. Kathmandu University Medical Journal. 2020;71(3):324-326",
"literaturereference_normalized": "pregnancy complicated by acute pancreatitis with ascariasis",
"qualification": "3",
"reportercountry": "NP"
},
"primarysourcecountry": "NP",
"receiptdate": "20211103",
"receivedate": "20210914",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19834543,
"safetyreportversion": 4,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Phenytoin toxicity masquerading as deterioration of neurological symptoms caused by interaction with chloramphenicol is a very rare but real risk. To the authors’ knowledge only one such case occurring in humans has been reported in the English literature. No case of clinical phenytoin toxicity occurring at less than double the serum phenytoin therapeutic levels, occurring as a result of chlorampenicol interaction has been documented, hence our report.\n\nA 17 year old man, whose frontal subdural empyema had been drained, had his seizures well controlled on phenytoin. Shortly after, he had a parasagital subdural empyema which was also drained. He was put on chloramphenicol. He improved tremendously until he then developed cerebellar symptoms. Phenytoin levels were noted to be almost twice the maximum therapeutic value. On stopping chloramphenicol, phenytoin levels normalized and symptoms resolved.\n\nPossibility of phenytoin toxicity should always be entertained in patients who are also taking chlorampenicol, presenting with new or worsening neurological symptoms.",
"affiliations": null,
"authors": "Jokonya|L|L|;Musara|A||",
"chemical_list": "D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D010672:Phenytoin; D002701:Chloramphenicol",
"country": "Zimbabwe",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-9176",
"issue": "61(9-12)",
"journal": "The Central African journal of medicine",
"keywords": null,
"medline_ta": "Cent Afr J Med",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D002701:Chloramphenicol; D004347:Drug Interactions; D013354:Empyema, Subdural; D006801:Humans; D008297:Male; D010672:Phenytoin; D012640:Seizures",
"nlm_unique_id": "0372566",
"other_id": null,
"pages": "73-6",
"pmc": null,
"pmid": "29144066",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neurological manifestation of phenytoin toxicity, resulting from drug interaction with chloramphenicol: a case report.",
"title_normalized": "neurological manifestation of phenytoin toxicity resulting from drug interaction with chloramphenicol a case report"
}
|
[
{
"companynumb": "ZW-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-167216",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CHLORAMPHENICOL"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "3",
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"abstract": "Double relapsed and/or refractory multiple myeloma (DRMM), MM that is relapsed and/or refractory to bortezomib and lenalidomide, carries a poor prognosis. The healthcare costs of DRMM have not previously been reported. We analyzed detailed medical resource utilization (MRU) costs, drug costs and outcomes for 39 UK patients receiving standard DRMM therapy. Median OS in this cohort was 5.6 months. The mean cost of DRMM treatment plus MRU until death was £23,472 [range: £1,411-£90,262], split between drug costs £11,191 and other resource use costs £12,281. The cost per assumed quality-adjusted life year (QALY) during DRMM was £66,983. These data provide a standard of care comparison when evaluating the cost-effectiveness of new drugs in DRMM.",
"affiliations": "Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, United Kingdom; MRC Human Immunology Unit, University of Oxford, Weatherall Institute of Molecular Medicine, Headley Way, Oxford, OX3 9DS, United Kingdom.;Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, United Kingdom.;Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, United Kingdom; Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford University Old Road Campus, Oxford, OX3 7LH, United Kingdom.;Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom.;Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom.;Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, United Kingdom.;BresMed Health Solutions, 84 Queen Street, North Church House, Sheffield, S1 2DW, United Kingdom.;BresMed Health Solutions, 84 Queen Street, North Church House, Sheffield, S1 2DW, United Kingdom.;BresMed Health Solutions, 84 Queen Street, North Church House, Sheffield, S1 2DW, United Kingdom.;Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, United Kingdom; Royal Berkshire Hospital NHS Trust, London Rd, Reading, RG1 5AN, United Kingdom.",
"authors": "Gooding|Sarah|S|;Lau|I-Jun|IJ|;Sheikh|Mimi|M|;Roberts|Pamela|P|;Wong|Julia|J|;Dickens|Emmy|E|;Bullement|Ash|A|;Elvidge|Jamie|J|;Lee|Dawn|D|;Ramasamy|Karthik|K|",
"chemical_list": "D000970:Antineoplastic Agents; D013792:Thalidomide; D000069286:Bortezomib; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0136207",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2636787410.1371/journal.pone.0136207PONE-D-15-08096Research ArticleDouble Relapsed and/or Refractory Multiple Myeloma: Clinical Outcomes and Real World Healthcare Costs DRMM: Outcomes and Real World Healthcare CostsGooding Sarah \n1\n\n2\n\n3\nLau I-Jun \n1\n\n2\nSheikh Mimi \n1\n\n2\n\n4\nRoberts Pamela \n1\nWong Julia \n1\nDickens Emmy \n1\n\n2\nBullement Ash \n5\nElvidge Jamie \n5\nLee Dawn \n5\nRamasamy Karthik \n1\n\n2\n\n6\n*\n1 \nDepartment of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom\n\n2 \nNational Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, United Kingdom\n\n3 \nMRC Human Immunology Unit, University of Oxford, Weatherall Institute of Molecular Medicine, Headley Way, Oxford, OX3 9DS, United Kingdom\n\n4 \nDepartment of Oncology, University of Oxford, Old Road Campus Research Building, Oxford University Old Road Campus, Oxford, OX3 7LH, United Kingdom\n\n5 \nBresMed Health Solutions, 84 Queen Street, North Church House, Sheffield, S1 2DW, United Kingdom\n\n6 \nRoyal Berkshire Hospital NHS Trust, London Rd, Reading, RG1 5AN, United Kingdom\nGupta Sudeep Editor\nACTREC (Advanced Centre for Treatment, Research and Education in Cancer) / Tata Memorial Centre, INDIA\nCompeting Interests: AB, JE and DL are employees of BresMed, which receives consultancy fees from Celgene. SG, IL, MS, PR, JW, ED, KR are members of a hospital department that has received an unrestricted educational grant from Celgene. KR is in receipt of honoraria from Celgene. No author has any direct financial interests whose value could be affected by this publication. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: SG KR. Performed the experiments: SG IL MS ED KR. Analyzed the data: SG AB JE DL KR. Contributed reagents/materials/analysis tools: PR JW. Wrote the paper: SG DL KR.\n\n* E-mail: [email protected] 9 2015 2015 10 9 e013620723 2 2015 31 7 2015 © 2015 Gooding et al2015Gooding et alThis 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 properly credited.Double relapsed and/or refractory multiple myeloma (DRMM), MM that is relapsed and/or refractory to bortezomib and lenalidomide, carries a poor prognosis. The healthcare costs of DRMM have not previously been reported. We analyzed detailed medical resource utilization (MRU) costs, drug costs and outcomes for 39 UK patients receiving standard DRMM therapy. Median OS in this cohort was 5.6 months. The mean cost of DRMM treatment plus MRU until death was £23,472 [range: £1,411–£90,262], split between drug costs £11,191 and other resource use costs £12,281. The cost per assumed quality-adjusted life year (QALY) during DRMM was £66,983. These data provide a standard of care comparison when evaluating the cost-effectiveness of new drugs in DRMM.\n\nSG was supported by Wellcome Trust Research Training Fellowship 2013–2016. Grant code 102341/Z/13/Z (http://www.wellcome.ac.uk/Funding/Biomedical-science/Fundingschemes/Fellowships/Clinical-fellowships/wtd004435.htm). IL was supported by Medical Research Council Clinical Research Training Fellowship 2014–2017. Grant code MR/M003221/1 (http://www.mrc.ac.uk/skills-careers/fellowships/clinical-fellowships/clinical-research-training-fellowship-crtf/). MS was supported by Oxford Cancer Research Centre Clinical Research Training Fellowship 2014–2017. Grant code OCRC-CRF14-MW (http://www.cancercentre.ox.ac.uk/graduate-studies/clinical-research-training-fellowships/). BresMed Health Solutions provided support in the form of salaries for authors AB, JE and DL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nPatients with treatment-refractory malignancy have poor outcomes and high healthcare costs. In Multiple Myeloma (MM), the introduction of the proteasome inhibitor bortezomib and immunomodulatory drugs (IMiDs) thalidomide and lenalidomide has improved survival over the last decade [1], but increased the cost of treatment. While these drugs can result in remission, most patients will relapse with increasing symptom burden and worsening prognosis [2]. Double relapsed and/or refractory multiple myeloma (DRMM), MM that is relapsed and/or refractory to bortezomib and lenalidomide [3], carries a poor prognosis and therapeutic options remain limited. An IMWG retrospective analysis of patients who relapsed following bortezomib and at least one of the IMiDs showed a median overall survival (OS) and progression-free survival (PFS) of 9 months and 5 months respectively [4]. Only those potentially eligible for further clinical trials with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–2 were included, indicating survival may have been overestimated relative to the entirety of this heavily treated population.\n\nStudies of healthcare costs for relapsed and/or refractory MM patients receiving bortezomib and/or lenalidomide based regimens have been undertaken in a variety of countries, using ‘real-world’ data and/or economic modelling, often from patients enrolled in clinical trials [5–9]. However, none of them address MRU for patients relapsed after bortezomib and lenalidomide. The third-generation IMiD pomalidomide and second-generation proteasome inhibitor carfilzomib have recently been licensed and have efficacy in DRMM [10]. The cost burden and clinical outcomes outside of trials of this phase of the disease has never been established, so new therapies with efficacy in DRMM have no published benchmark against which to judge cost-effectiveness. To ensure resources are allocated appropriately, the cost-effectiveness evaluation of these therapies in the DRMM setting must involve non-clinical trial, real world MRU data from relevant patients. Our data provides a standard of care comparison when evaluating cost-effectiveness of new drugs in DRMM.\n\nMethods\nEthics Statement\nAll patients whose data were included in this study had provided written consent for the use of their anonymised data for the purposes of audit and service improvement by the Thames Valley Cancer Network, UK. This study was appropriately registered using the clinical audit project proposal system at Oxford University Hospitals NHS Trust, UK. The Clinical Audit Lead reviewed and approved the proposal, and in line with the UK NHS National Research Ethics Service (NRES) guidance, deemed it not to require IRB or ethics committee approval.\n\nAnonymised data on clinical outcomes, anti-myeloma therapies prescribed and MRU were obtained for 39 DRMM patients pre-treated with or intolerant to bortezomib and lenalidomide in the Thames Valley Cancer Network, UK from 2011 to 2014 (Table A in S1 File). Based on the UK National Institute for Health and Care Excellence (NICE) guidelines, bortezomib-based therapy was used for first relapse unless contraindicated. Lenalidomide-dexamethasone combination was approved for second and subsequent relapse. Relapsed myeloma patients were identified using pharmacy-generated lists of all sequential lenalidomide recipients between January 2011 and July 2013 at Oxford University Hospitals and the Royal Berkshire Hospital, Reading, UK. The strategy of using hospital pharmacy dispensing data to identify subjects ensured all lenalidomide recipients during the study period were included in the analysis, as long as they had Multiple Myeloma and had progressed on or were refractory to lenalidomide, according to IMWG criteria [11]. 34 (87%) patients were pre-treated with lenalidomide and bortezomib, and had relapsed following, or failed to tolerate both therapies. 5 patients had not received bortezomib due to pre-existing peripheral neuropathy, sufficiently severe to contraindicate its use.\n\nOS and PFS were calculated from the start date of the first therapy following relapse after lenalidomide (‘1st DRMM therapy’) until either IMWG criteria for progression/relapse were reached or death. The data censor date was 10 January 2014 for patients still alive. For each patient the following occurrences of MRU were retrieved from health care records from the start of each successive DRMM therapy until death or censoring: detailed drug regimens, outpatient clinic and chemotherapy unit attendances, inpatient/hospice admissions, supportive therapies, medical procedures, radiological investigations, blood product transfusions and blood tests. Costings were calculated using NHS reference costs 2012–13. These were combined to give one MRU cost from the start of DRMM therapy to death or censoring, using a micro-costing approach. Drug costs were separately calculated for each successive DRMM therapy.\n\nResults\nWhen offered DRMM therapy, 67% of patients preferred active treatment to palliative care (Table 1). The median age of those who chose palliative care was 73.2 years compared to 59.9 for active therapy (p<0.001). The first DRMM treatment regimen was typically bendamustine, thalidomide and dexamethasone (43.6%) as published previously [12]. Retreatment with bortezomib (15.4%) or lenalidomide (33.3%) based regimens was used if poor bone marrow reserve precluded bendamustine use and suitable clinical trial alternatives were lacking.\n\n10.1371/journal.pone.0136207.t001Table 1 Patient characteristics.\n\nMedian age at diagnosis, years (range)\n*\n\t64.3 (45–79)\t\n\nMedian age by treatment intent: Active/ Palliative\n\t59.9 (n = 26)/ 73.2 (n = 13)\t\n\nIsotope: IgA/ IgG/ Light chain\n\t7 (51.3%)/ 20 (18.0%)/ 12 (30.8%)\t\n\nISS stage I at diagnosis\n\t6 (15.4%)\t\n\nISS stage II at diagnosis\n\t9 (23.1%)\t\n\nISS stage III at diagnosis\n\t10 (25.6%)\t\n\nISS stage at diagnosis unknown\n\t14 (35.9%)\t\n\nPrevious thalidomide-based treatment\n\t34 (87.2%)\t\n\nPrevious bortezomib-based treatment\n\t34 (87.2%)\t\n\nPrevious lenalidomide-based treatment\n\t39 (100.0%)\t\n\nPrevious high dose melphalan with stem cell rescue\n\t17 (43.5%)\t\n\nPrevious additional alternative treatment(s):\n\t\t\nVincristine-based regime\t7 (17.9%)\t\nMelphalan-based regime\t5 (12.8%)\t\nAllograft\t1 (2.6%)\t\n\nMedian years from diagnosis to DRMM point (range)*\n\t4 years 9.5 months (6.5 mo– 10.5 y)\t\n\nMedian number regimes prior to DRMM (range)\n\t4 (2–5)\t\n\n1st DRMM therapy contained bendamustine\n\t17 (43.6%)\t\n\n1st DRMM therapy contained bortezomib\n\t6 (15.4%)\t\n\n1st DRMM therapy DT-PACE\n\t1 (2.6%)\t\n\n1st DRMM therapy contained lenalidomide\n\t13 (33.3%)\t\n\nNo treatment given at DRMM\n\t2 (5.1%)\t\n\n2\nnd\nDRMM therapy (n = 7):\n\t\t\nBendamustine, thalidomide, dexamethasone\t2 (28.6%)\t\nMelphalan, dexamethasone\t2 (28.6%)\t\nThalidomide-based regime\t2 (28.6%)\t\nPomalidomide, dexamethasone\t1 (14.3%)\t\n\n3\nrd\nDRMM therapy (n = 4):\n\t\t\nBortezomib, cyclophosphamide, dexamethasone\t2 (50.0%)\t\nBortezomib, melphalan, prednisone\t1 (25.0%)\t\nBendamustine, thalidomide, dexamethasone\t1 (25.0%)\t\n\nResponse to 1\nst\nDRMM therapy:\n\t \t\nCR\t1 (2.6%)\t\nVGPR\t2 (5.1%)\t\nPR\t8 (20.5%)\t\nSD\t13 (33.3%)\t\nPD or death within first month\t14 (35.9%)\t\nUnknown\t1 (2.6%)\t\n\nDuration of treatment (SD)\n\t104.9 days (63.8)\t\n\nResponse to 2\nnd\nDRMM therapy:\n\t\t\nPR\t3 (42.9%)\t\nSD\t2 (28.6%)\t\nPD or death within first month\t2 (28.6%)\t\n\nResponse to 3\nrd\nDRMM therapy:\n\t\t\nPR\t2 (50.0%)\t\nPD or death within first month\t1 (25.0%)\t\nUnknown\t1 (25.0%)\t\n*Date of diagnosis unavailable in 2 cases. ISS: International Staging System; DRMM: Double Relapsed and/or Refractory Multiple Myeloma; CR: Complete response; VGPR: Very good partial response; PR: Partial response; SD: Stable disease; PD: Progressive disease [11]\n\nRegimen choice was made by the treating clinician and based on ECOG PS and response/ side effect profile of prior therapies. Third-generation IMiDs and second-generation proteasome inhibitors were not routinely available to this cohort, excepting pomalidomide in one patient. Two patients who had not previously received bortezomib due to neuropathy did receive it at DRMM with no recorded worsening of neuropathy; one had progressive disease despite its use and the other had a partial response of 6 months duration.\n\nMedian PFS was 5.2 months and median OS was 5.6 months from start of DRMM therapy (Fig 1). These statistics reflect a steep drop in survival early on with a few patients surviving significantly longer. 24/39 (61.5%) patients had died by the end of follow-up, of whom 79% died in hospital/ hospice. The cohort was deemed too small and heterogeneous for analysis of regimen effect on survival.\n\n10.1371/journal.pone.0136207.g001Fig 1 Kaplan Meier curve showing overall survival, progression free survival and time to treatment failure.\nMRU was high in this cohort in comparison with that usually observed at earlier lines of therapy (Table 2). 60 inpatient hospital admissions occurred during DRMM therapy in 39 patients. Admissions lasted 9.3 days on average, for indications including pain management, renal failure and most commonly neutropenic fever, with some cases of culture-confirmed septicaemia. Prolonged inpatient admissions, frequent AEs and high transfusion requirements reflect a poor quality of life (QoL) among these patients (Table 3). The most common recorded Grade 3–4 adverse events (AEs) were anaemia (43.6%), thrombocytopenia (28.2%) and bone pain (33.3%) (Table 3, Table B in S1 File).\n\n10.1371/journal.pone.0136207.t002Table 2 Medical Resource Utilisation Costs of Double Relapsed and/or Refractory Multiple Myeloma Therapy.\n\nMRU Category\n\t\nTreatment given\n\t\nOccurrences\n\t\nCost per Patient\n\t\n\nDrug costs\n\t\t\t\t\n\tBortezomib-based\t6/39\t£4,022\t\n\tLenalidomide-based\t13/39\t£3,913\t\n\n1\nst\nDRMM therapy (per 28 day cycle)\na\n\n\tDT-PACE\t1/39\t£946\t\nBendamustine-based\t17/39\t£1,332\t\n\tNo active treatment\t2/39\t£0\t\n\tAverage\t£2,532\t\n\tBen/ Thal/ Dex\t2/39\t£853\t\n\tMel/ Dex\t2/39\t£133\t\n\n2\nnd\nDRMM therapy (per 28 day cycle) \na\n\n\tThal\t2/39\t£298\t\nPom/ Dex\t1/39\t£8,887\t\n\tNo 2nd DRMM therapy\t32/39\t£0\t\n\tAverage\t£294\t\n\tBor/ Cyc/ Dex\t2/39\t£4,118\t\n\n3\nrd\nDRMM therapy (per 28 day cycle) \na\n\n\tBor/ Mel/ Pred\t1/39\t£3,847\t\nBen/ Thal/ Dex\t1/39\t£1,983\t\n\tNo 3rd DRMM therapy\t35/39\t£0\t\n\tAverage\t£361\t\nTotal 1st DRMM therapy drug costs (all cycles)\t£9,527\t\nTotal 2nd DRMM therapy drug costs (all cycles)\t£807\t\nTotal 3rd DRMM therapy drug costs (all cycles)\t£857\t\n\nTotal drug costs (all cycles)\n\t\n£11,191\n\t\n\t\t\nOccurrences during DRMM period\n\nd\n\n\t\t\t\n\nMRU Category\n\t\nMRU Item\n\t\nCost per Patient\n\t\nRange\n\t\n\t\t\nMean\n\t\nSD\n\t\t\t\n\nOther MRU costs\n\t\n\nInpatient admissions\n\tNight as inpatient\t9.3\t7.9\t£2,463\t£0, £16,169\t\n\tOutpatient\t4.2\t4.1\t£630\t£0, £3,012\t\n\nAttendances\n\tDay therapy unit\t12.8\t9.7\t£4,331\t£0, £11,848\t\n\tTriage, not admitted\t0.4\t0.9\t£46\t£0, £344\t\n\tCT scan\t0.4\t0.8\t£42\t£0, £435\t\n\nInvasive and radiological procedures\n\tMRI scan\t0.3\t0.6\t£57\t£0, £343\t\nX-ray\t1.1\t2.7\t£31\t£0, £311\t\nMaxillofacial\t0.1\t0.2\t£21\t£0, £406\t\n\tOther\nb\n\n\t0.3\t0.5\t£172\t£0, £3,225\t\n\nSupportive therapy\n\tBisphosphonate\nc\n\n\t2.6\t2.5\t£217\t£0, £713\t\n\tRadiotherapy\t1.1\t3.6\t£1,237\t£0, £21,643\t\n\nTransfusion\n\tRed blood cells (units)\t5.9\t6.0\t£1,684\t£0, £5,993\t\n\tPlatelets (units)\t2.3\t3.8\t£1,200\t£0, £6,784\t\n\tFull blood count\t21.6\t13.0\t£65\t£0, £196\t\n\nBlood tests\n\tBiochemistry\t20.6\t15.6\t£26\t£0, £110\t\n\tImmunology\t4.4\t2.9\t£22\t£0, £60\t\n\tMicrobiology\t5.6\t7.0\t£38\t£0, £278\t\n\nTotal other MRU costs\n\t\n£12,281\n\t\n£995,\n\t\n\t\t\n£40,274\n\t\n\nTotal (drug costs and other MRU costs)\n\t\n£23,472\n\t\n£1,411,\n\t\n\t\t\n£90,262\n\t\nMRU: Medical Resource Utilization; DRMM: Double Relapsed and/or Refractory Multiple Myeloma; Ben: Bendamustine; Thal: Thalidomide; Dex: Dexamethasone; Mel: Melphalan; Pom: Pomalidomide; Bor: Bortezomib; Cyc: Cyclophosphamide; Pred: Prednisone.\n\n\naDrug costs have been calculated as the average of all patients undertaking each regimen. Dosing changes have been incorporated where provided. Additional dosing regimen details have been taken from product SPCs. Costs are taken from BNF or eMIT; and are applied using the appropriate pack/ vial size. The average surface area of a patient (used for IV therapies) is taken from the MM-003 clinical trial (approximately 1.86m2). Differences in costs of the same treatment between treatment lines are caused by differences in dosing for individual patients.\n\n\nbOther medical procedures consisted of: 1 vertebroplasty; 1 facet joint injection; 1 endoscopy; 1 bronchoscopy; 1 hip fracture repair under general anaesthetic; 2 PET scans and 4 ultrasound scans.\n\n\ncBisphosphonate costs calculated assuming all patients on bisphosphonates are on an average dose. The figure shows the approximate number of cycles for which patients are on bisphosphonate treatment.\n\n\ndAll MRU occurrences were recorded from initiation of 1st DRMM therapy until the end of follow up (or death)\n\n10.1371/journal.pone.0136207.t003Table 3 Surrogates of Quality of Life during Double Relapsed and/or Refractory Multiple Myeloma Therapy.\nSurrogates of Quality of Life\na\n\n\tNumber of patients\t\n\nGrade 3–4 Adverse events during DRMM therapy:\n\nb\n\n\t\t\nAnaemia\t17 (43.6%)\t\nNeutropaenia\t7 (17.9%)\t\nThrombocytopaenia\t11 (28.2%)\t\nBleeding\t1 (2.6%)\t\nFebrile neutropaenia\t6 (15.4%)\t\nBone pain\t13 (33.3%)\t\nAcute renal failure\t4 (10.3%)\t\nDehydration / vomiting / diarrhoea\t2 (5.1%)\t\n\nAdmissions during DRMM therapy (SD)\n\t1.3 per patient (1.1)\t\n\nDuration of admissions (SD)\n\t9.3 days (7.9)\t\n\nOutpatient clinic appointments during DRMM therapy (SD)\n\t4.2 per patient (4.1)\t\n\nDay therapy unit visits during DRMM, including CT & MRI (SD)\n\t12.2 per patient (9.7)\t\n\nRBC units during DRMM therapy (SD)\n\t5.9 per patient (6.0)\t\n\nPlatelet units during DRMM therapy (SD)\n\t2.3 per patient (3.8)\t\n\naAll Surrogates of Quality of Life were recorded from initiation of 1st DRMM therapy until the end of follow up (or death)\n\n\nbAdverse events with no recorded grade are assumed to be grade 3 or 4.\n\nThe mean total MRU cost per patient from start of DRMM therapy until death or censor was £12,281 (Table 2). This comprises: clinic attendances £5,007 (41%); inpatient admissions £2,884 (20%); transfusions £2,479 (23%); supportive therapy £1,454 (12%); radiology/procedures £323 (3%); blood tests £151 (1%). The mean drug cost of DRMM therapy is estimated to be £11,191 per patient. The mean total cost of treatment plus MRU is therefore £23,472 [range: £1,411 - £90,262]; £760 per week of life with DRMM. Formal QoL data is lacking in this retrospective cohort but has been previously published for DRMM patients in the MM-003 trial [13]. Assuming that QoL was the same in this cohort (utility 0.59) and remained constant throughout patients’ lifetimes, our analysis indicated a cost per QALY of £66,983.\n\nConclusion\nAlthough the small sample size of this cohort limits the ability to draw definitive survival conclusions, PFS and OS were poor, with a wide range due to the inclusion of all patients whether treated with active or palliative intent, but were similar to published examples [4]. Despite the poor outcomes, up to two thirds of DRMM patients want to be treated with active intent to improve survival, reiterating the need to develop therapies that give patients an improved prognosis, whilst being cost-effective and well tolerated in a heavily pre-treated patient group. The heterogeneity of this cohort is acknowledged but intentional, representing a typical real world hospital cohort of patients, where a range of therapeutic options must be employed, constrained by varying patient-related factors such as ECOG PS, drug tolerance, social situation and patient choice.\n\nThis is the first report of non-clinical trial based ‘real-world’ MRU cost analysis in the setting of DRMM. These patients have high MRU costs. A comparable cost analysis report relates to a subset of 54 ‘4th line’ real world relapsed/refractory patients in a Netherlands study, recruited from a previous trial cohort [7]. However, it is likely that this cohort (data collected from 2001 to 2009) included patients who received bortezomib (n = 12) and/or lenalidomide (n = 20) for the first time at 4th line, as they were first made available during the study period. At €32,889 per patient (range: €1,055–€144,967), costs reported in that study are comparable to our findings. However an estimated cost per QALY of £66,983 is a significant increase on that reported by Brown et al in a UK study of the cost effectiveness of Lenalidomide-based therapies after one prior therapy [5], where cost was £30,153/QALY. The difference reflects the limited benefit to survival of any current therapy at DRMM, and the higher MRU costs at this later stage of disease.\n\nCompared with a decade ago, the price range of new anticancer agents has more than doubled [14], and the cost of care analysis of these agents is imperative. New MM therapies carfilzomib and pomalidomide have been priced significantly higher than currently available anti-myeloma drugs. Any subsequent cost benefit analysis comparisons performed in DRMM patients must be set in the context of the high background MRU as observed in our cohort. It is highly relevant that the cost per assumed QALY in this cohort is double that usually accepted by the UK National Institute for Health and Care Excellence [15]. In addition to improving survival, therapies that induce higher response rates or arrest disease progression could potentially increase therapy costs, but lower MRU costs and improve QoL if progression is halted. Biomarkers that focus use of new drugs to cohorts of patients where maximum benefit is obtained would improve cost-effectiveness further. New treatments should be compared with real-world non-trial outcomes such as that provided here, to give a realistic picture of the value of these new drugs.\n\nSupporting Information\nS1 File Table A: Complete Data collected (excepting adverse events) on 39 patients with Double Refractory Multiple Myeloma. Table B: Adverse Events recorded for 39 patients with Double Refractory Multiple Myeloma.\n(XLS)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nPozzi S , Marcheselli L , Bari A , Liardo EV , Marcheselli R , Luminari S , et al\nSurvival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis . British journal of haematology . 2013 ; 163 : 40 –46 . 10.1111/bjh.12465 \n23889344 \n2 \nJordan K , Proskorovsky I , Lewis P , Ishak J , Payne K , Lordan N , et al\nEffect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study . Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer . 2013 ; 22 : 417 –426 .\n3 \nMeadows JP and Mark TM \nManagement of Double-Refractory Multiple Myeloma . Curr Hematol Malig Rep . 2013 ; 8 : 253 –260 . 10.1007/s11899-013-0173-2 \n23975677 \n4 \nKumar SK , Lee JH , Lahuerta JJ , Morgan G , Richardson PG , Crowley J , et al\nRisk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study . Leukemia . 2012 ; 26 : 149 –157 . 10.1038/leu.2011.196 \n21799510 \n5 \nBrown RE , Stern S , Dhanasiri S and Schey S \nLenalidomide for multiple myeloma: cost-effectiveness in patients with one prior therapy in England and Wales . Eur J Health Econ . 2013 ; 14 : 507 –514 . 10.1007/s10198-012-0395-6 \n22572968 \n6 \nDurie B , Binder G , Pashos C , Khan Z , Hussein M and Borrello I \nTotal cost comparison in relapsed/refractory multiple myeloma . J Med Econ . 2013 ; 16 : 614 –622 . 10.3111/13696998.2012.760159 \n23281721 \n7 \nGaultney JG , Franken MG , Tan SS , Redekop WK , Huijgens PC , Sonneveld P , et al\nReal-world health care costs of relapsed/refractory multiple myeloma during the era of novel cancer agents . J Clin Pharm Ther . 2013 ; 38 : 41 –47 . 10.1111/jcpt.12020 \n23126374 \n8 \nGaultney JG and Uyl-de Groot CA \nEfficient allocation of novel agents in multiple myeloma: a work in progress . The oncologist . 2013 ; 18 : 5 –7 . 10.1634/theoncologist.2012-0484 \n23299778 \n9 \nTeitelbaum A , Ba-Mancini A , Huang H and Henk HJ \nHealth care costs and resource utilization, including patient burden, associated with novel-agent-based treatment versus other therapies for multiple myeloma: findings using real-world claims data . The oncologist . 2013 ; 18 : 37 –45 . 10.1634/theoncologist.2012-0113 \n23299776 \n10 \nLee HC , Shah JJ and Orlowski RZ \nNovel approaches to treatment of double-refractory multiple myeloma . Am Soc Clin Oncol Educ Book . 2013 : 302 –306 .\n11 \nRajkumar SV , Harousseau JL , Durie B , Anderson KC , Dimopoulos M , Kyle R , et al\nConsensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1 . Blood . 2011 ; 117 : 4691 –4695 . 10.1182/blood-2010-10-299487 \n21292775 \n12 \nLau IJ , Smith D , Aitchison R , Blesing N , Roberts P , Peniket A , et al\nBendamustine in combination with thalidomide and dexamethasone is a viable salvage option in myeloma relapsed and/or refractory to bortezomib and lenalidomide . Annals of hematology . 2014 .\n13 Palumbo A, Davies F, Lee D, Dhanasiri S, Facon T, Zaki M, et al. Quality of life weights (utilities) in refractory or relapsed and refractory multiple myeloma (RRMM) patients using EORTC-8D and EQ-5D. Lymphoma and Myeloma 2013: An International Congress on Hematologic Malignancies 2013: Poster P-03.\n14 \nKantarjian HM , Fojo T , Mathisen M and Zwelling LA \nCancer Drugs in the United States: Justum Pretium—The Just Price . Journal of Clinical Oncology . 2013 ; 31 : 3600 –3604 . 10.1200/JCO.2013.49.1845 \n23650428 \n15 National Institute for Health and Care Excellence. Guide to the methods of technology appraisal 2013 6. The appraisal of the evidence and structured decision-making. 2013; Available: http://publications.nice.org.uk/guide-to-the-methods-of-technology-appraisal-2013-pmg9/the-appraisal-of-the-evidence-and-structured-decision-making.\n\n",
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"issn_linking": "1932-6203",
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"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000069286:Bortezomib; D003362:Cost-Benefit Analysis; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D013792:Thalidomide; D006113:United Kingdom",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0136207",
"pmc": null,
"pmid": "26367874",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21292775;21799510;23126374;23299776;23299778;23281721;22572968;23889344;23650428;23975677;23714530;24122403;25345871",
"title": "Double Relapsed and/or Refractory Multiple Myeloma: Clinical Outcomes and Real World Healthcare Costs.",
"title_normalized": "double relapsed and or refractory multiple myeloma clinical outcomes and real world healthcare costs"
}
|
[
{
"companynumb": "GB-CELGENE-GBR-2015096415",
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}
],
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"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bone pain",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
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},
{
"reactionmeddrapt": "Renal failure",
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},
{
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},
{
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},
{
"reactionmeddrapt": "Thrombocytopenia",
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},
{
"reactionmeddrapt": "Neutropenia",
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},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haemorrhage",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile neutropenia",
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"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GOODING S, LAU I, SHEIKH M, ROBERTS P, WONG J, DICKENS E. DOUBLE RELAPSED AND/OR REFRACTORY MULTIPLE MYELOMA: CLINICAL OUTCOMES AND REAL WORLD HEALTHCARE COSTS. PLOS ONE (LECTRONIC RESOURCE). 2015?10(9):.",
"literaturereference_normalized": "double relapsed and or refractory multiple myeloma clinical outcomes and real world healthcare costs",
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},
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},
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{
"abstract": "The drug rash with eosinophilia and systemic symptoms syndrome also known as DRESS syndrome refers to an idiosyncratic drug reaction commonly characterized by rashes, fever, lymphadenopathy, and internal organ involvement. We report a case of this syndrome in a 40-year-old man presenting with a rash, generalized pruritus, lymphadenopathy, and eosinophilia after metformin treatment. To the best of our knowledge, this is the first report linking metformin to the DRESS syndrome. The patient improved remarkably with drug withdrawal. A high index of clinical suspicion is emphasized to facilitate prompt diagnosis of medication related adverse effect and its discontinuation. In this article, we review the recent literature on DRESS syndrome.",
"affiliations": "Department of Medicine, Presence St Joseph Hospital, Chicago, IL.",
"authors": "Voore|Prakruthi|P|;Odigwe|Chibuzo|C|;Mirrakhimov|Aibek E|AE|;Rifai|Dana|D|;Iroegbu|Nkemakolam A|NA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(6)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D003924:Diabetes Mellitus, Type 2; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D011565:Psoriasis; D013207:Staphylococcal Skin Infections",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1970-e1973",
"pmc": null,
"pmid": "27574928",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "DRESS Syndrome Following Metformin Administration: A Case Report and Review of the Literature.",
"title_normalized": "dress syndrome following metformin administration a case report and review of the literature"
}
|
[
{
"companynumb": "US-GLENMARK GENERICS (EUROPE) LTD-2016GMK024335",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "1",
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"drugindication": "TYPE 2 DIABETES MELLITUS",
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"medicinalproduct": "METFORMIN HYDROCHLORIDE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
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"drugdosageform": "CREAM",
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}
],
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}
],
"summary": null
},
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"literaturereference": "VOORE P, ODIGWE C, MIRRAKHIMOV A E, RIFAI D, IROEGBU N A.. DRESS SYNDROME FOLLOWING METFORMIN ADMINISTRATION A CASE REPORT AND REVIEW OF THE LITERATURE. AMERICAN JOURNAL OF THERAPEUTICS. 2016;23(6):E1970-E1973",
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},
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},
{
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},
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"medicinalproduct": "METFORMIN HYDROCHLORIDE ER"
}
],
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}
],
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},
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"literaturereference": "VOORE P, ODIGWE C, MIRRAKHIMOV AE, RIFAI D, IROEGBU NA. DRESS SYNDROME FOLLOWING METFORMIN ADMINISTRATION: A CASE REPORT AND REVIEW OF THE LITERATURE. AMERICAN JOURNAL OF THERAPEUTICS. 2016",
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},
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"abstract": "The use of antihypertensive medications in patients with pheochromocytomas and paragangliomas (PCC/PG) is usually a challenge. We report a case of familial paraganglioma that was successfully treated by esmolol and other antihypertensive medications without associated perioperative complications. Our patient was an 11-year-old girl who presented with classic symptoms and signs of PCC/PG and a CT scan of the abdomen that showed a right-sided paravertebral mass. Her father was diagnosed with paraganglioma a few years ago. Prazosin had been started but she continued to experience uncontrolled paroxysms of blood pressure (BP). She was known to have asthma; hence, she developed serious bronchospasm with atenolol. She was, therefore, switched to esmolol that successfully controlled her BP in addition to prazosin and intermittent doses of hydralazine prior to laparoscopic surgery with no side effects of medications or postoperative complications. Esmolol could be a good alternative to routinely used beta-blockers in children with PCC/PG with labile hypertension and related symptoms in the pre and intra-operative periods. It is titrable, effective, and can be weaned rapidly helping to avoid postoperative complications. Further larger studies on the use of esmolol in children with PCC/PG are needed to confirm our observation.\nIn addition to alpha-blockers, esmolol could be a good alternative for routinely used beta-blockers to control paroxysmal hypertension and tachycardia in the pre- and intra-operative periods. Esmolol is titrable and an effective beta-blocker. It can be weaned rapidly helping to avoid postoperative complications in children with PCC/PG. Children with PCC/PG and other comorbidity like asthma may particularly benefit from the use of esmolol due to no or less side effects on airway resistance and the advantage of rapid titration of the medication compared to other beta-blockers.",
"affiliations": "College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.;Department of Pediatrics, Ministry of the National Guard Health Affairs, Madinah, Saudi Arabia.;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia.",
"authors": "Babiker|Amir|A|0000-0001-7538-852X;Al Hamdan|Wejdan|W|;Kinani|Sondos|S|;Kazzaz|Yasser|Y|0000-0003-3590-4547;Habeb|Abdelhadi|A|;Al Harbi|Talal|T|;Al Dubayee|Mohammed|M|;Al Namshan|M|M|;Attasi|Abdul Aleem|AA|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573\nBioscientifica Ltd Bristol\n\n34280895\n10.1530/EDM-20-0101\nEDM200101\nPaediatric\nFemale\nAsian - other\nSaudi Arabia\nAdrenal\nAdrenal\nOncology\nSurgery\nInsight into Disease Pathogenesis or Mechanism of Therapy\nInsight into Disease Pathogenesis or Mechanism of Therapy\nPerioperative control of paroxysmal hypertension using esmolol with alpha-blockade in a child with a germline mutated paraganglioma\nA Babiker and others\nEffect of esmolol in a child with paragangelioma\nhttp://orcid.org/0000-0001-7538-852X\nBabiker Amir 123\nAl Hamdan Wejdan 1\nKinani Sondos 1\nhttp://orcid.org/0000-0003-3590-4547\nKazzaz Yasser 123\nHabeb Abdelhadi 4\nAl Harbi Talal 123\nAl Dubayee Mohammed 123\nAl Namshan M 123\nAttasi Abdul Aleem 123\n1 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, National Guard Health Affairs, Riyadh, Saudi Arabia\n2 King Abdullah Specialized Children Hospital, Ministry of the National Guard Health Affairs, Riyadh, Saudi Arabia\n3 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia\n4 Department of Pediatrics, Ministry of the National Guard Health Affairs, Madinah, Saudi Arabia\nCorrespondence should be addressed to A Babiker; Email: [email protected]\n25 6 2021\n2021\n2021 20-010124 4 2021\n25 6 2021\n© The authors\n2021\nThe authors\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..\nSummary\n\nThe use of antihypertensive medications in patients with pheochromocytomas and paragangliomas (PCC/PG) is usually a challenge. We report a case of familial paraganglioma that was successfully treated by esmolol and other antihypertensive medications without associated perioperative complications. Our patient was an 11-year-old girl who presented with classic symptoms and signs of PCC/PG and a CT scan of the abdomen that showed a right-sided paravertebral mass. Her father was diagnosed with paraganglioma a few years ago. Prazosin had been started but she continued to experience uncontrolled paroxysms of blood pressure (BP). She was known to have asthma; hence, she developed serious bronchospasm with atenolol. She was, therefore, switched to esmolol that successfully controlled her BP in addition to prazosin and intermittent doses of hydralazine prior to laparoscopic surgery with no side effects of medications or postoperative complications. Esmolol could be a good alternative to routinely used beta-blockers in children with PCC/PG with labile hypertension and related symptoms in the pre and intra-operative periods. It is titrable, effective, and can be weaned rapidly helping to avoid postoperative complications. Further larger studies on the use of esmolol in children with PCC/PG are needed to confirm our observation.\n\nLearning points\n\nIn addition to alpha-blockers, esmolol could be a good alternative for routinely used beta-blockers to control paroxysmal hypertension and tachycardia in the pre- and intra-operative periods.\n\nEsmolol is titrable and an effective beta-blocker. It can be weaned rapidly helping to avoid postoperative complications in children with PCC/PG.\n\nChildren with PCC/PG and other comorbidity like asthma may particularly benefit from the use of esmolol due to no or less side effects on airway resistance and the advantage of rapid titration of the medication compared to other beta-blockers.\n\nPatient Demographics\n\nPaediatric\nFemale\nAsian - other\nSaudi Arabia\nClinical Overview\n\nAdrenal\nAdrenal\nRelated Disciplines\n\nOncology\nSurgery\nPublication Details\n\nInsight into disease pathogenesis or mechanism of therapy\nJuly\n2021\n==== Body\nBackground\n\nPheochromocytomas and paragangliomas (PCC/PG) are rare neuroendocrine catecholamine-secreting tumors that originate from the paraganglionic cells of the autonomic nervous system. Most PCC/PG are considered to be benign. However, about 25% of PG and 10% of PCC are malignant (1). PCC/PG can be familial when they present as unilateral, solitary, frequently found in the abdomen and thorax, and secrete norepinephrine and/or dopamine in 34–70% of patients (2). The clinical presentation is usually variable as a result of the hemodynamic and metabolic actions of catecholamines that are secreted by these tumors. Hemodynamically, these tumors might lead to secondary endocrine hypertension due to catecholamine-releasing properties (3). Most of these tumors are diagnosed by biochemical testing of high catecholamine levels in addition to localizing the tumor by imaging. It was thought that only 10% of these tumors are familial but the improvement of genetic testing has led to more identification of cases and increasing prevalence (4). Approximately, 60% of PCC/PG are associated with germline mutations in children (5). Mutations affecting succinate dehydrogenase (SDH) complex subunit genes (SDHA, SDHB, SDHC, SDHD) and one of the SDH complex factor genes (SDHAF2) render patients more predisposed to PCC/PG with variable risks (6). SDHB is the most commonly mutated gene in children that usually result in extra-adrenal sympathetic tumors with a high risk of metastasis (1, 7). SDH complex gene mutations are also associated with renal cell carcinoma as well as gastrointestinal stromal tumors (8).\n\nSurgical resection is the optimal treatment for these tumors (9). However, the outcome is dependent on appropriate preoperative management. It is crucial to control the blood pressure (BP) preoperatively in order to avoid hypertensive crisis intra-operatively, and equally important to maintain stable BP postoperatively (3). Hypertensive crises might lead to mortality or severe morbidities such as myocardial ischemia, arrhythmias, or cerebral hemorrhage (10). The choice of medications used in the perioperative management of patients with PCC/PG to control paroxysmal hypertension can be challenging. However, adequate use of alpha-blockade in these patients before surgery was emphasized in previous reports (11, 12). For every patient, the blood pressure needs to be optimized initially using alpha-blockades such as phenoxybenzamine or prazosin. Then, a beta-blocking agent such as propranolol or atenolol should be added to control tachycardia and BP (3, 9). Some patients might develop a serious reaction to these beta-blockers due to comorbid conditions such as asthma and allergic reaction. Therefore, there is a need for a safe and effective alternative to these medications; especially in cases with comorbidity such as asthma. Esmolol, because of its short duration of action and relative lack of airway resistance, may be preferred over other beta-blockers like propranolol and atenolol in patients with asthma who require i.v. beta-blocking agents such as children with PCC/PG (13).\n\nWe report on a successful experience of using esmolol, in addition to the alpha-blockade, to control labile hypertension of PCC/PG in a child with asthma comorbidity, minimizing perioperative complications.\n\nCase presentation\n\nAn 11-year-old girl with a known case of bronchial asthma was referred from a district hospital that affiliates to our tertiary center in Riyadh for further investigations of paroxysms of tachycardia, hypertension, and sweating. Her symptoms started 5 months prior to presentation with attacks of palpitations, chest pain, headache, flushing, and abdominal pain. The frequency of her attacks progressed over the last month. She had a history of polyuria and polydipsia. The family history was impressive for neuroendocrine tumors. For instance, the patient’s father was diagnosed with retroperitoneal mass, her paternal aunt had PCC, and also her brother was diagnosed with a benign intestinal tumor. Her BP was maintained with the use of prazosin 0.05 mg/kg/day at the referring hospital, and she was clinically and vitally stable when admitted to our hospital. In our tertiary center, her management was guided by a pediatric multidisciplinary team including Pediatric Intensivist, Endocrinologist, Surgeon, Nephrologist, Oncologist, Radiologist, and Pediatric Anesthetist.\n\nInvestigation\n\nInitially, the biochemical and radiological investigations suggested the diagnosis of PCC/PG, and the images did not show evidence of metastasis (Fig. 1 and Table 1). Plasma normetanephrine and 24 h urine norpepinephrine were elevated that helped to make a biochemical diagnosis of PCC/PG (Table 1). MIBG showed avid focus in the right-sided paraspinal retroperitoneal mass at the level of lower pole of the right kidney compatible with a paraganglioma. Figure 1 Preoperative imaging showing right-sided paraganglioma.\n\nTable 1 Initial pre- and postoperative levels of catecholamines.\n\nInitial Result\tPlasma\tUrine\t\nPreoperatively\tCatecholamines (HPLC†)\nAdrenaline < 0.106 nmol/L (n = up to 0.435)\nNoradrenaline 99.7** nmol/L (n = up to 2.89)\nDopamine < 0.130 nmol/L (n = up to 0.377)\nResults from another laboratory:\nCatecholamines (LC-MS/MS‡)\nMetanephrine*** < 50 ng/L (n < 90)\nNormetanephrine*** 3760** ng/L (n < 129, borderline up to 320 ng/L)\tCatecholamines (HPLC)\nAdrenaline/creatinine 12.6 μg/g Creat* (n < 18)\nNoradrenaline/creatinine 1030** μg/g Creat (n = 5–53)\nDopamine/creatinine 260 μg/g Creat (n = 69–552)\nCreatinine 4.22 mmol/L (n = 2.56–20.0)\t\nPostoperatively\tCatecholamines (LC-MS/MS)\nMetanephrine < 50 ng/L (n < 90)\nNormetanephrine 123 ng/L (n < 129, borderline up to 320 ng/L)\tCatecholamines (HPLC)\nAdrenaline/creatinine 1.8 μg/g Creat (n < 18)\nNoradrenaline/creatinine 28.7 μg/g Creat (n = 5–53)\nDopamine/creatinine 547 μg/g Creat (n = 69–552)\nCreatinine 19.7 mmol/L (n = 2.56–20.0)\t\n*Creat, creatinine; **High levels of catecholamines; ***Metanephrine and normetanephrine – adrenaline and noradrenaline; †HPLC, high performance liquid chromatography; ‡LC-MS/MS, liquid chromatography mass spectrometry.\n\nTreatment\n\nHypertension was treated by using esmolol, prazosin, and intermittent doses of hydralazine in our patient. Atenolol was given initially; however, the patient developed an allergic bronchospasm reaction. Therefore, esmolol (1000 mg) infusion was used as an alternative to atenolol and gradually titrated to a dose of 50 μg/kg/min. That was effective in controlling the tachycardia and the BP in addition to prazosin at 0.1 mg/kg/day in four divided doses (i.e. 0.8 mg per dose every 6 h) and also an intermittent use of i.v. hydralazine push of 3 mg when the systolic BP exceeded 130 mm of mercury. A successful control of the paroxysms of hypertension and tachycardia using the above agents was achieved a week prior to surgery (Fig. 2). Following control of paroxysmal hypertension, an exploration laparotomy was performed to remove the right-sided paraspinal abdominal paraganglioma. Postoperatively, the pain was controlled with minimal settings of epidural anesthesia (Bupivacaine hydrochloride 0.1%) then epidural injections of fentanyl citrate (50 μg/mL) until day 2 after the operation. The patient remained hemodynamically stable after the removal of tumor with BP maintained between 109–120/60–67 mm of mercury. She required noradrenaline infusion (0.05 μg/kg/min) for only 8 h postoperatively; after which, no episodes of hypotension were recorded. Figure 2 Pre-operative paroxysms of hypertension and tachycardia in our patient.\n\nOutcome and follow-up\n\nThe diagnosis was confirmed later by histopathology and the genetic test (Fig. 3). Her genetic study showed a heterozygous p.R90 pathogenic mutation in the SDHB gene confirming the diagnosis of familial paraganglioma. Her family was counseled regarding the risks of tumour recurrence as well as the development of renal cell carcinoma and gastrointestinal stromal tumor. They were also told about the need for life-long tumor surveillance. Figure 3 Gross histopathology of paraspinal paraganglioma following surgical excision.\n\nOur patient was followed in oncology and endocrine clinics. She showed an excellent improvement in her general condition apart from infrequent episodes of palpitation that were assessed by a cardiologist who reassured the family. The screening for tumor recurrence included urine and blood tests for catecholamine levels every 4 months that was normal and a whole-body MRI imaging twice a year that was also reassuring of no recurrence.\n\nDiscussion\n\nPreoperative management using alpha- and beta-blockade is crucial to prevent intra-operative complications in PCC/PG. Combination of both is usually preferred for better control of BP. Phenoxybenzamine, a long-acting non-selective alpha-blockade, has been widely used since 1950s. In addition, prazosin, a selective alpha 1 blockade, has also been favorably used due to its short duration of action resulting in fewer side effects postoperatively (14). Beta blockade should never be used prior to initiating alpha-blockade agents as they might exacerbate vasoconstriction by blocking its vasodilator component, leading to hypertensive crisis. Nonetheless, beta-blockade is generally used after alpha-blockade to suppress the alpha-blocker-induced tachycardia, and they also help in control of BP (15). There is no evidence to support the use of beta 1 blockers such as atenolol over the non-selective beta-blockers, which include propranolol. Some previous reports suggested the use of esmolol in adults but there were only a few reports in Pediatrics (16, 17). Esmolol showed a good effect as adjuvant therapy to alpha-blockers and its very short half-life of approximately 9 min facilitated an easy titration, which helped to avoid postoperative hypotension that usually requires prolonged use of presser agents.\n\nPatients are commonly admitted 24–36 h prior to surgery and are given alpha and beta-blockers, as well as, in some cases, a tyrosine hydroxylase inhibitor in the night before surgery (18). Hypotension is a common complication in the immediate postoperative period due to the unopposed effect of long-acting alpha-blockade leading to vascular expansion. This is usually managed preoperatively with large volume i.v. fluids and consumption of high sodium diet (19). An important initial step in the management is to start with an alpha-blocking agent to reduce the BP then use beta-blockers to achieve heart rate control. The goal of BP reduction is to achieve <50 percentile for age and height. Echocardiography is necessary for the preoperative assessment to rule out dilated cardiomyopathy as a complication of chronic oversecretion of catecholamines (20).\n\nIn a previous report, with the use of alpha-blockade, the operative and postoperative complications decreased dramatically from 69% to 3% (17). The preferred agent for the alpha-blockade is phenoxybenzamine because of its long duration of action and a non-competitive blockade of alpha-receptors that favored its use (21). Nonetheless, the downsides of a long half-life duration of phenoxybenzamine are tachycardia and persistent postoperative hypotension. Other alternatives include terazosin, doxazosin, and prazosin that are mainly used in adults (15). Given the rarity of neuroendocrine tumors in pediatric and adult patients; to date, there are no reported randomized controlled trials looking at the superiority of the commonly used subtypes of medications. Although, the short duration of action of prazosin and doxazosin might suggest favoring their use in patients with PCC/PG, none of these alpha-blockers, neither the phenoxybenzamine, is currently evident to be superior in the perioperative management of patients with PCC/PG (22). The decision on a choice probably much depends on individual cases.\n\nFor beta-blockade, propranolol is commonly used in patients with PCC/PG following the use of alpha-blockers (23). In our case, the patient was also known to have bronchial asthma, for which propranolol was contraindicated. When atenolol was given, the patient developed serious allergic bronchospasm, so esmolol was given as an alternative. Esmolol is an ultra-short acting, cardio-selective, beta 1 blockade agent. The onset of action is within 1 to 2 min, and its half-life is only 9 min (24). The rapid onset and short half-life enable titration of the drug to the desired effect facilitating escalation and discontinuation of treatment to avoid postoperative complications. Esmolol has been approved for use only in adults by FDA (25). Nevertheless, it has been used in pediatrics for several indications including arrhythmia (e.g. supraventricular tachycardia), perioperative and postoperative tachycardia, as well as hypertension and hypertensive emergencies (25). It is usually administered as a loading dose of 100–500 μg/kg over 1 min, followed by an infusion of 50–500 μg/kg/min and titrated by 25–50 μg/kg/min (25). In our case, we were able to achieve adequate control of paroxysmal hypertension by using a minimal dose of esmolol in addition to other antihypertensive agents, mainly prazosin, without adverse events.\n\nConclusion\n\nEsmolol is titrable, effective, and can be weaned rapidly helping to avoid postoperative complications of hypotension in children with PCC/PG after the removal of a catecholamine-secreting tumor. In addition to alpha-blockers, esmolol could be a good alternative to routinely used beta-blockers such as propranolol and atenolol to control the BP and tachycardia in the pre- and intra-operative periods; especially when a patient has comorbidity of asthma.\n\nDeclaration of interest\n\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\n\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\n\nA written informed consent has been obtained from the patient’s guardian for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\n\nA B, W A and S K wrote and drafted the initial manuscript and approved the final manuscript. All other co-authors revised, amended, and approved the finally submitted manuscript. Y K designed Figure 2. M A provided the photo of Figure 3. A B (Pediatric Endocrinologist) named physician of the patient in the treatment center, A H (Pediatric Endocrinologist) named physician of the patient in the referring center, Y K (Intensivist, PICU), T A (Pediatric Oncologist), M A (attending Endocrinologist), M A (Pediatric Surgeon), A A (Pediatric Anesthetist), W A and S K (Medical interns).\n==== Refs\nReferences\n\n1 Young WF Elfiky A . Paraganglioma and pheochromocytoma: management of malignant disease. [Internet]. UpToDate; cited Jan 2021. (available at: https://www.uptodate.com/contents/paraganglioma-and-pheochromocytoma-management-of-malignant-disease)\n2 Jain A Baracco R Kapur G . Pheochromocytoma and paraganglioma: an update on diagnosis, evaluation, and management. Springerlink 2019 35 581–594. (10.1007/s00467-018-4181-2)\n3 Canu L Parenti G de Filpo G Mannelli M . Pheochromocytomas and paragangliomas as causes of endocrine hypertension. Frontiers in Endocrinology 2019 10 333. (10.3389/fendo.2019.00333)\n4 Plouin PF Amar L Dekkers OM Fassnacht M Gimenez-Roqueplo AP Lenders JW Lussey-Lepoutre C Steichen O & Guideline Working Group. European Society of Endocrinology clinical practice guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma. European Journal of Endocrinology 2016 174 G1–G10. (10.1530/EJE-16-0033)27048283\n5 Choat H Derrevere K Knight L Brown W Mack EH . SDHB-associated paraganglioma in a pediatric patient and literature review on hereditary pheochromocytoma-paraganglioma syndromes. Case Reports in Endocrinology 2014 2014 502734. (10.1155/2014/502734)25298897\n6 Rana HQ Rainville IR Vaidya A . Genetic testing in the clinical care of patients with pheochromocytoma and paraganglioma. Current Opinion in Endocrinology, Diabetes, and Obesity 2014 21 166–1 76. (10.1097/MED.0000000000000059)\n7 van Hulsteijn LT Dekkers OM Hes FJ Smit JW Corssmit EP . Risk of malignant paraganglioma in SDHB-mutation and SDHDmutation carriers: a systematic review and meta-analysis. Journal of Medical Genetics 2012 49 768–7 7 6. (10.1136/jmedgenet-2012-101192)23099648\n8 Gómez AM Soares DC Costa AAB Pereira DP Achatz MI Formiga MN . Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance. Archives of Endocrinology and Metabolism 2019 63 369–375. (10.20945/2359-3997000000145)31365623\n9 Corssmit EP Romijn JA . Clinical management of paragangliomas. European Journal of Endocrinology 2014 171 R231–R2 43. (10.1530/EJE-14-0396)25063320\n10 Lenders JWM Duh QY Eisenhofer G Roqueplo APG Grebe SKG Murad MH Naruse M Pacak K Young WF & Endocrine Society. Pheochromocytoma and paraganglioma: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2014 99 1915–1942. (10.1210/jc.2014-1498)24893135\n11 Challis BG Casey RT Simpson HL Gurnell M . Is there an optimal preoperative management strategy for phaeochromocytoma/paraganglioma? Clinical Endocrinology 2017 86 163–167. (10.1111/cen.13252)27696513\n12 García MIDO Palasí R Gómez RC Marco JLP Torres JFM . Paraganglioma A Multidisciplinary Approach. Brisbane (AU): Mariani-Costantini R, 2019. (https://doi.org/)\n13 Sheppard D DiStefano S Byrd RC Eschenbacher WL Bell V Steck J Laddu A . Effects of esmolol on airway function in patients with asthma. Journal of Clinical Pharmacology 1986 26 169–1 74. (https://doi.org/10.1002/j.1552-4604.1986.tb02929.x)2870080\n14 Nicholson Jr JP Vaughn Jr ED Pickering TG Resnick LM Artusio J Kleinert HD Lopez-Overjero JA Laragh JH . Pheochromocytoma and prazosin. Annals of Internal Medicine 1983 99 477–47 9. (https://doi.org/10.7326/0003-4819-99-4-477)6625381\n15 Mazza A Armigliato M Marzola MC Schiavon L Montemurro D Vescovo G Zuin M Chondrogiannis S Ravenni R Opocher G Anti-hypertensive treatment in pheochromocytoma and paraganglioma: current management and therapeutic features. Endocrine 2014 45 469–4 78. (https://doi.org/10.1007/s12020-013-0007-y)23817839\n16 Rodríguez González O Amador García I Martín Iglesias A Rodríguez Germa I Besada Estévez JC . Esmolol to control hemodynamic response during removal of a bilateral pheochromocytoma from a 10-year-old girl. Revista Española de Anestesiología y Reanimación 2010 57 454–457. (https://doi.org/10.1016/s0034-9356(10)70272-3)20857641\n17 Nicholas E Deutschman CS Allo M Rock P . Use of esmolol in the intraoperative management of pheochromocytoma. Anesthesia and Analgesia 1988 67 1114–111 7. (https://doi.org/10.1213/00000539-198811000-00021)2903700\n18 Ramachandran R Rewari V . Current perioperative management of pheochromocytomas. Indian Journal of Urology 2017 33 19–25. (https://doi.org/10.4103/0970-1591.194781)28197025\n19 Li L Zhu W Fang L Zeng Z Miao Q Zhang C Fang Q . Transthoracic echocardiographic features of cardiac pheochromocytoma: a single-institution experience. Echocardiography 2012 29 153–15 7. (https://doi.org/10.1111/j.1540-8175.2011.01556.x)22066682\n20 Bholah R Bunchman TE . Review of pediatric pheochromocytoma and paraganglioma. Frontiers in Pediatrics 2017 5 155. (https://doi.org/10.3389/fped.2017.00155)\n21 Carvalho MR Dias T Rodrigues A Machado AP Esteves R do Carmo I . Alpha blockade with doxazosin in pheochromocytoma: report of three cases. Revista Portuguesa de Cardiologia 2010 29 299–308.20545254\n22 Van der Zee PA de Boer A . Pheochromocytoma: a review on preoperative treatment with phenoxybenzamine or doxazosin. Netherlands Journal of Medicine 2014 72 190–201.\n23 Peco-Antić A Pejcić I . Savremni pristup u lecenju arterijske hipertenzije kod dece [Management of hypertension in children]. Srpski Arhiv za Celokupno Lekarstvo 1995 123 274–277.17974448\n24 Barbier GH Shettigar UR Appunn DO . Clinical rationale for the use of an ultra-short acting beta-blocker: esmolol. International Journal of Clinical Pharmacology and Therapeutics 1995 33 212–21 8.7620691\n25 Pevtsov A Kerndt CC Fredlund KL . Esmolol. In StatPearls. Treasure Island (FL): StatPearls Publishing; 2021.(available at: https://www.ncbi.nlm.nih.gov/books/NBK518965/)\n\n",
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"title": "Perioperative control of paroxysmal hypertension using esmolol with alpha-blockade in a child with a germline mutated paraganglioma.",
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"literaturereference": "BABIKER A, AL HAMDAN W, KINANI S, KAZZAZ Y, HABEB A, AL HARBI T, ET.AL. PERIOPERATIVE CONTROL OF PAROXYSMAL HYPERTENSION USING ESMOLOL WITH ALPHA?BLOCKADE IN A CHILD WITH A GERMLINE MUTATED PARAGANGLIOMA. ENDOCRINOL DIABETES METAB CASE REP. 2021 JUL 19?2021(20?0101):EDM200101.",
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"abstract": "BACKGROUND\nRing chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory seizure, mental retardation, and behavioral problems. Although there are reports of the effective treatment of patients with antiepileptic drugs (AEDs), no study has reported the effects of lacosamide(LCM) in children with this syndrome. We report a 7-year-old boy with this syndrome whose refractory and behavioral abnormalities have been remarkably improved by treatment with LCM.\n\n\nMETHODS\nThe patient was a 7-year-old boy with no medical or family history of epilepsy. He developed epilepsy with cessation of movement and derivation of the eyes followed by hyperkinetic seizures that made him squeak strangely and cling to his parents. The seizures lasted for less than a minute and were frequent (they occurred more than 30 times a day), particularly at night. Behavioral abnormalities such as hyperactivity also presented. Brain magnetic resonance imaging revealed no structural abnormalities, but an interictal electroencephalogram (EEG) indicated spikes and waves in the frontal lobe dominantly, and ictal single-photon emission computed tomography (SPECT) revealed a blood flow increase in the bilateral orbital frontal area in comparison to interictal SPECT. After chromosome examination, we diagnosed the patient with ring chromosome 20 syndrome (4/30 mosaic). Carbamazepine was ineffective, and seizures were exacerbated with levetiracetam (LEV). LCM was added to the treatment regimen with valproic acid (VPA) and lamotrigine (LTG); consequently, the seizures disappeared, and EEG results also improved. The patient's behavioral disorders, such as hyperactivity, were improved, and he was able to return to elementary school.\n\n\nCONCLUSIONS\nAlthough VPA and LTG are generally effective for the treatment of ring chromosome 20 syndrome, they do not completely suppress seizures. LCM can be considered an effective option for seizure control in patients with this syndrome.",
"affiliations": "Department of Pediatrics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan. Electronic address: [email protected].;Department of Pediatrics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; Division of Epilepsy Center, Tokushima University Hospital, Tokushima, Japan.;Department of Pediatrics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; Division of Epilepsy Center, Tokushima University Hospital, Tokushima, Japan.;Department of Pediatrics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; Division of Epilepsy Center, Tokushima University Hospital, Tokushima, Japan.;Department of Pediatrics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.",
"authors": "Tayama|Takahiro|T|;Mori|Tatsuo|T|;Goji|Aya|A|;Toda|Yoshihiro|Y|;Kagami|Shoji|S|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D000077287:Levetiracetam; D000078334:Lacosamide; D014635:Valproic Acid; D000077213:Lamotrigine",
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"keywords": "Lacosamide; Refractory seizures; Ring chromosome 20 syndrome",
"medline_ta": "Brain Dev",
"mesh_terms": "D000927:Anticonvulsants; D002220:Carbamazepine; D002648:Child; D004569:Electroencephalography; D004827:Epilepsy; D006801:Humans; D000078334:Lacosamide; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D012303:Ring Chromosomes; D012640:Seizures; D016896:Treatment Outcome; D014635:Valproic Acid",
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"pmc": null,
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"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Improvement of epilepsy with lacosamide in a patient with ring chromosome 20 syndrome.",
"title_normalized": "improvement of epilepsy with lacosamide in a patient with ring chromosome 20 syndrome"
}
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"abstract": "BACKGROUND\nLacosamide (LCM) is the antiepileptic drug approved by the U.S. Food and Drug Administration in 2008 that facilitates slow activation of the voltage-gated sodium channels. Neutropenia and cardiac events including sinus node dysfunction (SND) and atrioventricular block have been previously reported as adverse effects of LCM. To date, there have been no reports of severe agranulocytosis resulting in death associated with LCM. Additionally, there have been no reports of concomitant SND and agranulocytosis after LCM administration. Herein we report the first case of LCM-induced severe SND followed by agranulocytosis.\n\n\nMETHODS\nThe patient with focal epilepsy was initiated on LCM 100 mg/day and the dose was increased to 200 mg/day on the 9th hospital day. Severe SND developed on the 10th hospital day and LCM was discontinued. Thereafter agranulocytosis appeared on the 11th hospital day, and the patient died from septic shock on the 15th hospital day.\n\n\nCONCLUSIONS\nThis case illustrates the need for careful follow-up of the electrocardiogram and the complete blood cell counts when initiating LCM. Moreover, it should be noticed that various side effects may occur simultaneously in the early period of LCM use, even for a short time and at low dosages.",
"affiliations": "Department of Neurology, Takasaki General Medical Center, National Hospital Organization, 36 Takamatsu-cho, Takasaki, 370-0829, Gunma, Japan.;Department of Neurology, Takasaki General Medical Center, National Hospital Organization, 36 Takamatsu-cho, Takasaki, 370-0829, Gunma, Japan.;Department of Neurology, Takasaki General Medical Center, National Hospital Organization, 36 Takamatsu-cho, Takasaki, 370-0829, Gunma, Japan.;Department of Neurology, Takasaki General Medical Center, National Hospital Organization, 36 Takamatsu-cho, Takasaki, 370-0829, Gunma, Japan.;Department of Neurology, Takasaki General Medical Center, National Hospital Organization, 36 Takamatsu-cho, Takasaki, 370-0829, Gunma, Japan.;Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511, Gunma, Japan. [email protected].",
"authors": "Shibata|Makoto|M|http://orcid.org/0000-0003-2893-2005;Hoshino|Reona|R|;Shimizu|Chisato|C|;Sato|Masayuki|M|;Furuta|Natsumi|N|;Ikeda|Yoshio|Y|",
"chemical_list": "D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-021-02253-1",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377\nBioMed Central London\n\n2253\n10.1186/s12883-021-02253-1\nCase Report\nLacosamide-induced sinus node dysfunction followed by severe agranulocytosis\nhttp://orcid.org/0000-0003-2893-2005\nShibata Makoto 1\nHoshino Reona 1\nShimizu Chisato 1\nSato Masayuki 1\nFuruta Natsumi 1\nIkeda Yoshio [email protected]\n\n2\n1 grid.416698.4 Department of Neurology, Takasaki General Medical Center, National Hospital Organization, 36 Takamatsu-cho, Takasaki, 370-0829 Gunma Japan\n2 grid.256642.1 0000 0000 9269 4097 Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511 Gunma Japan\n8 6 2021\n8 6 2021\n2021\n21 21721 11 2020\n26 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.\nBackground\n\nLacosamide (LCM) is the antiepileptic drug approved by the U.S. Food and Drug Administration in 2008 that facilitates slow activation of the voltage-gated sodium channels. Neutropenia and cardiac events including sinus node dysfunction (SND) and atrioventricular block have been previously reported as adverse effects of LCM. To date, there have been no reports of severe agranulocytosis resulting in death associated with LCM. Additionally, there have been no reports of concomitant SND and agranulocytosis after LCM administration. Herein we report the first case of LCM-induced severe SND followed by agranulocytosis.\n\nCase presentation\n\nThe patient with focal epilepsy was initiated on LCM 100 mg/day and the dose was increased to 200 mg/day on the 9th hospital day. Severe SND developed on the 10th hospital day and LCM was discontinued. Thereafter agranulocytosis appeared on the 11th hospital day, and the patient died from septic shock on the 15th hospital day.\n\nConclusions\n\nThis case illustrates the need for careful follow-up of the electrocardiogram and the complete blood cell counts when initiating LCM. Moreover, it should be noticed that various side effects may occur simultaneously in the early period of LCM use, even for a short time and at low dosages.\n\nKeywords\n\nLacosamide\nNeutropenia\nAgranulocytosis\nSinus node dysfunction\nAdverse effects\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nLacosamide (LCM) is one of the well-tolerated anti-epileptic drugs (AEDs) that facilitates slow activation of voltage-gated sodium channels [1, 2]. It has been noted that LCM can cause adverse effects (AEs) similar to those of conventional sodium channel blockers (SCBs). Although rare, there are increasing reports of AEs associated with LCM [3].\n\nTo date, there have been several reports of neutropenia as common AEs of LCM; [4–8] however, there are no reports of severe agranulocytosis resulting in death. Additionally, several cases of sinus node dysfunction (SND) and atrioventricular (AV) block have been reported as serious AEs of LCM, [9–11] however, there have been no reports of concomitant SND and agranulocytosis.\n\nHerein we report a case of LCM-induced SND followed by agranulocytosis resulting in death from septic shock. Although concomitant occurrence of SND and agranulocytosis due to LCM is incidental and extremely rare, clinicians should be aware of the respective severe AEs.\n\nCase presentation\n\nA 78-year-old Japanese female was diagnosed with focal epilepsy two years prior to admission based on repeated right hemiconvulsion evolving into generalized tonic–clonic seizure with an electroencephalography finding of frequent sharp waves in the left parietal lobe. Her status was stable on treatment with levetiracetam (LEV) 2000 mg/day orally, however, episodic disturbance of consciousness appeared and gradually worsened one month prior to admission. Phenytoin (PHT) 200 mg/day was given in conjunction with LEV at another hospital 16 days prior to admission. Nevertheless, there was little improvement in the frequency of impaired consciousness, and she was transferred to our hospital to adjust AEDs.\n\nAt the time of admission, her level of consciousness was alert and there was no obvious evidence of epileptic seizures. Physical examination on admission revealed blood pressure (BP) 106/52 mm Hg, heart rate (HR) 76 beats per minute (bpm), body temperature (BT) 37.5 °C, and respiratory rate (RR) 22 breaths per minute, and the electrocardiogram (ECG) showed no arrhythmia and PR interval was normal (0.16 s). Her height, body weight, and body mass index (BMI) were 152 cm, 42 kg, and 18.2 kg/m2, respectively. Figure 1A shows the clinical course and the chronological laboratory findings of the patient. Her complete blood cell counts (CBCs) showed total white blood cell (WBC) counts of 7100 /μL with neutrophil counts of 5893 /μL, hemoglobin level of 7.0 mg/dL, red blood cell counts of 413 × 104 /μL, mean corpuscular volume of 63.7 fl, mean corpuscular hemoglobin concentration of 26.6%, and platelet counts of 19.6 × 104 /μL, indicating hypochromic microcytic anemia due to iron deficiency. Her blood chemistry tests showed normal liver and renal function: aspartate aminotransferase (AST) of 13 U/L, alanine aminotransferase (ALT) of 8 U/L, blood urea nitrogen (BUN) of 15.1 mg/dL, and creatinine (Cr) of 0.34 mg/dL. Her serum C-reactive protein (CRP) was mildly elevated to 6.6 mg/dL and chest computed tomography showed mild aspiration pneumonia in the left S10 segment of left lung. Since she was in good condition without decreased percutaneous oxygen saturation (SpO2), antibiotics were not administered. LEV 2000 mg/day was continued orally and PHT was discontinued, thereafter, the patient was initiated on LCM at 100 mg/day orally because the patient did not accept to increase the LEV dose due to drug-induced drowsiness. The stool occult blood on admission was positive, but the patient did not agree to undergo a gastrointestinal endoscopy, thereafter, the patient received a blood transfusion containing 4 units of red blood cell concentrates (RCC) on the 4th hospital day to treat anemia.Fig. 1 Clinical course, laboratory, and electrocardiogram findings of the present case. The patient’s clinical course and the chronological changes of HR and WBC counts (upper graph, A), laboratory results of WBC, neutrophils, Hb, Plt, CRP, and BT (lower table, A) are shown. An electrocardiogram finding on the 10th hospital day is also shown with a maximum sinus arrest of 5.6 s (B). Abbreviations: BT = body temperature; CRP = C-reactive protein; G-CSF = granulocyte-colony stimulating factor; Hb = hemoglobin; HR = heart rate; LCM = lacosamide; LEV = levetiracetam; MEPM = meropenem; NE = not examined; PHT = phenytoin; Plt = platelet; RCC = red blood cell concentrates; SND = sinus node dysfunction; VCM = vancomycin; WBC = white blood cell\n\nThe dose of LCM was increased to 200 mg/day on the 9th hospital day, as per the Japanese guidelines for maintenance doses, and subsequently on the 10th hospital day, a sinus bradycardia with HR of 20 bpm suddenly began to appear, with a maximum sinus arrest of 5.6 s (Fig. 1B). The PR interval was 0.16 s and did not change during her hospitalization. There was no decrease in BP or no symptomatic syncope due to SND, while WBC counts were decreased to 2300/μL on the 10th hospital day. The additional blood chemistry tests showed AST of 16 U/L, ALT of 10 U/L, BUN of 15.8 mg/dL, Cr of 0.33 mg/dL, and potassium of 4.45 mmol/L. Drug-induced SND and leukopenia were suspected and LCM was immediately discontinued. The bradycardia gradually improved until the next day with HR of 59 bpm. There was no evidence of sepsis causing neutropenia at this point, and CRP was decreased to 1.2 mg/dL.\n\nOn the 11th hospital day, a decrease in SpO2 requiring high-flow oxygen appeared. An analysis of arterial blood (O2 10 L/min via non-rebreather mask) showed a pH of 7.49, a partial pressure of carbon dioxide of 31.9 mm Hg, and a partial pressure of oxygen of 72.3 mm Hg. Although serum N-terminal pro-brain natriuretic peptide level was elevated to 1320 pg/mL (reference range < 125 pg/mL), a transthoracic echocardiogram showed a normal ejection fraction of the left ventricle (63%) without signs of asynergy and pulmonary hypertension, and normal inferior vena cava diameter (13 mm) with normal inspiratory collapse. A chest X-ray showed an infiltrative shadow in the left lung field, which was suspected to be exacerbation of the pneumonia recognized at admission. The WBC counts decreased to 500/μL and the neutrophil counts to 49/μL, leading to a diagnosis of drug-induced agranulocytosis. Fever of over 39 °C appeared. After blood, sputum, and urine cultures were submitted, meropenem (3 g/day) and granulocyte-colony stimulating factor (G-CSF) (100 μg/day) were administered. No bacterial growth was confirmed in the blood and urine cultures, while the sputum cultures showed a growth of Acinetobacter baumannii/calcoaceticus complex and Klebsiella pneumoniae that were sensitive to carbapenem antibiotics. Since LCM was discontinued, LEV was replaced from oral to intravenous administration, and the dose was increased to 3000 mg/day in order to reinforce the treatment of epilepsy.\n\nOn the 12th hospital day, the vital signs were worsened to BP 69/49 mm Hg, HR 123 bpm, BT 39.4 °C, RR 34 breaths per minute, and she became unresponsive to calls. Consequently, fluid resuscitation was started, and vancomycin was administered with dose adjustment based on therapeutic drug monitoring (TDM). Since hypotension did not improve even with adequate fluid resuscitation, norepinephrine was started and increased to maintain mean arterial pressure at 65 mm Hg. The WBC counts were 600/μL and the neutrophil counts were 24/μL with still no improvement in agranulocytosis, and serum procalcitonin level was markedly elevated at 25.55 ng/mL (reference range < 0.50 ng/mL), suggesting severe sepsis. Generally, 28–49% of severe sepsis cases are known to show negative cultures [12] Although the blood cultures of the patient were negative, septic shock was strongly suspected due to fever associated with agranulocytosis, hypotension unresponsive to adequate rehydration, tachypnea, disturbance of consciousness, and the absence of other diseases causing hypotension.\n\nOn the 14th hospital day, the patient’s WBC and neutrophil counts improved to 4000/μL and 3640/μL, respectively, therefore, G-CSF administration was discontinued. Although the SND and agranulocytosis improved, the patient could not recover from septic shock, and died on the 15th hospital day.\n\nDiscussion and conclusion\n\nThe present case represented two clinically important points. First, LCM can cause severe agranulocytosis leading to death. Second, LCM can cause both agranulocytosis and SND simultaneously, therefore, careful follow-up of CBCs and ECG are required especially in the early period of treatment.\n\nSince the patient received no additional medications other than LCM, and there was a rapid improvement of neutropenia after LCM discontinuation and G-CSF administration, LCM-induced neutropenia was strongly suspected. The Naranjo adverse drug reaction probability scale was 8 points, [13] indicating that LCM was a “probable” cause of agranulocytosis. Table 1 shows a summary of previous reports on LCM-induced neutropenia [4–8]. Agranulocytosis is diagnosed as a condition in which the number of neutrophils in the peripheral blood is less than 500/μL, and its cause is usually drug-induced [14, 15]. To date, only a single case of agranulocytosis due to LCM has been reported (Table 1) [6]. To our best knowledge, this is the first case of LCM-induced severe agranulocytosis leading to death due to septic shock. Among all AEDs, SCBs such as carbamazepine (CBZ) and PHT are known to cause agranulocytosis, [16] and CBZ had the highest potential for agranulocytosis [17]. LCM is a commonly used AED among SCBs, therefore, it is important to clarify which patients are at high risk for LCM-induced agranulocytosis as a future direction.Table 1 Summary of previous reports on lacosamide-induced neutropenia\n\nAuthor (year)\tNumber\nof patients\tAge, Sex\tLCM\ndosage\tLCM\nduration\tOther AEDs\tAdverse event\tClinical outcome (Days to remission)\t\nHusain et al. (2012)[4]\t2\tND\tND\tND\tND\tNeutropenia\tND\t\nNovy et al. (2013)[5]\t7(a)\tND\tND\tND\tND\tNeutropenia\n\nor Rash (a)\n\n\tND\t\nZadeh et al. (2015)[6]\t1\t25, M\t400 mg/day\t46 days\tLTG, LEV\n\n(Dose unknown)\n\n\tAgranulocytosis\tImproved\n\n(7 days after LCM\n\nwas discontinued)\n\n\t\nWelsh et al. (2017)[7]\t6\tND (children)\tND\tND\tND\tNeutropenia\tND\t\nRao et al. (2018)[8]\t1\t20, M\t200 mg/day\t10 days\tVPA 1000 mg/day,\n\nCLB 10 mg/day\n\n\tNeutropenia\tImproved\n\n(2 days after LCM\n\nwas discontinued)\n\n\t\nPresent case\t1\t80, F\t200 mg/day\t9 days\tLEV 2000 mg/day\tAgranulocytosis\tDeath from sepsis\t\nAbbreviations: ND Not described, M Male, F Female, LCM Lacosamide, AED Anti-epileptic drug, LTG Lamotrigine, LEV Levetiracetam, VPA Valproic acid, CLB Clobazam\n\n(a) The number of events is the sum of allergic events including neutropenia or rash\n\nIt is also important to note that agranulocytosis in the present case occurred at a low LCM dose of 200 mg/day. Previous reports have shown that the increased risk of drug-induced neutropenia is more pronounced in the first month of treatment and is not related to the daily dosage [18]. Careful follow-up of CBCs is required especially in the first month after initiation of LCM even at low doses. Additionally, it is important to discontinue LCM as soon as any suspicious signs appear.\n\nIt is especially important to note that LCM can cause agranulocytosis and SND simultaneously. LCM is known to cause various cardiac conduction disorders (CCDs), including dose-dependent prolongation of the PR interval, [19] second-degree AV block, [10] third-degree AV block, [11] and SND [9]. Previous reports of CCDs due to LCM are more common in patients with concomitant use of SCBs or drugs that prolong the PR interval [9, 10]. In this case, PHT was used until the time of admission, and was discontinued promptly after admission. Although there was no detailed evaluation of PHT blood levels, the recent use of PHT may have played a role in the development of SND. The risk of CCDs associated with LCM remains unknown except for concomitant medications. This patient had no prolongation of PR interval (0.16 s), sinus bradycardia (HR = 76 bpm), renal dysfunction, and hepatic dysfunction on admission. On the other hand, she was underweight (BMI = 18.2 kg/m2) and elderly, which may have affected her drug metabolism. Further evaluation of the details of LCM-induced CCDs risk factors is needed as more cases are accumulated.\n\nWe need to investigate whether the bradycardia in this patient was ictal bradycardia syndrome (IBS), but we believe it is likely to be LCM-induced bradycardia. First, the patient’s consciousness was alert at the time of onset of SND, and there were no findings suggestive of epilepsy. Second, the duration of IBS was previously reported to be an average of 23.2 s (range, 4–36 s), [20]. which was quite different from our case showing the bradycardia persisted for over 24 h.\n\nThere are several limitations in this case report. First, the patient was transfused with RCC before the appearance of SND and agranulocytosis, and the association between RCC transfusion and these rare complications cannot be excluded. However, the RCC transfusion was performed on the 4th hospital day, and SND and agranulocytosis appeared on the 10th and 11th hospital days, respectively. Considering the time lag of each event, it was unlikely that any of the complications were related to the RCC transfusion. Although the transfusion-related neutropenia has been reported as a rare side effect, it usually occurs within a few hours after transfusion and was not consistent with the present case [21]. Second, the blood concentration of LCM was not measured in this case. Under normal conditions, LCM is a drug that is not required a strict TDM like other anticonvulsants such as PHT or CBZ [22]. In this case, there was no severe renal dysfunction or drug interactions that could have increased LCM blood levels. Considering the dosage and duration of LCM administration, it is unlikely that the LCM blood levels were significantly elevated above the therapeutic range.\n\nIn conclusion, this report revealed that LCM, even used in low doses, can cause serious AEs including agranulocytosis and cardiac events such as SND. Thus, careful ECG and CBCs follow-up are required, especially in the first month after initiation of treatment. Additionally, if one AE associated with the use of AEDs occurs, clinicians should evaluate whether other AEs have also emerged or not.\n\nAbbreviations\n\nAEDs Anti-epileptic drugs\n\nAEs Adverse effects\n\nALT Alanine aminotransferase\n\nAST Aspartate aminotransferase\n\nAV Atrioventricular\n\nBMI Body mass index\n\nBP Blood pressure\n\nbpm Beats per minute\n\nBT Body temperature\n\nBUN Blood urea nitrogen\n\nCBCs Complete blood cell counts\n\nCBZ Carbamazepine\n\nCCDs Cardiac conduction disorders\n\nCr Creatinine\n\nCRP C-reactive protein\n\nECG Electrocardiogram\n\nG-CSF Granulocyte-colony stimulating factor\n\nHR Heart rate\n\nIBS Ictal bradycardia syndrome\n\nLCM Lacosamide\n\nLEV Levetiracetam\n\nPHT Phenytoin\n\nRCC Red blood cell concentrates\n\nRR Respiratory rate\n\nSCBs Sodium channel blockers\n\nSND Sinus node dysfunction\n\nSpO2 Percutaneous oxygen saturation\n\nTDM Therapeutic drug monitoring\n\nWBC White blood cell\n\nAcknowledgements\n\nThe authors sincerely thank the present patient for her participation in this study.\n\nAuthor’s contributions\n\nMS contributed to the conception, drafting, and reporting of the case. RH, CS, MS, NF, and YI contributed to the revision of the manuscript. 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\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s family for publication of this case report.\n\nCompeting interests\n\nThe authors declare that they have no conflict of interest.\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. Strzelczyk A Zöllner JP Willems LM Jost J Paule E Schubert-Bast S Lacosamide in status epilepticus: Systematic review of current evidence Epilepsia 2017 58 933 950 10.1111/epi.13716 28295226\n2. Errington AC Stöhr T Heers C Lees G The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels Mol Pharmacol 2008 73 157 169 10.1124/mol.107.039867 17940193\n3. Li J Sun M Wang X The adverse-effect profile of lacosamide Expert Opin Drug Saf 2020 19 131 138 10.1080/14740338.2020.1713089 31914330\n4. Husain A Chung S Faught E Isojarvi J McShea C Doty P Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a Phase III open-label extension trial Epilepsia 2012 53 521 528 10.1111/j.1528-1167.2012.03407.x 22372628\n5. Novy J Bartolini E Bell GS Duncan JS Sander JW Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation Epilepsy Res 2013 106 250 256 10.1016/j.eplepsyres.2013.05.002 23796862\n6. Zadeh WW Escartin A Byrnes W Tennigkeit F Borghs S Li T Efficacy and safety of lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset seizures: a multicentre open-label trial Seizure 2015 31 72 79 10.1016/j.seizure.2015.07.001 26362380\n7. Welsh SS Lin N Topjian AA Abend NS Safety of intravenous lacosamide in critically ill children Seizure 2017 52 76 80 10.1016/j.seizure.2017.09.019 29017081\n8. Rao NP Sheth S Varambally S Lacosamide Precipitated neutropenia in a patient with bipolar disorder and comorbid epilepsy Indian J Psychol Med 2018 40 496 497 10.4103/IJPSYM.IJPSYM_16_18 30275630\n9. Chinnasami S Rathore C Duncan JS Sinus node dysfunction: an adverse effect of lacosamide Epilepsia 2013 54 e90 e93 10.1111/epi.12108 23360388\n10. Nizam A Mylavarapu K Thomas D Briskin K Wu B Saluja D Lacosamide-induced second-degree atrioventricular block in a patient with partial epilepsy Epilepsia 2011 52 e153 e155 10.1111/j.1528-1167.2011.03212.x 21801173\n11. Krause LU Brodowski KO Kellinghaus C Atrioventricular block following lacosamide intoxication Epilepsy Behav 2011 20 4 725 727 10.1016/j.yebeh.2011.02.006 21411374\n12. Gupta S Sakhuja A Kumar G McGrath E Nanchal RS Kashani KB Culture-negative severe sepsis: nationwide trends and outcomes Chest 2016 150 6 1251 1259 10.1016/j.chest.2016.08.1460 27615024\n13. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508\n14. Andrès E Maloisel F Idiosyncratic drug-induced agranulocytosis or acute neutropenia Curr Opin Hematol 2008 15 15 21 10.1097/MOH.0b013e3282f15fb9 18043241\n15. Andersohn F Konzen C Garbe E Systematic review: agranulocytosis induced by nonchemotherapy drugs Ann Intern Med 2007 146 657 665 10.7326/0003-4819-146-9-200705010-00009 17470834\n16. Ibáñez L Vidal X Ballarín E Laporte JR Population-based drug-induced agranulocytosis Arch Intern Med 2005 165 869 874 10.1001/archinte.165.8.869 15851637\n17. Perucca P Gilliam FG Adverse effects of antiepileptic drugs Lancet Neurol 2012 11 792 802 10.1016/S1474-4422(12)70153-9 22832500\n18. van Staa TP Boulton F Cooper C Hagenbeek A Inskip H Leufkens HG Neutropenia and agranulocytosis in England and Wales: incidence and risk factors Am J Hematol 2003 72 248 254 10.1002/ajh.10295 12666135\n19. Ben-Menachem E Biton V Jatuzis D Abou-Khalil B Doty P Rudd GD Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures Epilepsia 2007 48 7 1308 1317 10.1111/j.1528-1167.2007.01188.x 17635557\n20. Britton JW Ghearing GR Benarroch EE Cascino GD The ictal bradycardia syndrome: localization and lateralization Epilepsia 2006 47 4 737 744 10.1111/j.1528-1167.2006.00509.x 16650140\n21. Hauck-Dlimi B Ruppel R Zimmermann R Strobel J Reil A Eckstein R Transfusion-related alloimmune neutropenia with no pulmonary complications: one donor-five cases Transfusion 2016 56 1 84 90 10.1111/trf.13333 26388439\n22. Schultz L Mahmoud SH Is therapeutic drug monitoring of lacosamide needed in patients with seizures and epilepsy? Eur J Drug Metab Pharmacokinet 2020 45 3 315 349 10.1007/s13318-019-00601-8 31950342\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "21(1)",
"journal": "BMC neurology",
"keywords": "Adverse effects; Agranulocytosis; Lacosamide; Neutropenia; Sinus node dysfunction",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000368:Aged; D000380:Agranulocytosis; D000927:Anticonvulsants; D004562:Electrocardiography; D004828:Epilepsies, Partial; D005260:Female; D006801:Humans; D000078334:Lacosamide; D012804:Sick Sinus Syndrome",
"nlm_unique_id": "100968555",
"other_id": null,
"pages": "217",
"pmc": null,
"pmid": "34102997",
"pubdate": "2021-06-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15851637;12666135;27615024;30275630;17635557;17940193;26388439;31950342;31914330;21411374;7249508;22832500;22372628;17470834;28295226;29017081;23360388;21801173;26362380;16650140;18043241;23796862",
"title": "Lacosamide-induced sinus node dysfunction followed by severe agranulocytosis.",
"title_normalized": "lacosamide induced sinus node dysfunction followed by severe agranulocytosis"
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"activesubstancename": "LACOSAMIDE"
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Agranulocytosis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Sinus node dysfunction",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Sinus bradycardia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Somnolence",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Shibata M, Hoshino R, Shimizu C, Sato M, Furuta N, Ikeda Y. Lacosamide-induced sinus node dysfunction followed by severe agranulocytosis. BioMed Central Neurology. 2021;21:217:1-5",
"literaturereference_normalized": "lacosamide induced sinus node dysfunction followed by severe agranulocytosis",
"qualification": "3",
"reportercountry": "JP"
},
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"receiptdate": "20211106",
"receivedate": "20210715",
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},
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},
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}
] |
{
"abstract": "Haemophagocytic lymphohistiocytosis (HLH) is a rare condition of uncontrolled immune activation as a result of an inherited genetic defect or in response to malignancy, autoimmune disease, rheumatological disease, AIDS infection or post-transplant immunosuppression. Described here is the case of a 19-year-old Caucasian man who presented with complaints of worsening fever, new-onset jaundice and lethargy after failing treatment for suspected infectious mononucleosis. Physical examination was significant for fever and splenomegaly while laboratory results revealed transaminitis, cytopaenia, indirect hyperbilirubinaemia and elevated ferritin, raising the likelihood of both autoimmune haemolytic anaemia and HLH. He tested positive for Epstein-Barr virus (EBV), and bone marrow biopsy revealed hypercellular marrow with haemophagocytosis and no evidence of malignancy. High dose steroids were initiated with significant improvement in haemoglobin, resulting in a final diagnosis of HLH secondary to acute EBV infection. The patient was discharged on continued high-dose prednisone with planned taper and consideration of outpatient rituximab therapy for 4 weeks. High clinical suspicion and prompt evaluation were critical to early treatment and decreased morbidity.",
"affiliations": "Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA.;Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA.;Department of Hematology and Oncology, William Beaumont Hospital, Royal Oak, Michigan, USA [email protected].;Department of Hematology and Oncology, William Beaumont Hospital, Royal Oak, Michigan, USA.",
"authors": "Zimmer|Markie|M|https://orcid.org/0000-0001-8217-7456;Gill|Inayat|I|http://orcid.org/0000-0001-5972-700X;Anusim|Nwabundo|N|http://orcid.org/0000-0002-6941-8312;Gaikazian|Susanna S|SS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-241348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "haematology (drugs and medicines); haematology (incl blood transfusion); immunology; infections; malignant disease and immunosuppression",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001853:Bone Marrow; D020031:Epstein-Barr Virus Infections; D005334:Fever; D004854:Herpesvirus 4, Human; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33952568",
"pubdate": "2021-05-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epstein-Barr virus induced haemophagocytic lymphohistiocytosis.",
"title_normalized": "epstein barr virus induced haemophagocytic lymphohistiocytosis"
}
|
[
{
"companynumb": "US-PFIZER INC-2021564044",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
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"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": "DOSE PAK",
"drugenddate": null,
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"drugindication": "INFECTIOUS MONONUCLEOSIS",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "METHYLPREDNISOLONE."
}
],
"patientagegroup": null,
"patientonsetage": "19",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZIMMER, M.. EPSTEIN?BARR VIRUS INDUCED HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. BMJ CASE REPORTS. 2021?14 (5):10.1136/BCR?2020?241348",
"literaturereference_normalized": "epstein barr virus induced haemophagocytic lymphohistiocytosis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210525",
"receivedate": "20210525",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19300108,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20210717"
}
] |
{
"abstract": "Thrombotic microangiopathy (TMA) commonly presents as a triad of acute kidney injury (AKI), jaundice, and hemolysis; however, tropical infections such as malaria, dengue, leptospira, and drugs like antimalarials can also have a similar presentation. They can cause AKI for many reasons including pre-renal causes but an important yet not relatively uncommon genetic cause of hemolytic anemia, that is, glucose 6-phosphate deficiency (G6PD) manifesting as jaundice, hemolysis, and AKI secondary to pigment nephropathy after receiving offending drugs needs to be worked up while evaluating such patients. Ofloxacin is not usually included in the lists of unsafe drugs in G6PD deficiency. Herein, we report a patient developing intravascular hemolysis secondary to G6PD deficiency associated with ofloxacin administration presenting as a rare cause for pigment nephropathy.",
"affiliations": "Consultant Nephrologist, Department of Medicine, Shree Krishna Hospital, Karamsad, India.;Consultant Nephrologist, Department of Medicine, Shree Krishna Hospital, Karamsad, India.;Resident in Medicine, Department of Medicine, Shree Krishna Hospital, Karamsad, India.;Consultant Pathologist, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India.;Professor and Head, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India.;Assistant Professor, Department of Medicine, Shree Krishna Hospital, Karamsad, India.",
"authors": "Parikh|Mital|M|;Shah|Maulin|M|;Hirapara|Jekishan|J|;Soni|Shailesh|S|;Vaishnav|Bhalendu|B|;Ghosh|Labani|L|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_138_20",
"fulltext": "\n==== Front\nIndian J Nephrol\nIndian J Nephrol\nIJN\nIndian Journal of Nephrology\n0971-4065\n1998-3662\nWolters Kluwer - Medknow India\n\nIJN-31-410\n10.4103/ijn.IJN_138_20\nCase Report\nOfloxacin Induced Hemolysis in G6PD-deficient Patient: A Rare Cause of Pigment Nephropathy\nParikh Mital 1\nShah Maulin 1\nHirapara Jekishan 2\nSoni Shailesh 3\nVaishnav Bhalendu 4\nGhosh Labani 5\n1 Consultant Nephrologist, Department of Medicine, Shree Krishna Hospital, Karamsad, India\n2 Resident in Medicine, Department of Medicine, Shree Krishna Hospital, Karamsad, India\n3 Consultant Pathologist, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India\n4 Professor and Head, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India\n5 Assistant Professor, Department of Medicine, Shree Krishna Hospital, Karamsad, India\nAddress for correspondence: Dr. Mital Parikh, A/5 Vrundavan Park Society, VIP Road, Karelibaug, Vadodara - 390 018, Gujarat, India. E-mail: [email protected]\nJul-Aug 2021\n20 2 2021\n31 4 410413\n07 4 2020\n23 7 2020\n29 8 2020\nCopyright: © 2021 Indian Journal of Nephrology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nThrombotic microangiopathy (TMA) commonly presents as a triad of acute kidney injury (AKI), jaundice, and hemolysis; however, tropical infections such as malaria, dengue, leptospira, and drugs like antimalarials can also have a similar presentation. They can cause AKI for many reasons including pre-renal causes but an important yet not relatively uncommon genetic cause of hemolytic anemia, that is, glucose 6-phosphate deficiency (G6PD) manifesting as jaundice, hemolysis, and AKI secondary to pigment nephropathy after receiving offending drugs needs to be worked up while evaluating such patients. Ofloxacin is not usually included in the lists of unsafe drugs in G6PD deficiency. Herein, we report a patient developing intravascular hemolysis secondary to G6PD deficiency associated with ofloxacin administration presenting as a rare cause for pigment nephropathy.\n\nG6PD deficiency\nhemolysis\nofloxacin\npigment nephropathy\n==== Body\npmcIntroduction\n\nAcute kidney injury (AKI), jaundice, and hemolysis in combination is a very common presentation of thrombotic microangiopathy (TMA); however, tropical infections such as malaria, dengue, leptospira, and drugs like antimalarial can also have a similar presentation causing AKI by many factors including prerenal causes but other important causes of hemolysis leading to pigment nephropathy. Important yet not relatively uncommon genetic predisposing factor of hemolytic anemia, that is, glucose 6-phosphate deficiency (G6PD) which can also manifest as jaundice, hemolysis, and AKI secondary to pigment nephropathy after receiving anti-malarial drugs.[12] Glucose-6-phosphate dehydrogenase (G6PD) deficiency was discovered while investigating the development of hemolysis in patients who had received primaquine, and subsequently, several drugs have been linked to acute hemolysis in G6PD-deficient individuals.[3] It is often difficult to establish whether a specific drug directly causes a haemolytic crisis in G6PD-deficient patients. Hemolysis following ciprofloxacin therapy has been described; however, definitive evidence for such an association is still lacking.[4] Hemolytic reactions to ofloxacin have been observed only in a few isolated cases and currently there are no published reports on an association between the two.[5] Therefore, ofloxacin is not usually included in the lists of unsafe drugs in G6PD deficiency.\n\nCase Report\n\nA 24 years young male with no previous known comorbidities was admitted in a private hospital with a history of intermittent fever, abdominal pain, vomiting (non-bloody containing food particles), and decreased appetite of 4-5 days duration followed by decreased urine output for 2 days. On general examination at admission, the patient was dehydrated with a blood pressure of 100/60 mm Hg; heart rate was 110/min and the respiratory rate was normal. Body temperature was 36.8°C. White blood cell count was 24,200/μL, haemoglobin was 8.6 g/dL, platelets were 2.01 lacs and serum creatinine was 2.98 mg/dL. Symptomatic treatment was initiated with dicyclomine administered intravenously every 8 h, paracetamol injection for fever as and when required and intravenous infusion of 5' glucose and normal saline solutions for re-hydration. Oral medications included ofloxacin 200 mg twice a day. However, there was no improvement and the lab reports showed downward trend in hemoglobin, worsening renal function and patient became completely anuric; hence referred to another hospital for further management.\n\nOn admission, he was anuric; vitals showed pulse of 108/mins, blood pressure of 130/70 mmHg in supine position and temperature of 37.9°C. Laboratory testing showed his hemoglobin of 4.1 g/dL, lactate dehydrogenaserose to 1503 U/L, total bilirubin was 2.62 mg/dL with indirect bilirubin of 1.47 mg/dL [Table 1]. Chest X-ray was normal and blood cultures were sent.\n\nTable 1 Lab parameters of our patient\n\nInvestigation\t03-Dec\tPatient started on the medications mentioned in case report at private clinic (including ofloxacin)\t04-Dec\tPatient shifted to Shree Krishna Hospital, Karamsad\t05-Dec\t07-Dec\t12-Dec\t16-Dec\t07-Jan\t12-Jan\t17-Jan\t31-Jan\t\nHb (g/dL)\t8.6\t\t5.8\t\t4.1\t5.2\t9.3\t8.3\t10\t11.4\t12.4\t12.3\t\nTLC (*1000/µL)\t24.2\t\t16.7\t\t12.2\t12.8\t11.7\t12.3\t12.4\t11.6\t9.3\t9.5\t\nPLT (*1000/ µL)\t201\t\t175\t\t167\t152\t193\t302\t212\t234\t270\t272\t\nReticulocyte Count (%)\t\t\t\t\t7.9\t\t0.4\t\t\t\t\t\t\nLDH (IU/L)\t\t\t\t\t1503\t\t\t612\t\t\t150\t\t\nBlood urea (mg/dL)\t\t\t80.1\t\t180\t\t102\t\t\t69\t30\t\t\nS. creatinine (mg/dL)\t2.98\t\t3.02\t\t10.01\t5.41\t6.78\t8.67\t4.02\t2.2\t1.13\t0.81\t\nS.Na+ (mEq/L)\t\t\t136\t\t139\t137\t132\t138\t145\t143\t140\t138\t\nS.K+ (mEq/L)\t4.19\t\t4.25\t\t3.8\t4.3\t4.4\t3.7\t3.5\t3.8\t4.2\t3.6\t\n\nThe patient's previous medications including ofloxacin was discontinued and replaced with inj. Cefoperazone + sulbactum 1.5 gms twice daily, folic acid 5 mg once a day and 2 packed red cell transfusion was given. He was initiated on hemodialysis via right internal jugular double-lumen non-cuffed catheter in view of significant renal dysfunction and anuria. He was also given Inj. Methylprednisolone 500 mg daily for 3 days. Workup for hemolysis was initiated simultaneously and it revealed a reticulocyte count of 7.9', peripheral smear showed anisopoikilocytes but no schistocytes and Coomb's test (indirect and direct) was negative. His urinalysis (urine being cola-colored) showed evidence of microscopic hematuria and proteinuia. Complement levels were low (C3-0.7 [normal range-0.9-1.8 g/L], C4- 0.09 [normal range-0.1-0.4 g/L]) and ANA profile was negative. His urinalysis showed +3 blood and protein with plenty of RBCs/HPF.\n\nHis G6PD levels were sent which came to be significantly low value of 2.1 despite evidence of ongoing hemolysis. We inquired about any other medication he might have received previously especially antimalarials; however, he denied, and all the bills of the medications didn't reveal any other injections/oral tablets except that mentioned earlier. He required alternate day hemodialysis in view of persistent oligoanuria and 2 more packed cell transfusions. After 4 sessions of hemodialysis, he underwent left renal biopsy to know the cause of renal nonrecovery and to rule out immune complex-mediated glomerular pathology. Renal biopsy showed normal glomerular morphology with no evidence of intraglomerular or extra-capillary hypercellularity. Tubules showed extensive dilatation and flattening of lining epithelium [Figure 1a] with red blood cell casts [Figure 1b]. Interstitium was mildly edematous and the blood vessels were largely unremarkable. Immunofluoroscence didn't reveal any evidence of deposition of immunogloubulin. A diagnosis of acute tubular injury with pigment nephropathy was suggested.\n\nFigure 1 (a) Microphotograph of kidney biopsy shows dilated tubules (arrows) with flattening of lining epithelium (H and E; ×100). (b) Microphotograph of kidney biopsy shows dilated tubules filled with red blood cell and pigment (arrows) (SMS; ×100)\n\nHe was continued on the same antibiotics for 10 days and then stopped in view of negative blood cultures and afebrile state. He was discharged on the 11th day with twice a week regular OPD follow up and hemodialysis was continued twice weekly till his urine output and renal function tests (monitored weekly) showed improvement. Gradually his urine output increased to 800–1000 mL/day and serum creatinine decreased to 4.4 mg/dL at which his hemodialysis was stopped, his hemoglobin remained stable at 9–10 g/dL requiring no further PCV transfusions, his steroids were also tapered serially by 10 mg/week and stopped at 4th week. He finally achieved s. creatinine of 1 mg/dL with good urine output of 2 lit/day and hemoglobin of 12 g/dL at the 45th day of his illness. His repeat urinalysis also showed no evidence of microscopic hematuria and proteinuria. His complement levels normalized. He is being followed up on OPD basis now.\n\nWe had also sent his genetic analysis (G6PD gene sequencing by NGS) which revealed a homozygous missence variation in the exon 3 of G6PD gene (pAla74Gly) which has been classified as likely pathogenic-G6PD Orissa variant in tribal populations of India.\n\nDiscussion\n\nThe incidence of G6PD deficiency is highly variable in different parts of the world; however, in Indian population it varies between 0' and 10' and more so in tribal population.[6] The case described in this report presented with severe hemolysis along with renal insufficiency. The precipitating cause appeared to be the administration of ofloxacin as no other drugs were given to the patient. Several drugs (analgesics, sulphonamides, anti-helminthics and antimalarials) have been known to precipitate hemolysis in G6PD-deficient patients.[7] The proposed mechanism appears to be interaction of these drugs with hemoglobin and oxygen, leading to the formation of free oxygen radicals, which in GSH (reduced glutathione) depleted cells, further promotes oxidation of intracellular proteins and resulting in cell death.[8] Apart from drugs, certain infections may also precipitate hemolysis in G6PD-deficient subjects[9] which were however not evident in our case. Our patient showed signs of intravascular hemolysis in the form of raised LDH, bilirubin levels, and reticulocyte counts. Following this, complete workup for hemolytic anemia was undertaken which showed G6PD deficiency. These values hold no accuracy at the time of injury and may be normal; however, in our patient, despite the inciting mechanism existing he had low values confirming the diagnosis.[1] Coombs tests were negative. Renal biopsy showed features of acute tubular injury with pigment deposition in tubules. Several studies have shown that various factors may contribute to renal injury following hemolysis, like blockage of renal tubules by hemolyzed red cells,[10] intravascular coagulation leading to release of thromboplastin factors, decreased renal blood flow and glomerular filtration rate, or by a combination of these factors.[11] In a study conducted by Choudhry et al. out of 20 G6PD-deficient children treated with drugs, 11 developed acute renal insufficiency and intravascular hemolysis, whereas 9 developed intravascular hemolysis alone.[12]\n\nThe fluoroquinolones have become an increasingly popular class of antibiotics for use in a variety of infections, with ciprofloxacin probably being most frequently marketed and prescribed in the past. The WHO working group 1989 doesn't mention fluoroquinolones as unsafe in G6PD deficiency however, Harrison's internal medicine 20th edition mentions ciprofloxacin and norfloxacin to be in a possible risk category for G6PD deficient. Some studies mention Ofloxacin to be safe in G6PDH deficiency;[13] however, the British National Formulatory Sept 2010 mentions ofloxacin and moxifloxacin in the definite risk category of hemolysis for G6PD-deficient candidates. Hemolytic anemia is listed among adverse reactions at low frequencies (less than 1'), however, not consistently associated with G6PD deficiency (e.g., norfloxacin,[14] ciprofloxacin[15]). Ciprofloxacin is classified as being unsafe in G6PD deficiency by the “Italian Favism-G6PD Deficiency Association” in the Mediterranean region and Asia[5]; however, hemolytic reactions to ofloxacin have been reported only in few unpublished cases. As per our knowledge, this case is 1st to be reported in the literature.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Alving AS Carson PE Flanagan CL Ickes CE Enzymatic deficiency in primaquinesensitive erythrocytes Science 1956 124 484 5\n2 Kirkman HN Hendrickson EM Sex-linked electrophoretic difference in glucose-6-phosphate dehydrogenase Am J Hum Genet 1963 15 241 58 14033020\n3 Cappellini MD Fiorelli G Glucose-6-phosphate dehydrogenasedeficiency Lancet 2008 371 64 74 18177777\n4 Luzzatto L Metha A Vulliamy T Scriver CR Beaudet AL Sly WS Glucose 6-phosphate dehydrogenase deficiency The Metabolic and Molecular Bases of Inherited Disease 2001 8th ed Columbus McGraw-Hill 4517 53\n5 Associazione Italiana di Favismo-Deficit di G6PD (2009) [Last accessed on 2009 Dec 11] Available from: http://www.g6pd.org/favism/english/index.mvc?pgid=avoid\n6 Kumar P Yadav U Rai V Prevalence of glucose-6-phosphate dehydrogenase deficiency in India: An updated meta-analysis Egypt J Med Hum Genet 2016 17 295 302\n7 Choudhry VP Madan N Sood SK Intravascular haemolysis and renal insufficiency in children with glucose-6-phosphate dehydrogenasedeficiency, following antimalarial therapy Indian J Med Res 1980 71 561 6 7390595\n8 Beutler E G6PD deficiency Blood 1994 84 3613 36 7949118\n9 Burka ER Weaver Z 3rd Marks PA Clinical spectrum of hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency Ann Intern Med 1966 64 817 25 23841200\n10 Dobrin RS Larsen CD Holliday MA The critically ill child: Acute renal failure Pediatrics 1971 48 286 93 4934698\n11 Jaenike JR The renal lesion associated with hemoglobinemia: A study of the pathogenesis of the excretory defect in the rat J Clin Invest 1967 46 378 87 6023773\n12 Choudhry VP Ghafary A Zaher M Qureshi MA Fazel I Ghani R Drug-induced haemolysis and renal failure in children with glucose-6-phosphate dehydrogenase deficiency in Afghanistan Ann Trop Paediatr 1990 10 335 8 1708959\n13 Gaetani GF Gallano S Miglino M Canepa L Ferrarie AM Absence of hemolytic potential of ofloxacin toward dehydrogenase deficient erythrocytes Curr Ther Res 1991 42 329 34\n14 Norfloxacin: Drug information. Copyright 1978-2009 Lexi-Comp, Inc (2009) [Last accessed on 2009 Dec 11] Available from: http://www.uptodate.com/online/content/topic.do; jsessionid=63A4FDC99FB1FD4EC3284871C6C67EFE.1003?topicKey=drug_l_z/183660&drug=true\n15 Sansone S Rottensteiner J Stocker J Rosanelli C Wiedermann C Ciprofloxacin-induced acute haemolytic anaemia in a patient with glucose-6-phosphate dehydrogenase Mediterranean deficiency: A case report Ann Hematol 2010 89 935 7 20127091\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "31(4)",
"journal": "Indian journal of nephrology",
"keywords": "G6PD deficiency; hemolysis; ofloxacin; pigment nephropathy",
"medline_ta": "Indian J Nephrol",
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"nlm_unique_id": "8914356",
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"pages": "410-413",
"pmc": null,
"pmid": "34584362",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "7390595;1708959;13360274;18177777;7949118;4934698;20127091;23841200;14033020;6023773",
"title": "Ofloxacin Induced Hemolysis in G6PD-deficient Patient: A Rare Cause of Pigment Nephropathy.",
"title_normalized": "ofloxacin induced hemolysis in g6pd deficient patient a rare cause of pigment nephropathy"
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"medicinalproduct": "OFLOXACIN."
}
],
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{
"reactionmeddrapt": "Glycogen storage disease type I",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal tubular injury",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pigment nephropathy",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Intravascular haemolysis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PARIKH M., SHAH M., HIRAPARA J., SONI S., VAISHNAV B., GHOSH L.. OFLOXACIN INDUCED HEMOLYSIS IN G6PD?DEFICIENT PATIENT: A RARE CAUSE OF PIGMENT NEPHROPATHY. INDIAN J. NEPHROL.. 2021?31:4:410?13",
"literaturereference_normalized": "ofloxacin induced hemolysis in g6pd deficient patient a rare cause of pigment nephropathy",
"qualification": "1",
"reportercountry": "IN"
},
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"receiptdate": "20210920",
"receivedate": "20210920",
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},
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},
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}
] |
{
"abstract": "Direct oral anticoagulants (DOACs) are at least as efficacious as conventional anticoagulation therapy for the initial and long-term treatment of cancer patients with venous thromboembolism (VTE). Whether DOACs are non-inferior to low-molecular-weight heparin for the management of cancer patients with VTE is under investigation. In addition, the efficacy of DOACs for the treatment of cancer patients with arterial thrombosis (e.g., ischemic stroke) remains unclear. Herein, we report on two cancer patients admitted to our hospital with Stage IV gastric adenocarcinoma who were being treated with DOACs due to a history of VTE and had developed their first ever ischemic stroke, which was diagnosed due to cancer-related hypercoagulation. Notably, neither patient had recurrence of VTE during the course of their disease. In cancer-related thrombosis, DOACs effectively reduce VTE, but may be insufficient for preventing ischemic stroke.",
"affiliations": "Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: [email protected].;Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.",
"authors": "Gon|Yasufumi|Y|;Sakaguchi|Manabu|M|;Takasugi|Junji|J|;Mochizuki|Hideki|H|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2017.03.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "154()",
"journal": "Thrombosis research",
"keywords": "Cancer-related thrombosis; Direct oral anticoagulant; Ischemic stroke; Venous thromboembolism",
"medline_ta": "Thromb Res",
"mesh_terms": "D000230:Adenocarcinoma; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants; D005260:Female; D006801:Humans; D008297:Male; D013274:Stomach Neoplasms; D020521:Stroke; D054556:Venous Thromboembolism",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "16-18",
"pmc": null,
"pmid": "28384442",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Ischemic stroke in cancer patients treated with direct oral anticoagulants for venous thromboembolism.",
"title_normalized": "ischemic stroke in cancer patients treated with direct oral anticoagulants for venous thromboembolism"
}
|
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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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"reaction": [
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},
{
"reactionmeddrapt": "Ischaemic stroke",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": null
},
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},
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20170830"
},
{
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}
],
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},
{
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},
{
"reactionmeddrapt": "Off label use",
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}
],
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},
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},
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},
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessother": 1,
"transmissiondate": "20170830"
},
{
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"patient": {
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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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"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Ischaemic stroke",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GON Y, SAKAGUCHI M, TAKASUGI J, MOCHIZUKI H.. ISCHEMIC STROKE IN CANCER PATIENTS TREATED WITH DIRECT ORAL ANTICOAGULANTS FOR VENOUS THROMBOEMBOLISM.. THROMB-RES. 2017;154:16-18",
"literaturereference_normalized": "ischemic stroke in cancer patients treated with direct oral anticoagulants for venous thromboembolism",
"qualification": "3",
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},
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},
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"seriousnessother": 1,
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}
] |
{
"abstract": "Sugammadex, with its novel mechanism of action of encapsulation and noncompetitive binding of aminosteroid neuromuscular-blocking agents (rocuronium and vecuronium), may offer distinct advantage to pediatric patients where residual neuromuscular blockade may be poorly tolerated. Data describing its use in the pediatric population are limited, and no large-scale studies are available evaluating the occurrence of adverse event across the full spectrum of ages. We sought to measure the occurrence of adverse events, assess the severity and clinical significance of the events, and quantify a surrogate measure of efficacy of sugammadex compared to neostigmine in a large population and in the full age range of children.\n\n\n\nBeginning in September 2016 through initiation of data collection, we identified from our data warehouse that all patients were treated with sugammadex for reversal of neuromuscular blockade, from birth through adolescence, and retrospectively matched, by case type and age group, to historical neostigmine-treated controls. From subsequent chart review, we quantified occurrence of adverse events and administration of medications to treat adverse events. All cases in the originally identified cohort treated with epinephrine after administration of sugammadex underwent chart review to elicit the cause, in the event that an infrequently occurring event was not captured after the case-matching process. \"End-Interval Time,\" the time from administration of reversal agent to time out of the procedure room, was measured as an indirect assessment of efficacy.\n\n\n\nFewer cases of bradycardia were observed in the sugammadex group compared to the neostigmine group in the overall cohort (P < .001) and in the subgroups of older children (P < .001) and adolescents (P < .001). End-interval time, the time measured from administration of neuromuscular blockade (NMB) reversal agent to time out of the operating room, was significantly shorter in sugammadex-treated groups in the overall cohort (mean difference, 2.8; 95% CI, 1.85-3.77; P < .001) and all age groups except for first year (31 days through 12 months). This observation was most pronounced in the neonatal subgroup (mean difference, 11.94 minutes; 95% CI, 4.79-19.1; P < .001). No other adverse events measured were found to be different between treatment groups.\n\n\n\nThis study provides data supporting the safe and effective use of sugammadex for reversal of neuromuscular blockade throughout the entire range of ages in the pediatric population. Within age groups, sugammadex demonstrates faster completion of operation compared with neostigmine, with the greatest difference observed in the neonatal population.",
"affiliations": "From the Department of Anesthesiology/Division of Pediatric Cardiac Anesthesiology and Division of Pediatric Anesthesiology, Vanderbilt Children's Hospital, Nashville, Tennessee.",
"authors": "Gaver|Renee S|RS|;Brenn|Bruce R|BR|;Gartley|Alison|A|;Donahue|Brian S|BS|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D000077122:Sugammadex; D009388:Neostigmine",
"country": "United States",
"delete": false,
"doi": "10.1213/ANE.0000000000004207",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "129(4)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000762:Anesthesia Recovery Period; D001919:Bradycardia; D002648:Child; D002675:Child, Preschool; D002800:Cholinesterase Inhibitors; D000073458:Data Warehousing; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009388:Neostigmine; D019148:Neuromuscular Blockade; D020127:Recovery of Function; D012189:Retrospective Studies; D012307:Risk Factors; D000077122:Sugammadex; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "1124-1129",
"pmc": null,
"pmid": "31584918",
"pubdate": "2019-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Retrospective Analysis of the Safety and Efficacy of Sugammadex Versus Neostigmine for the Reversal of Neuromuscular Blockade in Children.",
"title_normalized": "retrospective analysis of the safety and efficacy of sugammadex versus neostigmine for the reversal of neuromuscular blockade in children"
}
|
[
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"literaturereference": "GAVER RS, BRENN BR, GARTLEY AL AND DONAHUE BRIAN B.. RETROSPECTIVE ANALYSIS OF THE SAFETY AND EFFICACY OF SUGAMMADEX VERSUS NEOSTIGMINE FOR THE REVERSAL OF NEUROMUSCULAR BLOCKADE IN CHILDREN. ANESTHESIA ANALGESIA. 2019",
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},
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}
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"literaturereference": "GAVER R, BRENN B, GARTLEY A, DONAHUE B. RETROSPECTIVE ANALYSIS OF THE SAFETY AND EFFICACY OF SUGAMMADEX VERSUS NEOSTIGMINE FOR THE REVERSAL OF NEUROMUSCULAR BLOCKADE IN CHILDREN. ANESTHESIA AND ANALGESIA. 2019 OCT?129 (4):1124-1129.",
"literaturereference_normalized": "retrospective analysis of the safety and efficacy of sugammadex versus neostigmine for the reversal of neuromuscular blockade in children",
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},
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}
] |
{
"abstract": "We report a rare case of liver alveolar echinococcosis with an invasion of the hepaticocaval confluence, inferior vena cava, pericardium, right atrium, atrial septum, and superior vena cava, and its successful treatment by combined heart-liver transplantation.",
"affiliations": "Department of Aortic and Coronary Artery Surgery, Meshalkin National Medical Research Center, Novosibirsk, Russia.;Department of Aortic and Coronary Artery Surgery, Meshalkin National Medical Research Center, Novosibirsk, Russia.;Department of Transplantation and Liver Surgery, State Novosibirsk Regional Clinical Hospital, Novosibirsk, Russia.",
"authors": "Chernyavskiy|Alexander|A|;Alsov|Sergey|S|;Guliaeva|Kseniya|K|http://orcid.org/0000-0002-5717-6141;Porshennikov|Ivan|I|http://orcid.org/0000-0002-6969-6865",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/jocs.14932",
"fulltext": null,
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"issn_linking": "0886-0440",
"issue": "35(11)",
"journal": "Journal of cardiac surgery",
"keywords": "alveolar echinococcosis; combined heart-liver transplantation; vascular invasion",
"medline_ta": "J Card Surg",
"mesh_terms": "D000328:Adult; D004443:Echinococcosis; D004444:Echinococcosis, Hepatic; D005260:Female; D006325:Heart Atria; D006346:Heart Septum; D016027:Heart Transplantation; D006801:Humans; D016031:Liver Transplantation; D009205:Myocarditis; D010496:Pericardium; D016896:Treatment Outcome; D014682:Vena Cava, Inferior; D014683:Vena Cava, Superior",
"nlm_unique_id": "8908809",
"other_id": null,
"pages": "3199-3201",
"pmc": null,
"pmid": "32789914",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "The first case of combined heart-liver transplantation in a patient with alveolar echinococcosis.",
"title_normalized": "the first case of combined heart liver transplantation in a patient with alveolar echinococcosis"
}
|
[
{
"companynumb": "RU-TEVA-2020-RU-1857965",
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},
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{
"reactionmeddrapt": "Fungal sepsis",
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},
{
"reactionmeddrapt": "Bacterial sepsis",
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}
],
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},
"primarysource": {
"literaturereference": "CHERNYAVSKIY A, ALSOV S, GULIAEVA K, PORSHENNIKOV I. THE FIRST CASE OF COMBINED HEART-LIVER TRANSPLANTATION IN A PATIENT WITH ALVEOLAR ECHINOCOCCOSIS. J-CARDIAC-SURG 2020?35(11):3199-3201.",
"literaturereference_normalized": "the first case of combined heart liver transplantation in a patient with alveolar echinococcosis",
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},
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{
"abstract": "Spontaneous pneumomediastinum is an uncommon event, the clinical picture of which includes retrosternal chest pain, subcutaneous emphysema, dyspnea, and dysphonia. The pathophysiological mechanism involved is the emergence of a pressure gradient between the alveoli and surrounding structures, causing alveolar rupture with subsequent dissection of the peribronchovascular sheath and infiltration of the mediastinum and subcutaneous tissue with air. Known triggers include acute exacerbations of asthma and situations that require the Valsalva maneuver. We described and documented with HRCT scans the occurrence of pneumomediastinum after a patient with bleomycin-induced interstitial lung disease underwent pulmonary function testing. Although uncommon, the association between pulmonary function testing and air leak syndromes has been increasingly reported in the literature, and lung diseases, such as interstitial lung diseases, include structural changes that facilitate the occurrence of this complication.",
"affiliations": "University of São Paulo, School of Medicine, Hospital das Clínicas, São Paulo, Brazil.",
"authors": "Araujo|Mariana Sponholz|MS|;Fernandes|Frederico Leon Arrabal|FL|;Kay|Fernando Uliana|FU|;Carvalho|Carlos Roberto Ribeiro|CR|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D001761:Bleomycin",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nJ Bras PneumolJ Bras PneumolJornal Brasileiro de Pneumologia : Publicaça̋o Oficial da Sociedade Brasileira de Pneumologia e Tisilogia1806-37131806-3756Sociedade Brasileira de Pneumologia e Tisiologia Paulo 2431063510.1590/S1806-3713201300050001210.1590/S1806-37132013000500012Case ReportPneumomediastinum, subcutaneous emphysema, and pneumothorax\nafter a pulmonary function testing in a patient with bleomycin-induced interstitial\npneumonitis*\n Araujo Mariana Sponholz PulmonologistDepartment of Pulmonology, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas,\nSão Paulo, Brazil.Fernandes Frederico Leon Arrabal Physician in ChargePulmonary Function Laboratory, São Paulo Cancer Institute; and Attending Physician. Heart Institute,\nUniversity of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.Kay Fernando Uliana RadiologistImaging Department, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.Carvalho Carlos Roberto Ribeiro Tenured Associate ProfessorDepartment of Pulmonology, Heart Institute, University of São Paulo School of Medicine Hospital\ndas Clínicas, São Paulo, Brazil.Correspondence to: Mariana Sponholz Araujo. Rua Antônio Pietruza, 266,\napto. 181, Portão, CEP 80610-320, Curitiba, PR, Brasil. Tel. 55 11 98502-4275.\nE-mail: [email protected] 2013 Sep-Oct 2013 39 5 613 619 09 8 2012 30 11 2012 This is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License, which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.Spontaneous pneumomediastinum is an uncommon event, the clinical picture of which\nincludes retrosternal chest pain, subcutaneous emphysema, dyspnea, and dysphonia. The\npathophysiological mechanism involved is the emergence of a pressure gradient between\nthe alveoli and surrounding structures, causing alveolar rupture with subsequent\ndissection of the peribronchovascular sheath and infiltration of the mediastinum and\nsubcutaneous tissue with air. Known triggers include acute exacerbations of asthma\nand situations that require the Valsalva maneuver. We described and documented with\nHRCT scans the occurrence of pneumomediastinum after a patient with bleomycin-induced\ninterstitial lung disease underwent pulmonary function testing. Although uncommon,\nthe association between pulmonary function testing and air leak syndromes has been\nincreasingly reported in the literature, and lung diseases, such as interstitial lung\ndiseases, include structural changes that facilitate the occurrence of this\ncomplication.\n\nMediastinal emphysemaSubcutaneous emphysemaSpirometryBleomycin\n==== Body\nIntroduction\nSpontaneous pneumomediastinum is an uncommon event that primarily affects young males.\nIt is classified as primary or secondary on the basis of the presence or absence of\nunderlying lung disease predisposing to the event. Its clinical picture includes\nretrosternal chest pain (most common symptom), subcutaneous emphysema, dyspnea,\ndysphagia, dysphonia, asthenia, and the classical sign of Hamman's crunch (a crepitant\nsound that varies with the heartbeat on auscultation of the precordium).(\n\n1\n\n,\n\n2\n\n) In most cases, it is possible to identify a triggering event, such as acute\nexacerbations of asthma. Other known triggers include those related to the Valsalva\nmaneuver, such as strenuous exercise, weight lifting, inhalation of illicit drugs,\ncough, forced evacuation, and labor, as well as vomiting, respiratory infections,\nforeign body aspiration, and barotrauma.(\n\n1\n\n-\n\n5\n\n)\n\n\nThe disease usually follows a benign, self-limiting course.(\n\n1\n\n,\n\n2\n\n) Treatment is supportive, consisting of using painkillers, resting, and\navoiding maneuvers that generate an increase in transpulmonary pressure, such as the\nValsalva maneuver and spirometry.(\n\n6\n\n)\n\n\nCase report\nA 50-year-old male patient underwent orchiectomy for testicular swelling and an\nincreased alpha-fetoprotein level. The anatomopathological diagnosis was testicular\nembryonal carcinoma. In the staging evaluation, chest CT showed lung metastases. The\npatient was started on chemotherapy with cisplatin, etoposide, and bleomycin (cumulative\ndose at the end of the course, 300 IU). During treatment, the patient had an episode of\nfebrile neutropenia and received granulocyte colony-stimulating factor (G-CSF) at that\ntime.\n\nThree months after the start of chemotherapy, the patient had a medical visit in which\nhe complained of rapidly progressive dyspnea, presenting with hypoxemia (SpO2\n= 87%) and crackles at both lung bases. An HRCT scan (Figure 1) showed diffuse, relatively symmetric, reticular lung\nopacities in a peripheral and sometimes peribronchovascular distribution, predominantly\nat the lung bases, associated with irregular interlobular septal thickening, in addition\nto some foci of consolidation and areas of ground-glass opacity, bilaterally\ndistributed, predominantly in the subpleural regions. A presumptive diagnosis of\nbleomycin-induced interstitial pneumonitis was made, and corticosteroid treatment was\nstarted. The patient underwent pulmonary function testing (PFT), which revealed severe\nrestrictive lung disease and markedly reduced DLCO.\n\n\nFigure 1 In A, axial HRCT scan showing reticular opacities (dashed arrow)\nassociated with irregular interlobular septal thickening (solid arrow), as well\nas foci of consolidation and areas of ground-glass opacity (arrowhead),\nbilaterally distributed, predominantly in the subpleural regions. In B, coronal\nHRCT scan showing the distribution of those changes along the longitudinal axis\nof both lungs, with a slight basal predominance.\n\n\n\nTwo days after undergoing PFT, the patient presented to the emergency room with\nsignificantly worsened dyspnea. Physical examination revealed tachycardia (HR, 110 bpm),\ntachypnea (RR, 28 breaths/min), and hypoxemia (SpO2 = 75%), as well as\nsubcutaneous emphysema in the right cervical region. Lung auscultation revealed\ndecreased breath sounds in the lower thirds and crackles at both lung bases. Laboratory\ntests revealed leukocytosis (17,040 cells/mm3) with a shift to myelocytes,\nthrombocytopenia, an elevated level of nitrogenous compounds, and an increased level of\nC-reactive protein (43.9 mg/dL).\n\nA chest X-ray (Figure 2) allowed the visualization\nof pneumomediastinum and subcutaneous emphysema, with a small pneumothorax and an\nincrease in ground-glass opacities. The same changes were seen on HRCT (Figure 3), which showed extensive pneumomediastinum\nand subcutaneous emphysema, as well as a significant increase in reticular opacities and\nareas of ground-glass opacity, compared with the initial examination. The patient was\nstarted on treatment for an infectious etiology (piperacillin/tazobactam) and\nprogression of interstitial disease (methylprednisolone, 1 mg/kg). The patient continued\nto have fever despite further antibiotic therapy (vancomycin and\nsulfamethoxazole/trimethoprim were added) and developed respiratory failure requiring\norotracheal intubation, mechanical ventilation, and chest tube drainage. His acute renal\nfailure worsened, and he could not tolerate dialysis. The patient died from septic shock\nseven days admission.\n\n\nFigure 2 (Front view) chest X-ray showing an air-density band around the\nmediastinum (arrows), characterizing pneumomediastinum, which extends to the\ncervical region and chest wall, dissecting along the fibers of the pectoral\nmuscles (dashed arrow). Note the extensive involvement of the lungs by areas of\nconsolidation and reticular opacities, distributed in the lung periphery,\nespecially on the right side, where one can also see a small pneumothorax\n(arrowheads).\n\n\n\n\nFigure 3 In A, oblique sagittal reformatted HRCT scan showing air dissecting within\nthe lung interstitium along the right inferior pulmonary vein (arrow) and\nentering the mediastinum. In B, curved coronal reformatted HRCT scan showing\nthe upward path of the air around the right inferior pulmonary vein (arrow)\ninto the pneumomediastinum (arrowheads). Note the integration between the\npneumomediastinum and the cervical emphysema (dashed arrows). In C, curved\ncoronal reformatted HRCT scan showing the large amount of air that dissects\nalong the mediastinal fat planes and pneumomediastinum (arrowheads). In D,\naxial HRCT scan showing pneumomediastinum (arrowheads) associated with chest\nwall emphysema (asterisk, also found in A). Note also a small right\npneumothorax (arrow), as well as reticular lung opacities and areas of\ngroundglass opacity (dashed arrow).\n\n\n\nDiscussion\nThe pathophysiological mechanism involved in the genesis of pneumomediastinum is the\nemergence of a pressure gradient between the alveoli and surrounding structures that,\nupon reaching a critical level, causes alveolar rupture with an air leak into the\ninterstitium, causing interstitial emphysema. The air dissects along the bronchovascular\nbundle (Figures 3A and 3B) and, since the pressure\nis always lower in the mediastinum than in the lung parenchyma, the air tends to move\ntoward the hilum and spread through the mediastinum (Figure 3C). Because of the contiguity between the fasciae, the air can reach\nthe subcutaneous cellular tissue (Figures 3A and\n3D) and the peritoneum. When mediastinal pressure rises abruptly and\ndecompression by alternative pathways is insufficient to relieve pressure, there can be\nrupture of the mediastinal pleura and the development of pneumothorax (Figure 3D).(\n\n2\n\n)\n\n\nThe Brazilian Journal of Pulmonology has recently published a letter to the\neditor(\n\n7\n\n) describing a case of spontaneous pneumomediastinum and reporting, among\nother findings, pneumorrhachis, which is extremely rare. However, in that case, no\nimaging findings of dissection of air along the bronchovascular bundle were found. In a\ncase report of pneumomediastinum in a bone marrow transplant recipient, some HRCT\nfindings were similar to those of the present case, although they were of lesser\nmagnitude and there was no pneumothorax.(\n\n8\n\n)\n\n\nThis chain of events was described by Macklin & Macklin in the 1940s.(\n\n3\n\n) Those authors demonstrated that most air leak syndromes did not result from\nrupture of subpleural bullae, but rather from alveolar rupture. In addition, they\nintroduced the concept that the presence of positive pressure within the alveoli is not\nnecessary for rupture to occur. What is essential is the pressure gradient between the\nalveolus and the perivascular sheath of the adjacent septum. A very negative pressure in\nthe interstitial space could therefore lead to alveolar rupture even without the\noccurrence of extreme positive alveolar pressures. For this reason, intense respiratory\nefforts, adjacent atelectasis, and low intravascular pressure could be involved in the\ndevelopment of these syndromes.(\n\n3\n\n)\n\n\nThere have been reports of pneumomediastinum related to PFT.(\n\n4\n\n,\n\n9\n\n-\n\n11\n\n) In 1973, the first of such reports described a previously healthy\n23-year-old medical student who developed extensive pneumomediastinum and subcutaneous\nemphysema after undergoing PFT.(\n\n4\n\n)\n\n\nIn spirometry, the patient is instructed to inhale up to total lung capacity, hold his\nor her breath, and exhale vigorously.(\n\n10\n\n) When the patient inhales, there is a decrease in intrathoracic pressure, an\nincrease in alveolar air volume, and an increase in venous return, resulting in\nincreased pulmonary vein diameter. Therefore, there is no pressure gradient in the\ninterstitial space, since all compartments elongate and increase in diameter\nsymmetrically. However, when the patient \"holds his or her breath\", there is venous\nstasis, resulting in decreased pulmonary venous filling and vessel lumen reduction,\nallowing the emergence of the pressure gradient necessary to cause alveolar\nrupture.(\n\n3\n\n)\n\n\nSubsequent reports have documented pneumomediastinum as a complication of PFT associated\nwith extremely different underlying lung diseases, such as rheumatic diseases with\ninterstitial lung involvement.(\n\n11\n\n) In these situations, there is a summation of the aforementioned pressure\nchanges induced during the test, the existence of inflammation combined with increased\nelastic recoil as seen with fibrosis, and a collapse of adjacent regions, making the\nlung vulnerable to segmental hyperdistension and to the emergence of a pressure\ngradient.(\n\n3\n\n) We believe that this is the mechanism also applies in the present case.\n\nWhen reporting the case of a healthy medical student who developed pneumomediastinum\nafter use of marijuana, one group of authors understood that the event was caused by the\nfact that the young man performed various Valsalva-like maneuvers (holding his breath at\nmaximal inhalation against a partially closed or fully closed glottis) to prolong the\neffect of the drug.(\n\n12\n\n) The Valsalva maneuver is a factor classically related to air leak syndromes\nbecause it generates increased intrapulmonary pressure.(\n\n3\n\n,\n\n4\n\n,\n\n12\n\n) Therefore, labor and forced evacuation are associated with reports of\npneumomediastinum.(\n\n3\n\n)\n\n\nAs mentioned previously, pneumomediastinum usually follows a benign, self-limiting\ncourse. However, this apparent benignity should be regarded with caution, since, in\npatients with underlying lung diseases, the existence of air leak syndromes is\nassociated with greater severity. It is known that this syndrome can be associated with\nthe spread of infections and the release of inflammatory mediators. In addition, it can\nresult in the feared air-block syndrome (a condition in which the presence of air in the\ninterstitium and mediastinum does not find a way out, culminating in the generation of\nlarge pressures on the mediastinum, which affects circulation by compressing the vessels\nand the heart and prevents lung inflation and deflation).(\n\n2\n\n)\n\n\nIn the present case, it is possible that the pneumomediastinum acted as a contributing\nfactor to the fatal outcome because it facilitated the spread of infection and the\nperpetuation of inflammation, but without acting as a determinant of death, which was\nrelated to the interstitial lung disease and the severe, superimposed infectious\nprocess. In addition, it is of note that, in the present case, there was no indication\nfor specific treatment for pneumomediastinum, such as mediastinotomy. This type of\nprocedure would only be beneficial in cases of hypertensive pneumomediastinum, which are\nrare.(\n\n13\n\n)\n\n\nBecause PFT is often performed in patients with acute chronic respiratory disease, its\nassociation with air leak syndromes should be studied and reported.\n\nThe most common form of pulmonary toxicity associated with bleomycin is subacute\nprogressive pulmonary fibrosis. Other less common lesions include organizing pneumonia,\nhypersensitivity pneumonia, and acute chest pain syndrome. It occurs more frequently in\nelderly subjects, with higher cumulative doses of the medication, renal failure, use of\noxygen (especially when high FiO2 is used), combination of other\nchemotherapeutic agents (such as cisplatin and gemcitabine), thoracic radiation therapy,\nand use of G-CSF.(\n\n14\n\n) Bleomycin-induced interstitial pneumonitis is understood as a causative\nfactor for the occurrence of pneumomediastinum in the current literature, on the basis\nof two studies that reported three cases in which this association occurred.(\n\n15\n\n,\n\n16\n\n) Curiously, in at least two of those cases, PFT was performed before the\ndevelopment of pneumomediastinum; however, those authors did not infer a causal\nrelationship between PFT and the occurrence of the complication.(\n\n16\n\n) It is evident that interstitial pneumonitis includes previously mentioned\nfactors, such as local inflammation and alveolar collapse, that facilitate the\ndevelopment of pneumomediastinum. Under these conditions, there can be hyperinflation of\nadjacent regions, increased elastic recoil, and reduced lung compliance, predisposing to\nthe emergence of an increased pressure gradient, but it seems pertinent to investigate\nwhat role PFT might also have played in those reports.\n\nIn the present case, because of the strong temporal correlation between the patient\nhaving undergone PFT and the occurrence of pneumomediastinum, in addition to the\npathophysiological rationale, we consider that the \"trigger\" for the occurrence of air\nleak was the patient having undergone the test, although it is undeniable that the\npresence of bleomycin-induced interstitial pneumonitis created a predisposition to the\nevent.\n\nThe present report and a review of cases in the literature suggest the need for caution\nand proper orientation of patients with bleomycin-induced interstitial pneumonitis who\nperform PFT maneuvers.\n\n* Study carried out in the Department of Pulmonology, Heart Institute, University of\nSão Paulo School of Medicine Hospital das Clínicas, and in the São Paulo Cancer\nInstitute, São Paulo, Brazil.\n\nFinancial support: None.\n\nRelato De CasoPneumomediastino, enfisema subcutâneo e pneumotórax após\nprova de função pulmonar em paciente com pneumopatia intersticial por\nbleomicina*\n Araujo Mariana Sponholz Médica PneumologistaDivisão de Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade\nde São Paulo, São Paulo (SP) Brasil.Fernandes Frederico Leon Arrabal Médico ResponsávelLaboratório de Função Pulmonar, Instituto do Câncer do Estado de São Paulo; e Médico Assistente. Disciplina\nde Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo e, São Paulo\n(SP) Brasil.Kay Fernando Uliana Médico RadiologistaDepartamento de Imagem, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São\nPaulo (SP) Brasil.Carvalho Carlos Roberto Ribeiro Professor Associado Livre-DocenteDivisão de Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina,\nUniversidade de São Paulo, São Paulo (SP) Brasil.Endereço para correspondência: Mariana Sponholz Araujo. Rua Antônio\nPietruza, 266, apto. 181, Portão, CEP 80610-320, Curitiba, PR, Brasil. Tel. 55 11\n98502-4275. E-mail: [email protected] 2013 Sep-Oct 2013 39 5 613 619 09 8 2012 30 11 2012 This is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License, which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.O pneumomediastino espontâneo é um evento incomum, cujo quadro clínico inclui dor\npleurítica retroesternal, enfisema subcutâneo, dispneia e disfonia. O mecanismo\nfisiopatológico implicado é o surgimento de uma diferença de pressão entre os\nalvéolos e estruturas adjacentes, ocasionando ruptura alveolar com posterior\ndissecção da bainha peribroncovascular e infiltração do mediastino e do tecido\nsubcutâneo pelo ar. Desencadeantes conhecidos incluem exacerbação aguda de asma e\nsituações que exigem a realização de manobra de Valsava. Descrevemos e documentamos\npor imagens tomográficas a ocorrência de pneumomediastino após a realização de prova\nde função pulmonar em um paciente com pneumopatia intersticial induzida por\nbleomicina. Apesar de incomum, a associação entre provas de função pulmonar e\nsíndromes de vazamento de ar tem sido relatada cada vez mais na literatura, e doenças\npulmonares, como as pneumopatias intersticiais, contemplam alterações estruturais que\nfacilitam a ocorrência da complicação. \n\nEnfisema mediastínicoEnfisema subcutâneoEspirometriaBleomicinaIntrodução\nO pneumomediastino espontâneo é um evento incomum que acomete preferencialmente\njovens do sexo masculino. É classificado como primário ou secundário de acordo com a\nausência ou presença de doença pulmonar de base predispondo ao evento. O quadro\nclínico inclui dor pleurítica retroesternal (sintoma mais frequente), enfisema\nsubcutâneo, dispneia, disfagia, disfonia, astenia e o clássico sinal de Hamman\n(crepitação síncrona com os batimentos cardíacos, audível no precórdio).(\n\n1\n\n,\n\n2\n\n) Na maioria dos casos, é possível identificar um evento desencadeador,\ncomo a exacerbação aguda de asma. Outros desencadeantes conhecidos são aqueles\nrelacionados à realização da manobra de Valsalva, como exercício físico extenuante,\nlevantamento de peso, inalação de drogas ilícitas, tosse, esforço vigoroso de\nevacuação e trabalho de parto, além de vômitos, infecções respiratórias, aspiração de\ncorpo estranho e barotrauma.(\n\n1\n\n-\n\n5\n\n)\n\n\nA evolução geralmente é benigna e autolimitada.(\n\n1\n\n,\n\n2\n\n) O tratamento é de suporte, tendo por base o uso de analgésicos e o\nrepouso, além de evitar manobras que aumentam a pressão transpulmonar, como, por\nexemplo, a manobra de Valsalva e a espirometria.(\n\n6\n\n)\n\n\nRelato de caso\nPaciente masculino de 50 anos, submetido à orquiectomia por aumento de volume\ntesticular e elevação de alfa-fetoproteína. O diagnóstico anatomopatológico foi de\ncarcinoma embrionário de testículo. No estadiamento, foram evidenciadas metástases\npulmonares na TC de tórax. Foi iniciada quimioterapia com cisplatina, etoposídeo e\nbleomicina (dose acumulada ao final dos ciclos, 300 UI). Durante o tratamento, o\npaciente apresentou um episódio de neutropenia febril e fez uso de\ngranulocyte colony-stimulating factor (G-CSF, fator estimulador\nde crescimento de colônias de granulócitos) nessa ocasião. \n\nTrês meses após o início da quimioterapia, o paciente compareceu a consulta médica\nqueixando-se de dispneia rapidamente progressiva, apresentando hipoxemia (SpO2\n= 87%) e com estertores crepitantes bibasais. A TCAR (Figura 1) evidenciou opacidades pulmonares reticulares difusas,\nrelativamente simétricas, com distribuição periférica e, por vezes,\nperibroncovascular, com predominância nas regiões basais, associadas a um\nespessamento irregular dos septos interlobulares, além de alguns focos de\nconsolidação e áreas de vidro fosco, distribuídos bilateralmente, predominando nas\nregiões subpleurais. Foi feita a hipótese diagnóstica de pneumopatia intersticial por\nbleomicina e foi iniciado o tratamento com corticosteroides. Foi realizada a prova de\nfunção pulmonar (PFP), que mostrou distúrbio ventilatório restritivo acentuado e\nredução acentuada na DLCO. \n\n\nFigura 1 Em A, imagem axial de TCAR demonstrando opacidades reticulares (seta\ndescontínua), associadas a espessamento irregular dos septos interlobulares\n(seta contínua), além de alguns focos de consolidação e áreas de vidro fosco\n(cabeça de seta), distribuídas bilateralmente, predominando nas regiões\nsubpleurais. Em B, imagem coronal de TCAR demonstrando a distribuição dessas\nalterações ao longo do eixo longitudinal de ambos os pulmões, com leve\npredomínio nas bases.\n\n\n\nDois dias após a realização da PFP, o paciente procurou o pronto-socorro por piora\nintensa da dispneia. Ao exame físico, encontrava-se taquicárdico (FC, 110 bpm),\ntaquidispneico (FR, 28 ciclos/min) e hipoxêmico (SpO2 = 75%), com presença\nde enfisema subcutâneo em região cervical direita e ausculta pulmonar com murmúrio\nvesicular reduzido em terços inferiores e estertores crepitantes bibasais. Os exames\nlaboratoriais mostraram leucocitose (17.040 células/mm3) com desvio até\nmielócitos, plaquetopenia, elevação de escórias nitrogenadas e aumento de proteína C\nreativa (43,9 mg/dL). \n\nA radiografia de tórax (Figura 2) permitiu a\nvisualização de pneumomediastino e enfisema subcutâneo, com pequeno pneumotórax e\naumento de opacidades em vidro fosco. As mesmas alterações foram observadas à TCAR\n(Figura 3), que evidenciou grande extensão\nde pneumomediastino e enfisema subcutâneo, bem como um aumento significativo das\nopacidades reticulares e áreas de vidro fosco, comparativamente ao exame inicial. Foi\ninstituído um tratamento contemplando uma etiologia infecciosa\n(piperacilina/tazobactam) e progressão de doença intersticial (metilprednisolona, 1\nmg/kg). O paciente continuou apresentando febre a despeito do escalonamento da\nterapia antibiótica (foram acrescentados vancomicina e sulfametoxazol/trimetoprima) e\nevoluiu com insuficiência respiratória, sendo submetido a intubação orotraqueal,\nventilação mecânica e drenagem torácica. Houve piora da insuficiência renal aguda e a\ndiálise não foi tolerada. O paciente evoluiu a óbito por choque séptico sete dias\napós a admissão.\n\n\nFigura 2 Radiografia de tórax (frente) demonstrando faixa com densidade de ar\ncontornando o mediastino (setas), configurando pneumomediastino, que se\nestende para a região cervical e para a parede torácica, dissecando as\nfibras musculares peitorais (setas descontínuas). Notar o extenso\nacometimento pulmonar por áreas de consolidação e opacidades reticulares,\ndistribuídas na periferia pulmonar, especialmente à direita, onde também se\ndelimita um pequeno pneumotórax (cabeças de seta).\n\n\n\n\nFigura 3 Em A, reformatação sagital oblíqua de TCAR, que demonstra ar dissecando\no interstício pulmonar ao longo da veia pulmonar inferior direita (seta),\naté atingir o mediastino. Em B, reformatação coronal curva de TCAR mostrando\no trajeto ascendente do ar ao redor da veia pulmonar inferior direita\n(seta), continuando-se com o pneumomediastino (cabeças de seta). Notar a\ncontinuidade do pneumomediastino com o enfisema cervical (setas\ndescontínuas). Em C, reformatação coronal curva de TCAR demonstrando a\ngrande quantidade de ar que disseca os planos gordurosos mediastinais e\npneumomediastino (cabeças de seta). Em D, imagem axial de TCAR demonstrando\no pneumomediastino (cabeças de seta) associado ao enfisema da parede\ntorácica (asterisco, também observado em A). Notar também um pequeno\npneumotóraxà direita (seta) e as opacidades pulmonares reticulares e áreas\nde vidro fosco (seta descontínua).\n\n\n\nDiscussão\nO mecanismo fisiopatológico implicado na gênese do pneumomediastino é o surgimento de\numa diferença de pressão entre os alvéolos e estruturas adjacentes que, ao atingir um\nnível crítico, ocasiona ruptura alveolar, com extravasamento de ar para o\ninterstício, ocasionando enfisema intersticial. O ar disseca o feixe broncovascular\n(Figuras 3A e 3B) e, como a pressão no\nmediastino é sempre menor do que no parênquima pulmonar, o ar tende a se mover na\ndireção do hilo e se espalhar pelo mediastino (Figura\n3C). Devido à contiguidade entre as fáscias, o ar pode atingir o tecido\ncelular subcutâneo (Figuras 3A e 3D) e o\nperitônio. Quando a pressão mediastinal se eleva abruptamente e a descompressão por\nvias alternativas não é suficiente para aliviar a pressão, pode haver ruptura da\npleura mediastinal e o surgimento de pneumotórax (Figura 3D).(\n\n2\n\n)\n\n\nRecentemente, foi publicada no Jornal Brasileiro de Pneumologia uma carta ao\neditor(\n\n7\n\n) descrevendo um caso de pneumomediastino espontâneo e mostrando, entre\noutros achados, o raríssimo pneumorraque; porém, naquele caso, a imagem de dissecção\ndo feixe broncovascular não foi caracterizada. Em um relato de pneumomediastino em um\npaciente receptor de transplante de medula óssea, foi observada uma imagem\ntomográfica semelhante à do presente caso; porém, de menor magnitude e sem a presença\nde pneumotórax.(\n\n8\n\n)\n\n\nA descrição dessa cadeia de eventos foi feita por Macklin & Macklin na década de\n40.(\n\n3\n\n) Os autores demonstraram que a maioria das síndromes de vazamento de ar\nnão era resultante da ruptura de bolhas subpleurais, mas decorrente de ruptura\nalveolar. Além disso, apresentaram o conceito de que não é necessária a presença de\npressão positiva dentro dos alvéolos para a ocorrência da ruptura. O fundamental é a\ndiferença de pressão entre o alvéolo e a bainha perivascular do septo adjacente. Uma\npressão muito negativa no espaço intersticial poderia, portanto, levar a rotura\nalveolar mesmo sem a ocorrência de pressões positivas extremas no alvéolo. Dessa\nmaneira, esforços inspiratórios intensos, atelectasias adjacentes e baixa pressão\nintravascular poderiam estar implicados no surgimento dessas síndromes.(\n\n3\n\n)\n\n\nExistem descrições de pneumomediastino relacionado a PFP.(\n\n4\n\n,\n\n9\n\n-\n\n11\n\n) Em 1973, o primeiro relato dessa natureza descreveu o caso de um\nestudante de medicina de 23 anos, previamente hígido, que evoluiu com extenso\npneumomediastino e enfisema subcutâneo após realizar uma PFP.(\n\n4\n\n)\n\n\nEm uma espirometria, o paciente é instruído a realizar uma inspiração máxima até a\ncapacidade pulmonar total, prender a respiração e expirar vigorosamente.(\n\n10\n\n) No momento em que o indivíduo inspira, ocorre uma redução da pressão\nintratorácica, aumento do volume de ar nos alvéolos e aumento do retorno venoso, com\nconsequente aumento do diâmetro das veias pulmonares. Por isso, não ocorre diferença\nde pressão no espaço intersticial, já que todos os compartimentos se alongam e\naumentam de diâmetro de maneira simétrica. No entanto, quando o indivíduo \"prende a\nrespiração\", há estase venosa, com consequente redução do enchimento venoso pulmonar\ne redução do lúmen dos vasos, possibilitando o surgimento da diferença de pressão\nnecessária à ruptura alveolar.(\n\n3\n\n)\n\n\nRelatos que se seguiram notaram o pneumomediastino como uma complicação da PFP\nassociada a doenças pulmonares subjacentes extremamente diversas, como, por exemplo,\ndoenças reumatológicas com acometimento intersticial pulmonar.(\n\n11\n\n) Nessas situações, somam-se as já citadas alterações de pressão induzidas\nna realização do exame, a existência de inflamação combinada com aumento do\nrecolhimento elástico da fibrose e o colapso de áreas adjacentes que tornam o pulmão\nvulnerável a hiperdistensão segmentar e ao surgimento de gradiente de\npressão.(\n\n3\n\n) Esse é o mecanismo que acreditamos aplicar-se também no presente\ncaso.\n\nAo relatar o caso de um estudante saudável que desenvolveu pneumomediastino após o\nuso de maconha, um grupo de autores entendeu que o mesmo foi causado pelo fato de o\njovem ter realizado diversas manobras do tipo Valsalva (prendendo a respiração após\ninspiração máxima contra a glote parcial ou totalmente fechada) com o intuito de\nprolongar o efeito da droga.(\n\n12\n\n) A manobra de Valsalva é um fator clássico relacionado às síndromes de\nvazamento de ar por gerar um aumento de pressão intrapulmonar.(\n\n3\n\n,\n\n4\n\n,\n\n12\n\n) Por esse motivo, o trabalho de parto e esforços de evacuação vigorosos\nestão associados a relatos de pneumomediastino.(\n\n3\n\n)\n\n\nConforme já anteriormente citado, o pneumomediastino costuma ter uma evolução benigna\ne autolimitada. Entretanto, devemos olhar com cautela essa aparente benignidade, já\nque, em pacientes com doenças pulmonares subjacentes, a existência de síndromes de\nvazamento de ar está associada a maior gravidade. Sabemos que essa síndrome pode\nassociar-se a disseminação de infecções e liberação de mediadores inflamatórios. Além\ndisso, pode resultar na temida síndrome airblock (condição em que a\npresença de ar no interstício e no mediastino não encontra uma rota de saída,\nculminando na geração de grandes pressões sobre o mediastino, que interfere na\ncirculação por compressão dos vasos e do coração e impede a insuflação e\ndesinsuflação pulmonar).(\n\n2\n\n)\n\n\nNo presente caso, é possível que o pneumomediastino tenha atuado como um fator\ncontribuinte para o desfecho fatal por facilitar a disseminação da infecção e a\nperpetuação de inflamação; porém, sem atuar como o determinante do óbito, sendo esse\nrelacionado à intersticiopatia e ao grave processo infeccioso sobreposto. Vale ainda\nressaltar que, no presente caso, não existia a indicação de tratamento específico\npara o pneumomediastino como, por exemplo, mediastinotomia. Esse tipo de procedimento\nsó seria benéfico nos raros casos de pneumomediastino hipertensivo.(\n\n13\n\n)\n\n\nComo as PFP são frequentemente realizadas em portadores de doença respiratória aguda\ne crônica, sua associação com síndromes de vazamento de ar deve ser estudada e\nrelatada.\n\nA principal forma de toxicidade pulmonar associada à bleomicina é a fibrose pulmonar\nprogressiva subaguda. Outras lesões menos comuns são a pneumonia em organização, a\npneumonia de hipersensibilidade e a síndrome da dor torácica aguda. Ocorre mais\nfrequentemente em idosos, com maior dose acumulada da medicação, insuficiência renal,\nuso de oxigênio (principalmente quando em altas frações), associação de outros\nquimioterápicos, como cisplatina e gemcitabina, radioterapia torácica e uso de\nG-CSF.(\n\n14\n\n) A pneumopatia intersticial induzida por bleomicina é entendida na\nliteratura atual como um fator causal para a ocorrência de pneumomediastino baseado\nem dois estudos que relataram três casos nos quais essa associação\nocorreu.(\n\n15\n\n,\n\n16\n\n) Curiosamente, em pelo menos dois desses casos, a PFP foi realizada\npreviamente ao surgimento do pneumomediastino; porém, os autores não inferiram nexo\ncausal entre a PFP e a ocorrência da complicação.(\n\n16\n\n) Evidentemente que a pneumopatia intersticial contempla fatores já\nmencionados, como inflamação local e colapso alveolar, que facilitam o surgimento de\npneumomediastino. Nessas condições, pode ocorrer hiperinsuflação de áreas adjacentes,\naumento do recolhimento elástico e redução da complacência pulmonar, predispondo ao\nsurgimento de gradiente de pressão aumentado, mas nos parece pertinente investigar\nqual papel a PFP pode ter desempenhado também naqueles relatos.\n\nNo presente caso, devido à forte correlação temporal entre a realização da PFP e a\nocorrência do pneumomediastino, além do racional fisiopatológico, consideramos que o\n\"gatilho\" para a ocorrência do vazamento de ar foi a realização do exame, embora seja\ninegável a predisposição para o evento gerada pela presença de pneumopatia\nintersticial induzida por bleomicina.\n\nO presente relato e a revisão de casos na literatura sugerem a necessidade de cautela\ne orientação adequada de pacientes com pneumopatia intersticial induzida por\nbleomicina que realizam manobras de PFP.\n\n* Trabalho realizado na Divisão de Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade\nde São Paulo e no Instituto do Câncer do Estado de São Paulo, São Paulo (SP) Brasil.\n\nApoio financeiro: Nenhum.\n==== Refs\nReferences\n1 Abolnik I Lossos IS Breuer R Spontaneous pneumomediastinum. A report of 25\ncases Chest 1991 100 1 93 95 http://dx.doi.org/10.1378/chest.100.1.93 1824034 \n2 Iyer VN Joshi AY Ryu JH Spontaneous pneumomediastinum: analysis of 62\nconsecutive adult patients Mayo Clin Proc 2009 84 5 417 421 19411438 \n3 Macklin MT Macklin CC Malignant interstitial emphysema of lungs and\nmediastinum as important occult complications in many respiratory diseases and\nother conditions: interpretation of clinical literature in the light of laboratory\nexperiment Medicine 1944 23 281 358 http://dx.doi.org/10.1097/00005792-194412000-00001 \n4 Varkey B Kory RC Mediastinal and subcutaneous emphysema following\npulmonary function tests Am Rev Respir Dis 1973 108 6 1393 1396 4751724 \n5 Campillo-Soto A Coll-Salinas A Soria-Aledo V Blanco-Barrio A Flores-Pastor B Candel-Arenas M Spontaneous pneumomediastinum: descriptive study of our\nexperience with 36 cases [Article in Spanish] Arch Bronconeumol 2005 41 9 528 531 http://dx.doi.org/10.1157/13078656 16194517 \n6 Macia I Moya J Ramos R Morera R Escobar I Saumench J Spontaneous pneumomediastinum: 41 cases Eur J Cardiothorac Surg 2007 31 6 1110 1114 http://dx.doi.org/10.1016/j.ejcts.2007.03.008 17420139 \n7 Alves GR Silva RV Corrêa JR Colpo CM Cezimbra HM Haygert CJ Spontaneous pneumomediastinum (Hamman's\nsyndrome) J Bras Pneumol 2012 38 3 404 407 http://dx.doi.org/10.1590/S1806-37132012000300018 22782613 \n8 Dias OM Cavalcanti Coelho DL de Carvalho CR Interstitial emphysema leading to pneumomediastinum in\na bone marrow transplant patient Am J Respir Crit Care Med 2013 188 3 10.1164/rccm.201203-0385IM. \n9 Manço JC Terra-Filho J Silva GA Pneumomediastinum, pneumothorax and subcutaneous\nemphysema following the measurement of maximal expiratory pressure in a normal\nsubject Chest 1990 98 6 1530 1532 http://dx.doi.org/10.1378/chest.98.6.1530 2245704 \n10 Krasnick J Pneumomediastinum following spirometry Chest 2001 120 3 1043 1043 http://dx.doi.org/10.1378/chest.120.3.1043 11555557 \n11 Jun JB Song SY The development of pneumomediastinum after pulmonary\nfunction testing in a patient with systemic sclerosis Rheumatol Int 2007 27 11 1097 1098 http://dx.doi.org/10.1007/s00296-007-0369-7 17562046 \n12 Miller WE Spiekerman RE Hepper NG Pneumomediastinum resulting from performing Valsalva\nmaneuvers during marihuana smoking Chest 1972 62 2 233 234 http://dx.doi.org/10.1378/chest.62.2.233 5050235 \n13 Herlan DB Landreneau RJ Ferson PF Massive spontaneous subcutaneous emphysema. Acute\nmanagement with infraclavicular \"blow holes\" Chest 1992 102 2 503 505 http://dx.doi.org/10.1378/chest.102.2.503 1340766 \n14 Jules-Elysee K White DA Bleomycin-induced pulmonary toxicity Clin Chest Med 1990 11 1 1 20 1691067 \n15 White DA Stover DE Severe bleomycin-induced pneumonitis. Clinical features\nand response to corticosteroids Chest 1984 86 5 723 728 http://dx.doi.org/10.1378/chest.86.5.723 6207992 \n16 Sikdar T MacVicar D Husband JE Pneumomediastinum complicating bleomycin related lung\ndamage Br J Radiol 1998 71 851 1202 1204 10434917\n\n",
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"journal": "Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia",
"keywords": null,
"medline_ta": "J Bras Pneumol",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D004646:Emphysema; D017809:Fatal Outcome; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D011030:Pneumothorax; D012129:Respiratory Function Tests; D014057:Tomography, X-Ray Computed",
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"pages": "613-9",
"pmc": null,
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11555557;23905536;17420139;17562046;22782613;19411438;1340766;5050235;2245704;6207992;1691067;16194517;1824034;10434917;4751724",
"title": "Pneumomediastinum, subcutaneous emphysema, and pneumothorax after a pulmonary function testing in a patient with bleomycin-induced interstitial pneumonitis.",
"title_normalized": "pneumomediastinum subcutaneous emphysema and pneumothorax after a pulmonary function testing in a patient with bleomycin induced interstitial pneumonitis"
}
|
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{
"abstract": "Leptomeningeal metastasis occurs in approximately 5% of patients with metastatic solid carcinomas, and it is often diagnosed in patients with breast cancer, lung cancer, malignant melanoma, and digestive cancer. Herein, we report a case of a metastatic cancer of unknown primary origin. The leptomeningeal metastasis progressed quite rapidly, and the patient died despite achieving complete remission via second-line chemotherapy.",
"affiliations": "Dept. of Respiratory Medicine, Saiseikai Senri Hospital.",
"authors": "Akazawa|Yuki|Y|;Taniguchi|Yoshihiko|Y|;Mima|Hisanori|H|;Tagawa|Hiroshi|H|;Niki|Toshie|T|;Funakoshi|Toshiki|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D043823:Taxoids; D000077143:Docetaxel; D000068258:Bevacizumab",
"country": "Japan",
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"issue": "42(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000077143:Docetaxel; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009382:Neoplasms, Unknown Primary; D012074:Remission Induction; D043823:Taxoids",
"nlm_unique_id": "7810034",
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"pmc": null,
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"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of metastatic cancer of unknown primary origin that progressed rapidly after complete remission via second-line chemotherapy.",
"title_normalized": "a case of metastatic cancer of unknown primary origin that progressed rapidly after complete remission via second line chemotherapy"
}
|
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{
"reactionmeddrapt": "Epistaxis",
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"reactionoutcome": "6"
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{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "18.0",
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{
"reactionmeddrapt": "Headache",
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{
"reactionmeddrapt": "Neuropathy peripheral",
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{
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"narrativeincludeclinical": "CASE EVENT DATE: 2012"
}
},
"primarysource": {
"literaturereference": "AKAZAWA Y, TANIGUCHI Y, MIMA H, TAGAWA H, NIKI T AND FUNAKOSHI T. A CASE OF METASTATIC CANCER OF UNKNOWN PRIMARY ORIGIN THAT PROGRESSED RAPIDLY AFTER COMPLETE REMISSION VIA SECOND LINE CHEMOTHERAPY. G07 /JAPAN JOURNAL OF CANCER CHEMOTHERAPY 2015 FEB;42 (2):249-251.",
"literaturereference_normalized": "a case of metastatic cancer of unknown primary origin that progressed rapidly after complete remission via second line chemotherapy",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20150316",
"receivedate": "20150313",
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},
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"transmissiondate": "20150721"
}
] |
{
"abstract": "Background: Slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep reflects synaptic potentiation during preceding wakefulness. Epileptic activity may induce increases in state-dependent SWA in human brains, therefore, localization of SWA may prove useful in the presurgical workup of epileptic patients. We analyzed high-density electroencephalography (HDEEG) data across vigilance states from a reflex epilepsy patient with a clearly localizable ictal symptomatogenic zone to provide a proof-of-concept for the testability of this hypothesis. Methods: Overnight HDEEG recordings were obtained in the patient during REM sleep, NREM sleep, wakefulness, and during a right facial motor seizure then compared to 10 controls. After preprocessing, SWA (i.e., delta power; 1-4 Hz) was calculated at each channel. Scalp level and source reconstruction analyses were computed. We assessed for statistical differences in maximum SWA between the patient and controls within REM sleep, NREM sleep, wakefulness, and seizure. Then, we completed an identical statistical comparison after first subtracting intrasubject REM sleep SWA from that of NREM sleep, wakefulness, and seizure SWA. Results: The topographical analysis revealed greater left hemispheric SWA in the patient vs. controls in all vigilance states except REM sleep (which showed a right hemispheric maximum). Source space analysis revealed increased SWA in the left inferior frontal cortex during NREM sleep and wakefulness. Ictal data displayed poor source-space localization. Comparing each state to REM sleep enhanced localization accuracy; the most clearly localizing results were observed when subtracting REM sleep from wakefulness. Conclusion: State-dependent SWA during NREM sleep and wakefulness may help to identify aspects of the potential epileptogenic zone. Future work in larger cohorts may assess the clinical value of sleep SWA to help presurgical planning.",
"affiliations": "Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.;Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.;Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.;Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.;Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States.;Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.;Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States.;Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States.;Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.;Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.;Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States.;Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States.",
"authors": "Moffet|Eric W|EW|;Verhagen|Ruben|R|;Jones|Benjamin|B|;Findlay|Graham|G|;Juan|Elsa|E|;Bugnon|Tom|T|;Mensen|Armand|A|;Aparicio|Mariel Kalkach|MK|;Maganti|Rama|R|;Struck|Aaron F|AF|;Tononi|Giulio|G|;Boly|Melanie|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fnsys.2020.549309",
"fulltext": "\n==== Front\nFront Syst Neurosci\nFront Syst Neurosci\nFront. Syst. Neurosci.\nFrontiers in Systems Neuroscience\n1662-5137 Frontiers Media S.A. \n\n10.3389/fnsys.2020.549309\nNeuroscience\nBrief Research Report\nLocal Sleep Slow-Wave Activity Colocalizes With the Ictal Symptomatogenic Zone in a Patient With Reflex Epilepsy: A High-Density EEG Study\nMoffet Eric W. 12 Verhagen Ruben 134 Jones Benjamin 13 Findlay Graham 13 Juan Elsa 345 Bugnon Tom 13 Mensen Armand 3 Aparicio Mariel Kalkach 3 Maganti Rama 1 Struck Aaron F. 1 Tononi Giulio 3 Boly Melanie 13* 1Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States\n2Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States\n3Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States\n4Department of Philosophy, Vrije Universiteit Amsterdam, Amsterdam, Netherlands\n5Department of Psychology, University of Amsterdam, Amsterdam, Netherlands\nEdited by: Heiko J. Luhmann, Johannes Gutenberg University Mainz, Germany\n\nReviewed by: Mario Rosanova, University of Milan, Italy; Stefano Francione, “Claudio Munari” Epilepsy Surgery Centre—Niguarda Hospital, Italy\n\n*Correspondence: Melanie Boly [email protected]\n21 10 2020 \n2020 \n14 54930906 4 2020 17 9 2020 Copyright © 2020 Moffet, Verhagen, Jones, Findlay, Juan, Bugnon, Mensen, Aparicio, Maganti, Struck, Tononi and Boly.2020Moffet, Verhagen, Jones, Findlay, Juan, Bugnon, Mensen, Aparicio, Maganti, Struck, Tononi and BolyThis 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: Slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep reflects synaptic potentiation during preceding wakefulness. Epileptic activity may induce increases in state-dependent SWA in human brains, therefore, localization of SWA may prove useful in the presurgical workup of epileptic patients. We analyzed high-density electroencephalography (HDEEG) data across vigilance states from a reflex epilepsy patient with a clearly localizable ictal symptomatogenic zone to provide a proof-of-concept for the testability of this hypothesis.\n\nMethods: Overnight HDEEG recordings were obtained in the patient during REM sleep, NREM sleep, wakefulness, and during a right facial motor seizure then compared to 10 controls. After preprocessing, SWA (i.e., delta power; 1–4 Hz) was calculated at each channel. Scalp level and source reconstruction analyses were computed. We assessed for statistical differences in maximum SWA between the patient and controls within REM sleep, NREM sleep, wakefulness, and seizure. Then, we completed an identical statistical comparison after first subtracting intrasubject REM sleep SWA from that of NREM sleep, wakefulness, and seizure SWA.\n\nResults: The topographical analysis revealed greater left hemispheric SWA in the patient vs. controls in all vigilance states except REM sleep (which showed a right hemispheric maximum). Source space analysis revealed increased SWA in the left inferior frontal cortex during NREM sleep and wakefulness. Ictal data displayed poor source-space localization. Comparing each state to REM sleep enhanced localization accuracy; the most clearly localizing results were observed when subtracting REM sleep from wakefulness.\n\nConclusion: State-dependent SWA during NREM sleep and wakefulness may help to identify aspects of the potential epileptogenic zone. Future work in larger cohorts may assess the clinical value of sleep SWA to help presurgical planning.\n\nhigh-density EEGreflex epilepsysleepslow-wave activitydelta power\n==== Body\nIntroduction\nEpilepsy proves drug-refractory in 20–40% of cases (Liu et al., 2015). In these patients, surgical resection represents the gold standard intervention (Ryvlin et al., 2014; Liu et al., 2015). Clinical 10-20 electroencephalography (EEG) is used pre-surgically to identify areas of the epileptogenic zone (Kahane et al., 2006; Lüders et al., 2006), although muscle artifacts and electrode number limit its localizing power (Lantz et al., 2003; Islam et al., 2016). High-density EEG (HDEEG; i.e., >64 electrodes) offers enhanced artifact rejection and source localization (Lantz et al., 2003; Puce and Hämäläinen, 2017). This technique is most commonly utilized to source-localize interictal spikes. However, in patients with focal epilepsy, the irritative zone identified through source localization of spikes does not necessarily match the ictal onset zone (IOZ; Strobbe et al., 2016; Verhoeven et al., 2018).\n\nIn a previous HDEEG study, we detected local increases in non-rapid eye movement (NREM) sleep slow-wave activity (SWA; i.e., delta power, 1–4 Hz) that colocalized with IOZs (Boly et al., 2017). In animal studies, epileptic activity induces synaptic potentiation (Debanne et al., 2006; Staley and Dudek, 2006). Because local sleep SWA reflects synaptic potentiation during wakefulness (Tononi and Cirelli, 2014), and the increased sleep SWA we observed was correlated with epileptic spike and seizure frequency (Boly et al., 2017), it likely reflected synaptic potentiation induced by epileptic activity in human brains. Epilepsy-induced increased SWA is reminiscent of task-dependent local SWA observed during wakefulness and sleep after learning (Siclari and Tononi, 2017)—suggesting that epileptic disease may hijack the normal mechanisms of synaptic plasticity (Boly et al., 2017).\n\nWhile our previous findings were promising, not all patients in the study displayed NREM sleep SWA maximums that colocalized to their IOZ. One reason may be that we only assessed overall NREM sleep SWA, without considering state-dependence—for this manuscript, we use the term “state-dependent” to refer to how SWA varies across vigilance states, such as REM sleep, NREM sleep, wakefulness, or seizure. In neurological disease, focal SWA is a non-specific EEG finding, also occurring secondary to deafferentation in brain lesions caused by stroke or traumatic brain injury—in which case it may be independent of sleep-wakefulness processes (Dunkley et al., 2015; Rabiller et al., 2015; Rosanova et al., 2018). Given that REM sleep is thought to suppress epileptic activity (Shouse et al., 2000; Ng and Pavlova, 2013; Lambert et al., 2018; Kang et al., 2020), state-dependent SWA may more specifically localize epileptic foci, especially when comparing NREM sleep to REM sleep. This hypothesis is in line with our previous study where we reported no significant abnormality during REM sleep in patients’ HDEEG topographies but noted increases in SWA during NREM sleep compared to REM sleep (Boly et al., 2017). Consequently, we here aimed to evaluate the localizing value of state-dependent SWA during NREM sleep, wakefulness, and seizure—first, within each state in isolation, and then with each state initially subtracted by intrasubject REM sleep SWA.\n\nThe current study considers a patient with reflex epilepsy, providing an opportunity to test a proof-of-concept—that is, a pilot study to consider the feasibility of larger-scale analysis—for the localizing value of SWA across different vigilance states (Koepp et al., 2016). In the aforementioned previous study, we compared the location of HDEEG-detected local SWA to the location of IOZ, identified via the 10-20 clinical EEG montage in patients with focal epilepsy. The 10-20 EEG possesses limited spatiotemporal resolution. Also, non-lesional epilepsy often proves difficult to localize. The reflex epilepsy patient described here, although non-lesional, presented with a readily localizable ictal symptomatogenic zone due to her purely motor ictal semiology. Her seizures, triggered by eating, were characterized by stereotypic right facial twitching with fully preserved awareness, localizable to the left motor cortex. Ictal SPECT data was also available for the patient, which displayed an area of hyperperfusion in the left inferior frontal cortex. The case thus offered a chance to assess the localizing value of state-dependent SWA in focal epilepsy.\n\nIn this study, we statistically compared state-dependent SWA (i.e., delta power, 1–4 Hz) in a reflex epilepsy patient to 10 healthy controls utilizing 256-electrode HDEEG scalp level topographies and source reconstruction analyses. “Scalp level”, as utilized in this manuscript, refers to the topographic mapping of SWA (Nuwer, 1988). This approach provides a two-dimensional rendering of brain activity (Wang et al., 2017). “Source space” or “source reconstruction” analysis combined these data with a forward model and minimum norm plus smoothness priors to provide a three-dimensional location of SWA changes on the cortical surface (López et al., 2014; Michel and Brunet, 2019). Since recent literature emphasizes the presence of plasticity-induced local SWA not only during NREM sleep, but also during wakefulness (Tononi and Cirelli, 2014), we compared the patient’s SWA data to controls during REM sleep, NREM sleep, and wakefulness states, as well as during a seizure. Then, we subtracted each subjects’ REM sleep SWA from their own SWA during NREM sleep and wakefulness states, plus the seizure state for the patient, before running an identical analysis as above (in effect, utilizing the physiological observation that REM sleep inhibits epileptic activity). We hypothesized that maximum changes in state-dependent SWA (i.e., its variation across various vigilance states) in the patient vs. controls may colocalize with regions of the patient’s epileptogenic zone, especially when comparing other states to REM sleep.\n\nMaterials and Methods\nCase Presentation\nHDEEG data from a 61-year-old right-handed woman with drug-refractory reflex epilepsy was utilized for this study. She presented with right facial motor seizures caused by eating. The patient underwent EEG recording while at the University of Wisconsin’s Epilepsy Monitoring Unit (EMU). Clinical 10-20 EEG revealed left frontal interictal epileptic discharges (IED; Supplementary Figure 2). Several seizures were captured on 10-20 EEG but were uninterpretable due to movement artifacts. One seizure was recorded with HDEEG. An MRI during the patient’s EMU stay did not reveal structural lesions that correlated with her seizure semiology. A thorough clinical history of the patient may be found on page 9 of the Supplementary Materials.\n\nThe patient was initially referred to a general neurology clinic at age 45. She reported 5 years of 2-min episodes of dizziness, light-headedness, and flushes of warmth followed by chills, diaphoresis, and spells of “blank out.” MRI and EEG findings were nonspecific at that time. By age 49 she experienced a fine tongue tremor and dysarthria as well as facial twitching episodes, as the above-described semiology waned. Repeat MRI imaging was unremarkable. However, an ictal SPECT co-registered to MRI showed increased perfusion in the left inferior frontal lobe (unfortunately, only the official read found within the patient’s medical record was available, i.e., the images were not accessible, as they were obtained at an outside institution).\n\nRight facial seizures continued unabated 11 years status post initial presentation despite multiple anti-seizure drug (ASD) trials (including lamotrigine, zonisamide, levetiracetam, carbamazepine, topiramate, oxcarbazepine, and phenytoin). Events occurred up to twice daily and now included contraction of the right sternocleidomastoid muscle. At that point, the patient mentioned that her seizures were triggered by chewing food with the right side of her mouth. Fifteen years after the initial presentation she underwent the inpatient EMU stay, during which the present HDEEG data was recorded. Thereafter, seizures continued, as did trials of ASDs. The patient relocated and was lost to follow-up 18 years after the first presentation.\n\nHDEEG Monitoring and Analyses\nThe Institutional Review Board at the University of Wisconsin-Madison approved our study methods. A single overnight recording with a 256-electrode EEG net (EGI, Electrical Geodesics Inc.) was conducted on the patient and 10 healthy control volunteers. Controls from an unrelated study were utilized, having been recruited at the Wisconsin Sleep Laboratory; each was free of neurological disease, sleep disorders, and medications. The patient and each control gave written informed consent before participation in the EEG procedure.\n\nEEG data preprocessing was completed similarly to previous studies (Boly et al., 2017). For each subject, epochs of interest were extracted: an approximately 5-min epoch of clean REM sleep and N3 NREM sleep, a 2–3-min epoch of wakefulness; and an additional 70-s epoch of clinical ictal activity was extracted for the patient (full clinical seizure epoch). A certified epileptologist (MB) identified IEDs, which were then removed from the data. Using Matlab software, we filtered data from 1 to 40 Hz for NREM sleep and REM sleep epochs using EEGlab default FIR filter (as in Boly et al., 2017) and from 1 to 25 Hz for wakefulness and seizure epochs (to reduce muscle activity contribution). We first rejected and interpolated bad channels—for the patient this included seven channels during REM sleep, four for NREM sleep, five during wakefulness, and 75 during a seizure. Then, noisy epochs were rejected before conducting independent component analysis (runica EEGlab plugin, separately for each condition) to remove eye movement, cardiac, and muscle artifacts. All statistics utilized average-referenced EEG data. For all scalp level analyses, the root mean square of delta band activity (1–4 Hz) was computed to estimate SWA at each channel separately for REM sleep, NREM sleep, wakefulness, and seizure epochs; topographical images were generated to perform scalp statistics on the results using Statistical Parametric Mapping (SPM) software1. We also conducted a source reconstruction of pre-processed HDEEG data using Brainstorm software2 (Tadel et al., 2011). We used realistic template head models with the boundary element method plus minimum norm and smoothness (LORETA) priors. We then estimated source-space SWA using Welch’s power spectral density function (MATLAB pwelch).\n\nTo conduct statistical analyses, scalp topographical values of SWA were converted to 2D images, and source space SWA values were converted into gifti images (Kilner and Friston, 2010; Boly et al., 2017). Within-subject spatial normalization of SWA was conducted via\nz-scoring. SPM software was then utilized to run t-tests on consistent SWA differences between the patient and each control (on the difference images between the patient and each control), using a random-effects approach (Siegel et al., 2014). For both scalp topographies and source space models, the consistency of SWA differences between the patient and each control were assessed within isolated REM sleep, NREM sleep, and wakefulness vigilance states; for the patient’s ictal analysis, the wakefulness SWA of each control was compared to the patient’s seizure. Finally, an identical statistical analysis was completed using images wherein each participant’s REM sleep SWA was first subtracted from their NREM sleep SWA, wakefulness SWA, or seizure SWA (in the case of the patient); that is, before re-assessing for consistent SWA differences between the patient and each control within each vigilance state (excluding REM sleep). All results were thresholded at cluster-level or peak-level p < 0.05 corrected for multiple spatial comparisons using a family-wise error rate as implemented in SPM.\n\nResults\nDemographics and Sleep Architecture\nSupplementary Table 1 summarizes the control group’s demographics. The control group was age-matched with the patient. Patient and control sleep architecture data for the single-overnight HDEEG recording can also be found in this table. Sleep onset latency (SOL) and REM sleep latency (REML) was higher in the patient as compared to the control group average. The patient also had a higher proportion of N3 stage NREM sleep and a lower proportion of REM sleep (as compared to total sleep time) than controls. Other sleep architecture parameters were similar to controls.\n\nScalp Level Results\nDuring REM sleep, SWA maximally increased in the right frontal area in the patient vs. controls (Figures 1A–C). During NREM sleep, SWA increased bilaterally in front-temporal regions, with a maximum in the right frontal area (Figures 1D–F). When subtracting each participant’s REM sleep from their NREM sleep before completing an identical statistical analysis (Figures 1G,H), we observed focal increases in SWA within the left central region. For wakefulness, SWA increased maximally in a left centrotemporal region (Figures 2A–C)—a finding confirmed when comparing wakefulness to REM sleep as above (Figures 2D,E). Scalp-level topography during the patient’s seizure compared to the wakefulness of the controls (Figures 2F–H) revealed a maximum SWA increase in the left centrotemporal region. For seizure (i.e., the patient’s ictal period vs. controls’ wakefulness) compared to REM sleep (Figures 2I,J), the SWA maximal increase also localized to the left centrotemporal area. Supplementary Figure 1 shows a topographic rendering of the patient’s ictal data across wider frequency bands beyond SWA, with a special aim towards differentiating lower vs. higher frequency SWA. Supplementary Table 2 displays scalp topographic coordinates and statistical values for maximal differences in SWA in the patient vs. controls across all vigilance states.\n\nFigure 1 Slow-wave activity (SWA) power topographies for the patient and controls during REM sleep and non-rapid eye movement (NREM) sleep taken in isolation, and for intrasubject NREM sleep subtracted by REM sleep. Red stars denote SWA maximums. REM sleep and NREM sleep in isolation displayed SWA maxima in the right frontal areas. We observed a left fronto-temporal NREM sleep SWA maximum as referenced to intrasubject REM sleep SWA. (A) REM sleep mean SWA power for the patient. (B) REM sleep mean SWA power for controls. (C) Statistical Parametric Mapping (SPM) T map for the statistical difference between patient and controls REM sleep SWA; the red star shows the SWA maximum. (D) NREM sleep mean SWA power for the patient. (E) NREM sleep mean SWA power for controls. (F) SPM T map for the statistical difference between patient and controls NREM sleep SWA; the red star shows the SWA maximum. (G) Difference between patient and controls NREM sleep SWA subtracted by REM sleep SWA. (H) SPM T map for the difference between patient and controls SWA power during NREM sleep subtracted by REM sleep SWA; the red star shows the SWA maximum. Each T map pictured above is thresholded for a display of uncorrected p < 0.05. The rainbow color scale is utilized for regression slope values and the hot color scale for t-values.\n\nFigure 2 SWA power topographies for the patient and controls during wakefulness and seizure states, both in isolation and when subtracted by REM sleep. Red stars denote SWA maximums. Wakefulness SWA analysis showed a left frontal maximum; when referenced to REM sleep, wakefulness SWA localized to the left fronto-temporal region. The seizure state displayed an SWA maximum in the left temporal region. We observed a left fronto-temporal region SWA maximum in the seizure state when referenced to intrasubject REM sleep SWA. (A) Wakefulness mean SWA power for the patient. (B) Wakefulness mean SWA power for controls. (C) SPM T map for the statistical difference between patient and controls wakefulness SWA; the red star shows the SWA maximum. (D) Difference between patient and controls SWA power during wakefulness subtracted by REM sleep SWA. (E) SPM T map for the difference between patient and controls SWA power during wakefulness subtracted by REM sleep SWA; the red star shows the SWA maximum. (F) Seizure mean SWA power for the patient. (G) Wakefulness mean SWA power for controls. (H) SPM T map for the statistical difference in SWA power between patient seizure and controls wakefulness; the red star shows the SWA maximum. (I) The difference in mean SWA power between patient seizure and wakefulness of controls, both subtracted REM sleep SWA. (J) SPM T map for patient seizure and controls wakefulness subtracted by REM sleep SWA; the red star shows the SWA maximum. Each T map pictured above is thresholded for a display of uncorrected p < 0.05. The rainbow color scale is utilized for regression slope values and the hot color scale for t-values.\n\nSource Reconstruction Results\nDuring REM sleep, we noted an SWA maximum in the right frontal lobe (Figure 3A). Source reconstruction demonstrated a maximum SWA increase in the right frontal cortex during NREM sleep (Figure 3B). When the patient’s and each control’s NREM sleep SWA was first subtracted by their REM sleep SWA (Figure 3C), we found a maximum change in SWA within the left temporal region after running an identical statistical analysis. Wakefulness source-space data (Figure 4A), both in isolation and when compared to REM sleep, as above (Figure 4B), had the best localizing value with an SWA maximum increase found in the left inferior frontal cortex. Ictal source reconstruction data (Figure 4C) revealed bilateral limbic increases in SWA; comparing this data to REM sleep revealed a right temporal SWA maximum (Figure 4D). Supplementary Figure 1 shows the source space rendering of IEDs captured within NREM sleep during HDEEG monitoring. Supplementary Table 3 reports cortical coordinates and statistical values for maximal SWA changes when comparing the patient to controls across all vigilance states.\n\nFigure 3 Source space reconstruction of SWA power for the patient vs. controls during NREM sleep and REM sleep taken in isolation, and for NREM sleep subtracted by REM sleep. Red stars denote SWA maximums. We observed NREM sleep and REM sleep SWA maxima within the right frontal lobe. SWA maxima localized to the left temporal lobe when intrasubject NREM sleep SWA was subtracted by REM sleep SWA before statistical analysis. (A) Patient REM sleep SWA power subtracted by controls REM sleep SWA power; the red star shows the SWA maximum. (B) Patient SWA power subtracted by controls SWA power during NREM sleep; the red star shows the SWA maximum. (C) Patient vs. controls comparison for NREM sleep SWA power subtracted by REM sleep SWA power; the red star shows the SWA maximum. Each T map pictured above is thresholded for a display of uncorrected p < 0.05. The jet color scale indicates t-values. Abbreviations: RL = right lateral; LL = left lateral.\n\nFigure 4 Source space reconstruction of SWA power for the patient vs. controls during wake and seizure states, both taken in isolation and when subtracted by REM sleep. Red stars denote SWA maximums. We observed the SWA maximum during wakefulness in the left inferior frontal lobe. We observed the SWA maximum during seizure within the right limbic area. When these states were first subtracted by intrasubject REM sleep SWA before statistical re-analysis, we again observed the wakefulness SWA maximum in the left inferior frontal lobe, albeit with a higher power; and for the seizure state, we observed the SWA maximum within the right temporal lobe. (A) Patient vs. controls mean SWA power during wakefulness; the red star shows the SWA maximum. (B) SWA power in patient vs. controls for wakefulness subtracted by REM sleep; the red star shows the SWA maximum. (C) Patient seizure SWA power vs. controls wakefulness SWA power. (D) Patient seizure vs. controls wakefulness SWA power subtracted by REM sleep SWA power; the red star shows the SWA maximum. Each T map pictured above is thresholded for a display of uncorrected p < 0.05. The jet color scale indicates t-values. Abbreviations: RL = right lateral; LL = left lateral.\n\nDiscussion\nHere we present HDEEG analysis of SWA across different vigilance states in a patient with reflex epilepsy compared to 10 controls. Our results serve as a proof-of-concept, suggesting that validation studies may be feasible, for the localizing value of state-dependent increases in SWA to identify components of the epileptogenic zone. At the scalp level and in source space we observed no difference in REM sleep SWA between the patient and controls. Altogether, we observed localizing value for both scalp-level and source space SWA during NREM sleep and wakefulness states, with peak accuracy achieved when comparing states to REM sleep. Interestingly, the most robust SWA localizing power in source space was observed when comparing wakefulness to REM sleep.\n\nSleep SWA\nAlthough our previous work in focal epilepsy patients suggested some localizing value of scalp-level NREM sleep SWA increases (Boly et al., 2017), accurate localization power was present in only 11/15 patients. Here we performed a proof-of-concept analysis for the localization value of state-dependent SWA. At the scalp level, we observed a right frontal maximum during both REM sleep and NREM sleep, which did not correctly lateralize the IOZ. Correct scalp lateralization was however noted when we compared NREM sleep to REM sleep. Similarly, source localization of NREM sleep SWA taken in isolation did not correctly localize the IOZ. Once referenced to REM sleep, localization power improved.\n\nThese NREM sleep findings are in line with our previous observation of bilateral SWA changes during NREM sleep (Boly et al., 2017), which may be indicative of more widespread plastic changes occurring due to the ictal involvement of a bilateral epileptic network (Blumenfeld, 2014). What’s more, our results may be hindered by a lack of subject-specific head models utilized for source reconstruction (Klamer et al., 2015). These findings also match previous observations from our group (Boly et al., 2017), and others (Shouse et al., 2000; Ng and Pavlova, 2013; Frauscher et al., 2016; Lambert et al., 2018), that REM sleep inhibits not only overall SWA but more specifically SWA related to epileptic activity. REM sleep is a state characterized by EEG desynchronization, as demonstrated by decreased power in frequencies <30 Hz (Frauscher et al., 2016), probably mediated by cholinergic neurotransmission arising from subcortical inputs. This generalized tendency toward low voltage fast activity may favor the break-up of synchrony within epileptic networks (Shouse et al., 2000; Ng and Pavlova, 2013; Lambert et al., 2018; Kang et al., 2020). Overall, our results emphasize the importance of assessing local SWA across multiple vigilance states (i.e., comparing NREM sleep to REM sleep), suggesting that the opportunistic utilization of REM sleep SWA in the setting of epilepsy may assist to accentuate epilepsy-induced SWA maximums.\n\nWakefulness SWA\nIn contrast to NREM sleep, scalp level SWA during the patient’s waking state was lateralizing for the IOZ even when considered in isolation. When subtracting individual REM sleep SWA from wakefulness SWA before re-running an identical statistical analysis, we again observed enhanced localization, with more focal results pointing to the left inferior frontal gyrus—which correlates with the patient’s ictal SPECT imaging from an outside institution 15 years prior. These findings reiterate the added value of considering state-dependent SWA for epileptic focus identification. The powerful localization value of wakefulness SWA, both in isolation and when referenced to REM sleep, is especially interesting in the context of recent experiments documenting the presence of local increases in SWA during wakefulness after normal learning (Huber et al., 2004). For example, our group has shown that increased SWA during wakefulness localizes to task-dependent cortical regions during extended wakefulness (Hung et al., 2013); e.g., language task learning increased SWA in the left frontal cortex, and motor learning in the contralateral motor cortex (Siclari and Tononi, 2017). Because animal models suggest that epileptic activity leads to synaptic potentiation (Tononi and Cirelli, 2014), and increased synaptic strength saturation leads to the emergence of local sleep SWA during wakefulness (Vyazovskiy et al., 2011), plastic changes induced by seizures and interictal spikes may also induce local sleep during wakefulness within the epileptic focus. This phenomenon could be protective at some level, by decreasing the local propensity towards ictal processes. However, it may also prevent the epileptic cortex from participating in normal task functions even during wakefulness. Of note, somatostatin-positive interneurons (thought to correspond to Martinotti-cells) generate local SWA in mice (Funk et al., 2017) and are themselves potentiated by excitatory tone (Kroon et al., 2019). We, therefore, speculate that these interneurons may be involved in the generation of SWA during wakefulness in the hyperexcitable epileptic cortex, even if subcortical neuromodulatory tone favors the presence of wakefulness rhythms in the rest of the cortex. Such a hypothesis would however require testing in animal models.\n\nIctal SWA\nMaximum scalp level increases in SWA during the seizure, when compared to control wake images, were correctly lateralized (in the left temporal lobe). Comparing this state to intrasubject REM sleep, before completing an identical statistical analysis, provided enhanced localization (maximum in SWA observed in the left frontal lobe). These results again underscore the value of analyzing SWA changes across vigilance states. However, after source reconstruction, the maximum in SWA during the patient’s seizure did not co-localize with the ictal symptomatogenic zone. This was true when ictal SWA was taken in isolation and when first subtracted by REM sleep SWA. This finding may be because our EEG source reconstruction method did not incorporate an explicit noise model, and thus had difficulties dealing with the residual noise likely present in the ictal EEG dataset despite our artifact removal attempts. Further, we utilized default head models for the patient and all controls, instead of importing specific MRI data for each individual. This approach has been shown to decrease the precision of HDEEG localization (Klamer et al., 2015). Alternatively, our findings may again hint at larger recruitment of neuronal networks by SWA during the ictal state, extending beyond the epileptic focus itself (Blumenfeld, 2014).\n\nLimitations\nDrawbacks to collecting HDEEG data within the inpatient epilepsy monitoring unit include potential sleep disruptions. This may be reflected by the patient’s higher SOL, decreased total REM sleep time, and increased REML. However, these changes in sleep architecture were also reported in outpatient recordings in other epileptic patients and are not expected to alter the spatial topography of SWA within each sleep stage (Foldvary-Schaefer and Grigg-Damberger, 2006).\n\nAlthough independent component analysis has become state-of-the-art for the preprocessing of HDEEG studies (Strobbe et al., 2016), there remains some user-dependence on this method. Such user-dependence is most likely to affect the pre-processing of data collected during wakefulness and ictal states, which are more affected by movement artifacts. Future cohort studies in larger populations will permit sub-group analysis for epilepsies of different localization and severity, exploration of neuropsychological associations, and further assessment of the reproducibility in localization accuracy for state-dependent increases in SWA.\n\nSource space analysis in this study was limited given that we utilized template head models for the patient and all controls. HDEEG localization results have been shown to vary by up 2 cm (Klamer et al., 2015). Thus, discrepancies in the patient’s semiologic presentation may reflect varying aspects of her epileptogenic zone, wherein her semiology differs from her IOZ (as identified by our SWA localization and outside hospital SPECT analysis), or imprecise localization accuracy due to methodologic limitations. Future studies may aim to incorporate specific modeling parameters to enhance accuracy and thereby clarify such concerns.\n\nGiven that the patient has been lost to follow up, and that much of her medical care was obtained from outside of our institution, we lack comprehensive radiological imaging to include in this study. A larger-scale analysis probing the utility of SWA localization power in epilepsy patients might utilize advanced imaging such as FDG-PET, ictal SPECT, and comparative MRI analysis—all of which may improve spatial resolution and better characterize components of the epileptogenic zone. Finally, intracranial recording studies may further assess the spatial resolution of the ictal seizure localization provided by state-dependent SWA changes and correlate them with surgical outcomes.\n\nClinical Promise\nState-dependent SWA analysis may constitute a new and promising clinical tool to diagnose and localize focal epilepsy. HDEEG studies across vigilance states may provide meaningful methods to map focal epileptic networks while reducing the need to capture seizures. With further validation, these methods may assist with presurgical planning in epilepsy patients.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by The Institutional Review Board at the University of Wisconsin-Madison, Madison, WI, USA. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nEM, GT, and MB designed the study. EM and MB conducted EEG signal preprocessing and statistical analysis. EM and MB drafted the manuscript for intellectual content, plus edited and formatted the manuscript for submission. MB, RV, BJ, GF, EJ, TB, MA, and AM contributed to data acquisition. Each author critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\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\nFunding. This work was supported by NINDS 1R03NS096379 to MB, Swiss National Foundation grants 168437 and 177873 to EJ, funding from the Dutch Research Council to RV, and Tiny Blue Dot Foundation to MB and GT.\n\n1www.fil.ion.ucl.ac.uk/spm\n\n2https://www.nitrc.org/projects/bst/\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnsys.2020.549309/full#supplementary-material.\n\nClick here for additional data file.\n==== Refs\nReferences\nBlumenfeld H. (2014 ). What is a seizure network? Long-range network consequences of focal seizures\n. Adv. Exp. Med. Biol. \n813 , 63 –70\n. 10.1007/978-94-017-8914-1_5 25012367 \nBoly M. Jones B. Findlay G. Plumley E. Mensen A. Hermann B. . (2017 ). Altered sleep homeostasis correlates with cognitive impairment in patients with focal epilepsy\n. Brain \n140 , 1026 –1040\n. 10.1093/brain/awx017 28334879 \nDebanne D. Thompson S. M. Gähwiler B. H. (2006 ). 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"title": "Local Sleep Slow-Wave Activity Colocalizes With the Ictal Symptomatogenic Zone in a Patient With Reflex Epilepsy: A High-Density EEG Study.",
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"abstract": "BACKGROUND\nRecent studies have suggested that catheter-directed thrombolysis (CDT) reduces development of post-thrombotic syndrome (PTS). Ultrasound-assisted CDT (USCDT) might enhance the efficiency of thrombolysis. We aimed to compare USCDT with CDT on efficacy, safety, development of PTS, and quality of life after long-term follow-up.\n\n\nMETHODS\nWe describe a retrospective case series of 94 consecutive patients admitted with iliofemoral or more proximal deep vein thrombosis (DVT) to the University Hospital from 2002 to 2011, treated either with CDT or USCDT. Scheduled follow-up visits took place between April 2013 and January 2014. Venography measured the degree of residual luminal obstruction of the affected veins. Each patient completed the Short Form 36-item health survey assessment and the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms questionnaires. PTS was assessed using the Villalta scale.\n\n\nRESULTS\nRisk factors of DVT were equally distributed between groups. In the USCDT group, we observed a significant decline in the duration of thrombolytic treatment (<48 h: 27 vs. 10 %), shortened hospital stay (median 6.0 days (IQR 5.0-9.0) vs. 8.0 (IQR 5.8-12.0)), and less implantation of (intravenous) stents (30 vs. 55 %). There was no difference in patency (76 vs. 79 % fully patent), prevalence of PTS (52 vs. 55 %), or quality of life between groups after long-term follow-up (median 65 months, range: 15-141).\n\n\nCONCLUSIONS\nIn this observational study, USCDT was associated with shortened treatment duration, shorter hospital stay, and less intravenous stenting, compared to CDT alone without affecting the long-term prevalence of PTS or quality of life.",
"affiliations": "K. G. Jebsen - Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, 9037, Tromsø, Norway. [email protected].;K. G. Jebsen - Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, 9037, Tromsø, Norway.;K. G. Jebsen - Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, 9037, Tromsø, Norway.;K. G. Jebsen - Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, 9037, Tromsø, Norway.;Research Group Epidemiology of Chronic Diseases, Department of Community Medicine, UiT - The Arctic University of Norway, 9037, Tromsø, Norway.;Department of Radiology, University Hospital of North Norway, Tromsø, Norway.;Department of Radiology, University Hospital of North Norway, Tromsø, Norway.;Department of Radiology, University Hospital of North Norway, Tromsø, Norway.;K. G. Jebsen - Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, UiT - The Arctic University of Norway, 9037, Tromsø, Norway.",
"authors": "Tichelaar|Vladimir Y I G|VY|;Brodin|Ellen E|EE|;Vik|Anders|A|;Isaksen|Trond|T|;Skjeldestad|Finn Egil|FE|;Kumar|Satish|S|;Trasti|Nora C|NC|;Singh|Kulbir|K|;Hansen|John-Bjarne|JB|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": "10.1007/s00270-016-1367-5",
"fulltext": "\n==== Front\nCardiovasc Intervent RadiolCardiovasc Intervent RadiolCardiovascular and Interventional Radiology0174-15511432-086XSpringer US New York 136710.1007/s00270-016-1367-5Clinical InvestigationA Retrospective Comparison of Ultrasound-Assisted Catheter-Directed Thrombolysis and Catheter-Directed Thrombolysis Alone for Treatment of Proximal Deep Vein Thrombosis Tichelaar Vladimir Y. I. G. +47 776 208 [email protected] Brodin Ellen E. Vik Anders Isaksen Trond Skjeldestad Finn Egil Kumar Satish Trasti Nora C. Singh Kulbir Hansen John-Bjarne K. G. Jebsen – Thrombosis Research and Expertise Centre (TREC), Department of Clinical Medicine, UiT – The Arctic University of Norway, 9037 Tromsø, Norway Division of Hemostasis and Thrombosis, Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway Research Group Epidemiology of Chronic Diseases, Department of Community Medicine, UiT – The Arctic University of Norway, 9037 Tromsø, Norway Department of Radiology, University Hospital of North Norway, Tromsø, Norway 1 6 2016 1 6 2016 2016 39 1115 1121 7 1 2016 11 5 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.Background\nRecent studies have suggested that catheter-directed thrombolysis (CDT) reduces development of post-thrombotic syndrome (PTS). Ultrasound-assisted CDT (USCDT) might enhance the efficiency of thrombolysis. We aimed to compare USCDT with CDT on efficacy, safety, development of PTS, and quality of life after long-term follow-up.\n\nMethods\nWe describe a retrospective case series of 94 consecutive patients admitted with iliofemoral or more proximal deep vein thrombosis (DVT) to the University Hospital from 2002 to 2011, treated either with CDT or USCDT. Scheduled follow-up visits took place between April 2013 and January 2014. Venography measured the degree of residual luminal obstruction of the affected veins. Each patient completed the Short Form 36-item health survey assessment and the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms questionnaires. PTS was assessed using the Villalta scale.\n\nResults\nRisk factors of DVT were equally distributed between groups. In the USCDT group, we observed a significant decline in the duration of thrombolytic treatment (<48 h: 27 vs. 10 %), shortened hospital stay (median 6.0 days (IQR 5.0–9.0) vs. 8.0 (IQR 5.8–12.0)), and less implantation of (intravenous) stents (30 vs. 55 %). There was no difference in patency (76 vs. 79 % fully patent), prevalence of PTS (52 vs. 55 %), or quality of life between groups after long-term follow-up (median 65 months, range: 15–141).\n\nConclusions\nIn this observational study, USCDT was associated with shortened treatment duration, shorter hospital stay, and less intravenous stenting, compared to CDT alone without affecting the long-term prevalence of PTS or quality of life.\n\nKeywords\nCatheterThrombolysisUltrasoundVenous thrombosisQuality of lifePost-thrombotic syndromeissue-copyright-statement© Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2016\n==== Body\nIntroduction\nThe post-thrombotic syndrome (PTS) causes considerable morbidity in patients after deep vein thrombosis (DVT) of the lower extremity. After 2 years, 30–50 % of the patients will develop PTS, of which 10 % will have moderate and 3–5 % severe PTS [1, 2]. Risk factors for (severe) PTS are thrombus proximity and recurrent ipsilateral venous thrombosis [1, 3] where prevention of the latter is the only effective way to prevent the increased severity and frequency of PTS [4]. The wearing of compression stockings, still recommended by leading guidelines [5], has recently been questioned [6].\n\nRecent studies have shown that catheter-directed thrombolysis (CDT) reduces the development of PTS. The CAVENT study reported 14.4 % [95 % confidence interval (CI) 0.2–27.9] and 28 % (95 % CI 14–42) absolute risk reduction of PTS after 2 and 5 years of follow-up, respectively, when CDT was compared with standard treatment (anticoagulation and compression stockings) [7, 8]. A recent Cochrane review on CDT reported a relative reduction of 25 % of PTS [9]. As PTS is more common in patients with a proximal DVT [1, 10], guidelines recommend the use of CDT in selected patients with iliofemoral venous thrombosis [5, 11]. However, a recent cross-sectional study of patients with proximal lower-extremity DVT showed that CDT was resource-demanding and increased therapy-related adverse events [12]. Unfortunately, this study did not comprise outcomes such as recurrent venous thrombosis, late mortality, and incidence of PTS in the analyses [12].\n\nUltrasound-assisted CDT (USCDT), combining CDT with a catheter system that uses high frequency ultrasound, might enhance the efficiency of the thrombolytic process even more. In a case series of 53 patients, treatment with USCDT led to reduced total infusion time of the thrombolytic agent, a greater incidence of complete clot lysis, and a reduction in bleeding rates, compared with historical data [13]. In vitro data indicate that ultrasound facilitates thrombolysis by making more plasminogen receptor sites available for the thrombolytic agent [14]. A single center experience suggests that USCDT may be an equally safe and efficacious treatment for DVT as CDT alone [15]. Only one study has previously conducted a direct comparison of USCDT and CDT for the treatment of acute iliofemoral DVT of lower extremity [16]. Forty-eight patients were randomized between CDT and USCDT with a fixed-dose alteplase (20 mg/15 h). The primary outcome of residual thrombus load after 15 h of treatment did not differ between treatment modalities nor did the bleeding rate and quality of life, 3 months after therapy [16].\n\nThe incidence and severity of PTS among DVT patients tend to increase during the first 2 years after the DVT [1], and the CAVENT study showed that follow-up had to exceed 6 months in order to detect a benefit of CDT on the incidence of PTS [7]. Therefore, it is likely assumed that it will take more than 3 months to be able to observe differential impact of USCDT versus CDT on development of PTS. We aimed to compare USCDT with CDT in a case series of patients with DVT on efficacy, safety, degree of PTS, and quality of life after long-term (>12 months) follow-up.\n\nMethods\nOur study is a retrospective case series of consecutive patients admitted to the University Hospital from January 2002 to January 2012 with iliofemoral or vena cava inferior DVT, who were treated with CDT or USCDT. From 2009 on, the patients were preferentially treated with USCDT (85 % of all cases treated after 2009). Due to random lack of US catheters, a few patients were treated with CDT only. Our design thus closely resembles a historical cohort study. Inclusion criteria were an objectively diagnosed DVT using ultrasound examination (64 %) or venography (36 %), extending into vena iliaca externa or vena cava inferior. Exclusion criteria for any catheter-directed thrombolysis were prior cerebral bleeding, a thrombotic or embolic cerebral infarction in the last 3 months, head trauma or major surgery in the last 14 days, bleeding tendency, platelet counts below 100 × 109/L, pregnancy, hypertension (systolic blood pressure above 180 mmHg or diastolic blood pressure above 110 mmHg), renal failure, liver failure, and malignant disease with an expected survival of less than 1 year [17]. All patients alive as on April 1, 2013 were eligible for a follow-up visit at the hospital between April 2013 and January 2014, to clinically evaluate the effects of treatment. As it is the obligation of physicians to monitor the efficacy and safety of introduction of new treatment modalities, a review by the Institutional Review Board was not performed. Informed consent was obtained from all the participants included in this study.\n\nAll patients were treated with low molecular weight heparin (LMWH) directly after diagnosis of DVT and they underwent an initial venography, followed by thrombolytic therapy. Interventions were patency-driven, and venography was performed at intervals of 24 h. The treatment protocols of CDT and USCDT, including inclusion/exclusion criteria, type and dosage scheme of thrombolytic agent, and evaluations during treatment remained unchanged over the time period from 2002 to 2013, except for the catheters used. The responsible senior consultants at the radiology and hematology departments were experienced physicians and remained unchanged over the time period.\n\nIn the USCDT group, the EKOS EkoSonic® Endovascular System with MACH 4e (EKOS Corporation, 11911 South Bothell, WA 98011, USA) was used [18]. Frequency of the ultrasound was 2.05–2.35 MHz with a power of 50.0 W pulse power maximum (30.0 W average) resulting in 0.5 W per ultrasound transducer unit. In the CDT group, a catheter with multiple side holes (UNI-FUSE, AngioDynamics or Cragg-McNamara® Valved Infusion Catheter) was used.\n\nVenous access was obtained through popliteal vein in both groups. Balloon dilatation and deflation were performed when deemed necessary while evaluating treatment result. Self-expandable nitinol stents ranging in diameter from 10 to 16 mm were used when deemed necessary by the treating radiologist and hematologist (organized thrombus, clear signs of May–Thurner syndrome or when other external compression was suspected (e-Luminex, Bard; Protégé, EV3 or Sinus-XL stent, Optimed)). These criteria did not change during the study period.\n\nA bolus of 5000 IE unfractionated heparin (UFH) and 5 mg rt-PA (Actilyse; Boehringer Ingelheim, GmbH) was injected through the catheter at the start of both catheter-directed thrombolysis procedures, followed by continuous infusion of rt-PA, 0.01 mg/kg/h, and UFH, 300 IU/kg/24 h. The activated partial thromboplastin time (normal range 25–36 s) was measured twice daily and 6 h after adjustment of the UFH dose to keep the APTT between 50 and 70 s during treatment. Plasma fibrinogen was measured twice daily, and if fibrinogen was reduced to or below 1.0 g/L, the infusion of rt-PA was stopped for 2 h and then restarted at 50 % of the original dose. Hemoglobin, platelet count, PT-INR, and d-dimer were measured once daily during treatment. Blood pressure and heart rate were monitored, and inspection of the leg was performed regularly.\n\nAfter both thrombolytic procedures, anticoagulant therapy proceeded with standard DVT treatment. According to our treatment guidelines, oral anticoagulant treatment with warfarin was recommended for 1 year or indefinitely in patients with stent implantation, with a treatment intensity of 2.0–3.0 PT-INR.\n\nClot burden was categorized into three groups (length of <10, 10–30, and >30 cm). The degree of thrombolysis after the procedure was visualized by venography and categorized into no effect or progression, less than 50 % lysis (grade I), 50–90 % lysis (grade II), and more than 90 % lysis (grade III). Percentage clot lysis was estimated by the difference in the length of thrombus before versus after treatment. Major bleeding was defined as any clinically overt bleeding that resulted in the cessation of therapy, further hospitalization, death or that required transfusion or surgical intervention. All other bleedings were classified as minor. Lowering of the standard dosing regimen of rt-PA according to the plasma fibrinogen level (see paragraph above) was defined as the outcome ‘less thrombolytic dose.’\n\nAt follow-up, a new venography was performed to measure the degree of residual luminal obstruction. Patency were defined as open when there was no vessel stenosis and no collateral venous drainage, as stenosis when an open venous segment had significant stenosis (50–90 %) or in case of severe vessel stenosis (>90 %) with collateral venous drainage, and as occluded when total occlusion of a venous segment with collateral venous drainage was observed.\n\nThe diagnosis of post-thrombotic syndrome (PTS) was made using the Villalta Scale [19]. PTS is categorized by severity: mild (≥ 5 < 10 points), moderate (≥ 10 < 15 points), and severe (≥ 15 points). The presence of venous ulcers directly accrues 15 points on the Villalta Scale [20]. To assess quality of life, we included the Short Form Health Survey-36 (SF-36) [21] and the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms (VEINES-QOL/Sym) questionnaires [22].\n\nData were analyzed using IBM SPSS Statistics, version 22 (Armonk, NY, United States of America). Differences in categorical data between treatment modalities were analyzed using Pearson’s Chi-squared test, and differences in continuous data were analyzed with Student’s t-test or Mann–Whitney U-test when data were not normally distributed. The maximum percentage of missing data for a given variable was 11.8 % within the VEINES or SF-36 questionnaire, and appeared to have a random pattern. Values are expressed as means ± one standard deviation if data were normally distributed and as medians with 25 and 75th percentiles in parenthesis (IQR) if data were not normally distributed.\n\nResults\nWe included 94 patients with an iliofemoral or inferior vena cava DVT, accounting for 95 events since one patient experienced a second DVT. Sixty-two patients were treated with CDT (6 of these after 2009) and 33 with USCDT. Characteristics of patients, risk factors for DVT, location of thrombi, and duration of symptoms, stratified by treatment modality are shown in Table 1. There were no significant differences between groups.Table 1 Baseline characteristics of 94 patients with a proximal DVT of the leg, treated with (ultrasound-assisted) catheter-directed thrombolysis\n\n\tCDT (n = 62)\tUSCDT (n = 33)a\n\t\n% (n) or median (IQR)\t% (n) or median (IQR)\t\nAge (years)\t49.5 (34.0–62.3)\t34.0 (21.5–57.0)\t\nMen\t36 (22)\t21 (7)\t\nProvoking risk factors\t\t\t\n Surgery\t10 (6)\t12 (4)\t\n Trauma\t7 (4)\t9 (3)\t\n Immobilization\t3 (2)\t0 (0)\t\n Cancer\t11 (7)\t9 (3)\t\n Pregnancy\t0 (0)\t0 (0)\t\n Puerperium\t8 (3)\t12 (3)\t\n Estrogens\t33 (13)\t23 (6)\t\nOther risk factors\t\t\t\n Obesity\t20 (12)\t36 (12)\t\n Thrombophilia\t5 (3)\t9 (3)\t\n Previous VTE\t16 (10)\t21 (7)\t\n Acute non-surgical illness\t21 (13)\t12 (4)\t\nUnprovoked\t52 (32)\t55 (18)\t\nWith pulmonary embolism\t19 (12)\t21 (7)\t\nLocation of DVT\t\t\t\n Vena cava inferior\t27 (17)\t33 (11)\t\n V. iliaca ext./communis\t72 (45)\t67 (22)\t\nDuration of symptoms (days)\t4.0 (1.0–7.0)\t3.0 (1.0–9.0)\t\n\nCDT catheter-directed thrombolysis, USCDT ultrasound-assisted CDT, IQR interquartile range (25–75th percentile), VTE venous thromboembolic event, DVT deep vein thrombosis\n\n\naNo significant differences between groups\n\n\n\nTable 2 displays the characteristics of venous thrombus and short-term outcomes after treatment. The thrombus burden was equal in both groups before the start of treatment. The proportion of patients that achieved sufficient patency within 48 h was significantly higher after USCDT (27 vs. 10 %, P < 0.05). The median duration of total hospitalization was shorter for USCDT patients compared to those treated with CDT [6.0 days (IQR 5.0–9.0) vs. 8.0 (IQR 5.8–12.0), P < 0.05]. Finally, intravenous stenting of residual thrombosis after thrombolysis was less often deemed necessary by the treating team in the USCDT group (30 % vs. 55 %, P < 0.05). We did not observe any significant differences in the dose of thrombolytic agent used, nor in the degree of thrombolysis achieved immediately after treatment [>90 % of luminal recanalization in 88 % (CDT) vs. 76 % (USCDT)]. Exclusion of patients (n = 8) with symptoms of VTE longer than 14 days, an exclusion criterion in most guidelines [5, 11], did not change outcomes (data not shown).Table 2 Characteristics of venous thrombus and short-term outcomes after (ultrasound-assisted) catheter-directed thrombolysis in 95 cases of iliofemoral or inferior vena cava deep vein thrombosis\n\n\tCDT (n = 62)\tUSCDT (n = 33)\t\n\t% (n) or median (IQR)\t% (n) or median (IQR)\t\nLength of thrombus\t\t\t\n < 10 cm\t0 (0)\t0 (0)\t\n 10–30 cm\t25 (15)\t27 (9)\t\n > 30 cm\t75 (46)\t73 (24)\t\nDuration of intervention (hours)\t\t\t\n < 48\t10 (6)\t27 (9)*\t\n 49–72\t41 (26)\t33 (11)\t\n 72–119\t38 (23)\t25 (8)\t\n > 120\t11 (7)\t15 (5)\t\nAdditional intervention\t\t\t\n Balloon dilatation\t92 (57)\t94 (31)\t\n Stenting\t55 (34)\t30 (10)*\t\nLess thrombolytic dose\t21 (13)\t27 (9)\t\nDegree of thrombolysis\t\t\t\n No effect or progression\t2 (1)\t0 (0)\t\n Grade I (< 50 %)\t0 (0)\t0 (0)\t\n Grade II (50–90 %)\t10 (6)\t24 (8)\t\n Grade III (> 90 %)\t88 (54)\t76 (25)\t\nHospitalization time (days)\t8.0 (5.8–12.0)\t6.0 (5.0-9.0)*\t\nSafety outcomes\t\t\t\n Death by bleeding\t0 (0)\t0 (0)\t\n Minor bleeding\t21 (13)\t30 (10)\t\n Major bleeding\t3 (2)\t9 (3)\t\n Cessation of treatment\t2 (1)\t0 (0)\t\nDeath of any cause\t\t\t\n Within 1 year\t8 (5)\t0 (0)\t\n Cumulativea\n\t11 (7)\t3 (1)\t\nRecurrent VTE\t2 (1)\t3 (1)\t\nIntended duration of anticoagulant therapy\t\t\t\n 3 months\t5 (3)\t6 (2)\t\n 6 months\t2 (1)\t0 (0)\t\n 12 months\t38 (24)\t52 (17)\t\n Indefinite\t55 (34)\t42 (14)\t\n\nCDT catheter-directed thrombolysis, USCDT ultrasound-assisted CDT, IQR interquartile range (25–75th percentile), VTE venous thromboembolic event\n\n* P < 0.05\n\n\naIncluding deaths within the first year\n\n\n\nMajor non-fatal bleeding occurred in three patients in the USCDT group and in two patients in the CDT group (9 vs. 3 %). There were seven patients (11 %) in the CDT group and one patient (3 %) in the USCDT group who died from any cause during follow-up. In both treatment groups, one patient developed treatment-related recurrent thrombotic event.\n\nForty-seven of 62 CDT patients (75 %) and 21 of 33 of USCDT patients (64 %) attended the follow-up visit. Table 3 displays long-term follow-up outcomes. Median time to follow-up was 89 months in the CDT group (range 15–141) and 34 in the USCDT group (range 17–51). Twice as much patients were still on anticoagulation in the CDT group than in the USCDT group (70 vs. 33 %, P < 0.05). Incidence of recurrent events and use of compression stockings (data not shown) was similar between groups.Table 3 Long-term outcomes after (ultrasound-assisted) catheter-directed thrombolysis in 68 cases of iliofemoral or inferior vena cava deep vein thrombosis\n\n\tCDT (n = 47)\tUSCDT (n = 21)\t\n\t% (n)\t% (n)\t\nMedian follow-up, months (range)\t89 (15–141)\t34 (17–51)\t\nAnticoagulant therapy\t\t\t\n On therapy at follow-up\t70 (33)\t33 (7)*\t\n Median time, months (range)\t12 (6–75)\t12 (3–24)\t\nRecurrent VTE\t2 (1)\t0(0)\t\nPost-thrombotic syndrome\t\t\t\n None\t45 (21)\t48 (10)\t\n Mild\t32 (15)\t28 (6)\t\n Moderate\t13 (6)\t19 (4)\t\n Severe\t10 (5)\t5 (1)\t\nSF-36 (mean ± SD)\t\t\t\n Physical subscale\t40 ± 13\t45 ± 12\t\n Mental subscale\t53 ± 9\t48 ± 12\t\nVEINES-QOL/Sym (mean ± SD)\t\t\t\n QOL subscale\t50 ± 7\t51 ± 6\t\n Sym subscale\t48 ± 7\t50 ± 7\t\nPatency at venography\t\t\t\n Attendance (n)\t38\t17\t\n Open\t79 (30)\t76 (13)\t\n Stenosis\t8 (3)\t0 (0)\t\n Occluded\t13 (5)\t24 (4)\t\n\nCDT catheter-directed thrombolysis, USCDT ultrasound-assisted CDT, VTE venous thromboembolic event, SD standard deviation\n\n* P < 0.05\n\n\n\nFifty-five percent in the USCDT and 52 % in the CDT group developed PTS (Table 3). We observed non-significant lower prevalence of severe PTS in the USCDT group (5 vs. 10 %). There were no significant differences between groups regarding quality of life scores (Table 3). Vascular patency after long-term follow-up did not differ between groups [complete patency 79 (CDT) vs. 76 % (USCDT)].\n\nDiscussion\nWe found that USCDT was associated with a higher proportion of patients requiring short treatment (<48 h), shorter duration of the hospital stay, and less intravenous stenting of residual thrombosis after thrombolysis. Short-term vessel patency and bleeding complications did not differ between groups. Likewise, long-term vessel patency, prevalence of PTS, and quality of life scores were essentially similar. Thus, we were not able to confirm the previous findings of improved vessel patency [13–15, 23] or the decreased amount of thrombolytic agent used for USCDT. Our findings suggest that USCDT does not have any apparent clinical benefits over CDT alone.\n\nOur findings are in agreement with the randomized study by Engelberger et al. [16], who neither found any differences in thrombus load when comparing CDT with USCDT nor in vessel patency and incidence of PTS 3 months after treatment. These findings rejected their hypothesis [24, 25], assuming that USCDT would improve the reduction of thrombus load directly after diagnosis of an acute DVT, leading to a lower incidence of PTS in the future. Similarly, Baker et al. [15] did not find a difference between USCDT (n = 64) and CDT (n = 19) in thrombus resolution directly after the procedure. A possible explanation for the lack of differences between treatment modalities may be too low power of the ultrasound device used [16]. The EKOS MACH4 device that we used has an ultrasound frequency of 2.05–2.35 MHz and 0.5 W power per transducer. Experimental studies have suggested a thrombolysis optimum of around 2.2 MHz with a higher transmitted power (1, 2, 4, or 8 W per square centimeter) [14, 26]. Lysis of human clots has been shown to increase significantly when ultrasound was applied at 1.0 or 1.5 W [27]. The lower power may partly explain the lack of beneficial impact of USCDT treatment.\n\nOur study has some advantages. Most importantly, our study had longer follow-up of patients (minimally 15 months in both groups) than other studies (minimal 3 or 6 months). This allowed us to assess the prevalence of PTS at a time point when most patients are near reaching a stable level of their PTS [1], i.e., looking at real long-term sequels of DVT. Second, we performed a new venography in most attendees after the follow-up, allowing us to associate a subjective outcome as PTS with vessel patency.\n\nDue to the non-randomized design, confounding might have influenced our results. However, a systematic difference is unlikely as the patient and pretreatment characteristics were essentially similar between treatment modalities and between patients admitted for therapy before and after 2009. Second, medical specialists as well as treatment protocols remained the same over the years, thereby reducing the possibility of confounding. However, we cannot exclude the influence of minor unknown confounders that occurred because of time passing. Our study reflects a real life setting and is therefore less prone to selection bias compared to a randomized controlled trial, where participants tend to be younger and healthier compared to the population they are recruited from. An alternative explanation for our finding of a reduced treatment time in the USCDT group might be a learning effect: medical specialists are assumed to be more experienced over time with the techniques and logistics of an intravenous catheter-directed thrombolytic procedure in DVT patients. Shortening of the hospital stay in the USCDT group might reflect a change in general health care recommendations rather than the effect of adding ultrasound to the treatment. This might also be true for our finding that in the USCDT group less intravenous stenting was used, thus reflecting not a true effect of the treatment but more a general growth in insights in interventional radiology. Another minor drawback of our study is that the adjudicators of the Villalta Scale and quality of life were not blinded for treatment, but this generally increases the chance of a type I error and not that of type II. Finally, the prevalence of PTS (55 % in the CDT group and 52 % in the USCDT group) is somewhat higher than that reported in the literature [1]. This might be due to our long follow-up in both arms, and also by the fact that we included only patients with an iliofemoral or more proximal DVT, who are known to be more prone to develop PTS [1]. Selection of participants with PTS at the follow-up clinical examination might also contribute to the high prevalence of PTS.\n\nIn conclusion, we found that USCDT leads to a higher proportion of patients that needed short duration of thrombolysis, shorter hospital stay, and less frequent intravenous stenting. In accordance with previous studies, we showed that USCDT was not superior to CDT with regard to short- and long-term vessel patency, the long-term prevalence of PTS, and quality of life. Our findings suggest that USCDT does not have any apparent clinical benefits over CDT alone. However, due to limited available data, a large randomized trial comparing USCDT and CDT with long-term follow-up is warranted.\n\nTREC is supported by a grant of the K. G. Jebsen Foundation of Norway.\n\nCompliance with Ethical Standards\nConflicts of interest\nAll authors declare that they have no conflicts of interest.\n\nEthical Standards\n All procedures performed were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. As it is the duty of physicians by law to clinically evaluate the effects of new therapies or procedures, a review by the Institutional Review Board was not performed.\n==== Refs\nReferences\n1. Kahn SR Shrier I Julian JA Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis Ann Intern Med 2008 149 698 707 10.7326/0003-4819-149-10-200811180-00004 19017588 \n2. Galanaud JP Holcroft CA Rodger MA Comparison of the Villalta post-thrombotic syndrome score in the ipsilateral vs. contralateral leg after a first unprovoked deep vein thrombosis J Thromb Haemost 2012 10 1036 1042 10.1111/j.1538-7836.2012.04713.x 22646832 \n3. 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Braaten JV Goss RA Francis CW Ultrasound reversibly disaggregates fibrin fibers Thromb Haemost 1997 78 1063 1068 9308755 \n24. Comerota AJ Grewal N Martinez JT Postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis J Vasc Surg 2012 55 768 773 10.1016/j.jvs.2011.10.032 22277690 \n25. Grewal NK Martinez JT Andrews L Comerota AJ Quantity of clot lysed after catheter-directed thrombolysis for iliofemoral deep venous thrombosis correlates with postthrombotic morbidity J Vasc Surg 2010 51 1209 1214 10.1016/j.jvs.2009.12.021 20347543 \n26. Blinc A Francis CW Trudnowski JL Carstensen EL Characterization of ultrasound-potentiated fibrinolysis in vitro Blood 1993 81 2636 2643 8490172 \n27. Sehgal CM Leveen RF Shlansky-Goldberg RD Ultrasound-assisted thrombolysis Invest Radiol 1993 28 939 943 10.1097/00004424-199310000-00016 8262749\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0174-1551",
"issue": "39(8)",
"journal": "Cardiovascular and interventional radiology",
"keywords": "Catheter; Post-thrombotic syndrome; Quality of life; Thrombolysis; Ultrasound; Venous thrombosis",
"medline_ta": "Cardiovasc Intervent Radiol",
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"abstract": "Epidermal growth factor receptor (EGFR) mutations and amplifications are frequently reported in glioblastoma multiforme (GBM) patients. In this case report, we utilize next-generation sequencing (NGS) and EGFR molecular imaging to investigate intratumoral heterogeneity in a male patient presenting with GBM. Further, we describe the patient's clinical course as well as outcomes of targeted EGFR therapy with erlotinib, an EGFR tyrosine kinase inhibitor (TKI). NGS demonstrated the presence of an EGFR mutation and amplification in our patient. Molecular imaging revealed a heterogeneous expression pattern of EGFR in the frontal and temporal lobes. This patient briefly responded to erlotinib therapy. However, the patient relapsed and died from progressive neurological deterioration. Partial response and acquired secondary resistance may be attributed to intratumoral heterogeneity. Combination of NGS and EGFR molecular imaging may be helpful in understanding intratumoral molecular heterogeneity and may aid in developing individualized GBM treatments, thereby improving outcomes.",
"affiliations": "Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.;Department of Neurosurgery, The Jingjiang People's Hospital, Taizhou, China.;Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.",
"authors": "Zhou|Ke|K|;Yao|Hui|H|;Zhang|Xuewen|X|;Liu|Jiangang|J|;Qi|Zhenyu|Z|;Xie|Xueshun|X|;Xu|Xiaoting|X|;Zhou|Youxin|Y|;Yu|Zhengquan|Z|;Wang|Zhong|Z|;Che|Yanjun|Y|;Huang|Yulun|Y|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors",
"country": "United States",
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"doi": "10.18632/oncotarget.18148",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 286112891814810.18632/oncotarget.18148Case ReportNext generation sequencing and molecular imaging identify EGFR mutation and amplification in a glioblastoma multiforme patient treated with an EGFR inhibitor: a case report Zhou Ke 13Yao Hui 1Zhang Xuewen 1Liu Jiangang 1Qi Zhenyu 1Xie Xueshun 1Xu Xiaoting 2Zhou Youxin 1Yu Zhengquan 1Wang Zhong 1Che Yanjun 3Huang Yulun 11 Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China2 Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou, China3 Department of Neurosurgery, The Jingjiang People's Hospital, Taizhou, ChinaCorrespondence to:Yulun Huang,[email protected] Che,[email protected] 7 2017 24 5 2017 8 30 50305 50313 16 1 2017 14 4 2017 Copyright: © 2017 Zhou et al.2017This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.Epidermal growth factor receptor (EGFR) mutations and amplifications are frequently reported in glioblastoma multiforme (GBM) patients. In this case report, we utilize next-generation sequencing (NGS) and EGFR molecular imaging to investigate intratumoral heterogeneity in a male patient presenting with GBM. Further, we describe the patient's clinical course as well as outcomes of targeted EGFR therapy with erlotinib, an EGFR tyrosine kinase inhibitor (TKI). NGS demonstrated the presence of an EGFR mutation and amplification in our patient. Molecular imaging revealed a heterogeneous expression pattern of EGFR in the frontal and temporal lobes. This patient briefly responded to erlotinib therapy. However, the patient relapsed and died from progressive neurological deterioration. Partial response and acquired secondary resistance may be attributed to intratumoral heterogeneity. Combination of NGS and EGFR molecular imaging may be helpful in understanding intratumoral molecular heterogeneity and may aid in developing individualized GBM treatments, thereby improving outcomes.\n\nEGFR mutationglioblastomamolecular imageerlotinibnext-generation sequencing\n==== Body\nINTRODUCTION\nGlioblastoma multiforme (GBM) is a highly malignant tumor of the central nervous system. The overall median survival time of GBM is approximately 12-15 months [1, 2]. Currently, GBM is primarily treated with surgical resection, followed by a combination of radiotherapy and chemotherapy.\n\nEpidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase protein that has been associated with several human malignancies. EGFR associated mutations, amplification or overexpression are observed in approximately 50 % of glioblastoma patients [3]. EGFR amplification has been proposed as a marker of poor prognosis [4], however, EGFR-targeted therapy can be a promising treatment for GBM patients.\n\nErlotinib (Tarceva) is an oral EGFR tyrosine kinase inhibitor (TKI) that has been extensively clinically validated. However, patients’ response rate ranges from 10 to 20 % [5–7]. Phase II clinical trials revealed that the single-agent activity of erlotinib was marginally beneficial for GBM patients following radiotherapy [5]. Moreover, erlotinib demonstrated insufficient single-agent activity over standard therapies in GBM patients [8]. Therefore, identifying markers that can predict the outcome of erlotinib therapy may be beneficial for GBM patients and might uncover factors that improve treatment sensitivity. PTEN is a tumor suppressor gene that is commonly mutated in glioblastoma [9]. The expression of amplified and aberrant EGFR combined with the expression of wildtype PTEN were important predictors for the sensitivity towards EGFR kinase inhibition in glioblastoma xenografts [10]. In GBM patients, co-expression of EGFRvIII and PTEN was significantly associated with a favorable clinical response [11]. Moreover, GBM patients with higher levels of EGFR expression and lower levels of phosphorylated PKB/Akt demonstrated improved sensitivity to erlotinib treatment [12]. Nevertheless, to date, the molecular characteristics of GBM subpopulations of patients that demonstrate higher responses towards TKIs have not been fully elucidated [13]. Here we describe a GBM patient who had a short-term response to TKI. We used next generation sequencing (NGS) and molecular imaging to investigate the presence of EGFR mutations.\n\nCASE PRESENTATION\nA 31-year-old male was admitted to the First Affiliated Hospital of Soochow University, China complaining from headache, vomiting, and mild left hemiparesis. Magnetic resonance imaging (MRI) revealed a large abnormal mass in the left temporal parietal area with marked edema and a shift of the midline structures to the left side (Figure 1A and 1B). The patient was diagnosed with glioblastoma and underwent gross total resection in February 2015. The tumor tissue was preserved for immunohistochemical study which revealed immunopositive reactions against the GBM biomarkers GFAP, CD56, vimentin, nestin and Olig-2 (Figure 2A, 2B and 2C). Further, the ki67 labeling index was 70 % (Figure 2D). The gross total resection of the GBM was confirmed by a follow up MRI performed at one month post-operatively (Figure 1C and 1D). The patient received treatment according to Stuup et al [14] regimen of standard radiation and concomitant temozolomide chemotherapy. After radiation, MRI verified that the patient had not relapsed (Figure 1E and 1F). His therapeutic regimen was composed of six adjuvant temozolomide cycles (first cycle was 150 mg/m2/day, the remainder of the cycles were 200 mg/m2/day) for five days every 28 days. By September 2015, our patient successfully finished five cycles of adjuvant temozolomide, however, routine follow up MRI revealed the relapse of the GBM prior to commencement of the sixth temozolomide cycle (Figure 1G and 1H).\n\nFigure 1 MRI findings in a male patient presented with glioblastoma multiforme\nA. and B. MRI scans at the disease onset demonstrating a large mass in the left temporal parietal area with marked surrounding edema and a shift of the midline structures to the left side. C. and D. MRI scans captured at one month following surgical resection; MRI demonstrating gross total resection. E. and F. MRI scans at 5 months following surgical resection, standard radiation and concomitant chemotherapy demonstrated the absence of tumor relapse. G. and H. MRI scans at 7 months following surgical resection: MRI demonstrated tumor relapse.\n\nFigure 2 GBM biomarkers is immunopositive in patient specimen\nRepresentative IHC images are shown for vimentin A., nestin B., Olig-2 C. and the ki67 D. (which labeling index was 70 %)\n\nSubsequently, we performed NGS by using tissues obtained at diagnosis in order to investigate the molecular characteristics of the temozolomide resistant GBM and to identity new therapeutic strategies. Total DNA was extracted from tumor paraffin sections using the GeneReadTM DNA FFPE Kit (Qiagen, Germany), according to the manufacturer's protocol. Genomic DNA was fragmented into fragments ranging from 300-350 bp using a focused-ultrasonoscope (Covaris M220, USA). Agilent SureSelect XT reagents were used to prepare sequencing libraries according to the manufacturer's protocol. Hybrid capture was conducted using Agilent SureSelectXT Human All Exon V6. After PCR amplification, the library was created using Bioanalyzer 2100 (Agilent, USA) and AriaMx Real-Time PCR system (Agilent, USA). The library was sequenced on Illumina HiSeq4000 Analyzers (Illumina, USA) for 151 cycles to generate 150 bp paired-end reads. Image analysis and base calling were performed using the Illumina Pipeline. Sequencing depth was 500-8000X. NGS revealed the following results: EFGR amplification 14 times, EGFR p.A289V mutation, pP772 delinsPP mutation and FLNA point mutation (Table 1). Further, data analysis identified EGFR as a driver gene.\n\nTable 1 Mutation analysis of glioblastoma multiforme patient tumor\nGene\tVariation type\tNucleotide variation\tAmino acid variations\tSequencing depth\tMutation frequency\t\nEGFR\tpoint mutation\tc.C866T\tp.A289V\t7941\t95%\t\nEGFR\tinsertion mutation\tc.2318_2319insACC\tp.P773delinsPP\t7932\t9.50%\t\nFLNA\tpoint mutation\tc.G3718A\tp.V1240M\t250\t20.80%\t\nEGFR gene amplification 14 times\n\nNext, we evaluated EGFR expression in the patient's brain by molecular imaging at eight months post-operatively. EGFR antibody-18-FDG was used as a tracer agent. We injected the EGFR antibody-18-FDG and performed a PET/CT scan at 24, 48, 72 hours post-injection. We observed significant tracer uptake by the tumor at 24, 48, and 72 hours. The standardized uptake value (SUVmax) of tumor/ non-tumor was 6.4, 10, and 8.2 for the 24, 48 and 72 hours, respectively (Figure 3 and data not shown). Furthermore, the temporal lobe of the brain showed a strong positive signal while the frontal lobe showed a weak positive signal.\n\nFigure 3 MRI and EGFR-18F-FDG and PET/CT scans in a male patient presented with glioblastoma multiforme at eight months following surgical resection\nA. and B. MRI scans demonstrating the tumor relapse at eight months following surgical resection. The white arrow shows the tumor hollowing. C. and D. EGFR-18F-FDG, PET/CT scans demonstrate heterogeneous tumor characteristics at 48 hours post-tracer injection, yellow arrows demonstrate area with lower staining intensity in the frontal lobe and the red arrow demonstrates a higher staining intensity in the temporal lobe. E. and F. CT scan indicating tumor hollowing and significant edema.\n\nGiven the above-mentioned results, we decided to administer TRI therapy with erlotinib 150 mg/day starting from November 2015. The patient showed improvement over four days; he showed no dysarthria and no gait abnormalities. MRI scan revealed tumor hollowing and improvement in edema at 14 days post-erlotinib treatment (Figure 4A and 4B). Follow up MRI scans were carried out monthly. In the first three months, GBM tumor was improved with less observed edema and reduced compression of the lateral ventricles (Figure 4C and 4D). However, at the fourth month, our patient should progressive neurological deterioration and the MRI scan revealed the recurrence of GBM. In the frontal lobe, the tumor progressed rapidly, extended to corpus callosum and to the right lobe (Figure 4E and 4F). The patient died after three months from the secondary progression in May 2016. Overall survival time was 15 months for the patient. Progression of the patient's illness and the therapeutic regimen are summarized in Table 2\n\nFigure 4 MRI findings in a male patient presenting with glioblastoma multiforme after erlotinib 150 mg therapy A. and B. MRI scans after 14 days of daily erlotinib 150 mg therapy\nThe scans reveal tumor hollowing, lower grade edema and reduced compression of the lateral ventricles. C. and D. Three months after erlotinib 150 mg therapy, MRI scans shows that the tumor stabilized. Yellow arrow shows a stable frontal lobe while the red arrow show partial response in the temporal lobe. E. and F. Five months after erlotinib 150 mg therapy. MRI scans demonstrate the tumor relapsed for the second time with distant metastasis and the patient died two months later. The yellow arrow shows obvious metastasis in the frontal lobe and red arrow shows a stable temporal lobe.\n\nTable 2 Progression of the patient's illness and the therapeutic regimen\nTime\tPatient history and treatment regimen\t\nFeb, 2015\tHeadache, vomiting, and mild left hemiparesis. The patient was diagnosed with glioblastoma and underwent gross total resection.\t\nMarch/April, 2015\tStandard radiation and concomitant temozolomide chemotherapy.\t\nMay, 2015-Sept, 2015\tAdjuvant temozolomide 5 cycles (150mg/day in first cycle, 200mg/day in other cycle)\t\nSept, 2015\tThe relapse of the GBM\t\nOct, 2015\tNext generation sequencing demonstrates EGFR mutation\t\nOct, 2015\tPerform a PET/CT by EGFR antibody-18-FDG shows non-uniform EGFR positive reaction\t\nNov, 2015\tOral administration of erlotinib 150 mg/day\t\nNov, 2015-Feb, 2016\tSD (less edema and reduced compression of the lateral ventricles)\t\nMarch, 2016\tRecurrence of GBM\t\nMay,2016\tPatient death\t\nGBM: Glioblastoma multiforme SD: Stable Disease\n\nThe patient provided informed written consent for the publication of this case report and all accompanying images.\n\nDISCUSSION\nGMB is often associated with the mutation and amplification of the EGFR. Further, EGFR p.A289V mutation is most common mutation associated with GBM [15]. However, the presence of multiple or heterogeneous types of mutations is a hallmark of GBM. Using deep sequencing, Kumar et al. previously identified spatial heterogeneity in Tp53, EGFR, and PDGFRA genes in glial tumors [16]. Furthermore, Francis et al., developed a novel approach to identify distinct tumor subpopulations from the bulk tumor using single-cell whole-genome sequencing allowing them to infer the subclonal architecture. Detailed mutational analysis of tumors will aide in identifying mechanisms underpinning drug resistance which may ultimately improve the effectiveness of personalized cancer treatment [17]. The overexpression of EGFR is a predictive biomarker for response to different therapeutic regimens. Indeed, molecular imaging is a non-invasive technique that enables the detection of EGFR overexpression. Therefore, molecular imaging can aid in identifying the patient population with positive EGFR expression and hence can benefit from targeted TKI-based therapies.\n\nIn this case report, we described the molecular imaging and NGS in a male patient presenting with GBM. Results of EGFR-18F-FDG PET/CT scan demonstrated heterogeneous expression of EFGR protein in our male patient. We observed heterogeneity in the intensity of EGFR staining across the brain. The temporal lobe of the brain showed a strong positive signal while the frontal lobe showed a weakly positive signal. It is plausible to speculate that the heterogeneity of EFGR expression may result in variable efficacy of TKI therapy [18]. Further, NGS revealed the presence of EFGR amplification and the EGFR mutations p.A289V and pP772 delinsPPl, as well as the FLNA point mutation p.V120M. In the first three months of oral erlotinib treatment, the patient's symptoms improved. However, the efficacy of single erlotinib therapy declined with a relapse in the patient's condition. In the frontal lobe, the GBM expanded, extending to the corpus callosum and to the contralateral lobe. As discussed earlier, the frontal lobe showed lower EGFR activity which may have affected sensitivity towards erlotinib, leading to secondary resistance.\n\nThe existence of intratumoral heterogeneity has been demonstrated to possess prognostic implications and may affect the sensitivity towards chemotherapy [19]. Further, intratumorral diversity represented a probable cause for anti-EGFR therapeutic secondary resistance. Due to trimming of tissues obtained from surgical resection, tumor samples do not reflect the molecular representation of the whole tumor [19]. Moreover, Wei et al. previously demonstrated that tumors evolve in response to targeted therapies through the classical Darwinian selection and cellular adaptations at a variety of levels [18]. In this study, we demonstrated that the combination of NGS and molecule imaging may be instrumental in studying the complex molecular biology and intratumoral molecular heterogeneity. Further, we observed that single target inactivation was not sufficient to block downstream oncogenic signaling. Our male patient responded briefly to erlotinib before acquiring secondary resistance. It has been previously demonstrated that combining erlotinib with histone deacetylase inhibitors (HDACi), significantly inhibit the proliferation of erlotinib-resistant GBM cells and partially restore their sensitivity to erlotinib [20]. Moreover, targeting MET, a hepatocyte growth factor receptor, in GBM cases with EGFR amplification may delay the acquired secondary resistance that can develop during erlotinib treatment [21]. Taken together, the combination of erlotinib with other drugs can potentially prevent TKI secondary resistance. Therefore, we recommend combining two or more target drugs which may aide in prolonging survival in GBM patients [18].\n\nIn conclusion, NGS and molecular imaging can provide crucial information about the molecular composition of tumors which will help in developing individualized targeted therapy.\n\nThis study was supported by the National Natural Science Foundation of China (Grant No. NSFC81372689), Health and family planning commission of Jiangsu Province youth research subject (Q201606), Six talent peaks project in Jiangsu Province (2014-wsw-021) and Suzhou applied basic research (Sys201535).\n\nCONFLICTS OF INTEREST\n\nThe authors declare that they have no conflict of interests.\n==== Refs\nREFERENCES\n1 Lim SK Llaguno SR McKay RM Parada LF Glioblastoma multiforme: a perspective on recent findings in human cancer and mouse models BMB Rep 2011 44 158 164 21429292 \n2 Ma X Lv Y Liu J Wang D Huang Q Wang X Li G Xu S Li X Survival analysis of 205 patients with glioblastoma multiforme: clinical characteristics, treatment and prognosis in China J Clin Neurosci 2009 16 1595 1598 19793663 \n3 Frederick L Wang XY Eley G James CD Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas Cancer Res 2000 60 1383 1387 10728703 \n4 Huncharek M Kupelnick B Epidermal growth factor receptor gene amplification as a prognostic marker in glioblastoma multiforme: results of a meta-analysis Oncol Res 2000 12 107 112 11132923 \n5 Raizer JJ Abrey LE Lassman AB Chang SM Lamborn KR Kuhn JG Yung WK Gilbert MR Aldape KA Wen PY Fine HA Mehta M Deangelis LM A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy Neuro Oncol 2010 12 95 103 20150372 \n6 Halatsch ME Gehrke EE Vougioukas VI Bötefür IC A-Borhani F Efferth T Gebhart E Domhof S Schmidt U Buchfelder M Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines J Neurosurg 2004 100 523 533 15035290 \n7 Addeo R Zappavigna S Parlato C Caraglia M Erlotinib: early clinical development in brain cancer Expert Opin Investig Drugs 2014 23 1027 1037 \n8 van den Bent MJ Brandes AA Rampling R Kouwenhoven MC Kros JM Carpentier AF Clement PM Frenay M Campone M Baurain JF Armand JP Taphoorn MJ Tosoni A Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034 J Clin Oncol 2009 27 1268 1274 19204207 \n9 Cantley LC Neel BG New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway Proc Natl Acad Sci U S A 1999 96 4240 4245 10200246 \n10 Sarkaria JN Yang L Grogan PT Kitange GJ Carlson BL Schroeder MA Galanis E Giannini C Wu W Dinca EB James CD Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel Mol Cancer Ther 2007 6 1167 1174 17363510 \n11 Mellinghoff IK Wang MY Vivanco I Haas-Kogan DA Zhu S Dia EQ Lu KV Yoshimoto K Huang JH Chute DJ Riggs BL Horvath S Liau LM Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors N Engl J Med 2005 353 2012 2024 16282176 \n12 Haas-Kogan DA Prados MD Tihan T Eberhard DA Jelluma N Arvold ND Baumber R Lamborn KR Kapadia A Malec M Berger MS Stokoe D Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib J Natl Cancer Inst 2005 97 880 887 15956649 \n13 Thorne AH Zanca C Furnari F Epidermal growth factor receptor targeting and challenges in glioblastoma Neuro Oncol 2016 18 914 918 \n14 Stupp R Mason WP van den Bent MJ Weller M Fisher B Taphoorn MJ Belanger K Brandes AA Marosi C Bogdahn U Curschmann J Janzer RC Ludwin SK Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma N Engl J Med 2005 352 987 996 15758009 \n15 Brennan CW Verhaak RG McKenna A Campos B Noushmehr H Salama SR Zheng S Chakravarty D Sanborn JZ Berman SH Beroukhim R Bernard B Wu CJ The somatic genomic landscape of glioblastoma Cell 2013 155 462 477 24120142 \n16 Kumar A Boyle EA Tokita M Mikheev AM Sanger MC Girard E Silber JR Gonzalez-Cuyar LF Hiatt JB Adey A Lee C Kitzman JO Born DE Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes Genome Biol 2014 15 530 25608559 \n17 Francis JM Zhang CZ Maire CL Jung J Manzo VE Adalsteinsson VA Homer H Haidar S Blumenstiel B Pedamallu CS Ligon AH Love JC Meyerson M EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing Cancer Discov 2014 4 956 971 24893890 \n18 Wei W Shin YS Xue M Matsutani T Masui K Yang H Ikegami S Gu Y Herrmann K Johnson D Ding X Hwang K Kim J Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma Cancer cell 2016 29 563 573 27070703 \n19 Patel AP Tirosh I Trombetta JJ Shalek AK Gillespie SM Wakimoto H Cahill DP Nahed BV Curry WT Martuza RL Louis DN Rozenblatt-Rosen O Suva ML Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma Science 2014 344 1396 1401 24925914 \n20 Liffers K Kolbe K Westphal M Lamszus K Schulte A Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition Target Oncol 2016 11 29 40 26032687 \n21 Johnson J Ascierto ML Mittal S Newsome D Kang L Briggs M Tanner K Marincola FM Berens ME Vande Woude GF Xie Q Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma J Transl Med 2015 13 306 26381735\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(30)",
"journal": "Oncotarget",
"keywords": "EGFR mutation; erlotinib; glioblastoma; molecular image; next-generation sequencing",
"medline_ta": "Oncotarget",
"mesh_terms": "D000328:Adult; D066246:ErbB Receptors; D005909:Glioblastoma; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D057054:Molecular Imaging; D009154:Mutation; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "50305-50313",
"pmc": null,
"pmid": "28611289",
"pubdate": "2017-07-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24893890;20150372;15035290;26381735;19793663;19204207;16282176;24925914;24120142;26032687;10200246;11132923;24836441;26755074;17363510;25608559;10728703;21429292;27070703;15758009;15956649",
"title": "Next generation sequencing and molecular imaging identify EGFR mutation and amplification in a glioblastoma multiforme patient treated with an EGFR inhibitor: a case report.",
"title_normalized": "next generation sequencing and molecular imaging identify egfr mutation and amplification in a glioblastoma multiforme patient treated with an egfr inhibitor a case report"
}
|
[
{
"companynumb": "CN-MYLANLABS-2017M1058780",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "091002",
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"drugdosagetext": "150 MG/DAY",
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"drugindication": "GLIOBLASTOMA MULTIFORME",
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"medicinalproduct": "ERLOTINIB"
}
],
"patientagegroup": null,
"patientonsetage": "31",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZHOU K, YAO H, ZHANG X, LIU J, QI Z, XIE X, ET AL. NEXT GENERATION SEQUENCING AND MOLECULAR IMAGING IDENTIFY EGFR MUTATION AND AMPLIFICATION IN A GLIOBLASTOMA MULTIFORME PATIENT TREATED WITH AN EGFR INHIBITOR: A CASE REPORT. ONCOTARGET 2017;8(30):50305-50313.",
"literaturereference_normalized": "next generation sequencing and molecular imaging identify egfr mutation and amplification in a glioblastoma multiforme patient treated with an egfr inhibitor a case report",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20170928",
"receivedate": "20170928",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 14019776,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171128"
}
] |
{
"abstract": "Pituitary apoplexy is a rare medical emergency which results from hemorrhage or infarction in the pituitary gland. One of the predisposing factors is treatment with dopamine agonists, especially bromocriptine. We report a 20-year-old Chinese man with prolactinoma who developed pituitary apoplexy 6 weeks after initiation of cabergoline. He was treated conservatively with supportive therapy, and recovered well with no loss of pituitary function. A literature search was conducted and a review of the reported patients with pituitary apoplexy during treatment with dopamine agonists is discussed.",
"affiliations": "Department of Endocrinology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. Electronic address: [email protected].",
"authors": "Chng|Edwin|E|;Dalan|Rinkoo|R|",
"chemical_list": "D000970:Antineoplastic Agents; D018491:Dopamine Agonists; D004873:Ergolines; D000077465:Cabergoline",
"country": "Scotland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "20(12)",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Bromocriptine; Cabergoline; Dopamine agonist; Pituitary apoplexy; Prolactinoma",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000970:Antineoplastic Agents; D000077465:Cabergoline; D018491:Dopamine Agonists; D004873:Ergolines; D006801:Humans; D008297:Male; D010899:Pituitary Apoplexy; D010911:Pituitary Neoplasms; D015175:Prolactinoma; D055815:Young Adult",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "1637-43",
"pmc": null,
"pmid": "24113159",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pituitary apoplexy associated with cabergoline therapy.",
"title_normalized": "pituitary apoplexy associated with cabergoline therapy"
}
|
[
{
"companynumb": "SG-WATSON-2012-14907",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CABERGOLINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "078035",
"drugbatchnumb": "UNCONFIRMED",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "Unk",
"drugdosagetext": "0.25 MG, 2/WEEK",
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"medicinalproduct": "CABERGOLINE (UNKNOWN)"
},
{
"actiondrug": "4",
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"activesubstancename": "CABERGOLINE"
},
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"drugcharacterization": "1",
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"drugdosageform": "Unk",
"drugdosagetext": "0.5 MG, 2/WEEK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROLACTINOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
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"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": ".5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CABERGOLINE (UNKNOWN)"
}
],
"patientagegroup": null,
"patientonsetage": "20",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": "58",
"reaction": [
{
"reactionmeddrapt": "Pituitary haemorrhage",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Secondary hypothyroidism",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHNG E, DALAN R. PITUITARY APOPLEXY ASSOCIATED WITH CABERGOLINE THERAPY. J CLIN NEUROSCI. 2013;20(12):1637-43.",
"literaturereference_normalized": "pituitary apoplexy associated with cabergoline therapy",
"qualification": "3",
"reportercountry": "SG"
},
"primarysourcecountry": "SG",
"receiptdate": "20140812",
"receivedate": "20120904",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 8765956,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150326"
}
] |
{
"abstract": "OBJECTIVE\nTo confirm whether 7 days of phenytoin, an enzyme inducer, would decrease the elimination half-life of single-dose nevirapine and to investigate its effect on the development of nevirapine resistance in pregnant, HIV-infected women.\n\n\nMETHODS\nIn a pharmacokinetic pilot trial (NCT01187719), HIV-infected, antiretroviral (ARV)-naive pregnant women ≥18 years old from Zambia and Tanzania and with CD4 cell counts >350 cells/mm(3) were randomized 1 : 1 to a control (zidovudine pre-delivery, single-dose nevirapine/zidovudine/lamivudine at delivery and zidovudine/lamivudine for 7 days post-delivery) or an intervention (control plus 184 mg of phenytoin once daily for 7 days post-delivery) group. Primary endpoints were the pharmacokinetics of and resistance to nevirapine.\n\n\nRESULTS\nThirty-five and 37 women were allocated to the control and intervention groups, with median (IQR) ages of 27 (23-31) and 27 (23-33) years, respectively. Twenty-three and 23 women had detectable nevirapine levels at delivery and subsequent samples in the control and the intervention groups, respectively. Geometric mean (GM) (95% CI) plasma levels of nevirapine at delivery were 1.02 (0.58-1.78) mg/L and 1.14 (0.70-1.86) mg/L in the control and intervention groups, respectively (P = 0.76). One week after delivery, 0/23 (0%) and 15/22 (68%) control and intervention mothers, respectively, had undetectable levels of nevirapine (<0.05 mg/L; P<0.001). One week later, the figures were 10/21 (48%) and 18/19 (95%) mothers, respectively (P = 0.002). The GM (95% CI) half-life of nevirapine was 63.2 (52.8-75.7) versus 25.5 (21.6-30.1) h in the control group versus the intervention group (P < 0.001). New nevirapine mutations were found in 0/20 (0%) intervention-group mothers versus 1/21 (5%) control-group mothers. Overall, there was no difference in adverse events reported between the control and intervention arms (P > 0.28).\n\n\nCONCLUSIONS\nAdding 7 days of an enzyme inducer to single-dose nevirapine to prevent mother-to-child transmission of HIV significantly reduced subtherapeutic nevirapine levels by shortening the half-life of nevirapine. As prolonged subtherapeutic nevirapine dosage leads to the emergence of resistance, single-dose nevirapine could be used with phenytoin as an alternative if other ARVs were unavailable.",
"affiliations": "Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.",
"authors": "Fillekes|Quirine|Q|;Muro|Eva P|EP|;Chunda|Catherine|C|;Aitken|Susan|S|;Kisanga|Elton R|ER|;Kankasa|Chipepo|C|;Thomason|Margaret J|MJ|;Gibb|Diana M|DM|;Walker|A Sarah|AS|;Burger|David M|DM|",
"chemical_list": "D019380:Anti-HIV Agents; D000927:Anticonvulsants; D010672:Phenytoin; D019829:Nevirapine",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkt246",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "68(11)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": "Africa; PK; nevirapine; prevention of mother-to-child transmission of HIV",
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000927:Anticonvulsants; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D005260:Female; D006678:HIV; D015658:HIV Infections; D006207:Half-Life; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D019829:Nevirapine; D010672:Phenytoin; D010865:Pilot Projects; D011247:Pregnancy; D013636:Tanzania; D055815:Young Adult; D015024:Zambia",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "2609-15",
"pmc": null,
"pmid": "23864647",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single-dose nevirapine for perinatal HIV prevention: a randomized pilot trial.",
"title_normalized": "effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single dose nevirapine for perinatal hiv prevention a randomized pilot trial"
}
|
[
{
"companynumb": "ZM-ROXANE LABORATORIES, INC.-2014-BI-33389GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZM",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "020636",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "ORAL SUSPENSION",
"drugdosagetext": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "NEVIRAPINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": "020636",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": null,
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"drugindication": "PROPHYLAXIS AGAINST HIV INFECTION",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "NEVIRAPINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
"drugadministrationroute": "064",
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"drugindication": "PROPHYLAXIS AGAINST HIV INFECTION",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LAMIVUDINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": "076844",
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
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"drugindication": "PROPHYLAXIS AGAINST HIV INFECTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ZIDOVUDINE."
}
],
"patientagegroup": "1",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Overweight",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FILLEKES Q,MURO E,CHUNDA C,AITKEN S,KISANGA E,KANKASA C,ET AL. EFFECT OF 7 DAYS OF PHENYTOIN ON THE PHARMACOKINETICS OF AND THE DEVELOPMENT OF RESISTANCE TO SINGLE-DOSE NEVIRAPINE FOR PERINATAL HIV PREVENTION: A RANDOMIZED PILOT TRIAL. J ANTIMICROB CHEMOTHER 2013;68:11:2609-2615.",
"literaturereference_normalized": "effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single dose nevirapine for perinatal hiv prevention a randomized pilot trial",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "NL",
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},
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},
"serious": 1,
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150326"
},
{
"companynumb": "NL-CIPLA LTD.-2016NL10056",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": "3",
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"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "300 MG, BID,POST DELIVERY FOR 7 DAYS",
"drugenddate": null,
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"drugindication": null,
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosagenumb": "300",
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"medicinalproduct": "ZIDOVUDINE."
},
{
"actiondrug": "5",
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"activesubstancename": "LAMIVUDINE"
},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "UNK, EVERY 12 HOURS UNTIL DELIVERY",
"drugenddate": null,
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"drugindication": "PROPHYLAXIS AGAINST HIV INFECTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "LAMIVUDINE."
},
{
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"activesubstancename": "LAMIVUDINE"
},
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"drugdosagetext": "150 MG, BID,FOR 7 DAYS POST DELIVERY",
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"abstract": "A 74-year-old female was diagnosed with the autoimmune inflammatory disease temporal arteritis and treated with high and low doses of prednisone over a period of 6 years. During that time, she developed cancers of the lung and colon as well as a soft tumor mass on lumbar vertebrate L3. She also experienced a series of debilitating and disabling symptoms while on prednisone treatment. A temporal analysis of the association of prednisone therapy and immune markers to the successive appearance of the malignant tumors strongly suggests that in the absence of a functioning natural immune and surveillance system by treatment with the immune knockout drug prednisone, spontaneous, multiple independent mutations occurred in several sites in the organ systems of this patient. Over a period of time, these developed into malignant cancers, including a lung nodule which became cancerous 256 days later, as well as the cancers of the colon and a soft tumor mass on lumbar vertebrate L3.",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. 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] 10.1159/000484714cro-0010-1076Case ReportMultiple Tumor Induction after Treatment of Temporal Arteritis with Prednisone Piraino Frank F. **Frank F. Piraino, PhD, 517 Rupert Road, Waunakee, WI 53597 (USA), E-Mail [email protected] 2017 28 11 2017 28 11 2017 10 3 1076 1084 19 10 2017 31 10 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.A 74-year-old female was diagnosed with the autoimmune inflammatory disease temporal arteritis and treated with high and low doses of prednisone over a period of 6 years. During that time, she developed cancers of the lung and colon as well as a soft tumor mass on lumbar vertebrate L3. She also experienced a series of debilitating and disabling symptoms while on prednisone treatment. A temporal analysis of the association of prednisone therapy and immune markers to the successive appearance of the malignant tumors strongly suggests that in the absence of a functioning natural immune and surveillance system by treatment with the immune knockout drug prednisone, spontaneous, multiple independent mutations occurred in several sites in the organ systems of this patient. Over a period of time, these developed into malignant cancers, including a lung nodule which became cancerous 256 days later, as well as the cancers of the colon and a soft tumor mass on lumbar vertebrate L3.\n\nKeywords\nTemporal arteritisPrednisoneDrug side effectsInflammationAutoimmune diseaseAdenocarcinomasMutationsCancer immunity\n==== Body\nIntroduction\nTemporal arteritis (giant cell arteritis, TA) is an inflammatory autoimmune disease of devastating, extremely painful and sometimes fatal consequence. It is the commonest form of systemic large vessel vasculitis that may occur anywhere in the body. Pathologically, it is characterized by invasion of large blood vessels by giant mononuclear cells that promote damage to actin and elastin proteins in the lamella of blood vessels. The symptoms are caused by local ischemia due to endovascular damage and cytokine-mediated changes that include systemic vasculitis, blindness, severe head pain, generalized polymyalgia rheumatic, and aortic stenosis [1].\n\nPrednisone is the most commonly prescribed oral drug used in the treatment of TA and other autoimmune diseases. It is a corticosteroid synthetic drug that is effective as an immunosuppressant. It prevents the release of cytokines, interferons, interleukins, substances in the body that regulate the inflammation reaction and it results in the almost complete suppression of both natural and humoral immunity. It is usually the first drug of choice in the treatment of many severe inflammatory conditions including transplant rejection, autoimmune disease, and some forms of cancer. Prednisone is metabolized in the liver to its active form prednisolone and is roughly 4 times as potent as naturally occurring glucocorticoids. Glucocorticoid hormones synthesized in the adrenal cortex prevent or suppress inflammation and immune responses. At the molecular level, they cross cell membranes and bind to specific cytoplasmic receptors. This binding modifies transcription and ultimately protein synthesis. These actions include inhibition of leukocyte infiltration to the sites of inflammation and interference in the function of mediators of inflammatory and humoral immune responses. The net clinical effect is a general suppression of the immune process [2, 3].\n\nLong-term use of high doses of prednisone cause a variety of physically disabling and psychological disorders as side effects. Physical changes include edema of the face (moon face), edema of the legs and ankles, fatty deposits in the neck and shoulders (humpback), weakness of the limbs, unsteady gait, aortic stenosis, and premature aging. Psychologically, the individual may suffer confusion, depression, become argumentative with uncharacteristic explosive fits of anger, and contemplate suicide [4]. It is reasonable to suggest then that the drug also interferes with the amygdala-hippocampus emotional center of the brain [5].\n\nMalignant cancers following long-term treatment with prednisone and prednisone-like immunosuppressant drugs have been reported [6, 7, 8, 9, 10]. This is the first report of multiple cancers following long-term treatment of TA with prednisone.\n\nCase Report\nOn November 15, 2009, patient A.P. (female, age 74 years) presented at Dean Medical Ophthalmology Clinic, Madison, WI, USA, with symptoms of severe, unrelenting, temporal-region head pain and a drooping eyelid. A biopsy of the left temporal artery was performed at St. Mary's Hospital, Madison, WI, USA, and a diagnosis of giant cell arteritis with leukocyte infiltration was established together with Horner's syndrome [11]. The patient was placed on a regimen of 80 mg prednisone per day, which promptly relieved her symptoms. The strategy for control and treatment of TA for this patient was to monitor TA symptoms with the inflammatory markers, C-reactive protein, and the erythrocyte sedimentation rate [12]. When symptoms were present or markers elevated, prednisone dosage was increased, and when decreased, prednisone dosage was decreased (Fig. 1). Lymphocyte data that appear in this history were part of emergency room diagnostic studies taken during her many admissions to the Emergency Department of St. Mary's Hospital. Before prednisone therapy and the onset of TA, the patient was an attractive, healthy, active elderly person. During prednisone treatment of her long illness, she experienced a bewildering array of severe drug side effects, including generalized disfiguring edema of the face, shoulders, legs, and ankles, several life-threatening infections, multiple cancers, and unusual behavioral changes that were foreign to her personality. A summary of her clinical history including lab tests, imaging results, clinical diagnoses, physical and personality changes, surgeries, and infections is given in Table 1 in the order of appearance after initiation of prednisone medication.\n\nFigure 1 shows the quantitative data for prednisone dosage (mg/day), percent lymphocytes, and C-reactive protein on the ordinate and days following the beginning of treatment on the abscissa. Normal values for percent lymphocytes and the inflammatory marker, C-reactive protein, are given at the bottom of the figure. Erythrocyte sedimentation rates are not shown because these were consistently elevated throughout her illness and were not useful as a treatment marker, at least for this patients TA illness.\n\nAs seen in Figure 1, C-reactive protein was a reliable indicator of the TA status of A.P.'s autoimmune disease and a reliable prognostic marker for tracking the progress and treatment of her disease. When TA symptoms of temporal headache pain, polymyalgia rheumatic pain and other related symptoms were present, her C-reactive protein levels were elevated. When prednisone was given, her symptoms were promptly relieved and her C-reactive protein level was lowered to near normal values. Figure 1 also shows that prednisone not only controlled and relieved the inflammatory symptoms of TA, but also knocked down the patient's percent lymphocytes to dangerously low levels of 5% or less. Normal levels are between 17–25%. In effect, this decrease of lymphocytes severely compromised her natural cellular and humoral immunity to infection and cancer [3, 4, 6, 7, 8, 9, 10].\n\nTable 1 gives the clinical history of A.P. over a period of nearly 6 years. During this time, the patient suffered from nearly constant disfiguring physical and painful signs of edema with swollen legs and ankles, moon face, and humpback shoulders. The symptoms were associated with unsteady gait and balance problems. Following surgery for removal of an adenocarcinoma of the right lower lung on day 360, during recovery on day 374, she experienced a pneumothorax in the same lung. On day 725 she was diagnosed with coronary atrophy and after that was constantly out of breath with general weakness and was unable to walk more than 100 feet even with assistance. She developed 3 serious infections, each requiring emergency room admissions and hospitalization. On day 440, she was diagnosed with bronchopneumonia and on day 864 she was treated for viral enteritis and septic shock with symptoms of severe vomiting and diarrhea. On day 1,230, she developed a urinary tract infection. For the duration of drug treatment, the patient developed a range of personality changes. She was often depressed, confused, disoriented, argumentative, and angry. She was given psychological counseling and during one private session asked the psychologist what drugs she could take to end her life. The patient died on February 10, 2016, with widespread multiple cancers of the colon and spinal cord.\n\nThis is the first time that multiple cancers of the lung, colon, and spinal cord have been reported following long-term prednisone treatment for TA. The data presented in Figure 1 and Table 1 support a view that multiple cancers in this individual developed as a consequence of long-term exposure to high doses of the immune knockout drug prednisone. During the 6 years of her illness, 4 of the 6 times her percent lymphocytes were counted, they were decreased far below normal levels and during the first year, 3 of the 4 blood tests gave percent lymphocyte counts of 5% or less. As a result, her natural immunity to infection and cancer were severely compromised, particularly during the first year when she developed lung cancer. In Figure 1 the down-pointing arrows indicate the day post-prednisone treatment when cancers were diagnosed. Surgery usually followed within days except for the soft tumor mass on L3 when the patient refused treatment and surgery. Note particularly that on day 104 following prednisone treatment, a benign 5-mm nodule diagnosed by imaging developed into an adenocarcinoma of the right lower lung at the same site 256 days later. On day 1,209 the patient was operated on for an adenocarcinoma of the distal transverse colon and 193 days later on day 1,402 underwent a colectomy for an adenocarcinoma of the ilium descending colon. Multiple, heterogeneous, synchronous, unrelated colorectal cancers have been previously reported in patients with inflammatory disease [13]. Again, as in the instance of the lung cancer, the ilium descending colon cancer was detected almost 1 year later. Two years later on February 10, 2016, day 2,212 following prednisone treatment, the patient finally succumbed after diagnosis of the soft tumor mass on lumbar vertebrae L3.\n\nDiscussion\nThe deleterious and disabling side effects of long-term, high-dose prednisone usage are well known, but reports have not emphasized how the side effects affect the lifestyle and overall wellness of the patient. In this case, the explosive and devastating side effects she endured when weighed against its benefits, begs for the discovery and development of targeted new drugs for the treatment of TA and other inflammatory and autoimmune diseases.\n\nRegarding the unusual appearance of multiple cancers following long-term treatment with high doses of prednisone, it is unlikely that all 4 cancers at different sites and in different organ systems in 1 individual were caused by the spread of the primary lung tumor. Histologically the non-small cell lung cancer and cancers of the colon were diagnosed as adenocarcinomas. The soft tumor mass adjacent to caudal vertebrae L3 may have been a sarcoma, but since the patient refused surgery or treatment a biopsy was not performed. Staff pathologists were of the opinion that the appearance of multiple tumors in different organs in this patient in a relatively short period of time was an unusual outcome and provided no explanation. All pathology examinations were done at St. Mary's Hospital in Madison, WI, USA. Genomic sequence studies or immunological typing of the tumors were not performed, so the issue of relatedness could not be diagnostically resolved.\n\nThe argument for the appearance of multiple unrelated cancers in this patient comes from published reports on multiple unrelated cancers and routes of metastases. Tamura et al. [14], in a study of 729 cases of metastases in non-small-cell lung cancers, observed that metastases were observed in bone, lung, brain, adrenal glands, liver, and extra-thoracic lymph nodes, but none metastasized to the colon or tumors of the caudal vertebrae. Also Naxerova et al. [15], in a similar study, reported that metastases of positive colon cancers follow the lymphatic routes to the liver and not the lung and when biopsies reveal nodes are cancer free, the risk of metastases to distant organs is less than 5% [16]. The draining lymph nodes of all 4 cancers of this patient were cancer free. These reports support the argument that the appearance of multiple tumors in this patient did not occur after metastases but were independent events.\n\nSynchronous colonic multiple tumors in patients were studied by Cereda et al. [13]. In a study of 20 cases of genetically immunotyped synchronous colonic multiple tumors in patients with inflammatory diseases, they concluded that an environmental field effect, including the immune system, promotes multiple tumor formation in the background of inflammation which was the clinical situation with this patient.\n\nTo summarize, the development of multiple cancers in different organs of this patient did not correspond with published reports of routes of metastases from non-small cell lung cancer. The unusual clinical course of her metastatic illness while undergoing prednisone immunosuppressive therapy strongly suggests that the development of cancers were independent events and not the result of metastases from the original lung tumor.\n\nThe multiple cancers of this patient could have originated by two different mechanisms: (1) metastatic spread from any of the tumors or (2) developed after spontaneous independent mutations.\n\nIn either case, the absence of a functioning surveillance-immune system which is supported by her low lymphocyte counts would have permitted tumors from either one or both mechanisms to grow and thrive. Since tumor immunogenetic studies on this patient were not performed, the issue in her case is unresolved. However, since the patient was treated with high doses of prednisone during much of her illness, a favorable cellular immune environment existed that could have allowed multiple cancers to develop and thrive at the different organ sites.\n\nIn conclusion, it is reasonable to propose that in the absence of a functioning natural immune and surveillance system, spontaneous, multiple independent mutations occurred in several sites in the organ systems of this patient. Over a period of time, these mutations developed into malignant tumors, including the lung nodule which became cancerous 256 days later, as well as the cancers of the colon and soft tumor mass on L3.\n\nFinally, the risk of cancer inductions in patients receiving long-term, high-dose prednisone therapy needs to be recognized and emphasized by medical practitioners as a consequence of this and other anti-inflammatory drugs. It is generally accepted that once a cell becomes malignant and develops into a solid tumor, particularly in a weak or malfunctioning immune system, it is usually resistant to any known clinical therapy other than surgery, chemotherapy, and radiation regardless of the person's subsequent immune status.\n\nRecently, several novel strategies have been developed for the treatment of cancer: vaccinations using tumor-specific antigens attached to vaccinia and fowlpox viral carriers, and removing immuno-blocking checkpoints [17]. Genetically engineered CART cells that target tumor antigens have had some success against chronic and acute leukemias and prostate cancer. These treatments stimulate the release of cytokines by activated T cells, interleukins, and interferons that promote and coordinate the anti-tumor immune effects. Unfortunately, these early trials sometimes have resulted in fatalities but are in the preliminary stages of development [18, 19, 20, 21]. It is hoped that these new therapies will in time provide alternatives to steroid treatment.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient's family.\n\nDisclosure Statement\nThere are no conflicts of interests\n\nAcknowledgements\nThe author thanks the Medical Records Department of St. Mary's Hospital for providing voluminous laboratory and clinical documents relating to the patients illness and Dean Clinic staff for comments and suggestions. Many thanks to Inna Larsen of the Department of Ophthalmology and Visual Sciences of the University of Wisconsin School of Medicine and Public Health for her valuable assistance in the preparation of the manuscript.\n\nFig. 1. The temporal relationships of prednisone dosage, response of lymphocytes, and C-reactive protein levels are presented as days after prednisone treatment (normal value of C-reactive protein, <5 mg; normal value of percent lymphocytes, 17–25%). Pre-malignant nodules, cancers, and surgery are given as numbers. The development of benign nodules and cancers are given as numbers above the graph: 1. Day 104 post-prednisone treatment (PPT) - 5-mm nodule, right lower lung. 2. Day 360 PPT - right lower lung adenocarcinoma. 3. Day 1,209 PPT - adenocarcinoma of distal transverse colon. 4. Day 1,402 PPT - adenocarcinoma of ilium descending colon, colectomy. 5. Day 2,212 PPT - soft tissue mass sarcoma of L3 vertebra.\n\nTable 1 Clinical signs during prednisone treatment\n\nDay PPT\tPrednisone, mg\tSymptoms and clinical signs\t\n1\t80\tSevere headaches (temporal arteritis)\t\n\t\n30\t55\tSevere leg pain, edema of legs, face, and shoulders\t\n\t\n74\t30\tEdema of legs, face, and shoulders\t\n\t\n107\t25\t(Day 104 PPT - 5-mm nodule, right lower lung)\nEdema of legs, face, and shoulders, unsteady gait, osteoporosis, COPD\t\n\t\n166\t15\tOsteopenia, unsteady gait, COPD, edema of legs, face, and shoulders\t\n\t\n258\t8\tEdema of legs, face, and shoulders, general weakness\t\n\t\n276\t60\tSevere headache, edema of legs, temporal arteritis flare-up\t\n\t\n304\t30\tEdema of legs, general weakness, unsteady gait\t\n\t\n348\t20\tEdema of legs, general weakness, unsteady gait\t\n\t\n374\t20\t(Day 360 PPT - right lower lung adenocarcinoma)\nPneumothorax\t\n\t\n409\t10\tShortness of breath, general weakness, COPD, edema\t\n\t\n440\t10\tBronchopneumonia with fistula\t\n\t\n534\t7\tBilateral edema of limbs, unsteady gait, COPD\t\n\t\n653\t3\tBilateral edema of limbs, unsteady gait, general weakness\t\n\t\n725\t3\tSyncope, coronary atrophy, memory and visual problems\t\n\t\n780\t5\tPolymyalgia rheumatica, osteopenia\t\n\t\n864\t5\tSepsis, vomiting, diarrhea, severe hypotension, shock, and acidosis\t\n\t\n951\t1\tAortic stenosis\t\n\t\n1,140\t0\tVomiting, diarrhea, viral enteritis, eye pain\t\n\t\n1,213\t1\t(Day 1,209 PPT - adenocarcinoma of distal transverse colon)\nGeneral weakness, shortness of breath, COPD\t\n\t\n1,230\t1\tUrinary tract infection\t\n\t\n1,262\t15\tLower bilateral leg pain\t\n\t\n1,474\t40\t(Day 1,402 PPT - adenocarcinoma of ilium descending colon, colectomy)\nNon-productive cough, fatigue, shortness of breath, temporal arteritis, large artery involvement, right lower lobe pneumonia\t\n\t\n2,208\tNot taken\tSoft tumor mass sarcoma on L3 lumbar vertebrae with kidney involvement, severe bilateral back pain\t\n\t\n2,221\t\t(Day 2,212 PPT - soft tissue mass sarcoma of L3 vertebra)\nPatient expired (February 10, 2016)\t\nPPT, post-prednisone treatment.\n==== Refs\nReferences\n1 Barraclough K Mallen CD Helliwell T Hider SL Dasgupta B Diagnosis and management of giant cell arteritis Br J Gen Pract 2012 62 329 330 22687229 \n2 Hall S The red line Sci Am 2016 315 54 69 \n3 NCIthesaurus, version 17.04d 2017 https://ncit.nci.nih.gov/ncitbrowser/ \n4 Judd LL Schettler PJ Brown ES Wolkowitz OM Sternberg EM Bender BG Bulloch K Cidlowski JA de Kloet ER Fardet L Joëls M Leung DY McEwen BS Roozendaal B Van Rossum EF Ahn J Brown DW Plitt A Singh G Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects Am J Psychiatr 2014 171 1045 1051 25272344 \n5 Saladin KS Anatomy and Physiology: The Unity of Form and Function 2012 ed 6 New York McGraw-Hill \n6 Ondrus D Pribylincová V Breza J Bujdák P Miklosi M Reznícek J Zvara V The incidence of tumours in renal transplant recipients with long-term immunosuppressive therapy Int Urol Nephrol 1999 31 417 422 10668934 \n7 Sailler L Pugnet G Bienvenu B Treatment of giant cell arteritis Rev Med Interne 2013 34 431 437 23562185 \n8 Defuentes G Lecoules S Vedrine L Coutant G Baranger B Algayres JP Accelerated atheroma with prednisone and clopidogrel Presse Med 2006 35 421 422 16550133 \n9 Nair MP Schwartz SA Immunomodulatory effects of corticosteroids on natural killer and antibody-dependent cellular cytotoxic activities of human lymphocytes J Immunol 1984 132 2876 2882 6202765 \n10 Lipsmeyer EA Development of malignant cerebral lymphoma in a patient with systemic lupus erythematosus treated with immunosuppression Arthritis Rheum 1972 15 183 186 4554891 \n11 Knyazer B Smolar J Lazar I Rosenberg E Tsumi E Lifshitz T Levy J Iatrogenic Horner syndrome: etiology, diagnosis and outcomes Isr Med Assoc J 2017 19 34 38 28457112 \n12 Böyum A Isolation of mononuclear cells and granulocytes from human blood. Isolation of mononuclear cells by centrifugation and of granulocytes by combining centrifugation and sedimentation at 1 g J Clin Lab Invest Suppl 1968 97 77 89 \n13 Cereda M Gambardella G Benedetti L Iannelli F Patel D Basso G Guerra RF Mourikis TP Puccio I Sinha S Laghi L Spencer J Rodriguez-Justo M Ciccarelli FD Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes Nat Commun 2016 7 12072 12102 27377421 \n14 Tamura T Kurishima K Nakazawa K Kagohashi K Ishikawa H Satoh H Hizawa N Specific organ metastases and survival in metastatic non-small-cell lung cancer Mol Clin Oncol 2015 3 217 221 25469298 \n15 Naxerova K Reiter JG Brachtel E Lennerz JK van de Wetering M Rowan A Cai T Clevers H Swanton C Nowak MA Elledge SJ Jain RK Origins of lymphatic and distant metastases in human colorectal cancer Science 2017 357 55 60 28684519 \n16 Markowitz SD Cancer bypasses the lymph nodes Science 2017 357 35 36 28684492 \n17 Pardoll DM The blockage of immune checkpoints in cancer immunotherapy Nat Rev Cancer 2012 12 252 264 22437870 \n18 Kwek SS Cha E Fong L Unmasking the immune recognition of prostate cancer with CTLA4 blockade Nat Rev Cancer 2012 12 289 297 22378189 \n19 Maus MV Fraietta JA Levine BL Kalos M Zhao Y June CH Adoptive immunotherapy for cancer or viruses Annu Rev Immunol 2014 32 189 225 24423116 \n20 Li R Yan F Liu L Li H Ren B Hui Z Ren X Cytokine-induced killer cell therapy for the treatment of primary hepatocellular carcinoma subsequent to liver transplantation: a case report Oncol Lett 2016 11 1185 1888 \n21 Maude SL Frey N Shaw PA Aplenc R Barrett DM Bunin NJ Chew A Gonzalez VE Zheng Z Lacey SF Mahnke YD Melenhorst JJ Rheingold SR Shen A Teachey DT Levine BL June CH Porter DL Grupp SA Chimeric antigen receptor T cells for sustained remissions in leukemia N Engl J Med 2014 371 1507 1517 25317870\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "10(3)",
"journal": "Case reports in oncology",
"keywords": "Adenocarcinomas; Autoimmune disease; Cancer immunity; Drug side effects; Inflammation; Mutations; Prednisone; Temporal arteritis",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1076-1084",
"pmc": null,
"pmid": "29515399",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "25317870;28457112;22687229;10668934;4179068;26998094;27377421;22437870;22378189;28684492;6202765;25469298;27924883;24423116;16550133;23562185;25272344;28684519;4554891",
"title": "Multiple Tumor Induction after Treatment of Temporal Arteritis with Prednisone.",
"title_normalized": "multiple tumor induction after treatment of temporal arteritis with prednisone"
}
|
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},
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},
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"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gastroenteritis viral",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Urinary tract infection",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Chronic obstructive pulmonary disease",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Septic shock",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disorientation",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pain in extremity",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oedema peripheral",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lung adenocarcinoma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Confusional state",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Soft tissue sarcoma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Anger",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Balance disorder",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Suicidal ideation",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gait disturbance",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aggression",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Osteopenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fistula",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Memory impairment",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Face oedema",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acidosis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aortic stenosis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adenocarcinoma of colon",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PIRAINO FF. MULTIPLE TUMOR INDUCTION AFTER TREATMENT OF TEMPORAL ARTERITIS WITH PREDNISONE. CASE-REP-ONCOL 2017?10(3):1076-1084.",
"literaturereference_normalized": "multiple tumor induction after treatment of temporal arteritis with prednisone",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180215",
"receivedate": "20180215",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14537010,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": 1,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "BACKGROUND\nAlthough randomized clinical trials (ANCHOR and MARINA) have shown excellent results of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD), it is unclear whether such an outcome is achievable in daily practice. We evaluated the results of ranibizumab treatment for neovascular AMD in clinical practice in Australia.\n\n\nMETHODS\nA retrospective chart review of patients in four practices injected with ranibizumab in 2006 for AMD. Patients who had been diagnosed with subfoveal choroidal neovascular membrane in the preceding 6 months and had completed at least 6 months follow-up were enrolled. No standard treatment protocols were required. The main outcome measure was visual acuity (VA) at 6 and 12 months.\n\n\nRESULTS\nA total of 158 patients fulfilled the entry criteria. The mean baseline VA (decimal) was 0.35+/-0.21 (Snellen equivalent 6/17). At 6 months, the mean VA improved to 0.46+/-0.27 (6/13) and remained stable until month 12 (0.48+/-0.30). The improvement in VA between baseline and months 6 and 12 was statistically significant (P<0.0001). Both the mean and the median number of injections were four in the first 6 months and nine at 12 months. VA results were comparable with those of the ANCHOR and MARINA trials, and were achieved with a lower number of injections (P<0.0001).\n\n\nCONCLUSIONS\nVA results achieved in daily clinical practice using ranibizumab for neovascular AMD are similar to large prospective randomized trials.",
"affiliations": "Centre for Eye Research Australia, University of Melbourne, The Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.",
"authors": "Michalova|K|K|;Wickremasinghe|S S|SS|;Tan|T H|TH|;Chang|A|A|;Harper|C A|CA|;Downie|J A|JA|;Hunyor|A P|AP|;Guymer|R H|RH|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D000069579:Ranibizumab",
"country": "England",
"delete": false,
"doi": "10.1038/eye.2009.175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0950-222X",
"issue": "23(8)",
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001315:Australia; D020256:Choroidal Neovascularization; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008268:Macular Degeneration; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab; D012189:Retrospective Studies; D014792:Visual Acuity",
"nlm_unique_id": "8703986",
"other_id": null,
"pages": "1633-40",
"pmc": null,
"pmid": "19648888",
"pubdate": "2009-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ranibizumab treatment for neovascular age-related macular degeneration: from randomized trials to clinical practice.",
"title_normalized": "ranibizumab treatment for neovascular age related macular degeneration from randomized trials to clinical practice"
}
|
[
{
"companynumb": "AU-ROCHE-2109726",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "125156",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "0.3MG PER 0.05 ML",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NEOVASCULAR AGE-RELATED MACULAR DEGENERATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "2006",
"drugstartdateformat": "602",
"drugstructuredosagenumb": ".3",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LUCENTIS"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "125156",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHOROIDAL NEOVASCULARISATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"medicinalproduct": "LUCENTIS"
}
],
"patientagegroup": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Iridocyclitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MICHALOVA K, WICKREMASINGHE SS, TAN TH, CHANG A, HARPER CA, DOWNIE JA ET AL RANIBIZUMAB TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: FROM RANDOMIZED TRIALS TO CLINICAL PRACTICE. EYE 2009?23:1633-1640.",
"literaturereference_normalized": "ranibizumab treatment for neovascular age related macular degeneration from randomized trials to clinical practice",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20180418",
"receivedate": "20180418",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14772364,
"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"
},
{
"companynumb": "AU-ROCHE-2109233",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "125156",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "0.3MG PER 0.05 ML",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NEOVASCULAR AGE-RELATED MACULAR DEGENERATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "2006",
"drugstartdateformat": "602",
"drugstructuredosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LUCENTIS"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "125156",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHOROIDAL NEOVASCULARISATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LUCENTIS"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Transient ischaemic attack",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MICHALOVA K, WICKREMASINGHE SS, TAN TH, CHANG A, HARPER CA, DOWNIE JA ET AL. RANIBIZUMAB TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: FROM RANDOMIZED TRIALS TO CLINICAL PRACTICE.. EYE. 2009?23:1633-1640.",
"literaturereference_normalized": "ranibizumab treatment for neovascular age related macular degeneration from randomized trials to clinical practice",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20180418",
"receivedate": "20180418",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14773691,
"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": "NRG1 rearrangements produce chimeric ligands that subvert the ERBB pathway to drive tumorigenesis. A better understanding of the signaling networks that mediate transformation by NRG1 fusions is needed to inform effective therapeutic strategies. Unfortunately, this has been hampered by a paucity of patient-derived disease models that faithfully recapitulate this molecularly defined cancer subset.\n\n\n\nPatient-derived xenograft (PDX) and cell line models were established from NRG1-rearranged lung adenocarcinoma samples. Transcriptomic, proteomic, and biochemical analyses were performed to identify activated pathways. Efficacy studies were conducted to evaluate HER3- and MTOR-directed therapies.\n\n\n\nWe established a pair of PDX and cell line models of invasive mucinous lung adenocarcinoma (LUAD) (LUAD-0061AS3, SLC3A2-NRG1), representing the first reported paired in vitro and in vivo model of NRG1-driven tumors. Growth of LUAD-0061AS3 models was reduced by the anti-HER3 antibody GSK2849330. Transcriptomic profiling revealed activation of the MTOR pathway in lung tumor samples with NRG1 fusions. Phosphorylation of several MTOR effectors (S6 and 4EBP1) was higher in LUAD-0061AS3 cells compared with human bronchial epithelial cells and the breast cancer cell line MDA-MB-175-VII (DOC4-NRG1 fusion). Accordingly, LUAD-0061AS3 cells were more sensitive to MTOR inhibitors than MDA-MB-175-VII cells and targeting the MTOR pathway with rapamycin blocked growth of LUAD-0061AS3 PDX tumors in vivo. In contrast, MDA-MB-175-VII breast cancer cells had higher MAPK pathway activation and were more sensitive to MEK inhibition.\n\n\n\nWe identify the MTOR pathway as a candidate vulnerability in NRG1 fusion-positive lung adenocarcinoma that may warrant further preclinical evaluation, with the eventual goal of finding additional therapeutic options for patients in whom ERBB-directed therapy fails. Moreover, our results uncover heterogeneity in downstream oncogenic signaling among NRG1-rearranged cancers, possibly tumor type-dependent, the therapeutic significance of which requires additional investigation.",
"affiliations": "Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.;Anti-Tumor Assessment Core Facility, Department of Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Anti-Tumor Assessment Core Facility, Department of Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Anti-Tumor Assessment Core Facility, Department of Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.;Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: [email protected].;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Odintsov|Igor|I|;Mattar|Marissa S|MS|;Lui|Allan J W|AJW|;Offin|Michael|M|;Kurzatkowski|Christopher|C|;Delasos|Lukas|L|;Khodos|Inna|I|;Asher|Marina|M|;Daly|Robert M|RM|;Rekhtman|Natasha|N|;de Stanchina|Elisa|E|;Ganji|Gopinath|G|;Ladanyi|Marc|M|;Somwar|Romel|R|",
"chemical_list": "C094131:NRG1 protein, human; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtho.2021.03.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-0864",
"issue": "16(7)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": "GSK2849330; HER3 antibody; Lung adenocarcinoma; NRG1 fusion",
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; D040901:Proteomics; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "101274235",
"other_id": null,
"pages": "1149-1165",
"pmc": null,
"pmid": "33839363",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Novel Preclinical Patient-Derived Lung Cancer Models Reveal Inhibition of HER3 and MTOR Signaling as Therapeutic Strategies for NRG1 Fusion-Positive Cancers.",
"title_normalized": "novel preclinical patient derived lung cancer models reveal inhibition of her3 and mtor signaling as therapeutic strategies for nrg1 fusion positive cancers"
}
|
[
{
"companynumb": "US-009507513-2201USA005553",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "4",
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"drugdosagetext": "UNK, CYCLICAL; 4 CYCLES OF SYSTEMIC THERAPY",
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},
{
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},
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"drugdosagetext": "UNK, CYCLICAL; MAINTENACE PERIOD",
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},
{
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},
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"drugdosagetext": "UNK, CYCLICAL; 4 CYCLES OF SYSTEMIC THERAPY",
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"drugindication": "Lung adenocarcinoma",
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},
{
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},
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"drugdosagetext": "UNK, CYCLICAL; MAINTENACE PERIOD",
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"drugtreatmentduration": "4",
"drugtreatmentdurationunit": "802",
"medicinalproduct": "PEMETREXED"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
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"drugcharacterization": "2",
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"drugdosagetext": "UNK, CYCLICAL; 4 CYCLES OF SYSTEMIC THERAPY",
"drugenddate": null,
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"drugindication": "Lung adenocarcinoma",
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"medicinalproduct": "CARBOPLATIN"
}
],
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{
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},
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"literaturereference": "Odintsov Igor, Mattar Marissa S., Lui Allan J.W., Offin Michael, Kurzatkowski Christopher, Delasos Lukas. Novel Preclinical Patient-Derived Lung Cancer Models Reveal Inhibition of HER3 and MTOR Signaling as Therapeutic Strategies for NRG1 Fusion-Positive Cancers. Journal of Thoracic Oncology. 2021;16(7):1149-65",
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"qualification": "3",
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},
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"receiptdate": "20220217",
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}
] |
{
"abstract": "Purpose: To report a case of severe, recurrent bilateral panuveitis secondary to primary progressive multiple sclerosis responsive to ocrelizumab infusions.Observation: We describe the clinical progression of a 40 year old female who presented with a 3-week history of insidious bilateral visual loss that was clinically consistent with panuveitis. A diagnosis of multiple sclerosis was established with serial magnetic resonance imaging (MRI) that coincided with focal neurological events separated by time. There was initially good response to high dose oral prednisolone; however, the patient would have recurrent uveitis each time the dose was weaned. Under guidance of neurology, we had initiated treatment with ocrelizumab with stability of ocular inflammation for the past 24 months.Conclusion: Six-monthly 600mg ocrelizumab infusions may be effective as a steroid sparing option for patients with severe, recurrent bilateral panuveitis secondary to primary progressive multiple sclerosis.",
"affiliations": "Department of Ophthalmology, Queen Elizabeth Hospital, Adelaide, Australia.;Department of Ophthalmology, Queen Elizabeth Hospital, Adelaide, Australia.",
"authors": "Guo|Brad|B|;Little|Matthew|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2021.1980809",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": null,
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-3",
"pmc": null,
"pmid": "34735301",
"pubdate": "2021-11-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Case Report: Recurrent Severe Uveitis Secondary to Primary Progressive Multiple Sclerosis Responsive to Ocrelizumab.",
"title_normalized": "case report recurrent severe uveitis secondary to primary progressive multiple sclerosis responsive to ocrelizumab"
}
|
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}
],
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"qualification": "1",
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},
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},
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},
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"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "High-dose daptomycin (DAP) therapy failed in a neutropenic patient with bloodstream infection caused by a DAP-susceptible Enterococcus faecium (minimum inhibitory concentration, 3 µg/mL) harboring genetic changes associated with DAP resistance, with persistent bacteremia and selection of additional resistances. Daptomycin monotherapy should be used cautiously against DAP-susceptible E. faecium strains with minimum inhibitory concentrations >2 µg/mL.",
"affiliations": "Division of Infectious Diseases, Department of Internal Medicine Division of Infectious Diseases, Department of Medicine, Clinica Alemana de Santiago, Universidad del Desarrollo, Chile.;Geffen School of Medicine at University of California at Los Angeles Los Angeles Biomedical Research Institute, Torrance, California.;Geffen School of Medicine at University of California at Los Angeles.;Division of Infectious Diseases, Department of Internal Medicine.;Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogotá, Colombia.;Division of Infectious Diseases, Department of Internal Medicine Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogotá, Colombia.;Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogotá, Colombia.;Division of Infectious Diseases, Department of Internal Medicine Department of Microbiology and Molecular Genetics, University of Texas Medical School.;Division of Infectious Diseases, Department of Medicine, MD Anderson Cancer Center, Houston.;Geffen School of Medicine at University of California at Los Angeles Los Angeles Biomedical Research Institute, Torrance, California.;Division of Infectious Diseases, Department of Internal Medicine Department of Microbiology and Molecular Genetics, University of Texas Medical School Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogotá, Colombia.",
"authors": "Munita|Jose M|JM|;Mishra|Nagendra N|NN|;Alvarez|Danya|D|;Tran|Truc T|TT|;Diaz|Lorena|L|;Panesso|Diana|D|;Reyes|Jinnethe|J|;Murray|Barbara E|BE|;Adachi|Javier A|JA|;Bayer|Arnold S|AS|;Arias|Cesar A|CA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciu642",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "59(9)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "Enterococcus faecium; daptomycin; resistance; treatment failure",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D064146:Chemotherapy-Induced Febrile Neutropenia; D017576:Daptomycin; D016984:Enterococcus faecium; D017809:Fatal Outcome; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1277-80",
"pmc": null,
"pmid": "25107294",
"pubdate": "2014-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21803704;20010311;19887592;23507277;23882013;22664970;7494007;23959318;24366742;22952824;24867964;23114757;21899450",
"title": "Failure of high-dose daptomycin for bacteremia caused by daptomycin-susceptible Enterococcus faecium harboring LiaSR substitutions.",
"title_normalized": "failure of high dose daptomycin for bacteremia caused by daptomycin susceptible enterococcus faecium harboring liasr substitutions"
}
|
[
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{
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},
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Pneumonia fungal",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
},
{
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},
{
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}
],
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"qualification": "3",
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},
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},
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},
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},
{
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},
{
"reactionmeddrapt": "Candida infection",
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},
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}
],
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"literaturereference": "MUNITA JM, MISHRA NN, ALVAREZ D, TRAN TT, DIAZ L, PANESSO D ET AL. FAILURE OF HIGH-DOSE DAPTOMYCIN FOR BACTEREMIA CAUSED BY DAPTOMYCIN-SUSCEPTIBLE ENTEROCOCCUS FAECIUM HARBORING LIASR SUBSTITUTIONS. CLIN INFECT DIS. 2014?59(9):1277-80.",
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"qualification": "3",
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},
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"receiptdate": "20151023",
"receivedate": "20151023",
"receiver": {
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},
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},
"serious": 1,
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}
] |
{
"abstract": "Acute generalized exanthematous pustulosis (AGEP) is an abrupt cutaneous adverse reaction usually in response to medications. It is generally a self-limiting disease if diagnosed promptly and the offending agent discontinued. Cetirizine, a commonly used anti-histamine medication for the treatment of allergic diseases has few reported side effects and is normally well-tolerated and effective. Herein, the first reported case of cetirizine induced AGEP is presented, followed by a discussion of the clinical and pathological aspects of this adverse cutaneous reaction to a widely used drug. Awareness of this reaction is vital owing to the extensive use of cetirizine and the importance of drug cessation once the reaction is identified. Lastly, other pustular cutaneous reactions may present similarly and therefore accurate identification of this disease can prevent unnecessary diagnostic testing.",
"affiliations": "University of Kansas Medical Center.",
"authors": "Badawi|Ahmed H|AH|;Tefft|Kimberly|K|;Fraga|Garth R|GR|;Liu|Deede Y|DY|",
"chemical_list": "D018926:Anti-Allergic Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D017332:Cetirizine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "20(5)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D018926:Anti-Allergic Agents; D017332:Cetirizine; D002648:Child; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating; D006801:Humans; D006255:Rhinitis, Allergic, Seasonal",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "22613",
"pmc": null,
"pmid": "24852773",
"pubdate": "2014-05-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cetirizine-induced acute generalized exanthematous pustulosis: a serious reaction to a commonly used drug.",
"title_normalized": "cetirizine induced acute generalized exanthematous pustulosis a serious reaction to a commonly used drug"
}
|
[
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{
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"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
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"drugauthorizationnumb": "078615",
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"medicinalproduct": "CETIRIZINE HYDROCHLORIDE (AELLC)"
}
],
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}
],
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},
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"literaturereference": "BADAWI AH, TEFFT K, FRAGA GR, LIU DY. CETIRIZINE-INDUCED ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS: A SERIOUS REACTION TO A COMMONLY USED DRUG. DERMATOL ONLINE J. 2014;20(5):22613.",
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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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},
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},
{
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},
{
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{
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{
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"reactionmeddrapt": "Rash pustular",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "C-reactive protein increased",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Malaise",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BADAWI AH, TEFFT K, FRAGA GR, LIU DY.. CETIRIZINE-INDUCED ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS: A SERIOUS REACTION TO A COMMONLY USED DRUG.. DERMATOL-ONLINE-J. 2014;20(5)",
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"qualification": "3",
"reportercountry": "US"
},
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"receivedate": "20141125",
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},
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},
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"transmissiondate": "20150529"
},
{
"companynumb": "US-APOTEX-2014AP005799",
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{
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"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
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}
],
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{
"reactionmeddrapt": "Acute generalised exanthematous pustulosis",
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}
],
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},
"primarysource": {
"literaturereference": "BADAWI AH, TEFFT K, FRAGA GR, LIU DY.. CETIRIZINE-INDUCED ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS: A SERIOUS REACTION TO A COMMONLY USED DRUG.. DERMATOL-ONLINE-J. 2014;20",
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"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20141125",
"receivedate": "20141125",
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},
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},
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},
{
"companynumb": "US-MYLANLABS-2014M1011664",
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"occurcountry": "US",
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{
"actiondrug": "1",
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"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
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}
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],
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},
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"literaturereference": "BADAWI AH, TEFFT K, FRAGA GR, LIU DY. CETIRIZINE-INDUCED ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS: A SERIOUS REACTION TO A COMMONLY USED DRUG. DERMATOL-ONLINE-J 2014; 20 NO. 5",
"literaturereference_normalized": "cetirizine induced acute generalized exanthematous pustulosis a serious reaction to a commonly used drug",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
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},
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"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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}
] |
{
"abstract": "The present translational study aimed to verify whether serial 18F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive 18F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min-1 × g-1 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min-1 × g-1, P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min-1 × g-1, P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline 18F-FDG uptake. These results imply that low myocardial 18F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.",
"affiliations": "Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Clinic of Cardiovascular Diseases, IRCCS-AOU San Martino-IST, Genoa, Italy.;Unit of Experimental Therapy in Oncology, IRCCS Gaslini, Genoa, Italy.;Clinic of Cardiovascular Diseases, IRCCS-AOU San Martino-IST, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Haematology Clinic, University of Genoa, IRCCS-AOU San Martino-IST, Genoa, Italy.;Clinic of Cardiovascular Diseases, IRCCS-AOU San Martino-IST, Genoa, Italy.;Animal Facility, IRCCS-AOU San Martino-IST, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Clinic of Internal Medicine 3, IRCCS-AOU San Martino-IST, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Clinic of Cardiovascular Diseases, IRCCS-AOU San Martino-IST, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy.;Haematology Clinic, University of Genoa, IRCCS-AOU San Martino-IST, Genoa, Italy.;Unit of Experimental Therapy in Oncology, IRCCS Gaslini, Genoa, Italy.;Clinic of Cardiovascular Diseases, IRCCS-AOU San Martino-IST, Genoa, Italy.;Department of Research, Innovation, and Statistics, Lacassagne Cancer Centre, Nice, France.;Epidemiology Unit, IRCCS-AOU San Martino-IST, Genoa, Italy; and.;Nuclear Medicine, IRCCS-AOU San Martino-IST and University of Genoa, Genoa, Italy [email protected].;CNR Institute of Bioimaging and Molecular Physiology, Section of Genoa, Milan, Italy.",
"authors": "Bauckneht|Matteo|M|;Ferrarazzo|Giulia|G|;Fiz|Francesco|F|;Morbelli|Silvia|S|;Sarocchi|Matteo|M|;Pastorino|Fabio|F|;Ghidella|Alberto|A|;Pomposelli|Elena|E|;Miglino|Maurizio|M|;Ameri|Pietro|P|;Emionite|Laura|L|;Ticconi|Flavia|F|;Arboscello|Eleonora|E|;Buschiazzo|Ambra|A|;Massimelli|Elena Augusta|EA|;Fiordoro|Salvatore|S|;Borra|Anna|A|;Cossu|Vanessa|V|;Bozzano|Annalisa|A|;Ibatici|Adalberto|A|;Ponzoni|Mirco|M|;Spallarossa|Paolo|P|;Gallamini|Andrea|A|;Bruzzi|Paolo|P|;Sambuceti|Gianmario|G|;Marini|Cecilia|C|",
"chemical_list": "D019788:Fluorodeoxyglucose F18; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.2967/jnumed.117.191122",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0161-5505",
"issue": "58(10)",
"journal": "Journal of nuclear medicine : official publication, Society of Nuclear Medicine",
"keywords": "FDG PET/CT; doxorubicin; myocardial metabolism",
"medline_ta": "J Nucl Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000818:Animals; D001692:Biological Transport; D066126:Cardiotoxicity; D004317:Doxorubicin; D005260:Female; D019788:Fluorodeoxyglucose F18; D006321:Heart; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium; D000072078:Positron Emission Tomography Computed Tomography; D011379:Prognosis; D057170:Translational Research, Biomedical; D055815:Young Adult",
"nlm_unique_id": "0217410",
"other_id": null,
"pages": "1638-1645",
"pmc": null,
"pmid": "28646013",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational 18F-FDG PET/CT Observation.",
"title_normalized": "doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity a translational 18f fdg pet ct observation"
}
|
[
{
"companynumb": "IT-JNJFOC-20170820879",
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"occurcountry": "IT",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "050718",
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"drugcharacterization": "1",
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"drugdosageform": "LIPOSOME INJECTION",
"drugdosagetext": "40-50 MG/M2 PER CYCLIC",
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"medicinalproduct": "DOXORUBICIN HYDROCHLORIDE."
},
{
"actiondrug": "5",
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"activesubstancename": "BLEOMYCIN SULFATE"
},
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"medicinalproduct": "BLEOMYCIN"
},
{
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},
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},
{
"actiondrug": "5",
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"activesubstancename": "DACARBAZINE"
},
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"medicinalproduct": "DACARBAZINE."
},
{
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"activesubstancename": "DEXAMETHASONE"
},
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"medicinalproduct": "DEXAMETHASONE."
},
{
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"activesubstancename": "VINCRISTINE"
},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugindication": "HODGKIN^S DISEASE",
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"medicinalproduct": "VINCRISTINE"
}
],
"patientagegroup": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Left ventricular dysfunction",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Atrial fibrillation",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ejection fraction decreased",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Electrocardiogram T wave inversion",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BAUCKNEHT M, FERRARAZZO G, FIZ F, MORBELLI S, SAROCCHI M, PASTORINO F, ET AL. DOXORUBICIN EFFECT ON MYOCARDIAL METABOLISM AS A PREREQUISITE FOR SUBSEQUENT DEVELOPMENT OF CARDIAC TOXICITY: A TRANSLATIONAL 18F-FDG PET/CT OBSERVATION. CLINICAL AND TRANSLATIONAL IMAGING 2017?5 (SUPPL 1):S19- S20. SAMBUCETI G, MORBELLI S, COSSU V, MARINI C, BAUCKNEHT M. DOXORUBICIN EFFECT ON MYOCARDIAL METABOLISM AS A PREREQUISITE FOR SUBSEQUENT DEVELOPMENT OF CARDIAC TOXICITY: ARE THERE UNSUSPECTED CONFOUNDERS. J N",
"literaturereference_normalized": "doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity a translational 18f fdg pet ct observation",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20190510",
"receivedate": "20171102",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14152242,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "Lapatinib is an orally bioavailable dual inhibitor of the intracellular domain of both the HER2 protein and the epidermal growth factor receptor. This dual inhibitor can effectively prevent the downstream signal transduction initiated by a tyrosine kinase, thereby reducing the proliferation rate of tumor cells. Lapatinib was demonstrated to be beneficial in patients with HER2-positive locally advanced and metastatic breast cancer. We present here a case of interstitial pneumonitis that occurred after lapatinib treatment. A 79-year-old woman was diagnosed with Stage III infiltrating ductal carcinoma of the right breast. She underwent a modified radical mastectomy in January 2009, followed by anthracycline and paclitaxel plus trastuzumab administration. In November 2015, lung metastatic disease was detected. Therefore, lapatinib plus letrozole administration was initiated. Twelve days after starting treatment, she developed severe eruptions along with dyspnea. Radiography and a CT scan showed a diffuse ground glass shadow. Both her symptoms and the radiographic findings improved dramatically after the start of high-dose corticosteroid therapy. Clinicians should be aware that lapatinib has the potential to cause lung injury.",
"affiliations": "Dept. of Surgery, Kansai Medical University Medical Center.",
"authors": "Yamamoto|Daigo|D|;Yamamoto|Chizuko|C|;Yamamoto|Mitsuo|M|",
"chemical_list": "D009570:Nitriles; D011799:Quinazolines; D014230:Triazoles; D000077341:Lapatinib; D000077289:Letrozole; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D000077341:Lapatinib; D000077289:Letrozole; D017563:Lung Diseases, Interstitial; D009570:Nitriles; D011799:Quinazolines; D014230:Triazoles",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2059-2061",
"pmc": null,
"pmid": "28133221",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Interstitial Pneumonitis Induced by Lapatinib plus Letrozole.",
"title_normalized": "a case of interstitial pneumonitis induced by lapatinib plus letrozole"
}
|
[
{
"companynumb": "JP-INDICUS PHARMA-000478",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAPATINIB"
},
"drugadditional": "1",
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"drugcharacterization": "1",
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"drugindication": "METASTASES TO LUNG",
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"drugrecurrence": [
{
"drugrecuraction": "Interstitial lung disease"
}
],
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"drugstartdate": "201511",
"drugstartdateformat": "610",
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{
"abstract": "BACKGROUND\nThis pilot study evaluated the effect of short- and long-term ivacaftor treatment on hyperpolarized 3He-magnetic resonance imaging (MRI)-defined ventilation defects in patients with cystic fibrosis aged ≥12years with a G551D-CFTR mutation.\n\n\nMETHODS\nPart A (single-blind) comprised 4weeks of ivacaftor treatment; Part B (open-label) comprised 48weeks of treatment. The primary outcome was change from baseline in total ventilation defect (TVD; total defect volume:total lung volume ratio).\n\n\nRESULTS\nMean change in TVD ranged from -8.2% (p=0.0547) to -12.8% (p=0.0078) in Part A (n=8) and -6.3% (p=0.1953) to -9.0% (p=0.0547) in Part B (n=8) as assessed by human reader and computer algorithm, respectively.\n\n\nCONCLUSIONS\nTVD responded to ivacaftor therapy. 3He-MRI provides an individual quantification of disease burden that may be able to detect aspects of the disease missed by population-based spirometry metrics. Assessments by human reader and computer algorithm exhibit similar trends, but the latter appears more sensitive. www.clinicaltrials.gov identifier: NCT01161537.",
"affiliations": "Department of Radiology, One Hospital Drive, University of Missouri, Columbia, MO 65212, USA. Electronic address: [email protected].;Vertex Pharmaceuticals Incorporated, 50 Northern Ave Boston, MA 02210, USA. Electronic address: [email protected].;Vertex Pharmaceuticals Incorporated, 50 Northern Ave Boston, MA 02210, USA. Electronic address: [email protected].;Vertex Pharmaceuticals Incorporated, 50 Northern Ave Boston, MA 02210, USA. Electronic address: [email protected].;University of Virginia, 480 Ray C. Hunt Drive, Snyder Building, Office 124, Charlottesville, VA 22903, USA. Electronic address: [email protected].;University of Virginia, University Hospital, First Floor 1215 Lee St., Charlottesville, VA, 22908, USA. Electronic address: [email protected].;University of Virginia, University Hospital, First Floor 1215 Lee St., Charlottesville, VA, 22908, USA. Electronic address: [email protected].;University of Virginia, 100 Hospital Dr #5408, Charlottesville, VA 22903, USA. Electronic address: [email protected].;University of Virginia, Snyder Translational Research Building - Room 154, 480 Ray C. Hunt Drive, Charlottesville, VA 22903, USA. Electronic address: [email protected].",
"authors": "Altes|Talissa A|TA|;Johnson|Mac|M|;Fidler|Meredith|M|;Botfield|Martyn|M|;Tustison|Nicholas J|NJ|;Leiva-Salinas|Carlos|C|;de Lange|Eduard E|EE|;Froh|Deborah|D|;Mugler|John P|JP|",
"chemical_list": "D000627:Aminophenols; D065101:Chloride Channel Agonists; D007554:Isotopes; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; D006371:Helium; C000615206:Helium-3",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcf.2016.12.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1569-1993",
"issue": "16(2)",
"journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society",
"keywords": "cystic fibrosis transmembrane conductance regulator modulator; forced expiratory volume; pulmonary",
"medline_ta": "J Cyst Fibros",
"mesh_terms": "D000328:Adult; D000627:Aminophenols; D065101:Chloride Channel Agonists; D003550:Cystic Fibrosis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005541:Forced Expiratory Volume; D006371:Helium; D006801:Humans; D007554:Isotopes; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017063:Outcome Assessment, Health Care; D010865:Pilot Projects; D012123:Pulmonary Ventilation; D015363:Quinolones; D016037:Single-Blind Method",
"nlm_unique_id": "101128966",
"other_id": null,
"pages": "267-274",
"pmc": null,
"pmid": "28132845",
"pubdate": "2017-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Use of hyperpolarized helium-3 MRI to assess response to ivacaftor treatment in patients with cystic fibrosis.",
"title_normalized": "use of hyperpolarized helium 3 mri to assess response to ivacaftor treatment in patients with cystic fibrosis"
}
|
[
{
"companynumb": "US-VERTEX PHARMACEUTICALS-2018-000640",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IVACAFTOR"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": "203188",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "TABLET",
"drugdosagetext": null,
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"drugindication": "CYSTIC FIBROSIS",
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"drugrecurreadministration": "3",
"drugrecurrence": null,
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"medicinalproduct": "KALYDECO"
}
],
"patientagegroup": null,
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Infective pulmonary exacerbation of cystic fibrosis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ALTES TA, JOHNSON M, FIDLER M, BOTFIELD M, TUSTISON NJ, LEIVA-SALINAS C, ET AL.. USE OF HYPERPOLARIZED HELIUM-3 MRI TO ASSESS RESPONSE TO IVACAFTOR TREATMENT IN PATIENTS WITH CYSTIC FIBROSIS. J CYST FIBROS. 2017?16:267-274",
"literaturereference_normalized": "use of hyperpolarized helium 3 mri to assess response to ivacaftor treatment in patients with cystic fibrosis",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180129",
"receivedate": "20180129",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14454234,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Introduction Coronavirus pneumonia not only severely affects the lung tissue but is also associated with systemic autoimmune inflammation, rapid overactivation of cytokines and chemokines known as \"cytokine storm\", and a high risk of thrombosis and thromboembolism. Since there is no specific therapy for this new coronavirus infection (COVID-19), searching for an effective and safe anti-inflammatory therapy is critical.Materials and methods This study evaluated efficacy and safety of pulse therapy with high doses of glucocorticosteroids (GCS), methylprednisolone 1,000 mg for 3 days plus dexamethasone 8 mg for another 3-5 days, in 17 patients with severe coronavirus pneumonia as a part of retrospective comparative analysis (17 patients in control group). The study primary endpoint was the aggregate dynamics of patients' condition as evaluated by an original CCS-COVID scale, which included, in addition to the clinical status, assessments of changes in the inflammation marker, C-reactive protein (CRP); the thrombus formation marker, D-dimer; and the extent of lung injury evaluated by computed tomography (CT). Patients had signs of lung injury (53.2 % and 25.6 %), increases in CRP 27 and 19 times, and a more than doubled level of D-dimer (to 1.41 µg/ml and 1.15 µg/ml) in the active therapy and the control groups, respectively. The GCS treatment group had a more severe condition at baseline.Results The GCS pulse therapy proved effective and significantly decreased the CCS-COVID scores. Median score difference was 5.00 compared to the control group (р=0.011). Shortness of breath considerably decreased; oxygen saturation increased, and the NEWS-2 clinical status scale scores decreased. In the GCS group, concentration of CRP significantly decreased from 134 mg/dl to 41.8 mg/dl (р=0.009) but at the same time, D-dimer level significantly increased from 1.41 µg/ml to 1.98 µg/ml (р=0.044). In the control group, the changes were nonsignificant. The dynamics of lung injury by CT was better in the treatment group but the difference did not reach a statistical significance (р=0.062). Following the GCS treatment, neutrophilia increased (р=0.0001) with persisting lymphopenia, and the neutrophil/lymphocyte (N/L) ratio, a marker of chronic inflammation, increased 2.5 times (р=0.006). The changes in the N/L ratio and D-dimer were found to correlate in the GCS pulse therapy group (r =0.49, p=0.04), which underlined the relationship of chronic autoimmune inflammation with thrombus formation in COVID-19. No significant changes were observed in the control group. In result, four patients developed venous thromboembolic complications (two of them had pulmonary artery thromboembolism) after the GCS pulse therapy despite the concomitant antiplatelet treatment at therapeutic doses. Recovery was slower in the hormone treatment group (median stay in the hospital was 26 days vs 18 days in the control group, р=0.001).Conclusion Pulse therapy with high doses of GCS exerted a rapid anti-inflammatory effect but at the same time, increased the N/L ratio and the D-dimer level, which increased the risk of thromboembolism.",
"affiliations": "Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;National Medical Research Centre for Therapy and Preventive Medicine, Moscow, Russia Robertson Centre for Biostatistics. University of Glasgow.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.;Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia.",
"authors": "Mareev|V Yu|VY|;Orlova|Ya A|YA|;Pavlikova|E P|EP|;Matskeplishvili|S T|ST|;Krasnova|T N|TN|;Malahov|P S|PS|;Samokhodskaya|L M|LM|;Mershina|E A|EA|;Sinitsyn|V E|VE|;Mareev|Yu V|YV|;Kalinkin|A L|AL|;Begrambekova|Yu L|YL|;Kamalov|A A|AA|",
"chemical_list": "D013256:Steroids",
"country": "Russia (Federation)",
"delete": false,
"doi": "10.18087/cardio.2020.6.n1226",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9040",
"issue": "60(6)",
"journal": "Kardiologiia",
"keywords": null,
"medline_ta": "Kardiologiia",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D006801:Humans; D007249:Inflammation; D058873:Pandemics; D011024:Pneumonia, Viral; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D013256:Steroids; D020246:Venous Thrombosis",
"nlm_unique_id": "0376351",
"other_id": null,
"pages": "15-29",
"pmc": null,
"pmid": "32720612",
"pubdate": "2020-07-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Steroid pulse -therapy in patients With coronAvirus Pneumonia (COVID-19), sYstemic inFlammation And Risk of vEnous thRombosis and thromboembolism (WAYFARER Study).",
"title_normalized": "steroid pulse therapy in patients with coronavirus pneumonia covid 19 systemic inflammation and risk of venous thrombosis and thromboembolism wayfarer study"
}
|
[
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
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"abstract": "OBJECTIVE\nTo describe the pharmacodynamic monitoring of (immuno)proteasome inhibition following treatment with bortezomib in a therapy-refractory systemic lupus erythematosus (SLE) patient with life-threatening myocarditis and lupus nephritis.\n\n\nMETHODS\nInhibition of catalytic activities of the proteasome subunits β5 (constitutive proteasome), β5i and β1i (immunoproteasome) were measured in peripheral blood mononuclear cells using subunit-specific fluorogenic peptide substrates in a patient who received three cycles of bortezomib (1.3 mg/m(2) subcutaneously, days 1, 4, 8 and 11; every three weeks) along with plasma exchange during the first two cycles.\n\n\nRESULTS\nProteasome β5, β5i and β1i subunit activities were readily inhibited 1 h after bortezomib administration. Twenty-four hours post-bortezomib administration, β5 and β5i activities were largely restored, whereas inhibition of β1i activity was sustained. Clinically, after three cycles, cardiac function had improved, with concurrent improvement of haemodynamic stability during haemodialysis. Anti-ds-DNA dropped from >400 to 12 IU/mL along with normalisation of complement C3 and C4. Bortezomib therapy was well tolerated, and patient now has a sustained remission for >16 months.\n\n\nCONCLUSIONS\nThis case illustrates the potential benefit of pharmacodynamic monitoring of (immune)proteasome subunit-specific activity after bortezomib dosing in patients with therapy refractory SLE. This tool may hold potential to guide personalised/precision dosing aiming to achieve maximal efficacy and minimal toxicity.",
"affiliations": "Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.;Takeda Oncology, Cambridge, MA 02139, USA.;Department of Pathology and Cardiac Surgery, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.;Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.;Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.;Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands.;Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.",
"authors": "de Groot|Karina A|KA|;Tsang A Sjoe|Michel|M|;Niewerth|Denise|D|;Cloos|Jacqueline|J|;Blank|Jonathan L|JL|;Niessen|Hans W M|HW|;Zweegman|Sonja|S|;Voskuyl|Alexandre E|AE|;Jansen|Gerrit|G|;van der Heijden|Joost W|JW|",
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"fulltext": "\n==== Front\nLupus Sci MedLupus Sci MedlupusscimedlupusLupus Science & Medicine2053-8790BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR lupus-2015-00012110.1136/lupus-2015-000121Brief Communication1506Pharmacodynamic monitoring of (immuno)proteasome inhibition during bortezomib treatment of a critically ill patient with lupus nephritis and myocarditis de Groot Karina A 1Tsang a Sjoe Michel 2Niewerth Denise 3Cloos Jacqueline 3Blank Jonathan L 4Niessen Hans W M 5Zweegman Sonja 6Voskuyl Alexandre E 2Jansen Gerrit 2van der Heijden Joost W 11 Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands2 Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands3 Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands4 Takeda Oncology, Cambridge, MA 02139, USA5 Department of Pathology and Cardiac Surgery, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands6 Department of Hematology, VU University Medical Center, Amsterdam, The NetherlandsCorrespondence to Dr Joost W van der Heijden; [email protected] 18 12 2015 2 1 e00012111 8 2015 8 11 2015 12 11 2015 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/2015This is an Open Access article 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. See: http://creativecommons.org/licenses/by-nc/4.0/Objective\nTo describe the pharmacodynamic monitoring of (immuno)proteasome inhibition following treatment with bortezomib in a therapy-refractory systemic lupus erythematosus (SLE) patient with life-threatening myocarditis and lupus nephritis.\n\nPatient and methods\nInhibition of catalytic activities of the proteasome subunits β5 (constitutive proteasome), β5i and β1i (immunoproteasome) were measured in peripheral blood mononuclear cells using subunit-specific fluorogenic peptide substrates in a patient who received three cycles of bortezomib (1.3 mg/m2 subcutaneously, days 1, 4, 8 and 11; every three weeks) along with plasma exchange during the first two cycles.\n\nResults\nProteasome β5, β5i and β1i subunit activities were readily inhibited 1 h after bortezomib administration. Twenty-four hours post-bortezomib administration, β5 and β5i activities were largely restored, whereas inhibition of β1i activity was sustained. Clinically, after three cycles, cardiac function had improved, with concurrent improvement of haemodynamic stability during haemodialysis. Anti-ds-DNA dropped from >400 to 12 IU/mL along with normalisation of complement C3 and C4. Bortezomib therapy was well tolerated, and patient now has a sustained remission for >16 months.\n\nConclusions\nThis case illustrates the potential benefit of pharmacodynamic monitoring of (immune)proteasome subunit-specific activity after bortezomib dosing in patients with therapy refractory SLE. This tool may hold potential to guide personalised/precision dosing aiming to achieve maximal efficacy and minimal toxicity.\n\nSystemic Lupus ErythematosusLupus NephritisB cellsPharmacokinetics\n==== Body\nIntroduction\nSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogeneous presentation and involvement of multiple organ systems, resulting in high morbidity and a threefold higher mortality rate than the general population. Myocarditis is an uncommon manifestation and occurs particularly in conjunction with pericarditis. Active nephropathy is observed in nearly 30% of patients with SLE and is associated with a further increase in mortality risk.1 To date, beyond conventional immunosuppressive agents, various biologicals are used for therapy: rituximab and belimumab (targeting B cells), abatacept (inhibition of T cell activation) and eculizumab (interfering in the complement cascade), demonstrating variable efficacies.2 In spite of these therapies, a subgroup of patients with SLE are refractory to treatment and experience increasing morbidity due to ongoing disease activity and/or drug toxicity.\n\nProteasome inhibitors have been identified as a novel experimental treatment modality based on their mechanisms of action (depletion of long-lived plasma cells and inhibitory effects on critical signalling pathways) and have encouraging effects in animal models with lupus-like disease.3–5 The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma6 and has also been successfully applied in a small group of refractory patients with SLE7 and two patients with SLE with concomitant multiple myeloma.8 These observations warrant further clinical evaluation of bortezomib treatment in patients with refractory SLE, ideally in combination with pharmacodynamic end point assessments. Pharmacokinetic testing in multiple myeloma showed that subcutaneous administration of bortezomib confers similar area under the curve concentrations as intravenous administration, but with much lower peak levels and subsequently reduction of side effects (eg, polyneuropathy). Pharmacodynamic monitoring in these trials was performed by measuring the inhibition of the activity of the constitutive proteasome subunit β5 by bortezomib.9 Autoimmune diseases like SLE, however, are characterised by upregulation of immunoproteasome subunits.10\n11 New assays are now available to measure the specific catalytic activity of the subunits of the immunoproteasome, and these assays could be of value to optimise dosing of bortezomib in patients with SLE. Here, as a feasibility study, we measured the specific activity of the immunoproteasome subunits β5i and β1i, as well as the constitutive proteasome subunit β5, in blood cells during bortezomib treatment.\n\nMaterials and methods\nCatalytic activity of (immuno)proteasome subunits\nWhen feasible, blood samples were drawn prior to bortezomib therapy and 1 and 24 h after bortezomib administration during consecutive cycles of bortezomib. Peripheral blood mononuclear cells (PBMCs) were harvested by Ficoll density gradient centrifugation and stored at −80°C until analysis. Catalytic activity of constitutive proteasome subunit β5 and the immunoproteasome subunits β5i and β1i was analysed in cell extracts of PBMCs using specific fluorogenic peptide substrates; Ac-WLA-AMC, Ac-ANW-AMC and Ac-PAL-AMC, respectively, essentially as described previously.12\n\nPatient history\nA 43-year-old male patient from South American origin was diagnosed with SLE in 2009, based on pericarditis, arthritis, lymphadenopathy and positive autoimmune serology (antinuclear, anti-dsDNA, anti-Sm and anti-RNP antibodies). He had a history of persistent disease (arthritis, myopathy and lymphadenopathy) under successive treatments with hydroxychloroquine, azathioprine, rituximab and mycophenolate mofetil (MMF) in combination with prednisolone and courses of methylprednisolone (MPNS). Despite this treatment, he was diagnosed with proliferative lupus nephritis (ISN/RPS class IV-G) in August 2012 for which he was treated with cyclophosphamide according to the ‘Eurolupus’ regimen and subsequently with MMF. With this treatment, his kidney function recovered and urinalysis normalised.\n\nIn April 2013, he developed heart failure. A myocardial biopsy showed evidence of myocarditis with abundant infiltration of macrophages next to lymphocytes (figure 1). He was treated with MPNS and intravenous immunoglobulin. This resulted in a temporary clinical response, but in November 2013 he was admitted to the intensive care unit with respiratory failure caused by heart failure and acute kidney failure, despite maintenance therapy with corticoids and MMF. The acute kidney failure was induced by a flare of lupus nephritis (proteinuria increased to 1.6 g/day), probably concomitant with acute tubular necrosis due to heart failure. Treatment included non-invasive ventilation, renal replacement therapy and MPNS. At this stage, experimental therapy with bortezomib (1.3 mg/m2, subcutaneous, days 1, 4, 8 and 11; every three weeks) was started because of the otherwise expected fatal outcome, in combination with plasma exchange during the first two cycles. Bortezomib therapy was well tolerated (except for transient thrombocytopenia during the first cycle) and effective. After three cycles, cardiac function had improved, along with normalisation of anti-ds-DNA levels (>400 to 12 IU/mL) and complement C3 and C4 (figure 2). Maintenance therapy consisted of MMF 1000 mg twice daily and low-dose prednisolone. The patient now has a sustained remission for almost 2 years.\n\nFigure 1 Immunohistochemical staining of myocardial tissue before start of bortezomib treatment. (A) Lymphocytes (CD45) and (B) macrophages (CD68). Magnification ×200.\n\nFigure 2 Time course for laboratory parameters of a patient with systemic lupus erythematosus prior and during bortezomib therapy (arrow). (A) Anti-ds-DNA (normal range: <15 IU/mL), (B) erythrocyte sedimentation rate (ESR; normal: <10 mm/h), (C) complement C3 (normal range: 0.9–1.8 g/L) and (D) complement C4 (normal range: 0.15–0.4 g/L).\n\nFrom blood samples drawn during the first two cycles, pharmacodynamic monitoring of inhibition of catalytic activity of individual proteasome subunits known to be targeted by bortezomib, that is, constitutive β5 and the immunoproteasome subunits β5i and β1i, was assessed (figure 3). In PBMCs, 1 h after bortezomib administration, β5-activity was suppressed (mean 45% compared with untreated controls), but this activity was largely recovered 24 h later. Likewise, immunoproteasome β5i catalytic activity was potently inhibited 1 h after drug administration (mean 73% compared with untreated controls). After 24 h, residual β5i inhibition was 25% compared with untreated control. Finally, β1i activity was also potently inhibited 1 h after bortezomib administration (mean 74% compared with untreated controls), but remarkably, this inhibition was largely sustained (mean 65% compared with untreated controls) over 24 h.\n\nFigure 3 Bortezomib (BTZ)-induced inhibition of (immuno)proteasome activity in peripheral blood cells of a patient with systemic lupus erythematosus . Catalytic activity of β5, β5i and β1i is depicted at three time points during bortezomib treatment either prior to bortezomib dosing and 1 and 24 h post-bortezomib administration. NA, sample not available.\n\nDiscussion\nIn this study, we describe for the first time the dynamics of immunoproteasome inhibition in this patient with SLE by assessment of bortezomib-induced inhibition in PBMCs of the catalytic activities associated with the β5i and β1i immunoproteasome subunits, next to the β5 constitutive subunit. Consistent with bortezomib being a reversible proteasome inhibitor,3 inhibition of β5 and β5i shortly after bortezomib administration was largely relieved after 24 h. Interestingly, dynamics of β1i catalytic activity showed a different profile. First, inhibition by bortezomib was sustained for >24 h. Second, basal β1i activity appears to decrease during the course of bortezomib. The latter could reflect the loss of immune-competent cells with aberrant β1i activity during treatment. In this regard, Ghannam et al10 showed that active inflammation in myositis was associated with upregulation of β1i expression. Similarly, Morawietz et al11 showed that expression of β1i is significantly increased in inflammatory infiltrates of salivary glands in patients with Sjogren’s syndrome. As bortezomib targeting may involve various immune cells (B cells, plasma cells, T cells, macrophages and dendritic cells),3\n4\n13 it is conceivable that inhibition of β1i activity therein contributes to bortezomib's therapeutic effect, for example, by induction of apoptosis, suppression of pro-inflammatory cytokine release and/or altered generation of antigenic peptides with a consequently lower autoimmune response.\n\nTogether with the first two cycles of bortezomib, our patient received plasma exchanges that could have contributed to his recovery. Although plasma exchange is still recommended in life-threatening SLE disease activity, several studies did not show any benefits of plasma exchanges in patients with active lupus nephritis.14 Moreover, the sustained clinical response makes a plasma exchange-induced improvement less likely.\n\nGiven the fact that bortezomib therapy showed efficacy by inducing remission of disease activity in several individual cases and large case series of patients with therapy-refractory SLE,7\n8\n15 further exploration of proteasome inhibitor-based therapies is warranted.\n\nAlthough bortezomib therapy over three cycles was well tolerated by our patient (except for transient thrombocytopenia), awareness of potential toxic side effects should be considered in case of repeated treatments.6 Specific adverse events may include peripheral neuropathy, thrombocytopenia, diarrhoea and infectious complications, among which the latter were reported by Alexander and colleagues in a series of 12 patients with SLE treated with bortezomib7 according to schedules applied for multiple myeloma treatment.6\n15\n\nAssessment of ‘molecular therapeutic efficacy’ by measuring (immuno)proteasome subunit inhibition, particularly of the β1i subunit, would be helpful to design optimal dosing strategies in future clinical studies with bortezomib to achieve maximal efficacy and minimal toxicity for patients with refractory SLE.\n\nThe authors thank Johan van Meerloo for technical assistance.\n\nContributors: Design of study: JWvdH, SZ and GJ. Clinical data acquisition: KAdG, MTS, HMWN, SZ, AEV and JWvdH. Conducted experiments: DN, JC and GJ. Contributed to reagents and analytic tools: DN and JLB. Data analysis: KAdG, DN, JC, HWMN, GJ and JWvdH. Writing of the manuscript: KAdG, SZ, AEV, GJ and JWvdH.\n\nCompeting interests: SZ reports grant from Janssen, Celgene and Takeda, outside the submitted work. JC reports speakers fees from Takeda, outside the submitted work. JLB is employee of Takeda Oncology.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Cervera R , Khamashta MA , Hughes GR \nThe Euro-lupus project: epidemiology of systemic lupus erythematosus in Europe . Lupus \n2009 ;18 :869 –74 . doi:10.1177/096120330910683119671784 \n2 Isenberg DA , Rahman A \nSystemic lupus erythematosus in 2013. Taking a closer look at biologic therapy for SLE . Nat Rev Rheumatol \n2014 ;10 :71 –2 . doi:10.1038/nrrheum.2013.20324342984 \n3 Verbrugge SE , Scheper RJ , Lems WF \nProteasome inhibitors as experimental therapeutics of autoimmune diseases . Arthritis Res Ther \n2015 ;17 :17 \ndoi:10.1186/s13075-015-0529-125889583 \n4 Neubert K , Meister S , Moser K \nThe proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis . Nat Med \n2008 ;14 :748 –55 . doi:10.1038/nm176318542049 \n5 Ichikawa HT , Conley T , Muchamuel T \nBeneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells . Arthritis Rheum \n2012 ;64 :493 –503 . doi:10.1002/art.3333321905015 \n6 Moreau P , Richardson PG , Cavo M \nProteasome inhibitors in multiple myeloma: 10 years later . Blood \n2012 ;120 :947 –59 . doi:10.1182/blood-2012-04-40373322645181 \n7 Alexander T , Sarfert R , Klotsche J \nThe proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus . Ann Rheum Dis \n2015 ;74 :1474 –8 . doi:10.1136/annrheumdis-2014-20601625710470 \n8 Frohlich K , Holle JU , Aries PM \nSuccessful use of bortezomib in a patient with systemic lupus erythematosus and multiple myeloma . Ann Rheum Dis \n2011 ;70 :1344 –5 . doi:10.1136/ard.2010.13325621173019 \n9 Moreau P , Karamanesht II , Domnikova N \nPharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma . Clin Pharmacokinet \n2012 ;51 :823 –9 . doi:10.1007/s40262-012-0010-023018466 \n10 Ghannam K , Martinez-Gamboa L , Spengler L \nUpregulation of immunoproteasome subunits in myositis indicates active inflammation with involvement of antigen presenting cells, CD8 T-cells and IFNGamma . PLoS ONE \n2014 ;9 :e104048 \ndoi:10.1371/journal.pone.010404825098831 \n11 Morawietz L , Martinez-Gamboa L , Scheffler S \nExpression of proteasomal immunosubunit beta1i is dysregulated in inflammatory infiltrates of minor salivary glands in Sjogren's syndrome . J Rheumatol \n2009 ;36 :2694 –703 . doi:10.3899/jrheum.08109819833746 \n12 Niewerth D , Kaspers GJ , Assaraf YG \nInterferon-gamma-induced upregulation of immunoproteasome subunit assembly overcomes bortezomib resistance in human hematological cell lines . J Hematol Oncol \n2014 ;7 :7 \ndoi:10.1186/1756-8722-7-724418325 \n13 van der Heijden JW , Oerlemans R , Lems WF \nThe proteasome inhibitor bortezomib inhibits the release of NFkappaB-inducible cytokines and induces apoptosis of activated T cells from rheumatoid arthritis patients . Clin Exp Rheumatol \n2009 ;27 :92 –8 .19327235 \n14 Lewis EJ , Hunsicker LG , Lan SP \nA controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group . N Engl J Med \n1992 ;326 :1373 –9 . doi:10.1056/NEJM1992052132621011569973 \n15 Quartuccio L , Rupolo M , Michieli M \nEfficacy and tolerability of repeated cycles of a once-weekly regimen of bortezomib in lupus . Rheumatology (Oxford) \n2014 ;53 :381 –2 . doi:10.1093/rheumatology/ket28423962626\n\n",
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"abstract": "Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder involving abnormal motility. The patients are commonly started on symptom control management for IBS - diarrhea subtype by prescribing antimotility agents, usually having opioid agonist activity, and newer medications have been emerging for this as well. Patients sometimes self-medicate themselves to exceedingly high doses of these medications to achieve symptoms control. There are only a few cases of opioid-induced arrhythmia in the literature, primarily loperamide being used as a drug substitute by substance abusers. Still, it has been rarely reported to cause arrhythmia in a patient with IBS. We present a case of a 33-year-old female with a past medical history of hypertension and depression who presented to the emergency department for evaluation of syncope. She had wide complex tachycardia on electrocardiogram (EKG) with prolonged rate-corrected QT interval (QTc). Her medications, including eluxadoline, Lomotil, and loperamide, were held and she was discharged on mexiletine with normal QTc. She did not have any more incidences of arrhythmia. This case highlights the importance of not overdosing on opioid agonist medications prescribed to treat IBS as these can lead to potentially fatal complications. Physicians have to be judicious in promptly determining that the cause of arrhythmia can also be over-the-counter (OTC) medications.",
"affiliations": "Internal Medicine, Charleston Area Medical Center, Charleston, USA.;Internal Medicine, Rapides Regional Medical Center, Alexandria, USA.;Cardiology, Rapides Regional Medical Center, Alexandria, USA.",
"authors": "Rawala|Muhammad Shabbir|MS|;Gulati|Rajat|R|;Rizvi|Syed|S|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8243\nCardiology\nInternal Medicine\nCardiac Dysrhythmia Associated With Opioid Toxicity\nMuacevic Alexander Adler John R Rawala Muhammad Shabbir 1 Gulati Rajat 2 Rizvi Syed 3 \n1 \nInternal Medicine, Charleston Area Medical Center, Charleston, USA \n\n2 \nInternal Medicine, Rapides Regional Medical Center, Alexandria, USA \n\n3 \nCardiology, Rapides Regional Medical Center, Alexandria, USA \n\nMuhammad Shabbir Rawala [email protected]\n22 5 2020 \n5 2020 \n12 5 e82434 5 2020 22 5 2020 Copyright © 2020, Rawala et al.2020Rawala 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/32471-cardiac-dysrhythmia-associated-with-opioid-toxicityIrritable bowel syndrome (IBS) is a functional gastrointestinal disorder involving abnormal motility. The patients are commonly started on symptom control management for IBS - diarrhea subtype by prescribing antimotility agents, usually having opioid agonist activity, and newer medications have been emerging for this as well. Patients sometimes self-medicate themselves to exceedingly high doses of these medications to achieve symptoms control. There are only a few cases of opioid-induced arrhythmia in the literature, primarily loperamide being used as a drug substitute by substance abusers. Still, it has been rarely reported to cause arrhythmia in a patient with IBS.\n\nWe present a case of a 33-year-old female with a past medical history of hypertension and depression who presented to the emergency department for evaluation of syncope. She had wide complex tachycardia on electrocardiogram (EKG) with prolonged rate-corrected QT interval (QTc). Her medications, including eluxadoline, Lomotil, and loperamide, were held and she was discharged on mexiletine with normal QTc. She did not have any more incidences of arrhythmia.\n\nThis case highlights the importance of not overdosing on opioid agonist medications prescribed to treat IBS as these can lead to potentially fatal complications. Physicians have to be judicious in promptly determining that the cause of arrhythmia can also be over-the-counter (OTC) medications.\n\ncardiac dysrhythmialong qtirritable bowel syndromeThe 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\nThe use of opioid-containing medications has been increasing globally. Most are regulated; however, a few of them are readily available over-the-counter (OTC) due to the low dose of opioids in them and without central effects. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder and is estimated to affect approximately 11% of the world’s population [1]. IBS is characterized by many subtypes, but our focus is the diarrhea-predominant type (IBS-D).\n\nThe mainstay of IBS-D treatment is lifestyle modification along with pharmacologic therapies. Amongst many of the pharmacological treatments are loperamide and Lomotil, with eluxadoline being recently approved [2].\n\nLoperamide is peripherally acting, μ-opioid receptor agonist used for the treatment of diarrhea. Eluxadoline is a mixed mu-opioid receptor agonist with delta-opioid receptor antagonist activity and kappa-opioid agonist. Lomotil (diphenoxylate and atropine) have opioid and anticholinergic activity [2-4].\n\nIn November 2016, the US Food & Drug Administration (FDA) released a statement highlighting the potential heart effects and risk of death with high doses of loperamide [5]. The recommended dose of loperamide is usually 8 mg/day; however, in higher amounts, it can theoretically cause symptoms of opioid toxicity, including rate-corrected QT interval (QTc) prolongation. We present a case of a young female affected by IBS-D. She had been self-medicating with an exceedingly high dose of OTC loperamide, causing her to have syncope secondary to dysrhythmia.\n\nCase presentation\nThe patient is a 33-year-old female with a past medical history of hypertension, depression, and IBS who presented to the emergency department (ED) for evaluation of syncope. She was transferred from an outside facility for a higher level of care. The patient was evaluated in the ED and found to have an electrocardiogram (EKG) with QTc of 647 milliseconds and wide complex tachycardia (Figure 1). She was recently placed on eluxadoline, which has opioid agonist activity and was taking supra-therapeutic doses of loperamide and Lomotil to gain symptom control of IBS. On examination, the patient’s physical exam findings were unremarkable, including orthostatic signs. On her cardiac exam, her S1 and S2 were audible, no murmurs, no rubs or gallops were appreciated. She was admitted to the intensive care unit for observation and started on amiodarone intravenously.\n\nFigure 1 Electrocardiogram with QTc of 647 milliseconds and wide complex tachycardia\nThe patient’s initial workup revealed normal electrolytes, no family history, or any prior history of prolonged QTc or cardiac arrhythmias. She had been taking duloxetine for her depression for a long time, which had been held at the time of admission. Her medications, including eluxadoline, loperamide, and Lomotil, were believed to be causing prolong QTc as the patient had been taking supratherapeutic doses of each with approximately 100 tablets of loperamide and 20-25 tablets of eluxadoline; therefore, these were held, and QT interval spontaneously improved in a few days. The subsequent EKGs showed sinus bradycardia and first-degree atrioventricular (AV) block (Figure 2). Echocardiogram identified normal ejection fraction and did rule out cardiomyopathy.\n\nFigure 2 Electrocardiogram showing sinus bradycardia and first-degree atrioventricular (AV) block\nThe patient was evaluated by an electrophysiologist who had recommended holding loperamide, Lomotil, and eluxadoline on discharge. The patient was started on mexiletine to shorten QTc interval as even after holding her home medications, QTc was borderline on higher limits. She was discharged on mexiletine with a normal QTc.\n\nDiscussion\nIt was believed that potential opioid toxicity due to multiple medications having opioid agonist activity was responsible for prolonged QTc and arrhythmia.\n\nThe FDA has received formal reports of 48 cases (since 1976) of cardiovascular morbidity and mortality associated with the use of loperamide. Eventually, in June of 2016, they released a warning statement about the high-dose of loperamide and its association with a QT interval prolongation [5].\n\nMany cases in the literature have reported ventricular arrhythmias and torsade de pointes, which resolved after discontinuing loperamide therapy [6,7]. In a small series of five patients, high dose chronic use of loperamide was shown to be associated with QRS and QTc prolongation, and a variety of events with ventricular dysrhythmias [8]. In all the case reports reviewed, the dosage of loperamide varied, ranging from 60 mg to 400 mg per day, which is far above the recommended daily dose. The maximum approved daily dose for adults is 8 mg per day for OTC use and 16 mg per day for prescription use.\n\nThe potential mechanism behind this toxicity includes inhibition of potassium channels and, therefore, QTc prolongation leading to dysrhythmia. The actual mechanism, however, is still uncertain. One study showed loperamide induced QRS and QT interval prolongation and subsequent arrhythmias from high-affinity inhibition of cardiac sodium channel (Nav1. 5) and human ether-a-go-related gene (hERG), one of the two main repolarizing cardiac K+ channels of the human heart [9]. Another study (small case series) postulated that there is a dose-dependent inhibition of inward-rectifier potassium ion channel [8]. These effects are usually seen with supratherapeutic doses of the drug [10].\n\nBecause of the lack of sufficient data in the literature, it is unclear at what doses the cardiac action potential starts getting affected by loperamide. In our case, the potential temporal association with medications and cardiac dysrhythmia possibly relates to opioid activity as the etiology of dysrhythmia, especially as QTc prolongation resolved after withholding medications.\n\nThe patient self-medicated herself on OTC medications in addition to euxadoline to achieve symptom control of her IBS. We believe better education and awareness regarding medication overdosing could have prevented this episode as it could have very quickly turned into a fatal consequence if the wide complex tachycardia had converted into a lethal arrhythmia such as ventricular fibrillation. The patient had assumed the OTC medications to be safe due to its accessibility but was unaware of the consequences of exceeding the recommended dosages.\n\nConclusions\nThere are only a few cases of opioid-induced arrhythmia in the literature, and the presentation is still a rare occurrence. Our case highlights the importance of not combining and overdosing on opioid agonist medications being prescribed to treat IBS, as these can lead to potentially fatal complications.\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 The epidemiology of irritable bowel syndrome Clin Epidemiol Canavan C West J Card T 71 80 6 2014 24523597 \n2 Current and emergent pharmacologic treatments for irritable bowel syndrome with diarrhea: evidence-based treatment in practice Therap Adv Gastroenterol Lucak S Chang L Halpert A Harris LA 253 275 10 2017 \n3 Eluxadoline in the treatment of diarrhea-predominant irritable bowel syndrome Drug Des Devel Ther Ozdener AE Rivkin A 2827 2840 11 2017 \n4 Loperamide-induced torsades de pointes: a case series J Emerg Med Katz KD Cannon RD Cook MD 339 344 53 2017 28755998 \n5 FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse 5 2020 2016 https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-heart-problems-high-doses-antidiarrheal \n6 High-dose loperamide abuse-associated ventricular arrhythmias HeartRhythm Case Rep O'Connell CW Schricker AA Schneir AB Metushi IG Birgersdotter-Green U Minns AB 232 236 2 2016 28491676 \n7 Dysrhythmias with loperamide used for opioid withdrawal J Am Board Fam Med Vithalani ND Heron C Rao RE Cardell AF Stephens MB 832 834 30 2017 29180560 \n8 Cardiac conduction disturbance after loperamide abuse Clin Toxicol Marraffa JM Holland MG Sullivan RW Morgan BW Oakes JA Wiegand TJ Hodgman MJ 952 957 52 2014 \n9 Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic Naunyn Schmiedebergs Arch Pharmacol Kang J Compton DR Vaz RJ Rampe D 1133 1137 389 2016 27530870 \n10 Loperamide abuse and life-threatening arrhythmias: a case report and literature review Psychosomatics Caro MA Shah SA Jerry JM Tesar GE Khawam EA 441 445 58 2017 28413089\n\n",
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"title": "Cardiac Dysrhythmia Associated With Opioid Toxicity.",
"title_normalized": "cardiac dysrhythmia associated with opioid toxicity"
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"abstract": "OBJECTIVE\nAdalimumab [ADA] was approved for the treatment of ulcerative colitis [UC] refractory to conventional therapy in 2012 in Europe. Due to the observed discrepancies between clinical trials and practice, data on the outcome of ADA therapy are really needed from the real life. The aim of this study was to estimate the short- and long-term efficacy and safety of ADA in UC patients from each Hungarian biological centre.\n\n\nMETHODS\nThis prospective study consisted of UC patients treated with ADA in 10 Hungarian inflammatory bowel disease centres. The primary endpoints of the study were rates of continuous clinical response, remission, non-response and loss of response at Weeks 12, 30, and 52.The secondary endpoints included mucosal healing at Week 52 and the comparison of the efficacy of ADA between biological naive and infliximab [IFX]-treated groups. Colonoscopy was performed before starting the therapy and at Week 52.\n\n\nRESULTS\nIn all, 73 active UC patients were enrolled in the study: 67.1% of the patients received previous IFX therapy; 75.3% of the patients showed short-term clinical response at Week 12. The probability of maintaining ADA was 48.6% at Week 52 with a continuous clinical response in 92% of these remaining patients. Mucosal healing was achieved in 48.1% of the patients at Week 52. Escalation of ADA was performed in 17.6%, and minor side effects developed in 4% of the patients; 5.4% of the patients underwent colectomy during the 1-year treatment period.\n\n\nCONCLUSIONS\nUC is a progressive disease that may need early aggressive therapy to prevent structural and functional complications. The results of our study demonstrated the favourable efficacy of short- and long-term ADA treatment for patients with UC.",
"affiliations": "1st Department of Medicine, University of Szeged, Szeged, Hungary.;1st Department of Medicine, University of Szeged, Szeged, Hungary.;2nd Department of Medicine, University of Debrecen, Debrecen, Hungary.;Markusovszky University Hospital, Szombathely, Hungary.;2nd Department of Medicine, Semmelweis University, Budapest, Hungary.;Petz Aladár Country Hospital, Győr, Hungary.;Péterfy Sándor Street Hospital-Clinic and Emergency Center, Budapest, Hungary.;1st Department of Internal Medicine, University of Pécs, Pécs, Hungary.;Semmelweis Hospital and University Hospital [MISEK], Miskolc, Hungary.;Petz Aladár Country Hospital, Győr, Hungary.;1st Department of Medicine, University of Szeged, Szeged, Hungary.;1st Department of Medicine, University of Szeged, Szeged, Hungary.;Semmelweis Hospital and University Hospital [MISEK], Miskolc, Hungary.;Military Hospital, Budapest, Hungary.;Kazincbarcika Hospital, Kazincbarcika, Hungary.;2nd Department of Medicine, Semmelweis University, Budapest, Hungary.;2nd Department of Medicine, Semmelweis University, Budapest, Hungary.;Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.;1st Department of Medicine, University of Szeged, Szeged, Hungary.;1st Department of Medicine, University of Szeged, Szeged, Hungary.;1st Department of Medicine, University of Szeged, Szeged, Hungary.;1st Department of Medicine, University of Szeged, Szeged, Hungary [email protected].",
"authors": "Bálint|Anita|A|;Farkas|Klaudia|K|;Palatka|Károly|K|;Lakner|Lilla|L|;Miheller|Pál|P|;Rácz|István|I|;Hegede|Gábor|G|;Vincze|Áron|Á|;Horváth|Gábor|G|;Szabó|Andrea|A|;Nagy|Ferenc|F|;Szepes|Zoltán|Z|;Gábor|Zoltán|Z|;Zsigmond|Ferenc|F|;Zsóri|Ágnes|Á|;Juhász|Márk|M|;Csontos|Ágnes|Á|;Szűcs|Mónika|M|;Bor|Renáta|R|;Milassin|Ágnes|Á|;Rutka|Mariann|M|;Molnár|Tamás|T|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjv169",
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"issue": "10(1)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Ulcerative colitis; adalimumab; continuous clinical response; mucosal healing",
"medline_ta": "J Crohns Colitis",
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"pages": "26-30",
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"pmid": "26392413",
"pubdate": "2016-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
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"title_normalized": "efficacy and safety of adalimumab in ulcerative colitis refractory to conventional therapy in routine clinical practice"
}
|
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{
"abstract": "The elevated prevalence of neuropsychiatric symptoms and disorders among patients with multiple sclerosis (MS) is well recognized, as are potential neuropsychiatric side effects of treatment with corticosteroids. Both methylprednisolone (MP) and repository corticotropin injection (HP Acthar(®) gel) have demonstrated efficacy in reducing short-term disability after exacerbations of MS. Although historical data are limited, repository corticotropin injection has not generally been associated with detrimental neuropsychiatric effects. We describe six cases of patients with relapsing-remitting MS who had previously experienced detrimental mood changes with MP treatment. Some of these patients had previous histories of mood disorders or other neuropsychiatric symptoms prior to MS diagnosis. All six patients were subsequently treated with repository corticotropin injection for MS exacerbations and each demonstrated improvements in MS symptoms. This clinical experience suggests that repository corticotropin injection should be considered as an alternative for patients who do not tolerate corticosteroids or have difficulties associated with intravenous medication. Furthermore, the rate of neuropsychiatric side effects observed in these patients was low. These observations support repository corticotropin injection as a viable alternative for the treatment of acute exacerbations of MS, particularly in patients who have a history of neuropsychiatric disorders or symptoms either independently or in response to MP treatment. In reviewing both the published data and our own clinical experience regarding potential neuropsychiatric adverse events with treatment for MS exacerbations, we hope to stimulate further research into the potential efficacy and safety of repository corticotropin injection among patients with some form of neuropsychiatric complications that must be considered when establishing a treatment plan for MS.",
"affiliations": "Neuro Institute of New England, 16 Chestnut Street, Suite 100, Foxboro, MA 02035, USA.;Santa Monica Neurological Consultants, Santa Monica, CA, USA.",
"authors": "Murray|Stacey|S|;Woo|Andrew|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1756285615618642",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-2856",
"issue": "9(3)",
"journal": "Therapeutic advances in neurological disorders",
"keywords": "adrenocorticotrophic hormone; case reports; corticotropin injection; methylprednisolone; multiple sclerosis; neuropsychiatric symptoms; repository",
"medline_ta": "Ther Adv Neurol Disord",
"mesh_terms": null,
"nlm_unique_id": "101480242",
"other_id": null,
"pages": "189-97",
"pmc": null,
"pmid": "27134674",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "6319464;19153176;11034713;2984332;15191017;21546839;6311774;24587825;19409854;9990556;2544829;9710030;3904340;23740464;19949030;22146321;1442465;9415535;14474011;3295122;26120075;20233111;7212976;6259680;17036562;4314823",
"title": "Clinical experience with repository corticotropin injection in patients with multiple sclerosis experiencing mood changes with intravenous methylprednisolone: a case series.",
"title_normalized": "clinical experience with repository corticotropin injection in patients with multiple sclerosis experiencing mood changes with intravenous methylprednisolone a case series"
}
|
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}
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"abstract": "Nivolumab, a programmed death-1 checkpoint inhibitor, is worldwide available for metastatic renal cell carcinoma (mRCC). Limited data exist on the response to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (TKI) therapy after administration of nivolu-mab. In this case study, we report on a patient with tumor lysis syndrome (TLS), which was induced by pazopanib after the administration of nivolumab. A 69-year-old woman with a primary diagnosis of mRCC received pazopanib as a fourth-line therapy, after sunitinib, axitinib, and nivolumab as first-, second-, and third-line therapies, respectively. Two weeks after the administration of pazopanib, she presented to the emergency room of our institution, complaining of fatigue associated with nausea and diarrhea. Her laboratory results showed hyperphosphatemia, hyperuricemia, hypocalcemia, and possible acute kidney injury; the results were consistent with TLS. Our case report highlights TLS as a potential reaction to pazopanib following nivolumab; and we consider careful observation is necessary when administering TKI after immune checkpoint inhibitors.",
"affiliations": "Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.",
"authors": "Narukawa|Tsukasa|T|;Hongo|Fumiya|F|;Fujihara|Atsuko|A|;Ueno|Akihisa|A|;Matsugasumi|Toru|T|;Ukimura|Osamu|O|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000506196",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. 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] \n\n10.1159/000506196\ncro-0013-0249\nCase Report\nPazopanib after Nivolumab-Induced Tumor Lysis Syndrome in a Patient with Metastatic Clear-Cell Renal Cell Carcinoma\nNarukawa Tsukasa Hongo Fumiya * Fujihara Atsuko Ueno Akihisa Matsugasumi Toru Ukimura Osamu Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan\n*Fumiya Hongo, Department of Urology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566 (Japan), [email protected]\nJan-Apr 2020 \n24 3 2020 \n24 3 2020 \n13 1 249 254\n24 1 2020 28 1 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Nivolumab, a programmed death-1 checkpoint inhibitor, is worldwide available for metastatic renal cell carcinoma (mRCC). Limited data exist on the response to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (TKI) therapy after administration of nivolumab. In this case study, we report on a patient with tumor lysis syndrome (TLS), which was induced by pazopanib after the administration of nivolumab. A 69-year-old woman with a primary diagnosis of mRCC received pazopanib as a fourth-line therapy, after sunitinib, axitinib, and nivolumab as first-, second-, and third-line therapies, respectively. Two weeks after the administration of pazopanib, she presented to the emergency room of our institution, complaining of fatigue associated with nausea and diarrhea. Her laboratory results showed hyperphosphatemia, hyperuricemia, hypocalcemia, and possible acute kidney injury; the results were consistent with TLS. Our case report highlights TLS as a potential reaction to pazopanib following nivolumab; and we consider careful observation is necessary when administering TKI after immune checkpoint inhibitors.\n\nKeywords\nNivolumabRenal cell carcinomaTyrosine kinase inhibitorTumor lysis syndrome\n==== Body\nIntroduction\nClear-cell renal cell carcinoma (ccRCC) is associated with mutations in the VHL gene, and therefore, vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKI) have been developed as anticancer therapies in ccRCC [1]. From 2006 to 2017, the standard first-line therapies of metastatic ccRCC (mccRCC) were VEGF-targeted therapies [2]. In contrast, nivolumab, a programmed death-1 (PD-1) checkpoint inhibitor, was the first immune checkpoint inhibitor (ICI) to be approved for advanced RCC in Japan, showing an overall survival superior to everolimus [3]. In addition, the combination of nivolumab and ipilimumab is the standard first-line treatment for patients with international metastatic data-base consortium (IMDC) intermediate- or poor-risk disease, based on the clinical trial of checkmate 214 [4]. Since 2017, VEGFR-TKIs, mammalian target of rapamycin (mTOR) inhibitors, and nivolumab have been frequently used as second- and subsequent-line therapies in Japan [5]. Previous reports revealed the durable response to ICIs [6], which may suggest that the influence of ICIs remains after interrupting their use. Therefore, VEGF-targeted therapies after ICIs may achieve a mutual effect or may result in completely unexpected adverse events (AEs). In this case study, we report a case of tumor lysis syndrome (TLS), which was induced by the administration of pazopanib after nivolumab.\n\nCase Report\nA 66-year-old woman with suspected crown tumor went to the local hospital. A biopsy of the cranial bone tumor revealed clear-cell carcinoma. Computed tomography (CT) showed a right renal tumor with multiple lung and bone metastases. The patient was diagnosed with metastatic right renal cell carcinoma (cT1bN0M1) and came to our hospital for treatment. First, she underwent laparoscopic right renal resection. Then, she was categorized as IMDC intermediate risk and received sunitinib for an initial 7 months, axitinib for the next 6 months as second-line therapy, and nivolumab for the following 6 months as third-line therapy. In spite of these treatments, CT revealed that the cranial bone tumors had increased in size, infiltrating the surrounding tissue as an extra bone mass (Fig. 1), and a new liver lesion had appeared. After that, she was admitted to our hospital to start pazopanib as fourth-line therapy in February 2019. At this point, she was categorized as IMDC intermediate risk, and her serum uric acid level was normal with 5.4 mg/dL.\n\nDuring hospitalization, she received 800 mg pazopanib daily without any AEs and was discharged on Day 10 after administration of pazopanib. Two days after discharge from the hospital, she presented to the emergency room with complaints of CTCAE v4.0 grade 2 fatigue associated with CTCAE v4.0 grade 2 nausea and grade 1 diarrhea. Physical examination showed a temperature of 40.5°C, a blood pressure of 132/48 mm Hg, and a heart rate of 120 beats per minute. She denied any abdominal pain during palpation. Her chest and abdomen CT showed that the lung metastasis had decreased (Fig. 2). The laboratory results are shown in Table 1\n\nIn the emergency room, a CTCAE grade 2 acute kidney injury was discovered, and disseminated intravascular coagulation was diagnosed according to the Japanese Association of Acute Medicine (JAAM) criteria [7]. At that point, she discontinued pazopanib and was treated with hydration at 200 mL/h, thrombomodulin alpha, and broad-spectrum antibiotics meropenem, which was started empirically due to the possibility of sepsis in the setting of immunocompromised state. Within 24 h, her laboratory values showed hyperphosphatemia (5.9 mmol/L), hyperuricemia (10.1 mg/dL), and hypocalcemia (7.0 mg/dL), and acute renal failure got worse (creatinine: 2.3–2.95 mg/dL), which were all consistent findings with laboratory TLS (according to the Cairo and Bishop classification) [8]. The laboratory results are also shown in Table 1. Then, she was admitted to the intensive care unit for the management of TLS. Despite intensive medical care, including renal replacement therapy, her renal function did not recover. Due to her poor prognosis, the attending physicians consulted her family, and they decided not to do further life-prolonging therapy. Eventually, our patient died under palliative care the next day following intensive care unit admission.\n\nDiscussion\nTLS is an oncologic emergency, characterized by the extensive destruction of tumor cells, which results in the release of intracellular content, including uric acid, potassium, phosphorus, and calcium. Hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia occur in the process and can lead to acute kidney injury, cardiac arrhythmias, seizures, or death [8]. In our case, a serum lactate dehydrogenase concentration of 1,380 U/L and decrease of the lung lesion may reveal cell lysis, which is consistent with TLS. TLS is most commonly seen during the treatment of hematological malignancies, such as Burkitt lymphoma or acute leukemia [8]; however, there has been an increase of TLS reports in RCC recently [9, 10, 11].\n\nPazopanib is a VEGFR-TKI which has been approved for first-line treatment of patients with IMDC low-risk disease in Japan [5], and pazopanib-related TLS in mRCC has previously been reported [11]. Pazopanib is almost completely (>99.9%) bound to serum albumin, and a low serum albumin level may lead to a higher free fraction of pazopanib, and this may result in a higher toxicity of pazopanib. In our case, serum albumin level was decreasing gradually, and it may be one factor for TLS progression. TLS induced by other TKI, such as sunitinib, has previously been described in patients with RCC [9, 10]. However, in these reported cases, TKI was used as first-line treatment, and it has never been described in a patient with RCC and a history of TKI use, treated with other TKIs.\n\nRecently, the JAVELIN Renal 101 Phase 3 trial has been published, a TKI/ICI registration trial, and has demonstrated superior progression-free survival (PFS) for the combination of axitinib and avelumab over sunitinib (13.8 vs. 8.4 months, HR 0.69) [12]. Furthermore, the KEYNOTE-426 trial has demonstrated both PFS and overall survival advantage of axitinib plus pembrolizumab over sunitinib (median PFS 15.1 vs. 11.1 month, HR 0.69) [13]. These trials indicate that the combination of TKI and ICI may have more impact on cancer than TKI monotherapy.\n\nIn contrast, a durable response to ICI has previously been reported [6], and in our case, the combination of pazopanib and the prolonged effect of nivolumab may have cause TLS, similar to TKI/ICI combination therapy. Previous reports on second-line TKI after ICI are summarized in Table 2 [14, 15]. Each treatment has a certain level of therapeutic effect and AEs. Shah et al. [15] reported that 8 of 19 (42%) patients treated with pazopanib after ICI discontinued treatment due to its toxicity, and the most frequent reason (5 of 8, 63%) was transaminitis. The discontinuation rate of pazopanib was higher than that of other TKIs (13% for axitinib, 17% for sunitinib, 0% for cabozantinib). Although the numbers are not large, they may reveal that a type of TKI is not suitable for sequential treatment after ICI. In any case, we considered close follow-up is necessary when administrating TKI after ICI.\n\nConclusion\nTo the best of our knowledge, this is the first report of TLS induced by pazopanib after nivolumab; it suggests the need of careful observation when administrating TKI after ICI.\n\nStatement of Ethics\nOur patient provided written informed consent for the publication of her clinical course.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAuthor Contributions\nTsukasa Narukawa designed the study and wrote the initial draft of the manuscript. Fumiya Hongo and Osamu Ukimura contributed to revise it critically for important intellectual content. All other authors have contributed to data collection and interpretation and reviewed the manuscript. All authors approved the final version of the manuscript and agree 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.\n\nFig. 1. CT scan showing a cranial bone tumor which has infiltrated the surrounding tissue as an extra bone mass (arrows).\n\nFig. 2. \na CT scan showing a lung metastatic lesion (arrow) before the introduction of pazopanib. b CT scan showing a decreased lung metastatic lesion (arrow) on Day 12 after the initiation of pazopanib.\n\nTable 1 Laboratory values on Days 8, 12 (day of ER admission), and 13 (day of ICU admission) after the initiation of pazopanib therapy\n\nParameter\tReference range\tDay 8\tDay 12\tDay 13\t\nWBC,/µL\t3,300–8,600\t4,400\t6,200\t3,300\t\nRBC, × 104/µL\t386–492\t459\t441\t474\t\nHb, g/dL\t11.6–14.8\t13.3\t12.9\t13.5\t\nPlatelets, × 104/µL\t15.8–34.8\t26.9\t3.6\t3.0\t\nPT, %\t73–140\t−\t65\t52\t\nPT-INR\t0.87–1.12\t−\t1.20\t1.35\t\nFDP,/µg/mL\t0–5\t−\t41.6\t54.9\t\nAST, U/L\t13–30\t17\t277\t339\t\nALT, U/L\t7–23\t10\t66\t83\t\nLDH, U/L\t124–222\t247\t1,380\t1,762\t\nALB, g/dL\t4.1–5.1\t3.8\t3.4\t2.4\t\nBUN, mg/dL\t8.0–20.0\t19.5\t57.5\t64.7\t\nCr, mg/dL\t0.46–0.79\t0.80\t2.30\t2.95\t\nUA, mg/dL\t2.6–5.5\t−\t−\t10.1\t\nCRP, mg/dL\t0–0.14\t0.60\t19.56\t22.21\t\nNa, mEq/L\t138–145\t139\t131\t131\t\nK, mEq/L\t3.6–4.8\t4.5\t4.0\t4.4\t\nCa, mg/dL\t8.8–10.1\t9.2\t8.5\t7.0\t\nP, mg/dL\t2.7–4.6\t3.3\t−\t5.9\t\nALB, albumin; ALT, alanine phosphatase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; Cr, creatinine; CRP, C-reactive protein; ER, emergency room; FDP, fibrinogen/fibrin degradation product; Hb, hemoglobin; ICU, intensive care unit; INR, international normalized ratio; K, potassium; LDH, lactate dehydrogenase; Na, sodium; P, phosphorus; PT, prothrombin time; RBC, red blood cell count; UA, uric acid; WBC, white blood cell count.\n\nTable 2 Summary of reported cases treated with TKIs as second-line therapy after ICIs\n\n1L ICI\tN (%)\t2L TKI\tN (%) mPFS, months\tmOS, months\tToxicity, n (%)\t\nAuvry et al. [14] (n = 33)\t\t\t\t\t\nPD-1+CTLA-4 blockade\t33 (100)\tAll\t8\t−\tG3 and G4 AEs\t\n(followed by maintenance anti-PD-1)\tSunitinib\t17 (52) 8\t11\t14 (42)\t\n\tPazopanib\t6 (18)\t\t\t\n\tAxitinib\t8 (24) 7\tNR\t\t\n\tCabozantinib\t2 (6)\t\t\t\n\tOther\t5\t13\t\t\n\t\nShah et al. [15] (n = 70)\t\t\t\tDiscontinuation of 2L TKI due to its toxicity\t\nAnti-PD-(L)1 single agent\t12 (17)\tAll\t13.2\tNR\t12 (17)\t\nPD-1+CTLA-4 blockade (followed by maintenance anti-PD-1)\t33 (47)\tSunitinib\t6 (9)\t\t1 (17)\t\nPD-(L)1+ anti-VEGF therapy\t25 (36)\tPazopanib\t19 (27)\t\t8 (42)\t\n\tAxitinib\t25 (36)\t\t3 (12)\t\n\t\tCabozantinib\t20 (28)\t\t0 (0)\t\n1L, first line; 2L, second line; CTLA-4, cytotoxic T lymphocyte-associated protein 4; ICI, immune checkpoint inhibitors; mOS, median overall survival; mPFS, median progression-free survival; PD-1, programmed death-1; PD-L1, programmed death ligand-1; VEGF, vascular endothelial growth factor TKI, tyrosine kinase inhibitor.\n==== Refs\nReferences\n1 Choueiri TK Motzer RJ Systemic therapy for metastatic renal-cell carcinoma N Engl J Med 2017 1 376 (4) 354 66 28121507 \n2 Barata PC Rini BI Treatment of renal cell carcinoma: current status and future directions CA Cancer J Clin 2017 11 67 (6) 507 24 28961310 \n3 Motzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S Nivolumab versus everolimus in advanced renal-cell carcinoma N Engl J Med 2015 11 373 (19) 1803 13 26406148 \n4 Motzer RJ Tannir NM McDermott DF Aren Frontera O Melichar B Choueiri TK Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma N Engl J Med 2018 4 378 (14) 1277 90 29562145 \n5 Bamias A Escudier B Sternberg CN Zagouri F Dellis A Djavan B Current clinical practice guidelines for the treatment of renal cell carcinoma: a systematic review and critical evaluation Oncologist 2017 6 22 (6) 667 79 28592625 \n6 McDermott DF Drake CG Sznol M Choueiri TK Powderly JD Smith DC Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab J Clin Oncol 2015 6 33 (18) 2013 20 25800770 \n7 Gando S Saitoh D Ogura H Fujishima S Mayumi T Araki T A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis Crit Care 2013 6 17 (3) R111 23787004 \n8 Cairo MS Bishop M Tumour lysis syndrome: new therapeutic strategies and classification Br J Haematol 2004 10 127 (1) 3 11 15384972 \n9 Nicholaou T Wong R Davis ID Tumour lysis syndrome in a patient with renal-cell carcinoma treated with sunitinib malate Lancet 2007 6 369 (9577) 1923 4 17560435 \n10 Michels J Lassau N Gross-Goupil M Massard C Mejean A Escudier B Sunitinib inducing tumor lysis syndrome in a patient treated for renal carcinoma Invest New Drugs 2010 10 28 (5) 690 3 19547920 \n11 van Kalleveen MW Walraven M Hendriks MP Pazopanib-related tumor lysis syndrome in metastatic clear cell renal cell carcinoma: a case report Invest New Drugs 2018 6 36 (3) 513 6 29464464 \n12 Motzer RJ Penkov K Haanen J Rini B Albiges L Campbell MT Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma N Engl J Med 2019 3 380 (12) 1103 15 30779531 \n13 Rini BI Plimack ER Stus V Gafanov R Hawkins R Nosov D Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma N Engl J Med 2019 3 380 (12) 1116 27 30779529 \n14 Auvray M Auclin E Barthelemy P Bono P Kellokumpu-Lehtinen P Gross-Goupil M Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma Eur J Cancer 2019 2 108 33 40 30616146 \n15 Shah AY Kotecha RR Lemke EA Chandramohan A Chaim JL Msaouel P Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors Eur J Cancer 2019 6 114 67 75 31075726\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Nivolumab; Renal cell carcinoma; Tumor lysis syndrome; Tyrosine kinase inhibitor",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "249-254",
"pmc": null,
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"references": "26406148;19547920;30779529;29562145;31075726;25800770;30779531;15384972;28592625;28961310;30616146;23787004;28121507;29464464;17560435",
"title": "Pazopanib after Nivolumab-Induced Tumor Lysis Syndrome in a Patient with Metastatic Clear-Cell Renal Cell Carcinoma.",
"title_normalized": "pazopanib after nivolumab induced tumor lysis syndrome in a patient with metastatic clear cell renal cell carcinoma"
}
|
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}
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"literaturereference": "NARUKAWA T, HONGO F, FUJIHARA A, UENO A, MATSUGASMI T, UKIMURA O. PAZOPANIB AFTER NIVOLUMAB?INDUCED TUMOR LYSIS SYNDROME IN A PATIENT WITH METASTATIC CLEAR CELL RENAL CELL CARCINOMA. CASE REPORTS IN ONCOLOGY. 2020?13:249?54",
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"abstract": "The treatment of cancer, whether a solid tumor or a malignant hemopathy, is accompanied by bouts of infection, the severity and prognosis of which are often correlated to the patient's immune status. In Gabon, where the transmission of Plasmodium falciparum malaria is perennial, the prevalence - around 36% in Libreville - increases in older children and adults. Few authors have described the involvement of this parasite during fever after chemotherapy for hematological malignancies. This work reports three cases of malaria including two severe and one with neutropenia occurring in patients treated for hematological neoplasms.",
"affiliations": "Université des sciences de la santé, Faculté de médecine et de pharmacie, Libreville, Gabon.;Université des sciences de la santé, Faculté de médecine et de pharmacie, Libreville, Gabon.;Centre hospitalier universitaire de Libreville, Libreville, Gabon.;Centre hospitalier universitaire de Libreville, Libreville, Gabon.;Université des sciences de la santé, Faculté de médecine et de pharmacie, Libreville, Gabon.;Université des sciences de la santé, Faculté de médecine et de pharmacie, Libreville, Gabon.",
"authors": "Igala|M|M|;Ledaga Lentombo|L E|LE|;Kouégnigan Rerambiah|L|L|;Ntsame Ngoua|S|S|;Bouyou Akotet|M|M|;Boguikouma|J B|JB|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "France",
"delete": false,
"doi": "10.1684/mst.2019.0956",
"fulltext": null,
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"issn_linking": "2261-3684",
"issue": "29(4)",
"journal": "Medecine et sante tropicales",
"keywords": "Gabon; Plasmodium falciparum; hematological malignancies; malaria",
"medline_ta": "Med Sante Trop",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008288:Malaria; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D055815:Young Adult",
"nlm_unique_id": "101581406",
"other_id": null,
"pages": "399-401",
"pmc": null,
"pmid": "31884994",
"pubdate": "2019-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Malaria after chemotherapy for hematological malignancies.",
"title_normalized": "malaria after chemotherapy for hematological malignancies"
}
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{
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{
"abstract": "Transradial coronary angiography has been known as an alternative to the transfemoral approach with fewer serious complications. Radial artery pseudoaneurysms present as a rare complication of transradial catheterization. Although some methods have been applied for the obliteration of pseudoaneurysms, the use of radial bands such as the TR Band® (Terumo Medical Corporation, Somerset, NJ) is a novel efficient technique only suggested by a few reports. We describe a 34-year-old man, who underwent transradial primary coronary angiography due to ST-elevation myocardial infarction. Two months later, he noticed a pulsatile mass on his hand where the catheterization was done. Ultrasonography proved the diagnosis of a pseudoaneurysm. Consequently, a TR Band® was applied to compress the mass. Interestingly, 24 hours later, ultrasonography confirmed a thrombosed pseudoaneurysm and the pulsatile mass had completely disappeared gradually without recurrence at 2 months' follow-up. Hence, this case report aims to propose the TR Band® as an effective noninvasive method for the treatment of pseudoaneurysms following catheterization.",
"affiliations": "Rasoul Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran.;Functional Neurosurgery Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Functional Neurosurgery Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Ghanavati|Reza|R|;Arab Ahmadi|Mehran|M|;Behnam|Behdad|B|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nJ Tehran Heart CentJ Tehran Heart CentJTHCThe Journal of Tehran University Heart Center1735-53702008-2371Tehran University of Medical Sciences, 2006- Tehran, Iran JTHC-12-82Case ReportSuccessful Nonsurgical Treatment of a Radial Artery Pseudoaneurysm Following Transradial Coronary Angiography Ghanavati Reza MD1Arab Ahmadi Mehran MD2Behnam Behdad MD2*\n1 \nRasoul Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran\n.\n\n2 \nFunctional Neurosurgery Research \nCenter, \nShahid Beheshti University of Medical Sciences, Tehran, Iran.\n* Corresponding Author: Behdad Behnam, Functional Neurosurgery Research Center, Shohada Tajrish Hospital, Tajrish Square, Tehran, Iran. 1989934148. Tel: +98 21 22701022. Fax: +98 21 [email protected] 2017 12 2 82 84 26 12 2015 16 4 2016 Copyright © 2015 Tehran Heart Center, Tehran University of Medical SciencesThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Transradial coronary angiography has been known as an alternative to the transfemoral approach with fewer serious complications. Radial artery pseudoaneurysms present as a rare complication of transradial catheterization. Although some methods have been applied for the obliteration of pseudoaneurysms, the use of radial bands such as the TR Band® (Terumo Medical Corporation, Somerset, NJ) is a novel efficient technique only suggested by a few reports. We describe a 34-year-old man, who underwent transradial primary coronary angiography due to ST-elevation myocardial infarction. Two months later, he noticed a pulsatile mass on his hand where the catheterization was done. Ultrasonography proved the diagnosis of a pseudoaneurysm. Consequently, a TR Band® was applied to compress the mass. Interestingly, 24 hours later, ultrasonography confirmed a thrombosed pseudoaneurysm and the pulsatile mass had completely disappeared gradually without recurrence at 2 months’ follow-up. Hence, this case report aims to propose the TR Band® as an effective noninvasive method for the treatment of pseudoaneurysms following catheterization.\n\nKey Words\nCoronary angiographyAngioplastyComplicationsAneurysm, false\n==== Body\nIntroduction\nTransradial coronary angiography (TRA) was first suggested by Campeau 1 more than 20 years ago. Transradial percutaneous coronary intervention has been known as an effective intervention with better outcomes and fewer vascular complications than any other procedure, although it is associated with a few rare complications.2 \n\nBased on previous meta-analyses, major complications in the site of catheterization are seen in 0.3% of the radial approach versus 2.8% of the femoral intervention. 3 Pseudoaneurysms have been known as a rare complication, affecting 3 per 10000 patients after days to weeks following TRA.4 Common manifestations include localized swelling and pain in the wrist, antecubital fossa, or forearm area. 4 It is usually diagnosed based on physical examination, Doppler ultrasound, or angiography. \n\nHere in, we report a case of a radial artery pseudoaneurysm, which was treated successfully with the local compression technique (a TR Band®). To our knowledge, there are only a few cases of this novel method for the treatment of radial pseudoaneurysms following TRA.\n\nCase Report\nThe patient was a 32-year-old man, who referred to our emergency department with the complaint of chest pain. At the time, he was diagnosed with anterior ST-elevation myocardial infarction (STEMI) based on history taking and electrocardiogram (ECG). The patient underwent primary percutaneous coronary intervention on the proximal portion of his left anterior descending artery through the right radial approach with a 6-F hydrophilic radial sheath, a 5-F Merit Performa catheter, and a 6-F guiding catheter. He had an uncomplicated hospital course of stay and on discharge, his echocardiography revealed an ejection fraction of 25%, accompanied by a severely smokey pattern in the left ventricle with anteroseptal wall motion abnormality.\n\nBased on the echocardiographic findings, triple antithrombotic therapy - comprising Aspirin (80 mg daily), clopidogrel (75 mg daily), and warfarin (goal international normalized ratio [INR] = 2) - was started for him.\n\nThe patient was well at his follow-up visit until 2 months after the first admission, when he developed a pulsatile painful mass in his right wrist (Figure 1A, 1B), which appeared when he was lifting a heavy box. Physical examination was unremarkable, except for the pulsatile wrist mass, about 3 × 3 cm in size, with a normal capillary filling of the 5th finger.\n\nColor Doppler ultrasonography showed a 2.5 × 2 cm pseudoaneurysm with a 4-mm neck and a to-and-fro flow. Warfarin was discontinued, and the pulsatile mass was compressed using a TR Band® (Terumo Medical Corporation, Somerset, NJ) for 24 hours. The TR Band® was placed on his right wrist, just at the site of the pseudoaneurysm and was inflated with 8 cc of air with a normal pulse oximeter waveform at the 5th finger.\n\nDuring the compression, the patient experienced mild pain in his right hand without any evidence of cyanosis on examination. After the first 24 hours, the pulsations disappeared and follow-up ultrasonography showed a thrombosed pseudoaneurysm without a to-and-fro flow. It completely improved with no relapse at his 2 months’ follow-up (Figure 2).\n\nFigure 1 Pulsatile mass (arrow) at the site of catheterization on the right hand (before treatment)\n\nFigure 2 Pseudoaneurysm has completely disappeared (arrow) without recurrence at 2 months’ follow-up on the right hand (after treatment).\n\nDiscussion\nHerein, we reported a case of a radial artery pseudoaneurysm after cardiac catheterization that was successfully treated through a noninvasive compressive technique with a TR Band®. \n\nInappropriate catheter sheath size (large size), massive use of antiplatelet agents, infection at the site of intervention, and insufficient postprocedural compression are known as predisposing factors to the development of pseudoaneurysms. 5 Accordingly, adequate compression at the site of intervention and observation for any sign of pain or swelling after the procedure are very useful in the prevention of pseudoaneurysms. \n\nIn most case reports and also in our patient, the most possible factor in developing pseudoaneurysms was antiplatelet therapy. However, based on the 2013 guideline of the American College of Cardiology/American Heart Association (ACC/AHA)for the management of patients with STEMI, aspirin plus a P2Y12 receptor antagonist and vitamin K antagonist(class of recommendation: IIb, level of evidence: C)should be considered for patients who are diagnosed with anterior STEMI, have undergone percutaneous coronary intervention, and have anterior wall motion abnormalities on echocardiography (as was seen in our patient), 6 particularly in cases with a low risk of bleeding.\n\nCurrently, the available proven techniques for the treatment of pseudoaneurysms include surgical repair, ultrasound-guided compression repair (UGCR), and ultrasound-guided thrombin injection (UGTI).7\n\nAlong with the development of nonoperative minimally invasive methods, surgery for repairing post-catheterization pseudoaneurysms has gradually become less important. 8 UGCR is a time-consuming technique that includes 10-minute intervals until the obliteration of the pseudoaneurysm. 9 \n\nRecently, UGTI has provided a new alternative method with higher success and rapid response. In this procedure, thrombin is injected directly to the pseudoaneurysm sac under ultrasound guide.10 However, it is probable that thrombin escapes from the pseudoaneurysm, which can occlude the distal vessels and cause pain, paresthesia, and skin necrosis. 10 \n\nBeside common conventional treatments, a novel strategy by applying external compression has been suggested as a cost-effective and simple method that can be considered a first-line treatment for patients with small-to-moderate-sized radial arteries. 11 \n\nDuring the recent years, a few case reports have applied different devices for external compression in radial artery treatment for pseudoaneurysms. Accordingly, the TR Band® has been designed for external compression with 2 adjustable, inflatable balloons on the radial artery. Although it compresses the radial artery, it causes neither local nerve compression nor venous stasis. 12 \n\nFor the first time, Liouet al.11 in 2010 reported successful treatment of radial artery pseudoaneurysms by using the TR Band®. Four years later, Cauchiet al.12 suggested the TR Band® for a post-catheterization pseudoaneurysm in a 45-year-old patient, who developed a pseudoaneurysm following TRA.\n\nOn the other hand, except for the TR Band®, other devices with a similar mechanism have been found useful by a few reports. In this regard, Nazeret al.13 used the HemoBand (Hemoband Corporation), which showed some relapses.\n\nTo our knowledge, this is a rare report of the successful treatment of a radial pseudoaneurysm in the site of catheterization with a TR Band® in a young man. The pseudoaneurysm completely disappeared without any complication within a 2-month follow-up period.\n\nConclusion\nThis case is presented to encourage cardiologists to consider the TR Band® as an advantageous, noninvasive, and cost-effective device for the treatment of pseudoaneurysms, especially in patients who have received anticoagulant therapy. \n\nNotes:\n\nThis paper should be cited as: Ghanavati R, Arab Ahmadi M, Behnam B. Successful Nonsurgical Treatment of a Radial Artery Pseudoaneurysm Following Transradial Coronary Angiography. J Teh Univ Heart Ctr 2017;12(2):82-84.\n==== Refs\nReferences\n1 Campeau L Percutaneous radial artery approach for coronary angiography Cathet Cardiovasc Diagn 1989 16 3 7 2912567 \n2 Shroff A Siddiqui S Burg A Singla I Identification and management of complications of transradial procedures Curr Cardiol Rep 2013 15 350 23420446 \n3 Agostoni P Biondi-Zoccai GG de Benedictis ML Rigattieri S Turri M Anselmi M Vassanelli C Zardini P Louvard Y Hamon M Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures: systematic overview and meta-analysis of randomized trials J Am Coll Cardiol 2004 44 349 356 15261930 \n4 Blasco A Oteo JF Fontanilla T Salamanca J Ocaranza R Goicolea J Unusual complications of cardiac catheterization via the radial artery Rev Esp Cardiol 2005 58 1233 1235 16238993 \n5 Collins N Wainstein R Ward M Bhagwandeen R Dzavik V Pseudoaneurysm after transradial cardiac catheterization: case series and review of the literature Catheter Cardiovasc Interv 2012 80 283 287 21735525 \n6 American College of Emergency Physicians Society for Cardiovascular Angiography Interventions O'Gara PT Kushner FG Ascheim DD Casey DE Jr Chung MK de Lemos JA Ettinger SM Fang JC Fesmire FM Franklin BA Granger CB Krumholz HM Linderbaum JA Morrow DA Newby LK Ornato JP Ou N Radford MJ Tamis-Holland JE Tommaso CL Tracy CM Woo YJ Zhao DX Anderson JL Jacobs AK Halperin JL Albert NM Brindis RG Creager MA DeMets D Guyton RA Hochman JS Kovacs RJ Kushner FG Ohman EM Stevenson WG Yancy CW 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013 61 e78 140 23256914 \n7 Mohamed MO Saif M Townend JN Khan SQ Successful treatment of a radial artery pseudoaneurysm in an octogenarian BMJ Case Rep 2015 2015 bcr2015211513 \n8 Bhat T Teli S Bhat H Akhtar M Meghani M Lafferty J Gala B Access-site complications and their management during transradial cardiac catheterization Expert Rev Cardiovasc Ther 2012 10 627 634 22651838 \n9 Joseph V Sambhaji C Prakashini K Radial artery pseudoaneurysm managed by prolonged ultrasound-guided compression repair and aided by interval application of compression device Australas Med J 2013 6 192 195 23671465 \n10 Pozniak MA Mitchell C Ledwidge M Radial artery pseudoaneurysm: a maneuver to decrease the risk of thrombin therapy J Ultrasound Med 2005 24 119 122 15615938 \n11 Liou M Tung F Kanei Y Kwan T Treatment of radial artery pseudoaneurysm using a novel compression device J Invasive Cardiol 2010 22 293 295 20516511 \n12 Cauchi MP Robb PM Zemple RP Ball TC Radial artery pseudoaneurysm: a simplified treatment method J Ultrasound Med 2014 33 1505 1509 25063417 \n13 Nazer B Boyle A Treatment of recurrent radial artery pseudoaneurysms by prolonged mechanical compression J Invasive Cardiol 2013 25 358 359 23813066\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1735-5370",
"issue": "12(2)",
"journal": "The journal of Tehran Heart Center",
"keywords": "Aneurysm, false; Angioplasty; Complications; Coronary angiography",
"medline_ta": "J Tehran Heart Cent",
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"pubdate": "2017-04",
"publication_types": "D002363:Case Reports",
"references": "23671465;26243752;20516511;15615938;16238993;2912567;23813066;22651838;25063417;23420446;23256914;21735525;15261930",
"title": "Successful Nonsurgical Treatment of a Radial Artery Pseudoaneurysm Following Transradial Coronary Angiography.",
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{
"abstract": "Human adenovirus (HAdV) is an important cause of the common cold and epidemic keratoconjunctivitis in immunocompetent individuals. In immunocompromised patients, HAdV can sometimes cause severe infection such as cystitis, gastroenteritis, pneumonia, encephalitis, hepatitis, or disseminated disease, resulting in significant morbidity and also mortality. In particular, severe cases have been reported in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Indeed HAdV has been recognized as a pathogen that requires careful monitoring in allo-HSCT patients. While HAdV hepatitis leading to severe acute liver failure is rare, such liver failure progresses rapidly and is often fatal. Unfortunately, HAdV hepatitis has few characteristic symptoms and physical findings, which makes it difficult to promptly confirm and start treatment. We report here four cases of HAdV hepatitis after allo-HSCT and their autopsy findings.",
"affiliations": "Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Osaka, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Osaka, Japan.;Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Osaka, Japan.;Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Osaka, Japan.;Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Osaka, Japan.;Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Osaka, Japan.;Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.;Department of Diagnostic Pathology, Takatsuki Red Cross Hospital, Osaka, Japan.;Center for Infectious Disease Risk Management, National Institute of Infectious Diseases, Tokyo, Japan.;Center for Infectious Disease Risk Management, National Institute of Infectious Diseases, Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
"authors": "Onda|Yoshiyuki|Y|https://orcid.org/0000-0003-3093-4974;Kanda|Junya|J|https://orcid.org/0000-0002-6704-3633;Sakamoto|Soichiro|S|;Okada|Mutsumi|M|;Anzai|Naoyuki|N|;Umadome|Hiroshi|H|;Tashima|Masaro|M|;Haga|Hironori|H|;Watanabe|Chihiro|C|;Hanaoka|Nozomu|N|;Fujimoto|Tsuguto|T|;Takaori-Kondo|Akifumi|A|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "acute liver failure; adenovirus hepatitis; allo-HSCT",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000257:Adenoviridae Infections; D000260:Adenoviruses, Human; D003556:Cystitis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017114:Liver Failure, Acute",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13496",
"pmc": null,
"pmid": "33075208",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Detection of adenovirus hepatitis and acute liver failure in allogeneic hematopoietic stem cell transplant patients.",
"title_normalized": "detection of adenovirus hepatitis and acute liver failure in allogeneic hematopoietic stem cell transplant patients"
}
|
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"abstract": "We report the case of a 44-year-old patient who experienced severe toxicity while being treated with capecitabine at standard dose for metastatic breast cancer. As the patient had already received 5-FU within the FEC protocol (5-FU 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) 10 years ago without experiencing any severe adverse event, no DPD deficiency testing was performed before capecitabine treatment. Nevertheless, she experienced severe diarrhea and grade 2 hand-foot syndrome from the first cycle, forcing her to stop the treatment. Phenotypic and genotypic investigation of DPD activity revealed that the patient had a partial deficiency and had therefore been exposed to a higher risk of developing severe toxicities on fluoropyrimidines. This case proves that tolerance to low-dose fluoropyrimidines does not preclude DPD deficiency and the occurrence of severe toxicities if higher doses of fluoropyrimidines are used as a second-line treatment. It emphasizes the role of DPD phenotyping testing based on uracilemia in patients scheduled for fluoropyrimidine drugs, even if previous courses with low-dose 5-FU were safely administered.",
"affiliations": "Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.;Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.;Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.;Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.;Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.;Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.;Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.;Laboratoire de Biologie Médicale Oncologique, Secteur Pharmacologie, Institut Claudius-Regaud, Institut Universitaire du Cancer (IUCT), Oncopole, 1 Avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France. [email protected].",
"authors": "Maillard|Maud|M|;Eche-Gass|Audrey|A|;Ung|Mony|M|;Brice|Aurélie|A|;Marsili|Sabrina|S|;Montastruc|Marion|M|;Puisset|Florent|F|;Thomas|Fabienne|F|0000-0001-9886-412X",
"chemical_list": "D000069287:Capecitabine; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-021-04233-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "87(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "5-Fluorouracil; Breast cancer; Capecitabine; DPD deficiency",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D000069287:Capecitabine; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D005260:Female; D005472:Fluorouracil; D006801:Humans",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "579-583",
"pmc": null,
"pmid": "33587160",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28481884;26794347;28395758;29152729;17064846;11895907;31486738;26265035;24648345;30348537;3049954;11014408",
"title": "Severe toxicity of capecitabine in a patient with DPD deficiency after a safe FEC-100 experience: why we should test DPD deficiency in all patients before high-dose fluoropyrimidines.",
"title_normalized": "severe toxicity of capecitabine in a patient with dpd deficiency after a safe fec 100 experience why we should test dpd deficiency in all patients before high dose fluoropyrimidines"
}
|
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"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "23.1",
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},
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"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
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"reactionmeddraversionpt": "23.1",
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"literaturereference": "MAILLARD M, ECHE?GASS A, UNG M, BRICE A, MARSILI S, MONTASTRUC M ET AL. SEVERE TOXICITY OF CAPECITABINE IN A PATIENT WITH DPD DEFICIENCY AFTER A SAFE FEC?100 EXPERIENCE: WHY WE SHOULD TEST DPD DEFICIENCY IN ALL PATIENTS BEFORE HIGH?DOSE FLUOROPYRIMIDINES. CANCER CHEMOTHERAPY AND PHARMACOLOGY. 2021. DOI:10.1007/S00280?021?04233?1.",
"literaturereference_normalized": "severe toxicity of capecitabine in a patient with dpd deficiency after a safe fec 100 experience why we should test dpd deficiency in all patients before high dose fluoropyrimidines",
"qualification": "3",
"reportercountry": "FR"
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"receiptdate": "20210316",
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{
"abstract": "Background and Purpose: The role of intra-arterial (IA) thrombolysis in modern endovascular therapy is not well-understood. Here, we surveyed neurointerventionalists to understand their current clinical practices and opinions of IA thrombolysis in the new era of mechanical thrombectomy (MT). Method: A 24-question anonymous survey was distributed via email to the members of the Society of Vascular and Interventional Neurology. Results: One hundred and four responses were included in the analysis. Most respondents were interventional neurologists (76.9%) and had ≥5-years in neuro-interventional practice (80.8%). IA thrombolytics are presently used by 60.6%. Aspiration plus stent-retriever was the most common MT approach used with IA-thrombolysis (66.0%). IA-thrombolysis was used in mainly three approaches: (1) treatment of primary distal occlusions, (2) as rescue after proximal occlusion thrombectomy, and (3) or as adjunct therapy to primary MT approach. The most frequent IA-rtPA dose was 3-10 mg, with 1 mg/min infusion rate (56.6%). 84.9% do not have a standardized protocol for administering IA-rtPA. About half (50.9%) believed there should be no time limit for administering IA lytic if there is a favorable imaging profile, while 30.2% indicated ≤6 h. Most respondents (76.5%) would consider using IA-tenecteplase in a trial setting. Only 12.9% felt there was no role for IA thrombolysis in modern endovascular practice. Respondents with ≥10-years' experience were less supportive of the future of IA lytic (98.0 vs. 76.4%, p = 0.006). Conclusion: IA-thrombolysis is currently used in clinical practice; however, there is no clear consensus on best practices or criteria for administration. Further studies are needed to define the role of IA-thrombolysis in the context of MT.",
"affiliations": "Department of Neurology, The University of Toledo Health Science Campus, Toledo, OH, United States.;Department of Neurology, The University of Toledo Health Science Campus, Toledo, OH, United States.;St. Vincent Mercy Hospital, Toledo, OH, United States.;Department of Neurology and Neurosurgery, Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, Atlanta, GA, United States.;Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.;Department of Neurology, The University of Toledo Health Science Campus, Toledo, OH, United States.;Department of Neurology, The University of Toledo Health Science Campus, Toledo, OH, United States.",
"authors": "Castonguay|Alicia C|AC|;Jumaa|Mouhammad A|MA|;Zaidat|Osama O|OO|;Haussen|Diogo C|DC|;Jadhav|Ashutosh|A|;Salahuddin|Hisham|H|;Zaidi|Syed F|SF|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2019.01195",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2019.01195NeurologyBrief Research ReportInsights Into Intra-arterial Thrombolysis in the Modern Era of Mechanical Thrombectomy Castonguay Alicia C. 1†Jumaa Mouhammad A. 1Zaidat Osama O. 2Haussen Diogo C. 3Jadhav Ashutosh 4Salahuddin Hisham 1Zaidi Syed F. 1*†1Department of Neurology, The University of Toledo Health Science Campus, Toledo, OH, United States2St. Vincent Mercy Hospital, Toledo, OH, United States3Department of Neurology and Neurosurgery, Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Emory University School of Medicine, Atlanta, GA, United States4Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, United StatesEdited by: Shakir Husain Hakim, University Hospital Zürich, Switzerland\n\nReviewed by: Sombat Muengtaweepongsa, Thammasat University, Thailand; Edgar A. Samaniego, The University of Iowa, United States\n\n*Correspondence: Syed F. Zaidi [email protected] article was submitted to Endovascular and Interventional Neurology, a section of the journal Frontiers in Neurology\n\n†These authors have contributed equally to this work\n\n13 11 2019 2019 10 119516 8 2019 28 10 2019 Copyright © 2019 Castonguay, Jumaa, Zaidat, Haussen, Jadhav, Salahuddin and Zaidi.2019Castonguay, Jumaa, Zaidat, Haussen, Jadhav, Salahuddin and ZaidiThis 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 and Purpose: The role of intra-arterial (IA) thrombolysis in modern endovascular therapy is not well-understood. Here, we surveyed neurointerventionalists to understand their current clinical practices and opinions of IA thrombolysis in the new era of mechanical thrombectomy (MT).\n\nMethod: A 24-question anonymous survey was distributed via email to the members of the Society of Vascular and Interventional Neurology.\n\nResults: One hundred and four responses were included in the analysis. Most respondents were interventional neurologists (76.9%) and had ≥5-years in neuro-interventional practice (80.8%). IA thrombolytics are presently used by 60.6%. Aspiration plus stent-retriever was the most common MT approach used with IA-thrombolysis (66.0%). IA-thrombolysis was used in mainly three approaches: (1) treatment of primary distal occlusions, (2) as rescue after proximal occlusion thrombectomy, and (3) or as adjunct therapy to primary MT approach. The most frequent IA-rtPA dose was 3–10 mg, with 1 mg/min infusion rate (56.6%). 84.9% do not have a standardized protocol for administering IA-rtPA. About half (50.9%) believed there should be no time limit for administering IA lytic if there is a favorable imaging profile, while 30.2% indicated ≤6 h. Most respondents (76.5%) would consider using IA-tenecteplase in a trial setting. Only 12.9% felt there was no role for IA thrombolysis in modern endovascular practice. Respondents with ≥10-years' experience were less supportive of the future of IA lytic (98.0 vs. 76.4%, p = 0.006).\n\nConclusion: IA-thrombolysis is currently used in clinical practice; however, there is no clear consensus on best practices or criteria for administration. Further studies are needed to define the role of IA-thrombolysis in the context of MT.\n\nintra-arterialthrombolysisthrombectomystrokeocclusion\n==== Body\nIntroduction\nAlthough mechanical thrombectomy (MT) has become the gold standard for the treatment of large vessels occlusions (LVOs), limited complete reperfusion rates by current generation stent-retrievers give way for adjunctive therapies to potentially augment their revascularization effectiveness. Complete or near-complete rates of reperfusion correlate with better functional outcomes in acute ischemic stroke patients (1).\n\nIntra-arterial (IA) thrombolysis, once a first-line therapy for LVOs prior to the advent of MT, has reemerged with a potential new role in the modern endovascular era. Recent studies have demonstrated promising results of IA recombinant tissue plasminogen activator (rtPA) in the context of MT (2–4); however, the role of IA thrombolysis in contemporary endovascular therapy is not well-understood and limited data exists on its current use in real-world practice. Here, we surveyed the neuro-interventional field to evaluate the current clinical practices and opinions of IA thrombolysis in the context of MT and to better understand its future role in endovascular stroke therapy.\n\nMethods\nA 24-question survey was developed to understand current practices and opinions of physicians on the use of IA thrombolytics in endovascular stroke therapy. The survey was designed using SurveyMonkey (SurveyMonkey, Inc., San Mateo, CA, www.surveymonkey.com), an online survey development cloud-based software. This survey was classified as exempt human subject research by the University of Toledo institutional review board. As such, written informed consent was not required. The survey link was distributed to the Society of Vascular and Interventional Neurology members (SVIN) via email. All responses were anonymous, and the survey link allowed for only one completion per individual. Questions were presented in the following categories: (1) clinical and practice background, (2) IA thrombolytic use, (3) case examples, and (4) IA thrombolysis in modern endovascular practice (Table 1). Skip logic was incorporated to promote efficiency and ease of survey navigation. For analysis, all survey data were presented as frequencies of responses.\n\nTable 1 Intra-arterial thrombolysis survey questions and responses.\n\nQuestions\tAnswers\t\nClinical and practice background\t\n1. What is your clinical background?\tInterventional neurologist (80/104; 76.9%)\nEndovascular Neurosurgeon (8/104; 7.7%)\nInterventional Neuro-radiologist (16/104; 15.4%)\t\n2. How long have you been in neuro-interventional practice?\t0–4 years (20/104; 19.2%)\n5–9 years (43/104; 41.3%)\n≥10 years (41/104; 39.4%)\t\n3. What is the setup of your neuro-interventional practice?\tAcademic (51/104; 49.0%)\nPrivate-academic (with residents and/or fellows) (29/104; 27.9%)\nPrivate (no fellows or residents) (24/104; 23.1%)\t\n4. What is your center's certification status?\tJC Comprehensive Stroke Center (55/104; 52.9%)\nDNV Comprehensive Stroke Center (25/104; 24.0%)\nPrimary Stroke Center with interventional capabilities (14/104; 13.5%)\nCertified Thrombectomy Ready Hospital (10/104; 9.6%)\t\n5. On average, how many mechanical thrombectomies do you perform per year?\t0–23 per year (14/104; 13.5%)\n24–47 per year (23/104; 22.1%)\n48–74 per year (23/104; 22.1%)\n≥75 per year (44/104; 42.3%)\t\n6.Were you a participating investigator in IMSIII and/or PROACT II?\tYes (24/104; 23.1%)\nNo (80/104; 76.9%)\t\nIA thrombolytic use\t\n7. How often do you use IA thrombolytic for treatment for acute ischemic stroke?\tNever (41/104; 39.4%)\n1–5 cases per year (49/104; 47.1%)\n6–10 cases per year (6/104; 5.8%)\n11–20 cases per year (4/104; 3.8%)\n>20 cases per year (4/104; 3.8%)\t\n8. How is IA rt-PA used in your practice? (check all that apply)\tPrimary therapy alone for the target occlusion (similar to PROACT II or MELT trials) (2/53; 3.8%)\nPrimary distal occlusion (M3/4, A2, P2, etc) (22/53; 41.5%)\nRescue therapy to the primary target occlusion that failed mechanical thrombectomy (19/53; 35.9%)\nRescue therapy for unsatisfactory results of the primary modality to address distal embolization (34/53; 64.2%)\nRescue therapy for unsatisfactory results of the primary modality to address embolization into new territory (28/53; 52.8%)\nAdjunctive therapy in conjunction with mechanical thrombectomy from the beginning of the procedure (as an add-on and not to address failed MT or unsatisfactory results) (3/53; 5.7%)\t\n9. What is the average dosage of IA rt-PA administered for large vessel occlusions of the anterior circulation?\t0–2 mg (5/53; 9.4%)\n3–5 mg (19/53; 35.9%)\n6–10 mg (17/53; 32.1%)\n11–15 mg (5/53; 9.4%)\n16–20 mg (4/53; 7.6%)\n>20 mg (0/53; 0%)\nI do not use IA rt-PA for anterior circulation LVOs (3/53; 5.7%)\t\n10. In the case of distal M3/M4 occlusion, where would you generally administer IA rt-PA?\tWithin the clot itself (14/53; 26.4%)\nWithin the occluded branch proximal to the clot (33/53; 62.3%)\nDistal MCA M1 (3/53; 5.7%)\nProximal MCA (0/53; 0%)\nICA (0/53; 0%)\nI do not use IA rt-PA to treat distal occlusions (3/53; 5.7%)\t\n11. In your practice, what is the average dose of IA rt-PA administered for distal M3 or distal A2 occlusions?\t0–2 mg (7/53; 13.2%)\n3–5 mg (23/53; 43.4%)\n6–10 mg (15/53; 28.3%)\n11–15 mg (4/53; 7.6%)\n16–20 mg (1/53; 1.9%)\n>20 mg (0/53; 0%)\nI do not use IA rt-PA for distal occlusions (3/53; 5.7%)\t\n12. If you encounter a tandem lesion, what would be your opinion about giving IA rt-PA?\tNever use IA rt-PA for a tandem lesion (23/53; 43.4%)\nOnly use IA rt-PA if performing angioplasty only (8/53; 15.1%)\nIt doesn't matter as long as no dual anti-platelets are given PO or IV GP IIb/IIIa (6/53; 11.3%)\nI would use IA rt-PA regardless of the tandem lesion treatment approach (16/53; 30.2%)\t\n13. Do you have a standardized protocol for giving IA rt-PA?\tYes (8/53; 15.1%)\nNo (45/53; 84.9%)\t\n14. In general, how long do you infuse IA rt-PA?\t5 min/1 mg (10/53; 18.9%)\n2 min/1 mg (11/53; 20.8%)\n1 min/1 mg (30/53; 56.6%)\nOther (2/53; 3.8%)\t\n15. When using IA rt-PA, do you also use microwire maceration?\tYes, sometimes (29/53; 54.7%)\nYes, I always use if technically feasible (5/53; 9.4%)\nNo (19/53; 35.9%)\t\n16. Which type(s) of mechanical thrombectomy do you use with IA rt-PA? (check all that apply)\tAspiration only (17/53; 32.1%)\nAspiration plus stent-retriever (35/53; 66.0%)\nStent-retriever only (14/53; 26.4%)\nNone, I would use IA rtPA alone (11/53; 20.8%)\t\n17. Check which scenario(s) you would NOT feel comfortable giving a patient IA rt-PA (check all that apply)\tAge more than 85 (9/53; 17.0%)\nNIHSS >25 (8/53; 15.1%)\nIV rt-PA prior to endovascular therapy (20/53; 37.7%)\nNone of the above (26/53; 49.1%)\t\n18. What would be your ASPECTS cut off for use of IA rt-PA during MT?\t8–10 (11/53; 20.8%)\n7–10 (9/53; 17.0%)\n6–10 (19/53; 35.9%)\nNo cut off (14/53; 26.4%)\t\n19. What would be your core infarct volume (using MR perfusion or CT perfusion) cut off for NOT giving IA rt-PA?\t0–25 ml (7/53; 13.2%)\n26–50 ml (8/53; 15.1%)\n51–70 ml (17/53; 32.1%)\n71–100 ml (15/53; 28.3%)\n>100 ml (6/53; 11.3%)\t\n20. IA thrombolysis should be administered in which time window?\t≤6 h (16/53; 30.2%)\n ≤8 h (7/53; 13.2%)\n ≤12 h (0/53; 0%)\n ≤16 h (0/53; 0%)\n ≤24 h (3/53; 5.7%)\nNo time limit with favorable imaging profile (27/53; 50.9%)\t\nCase Examples\t\n21. For case example #1, what would be your preferred treatment approach?\tNo further treatment (19/90; 21.1%)\nAspiration only (16/90; 17.8%)\nStent-retriever only (14/90; 15.6%)\nAspiration + stent-retriever (18/90; 20.0%)\nIA rt-PA only (23/90; 25.6%)\t\n22. For case example #2, what would be your preferred treatment approach?\tNo further treatment (41/87; 47.1%)\nAspiration only (3/87; 3.5%)\nStent-retriever only (4/87; 4.6%)\nAspiration + stent-retriever (3/87; 3.5%)\nIA rt-PA only (36/87; 41.4%)\t\nIA Thrombolysis in Modern Endovascular Practice\t\n23. In a trial setting, would you consider using IA tenecteplase (TNK) for treatment of distal occlusions?\tYes (65/85; 76.5%)\nNo (7/85; 8.2%)\nMaybe (13/85; 15.3%)\t\n24. I believe that IA thrombolysis has a role in modern endovascular practice?\tYes, IA thrombolysis has a role in modern endovascular practice (32/85; 37.6%)\nNo, IA thrombolysis does not have a role in modern endovascular practice. (11/85; 12.9%)\nMaybe, more evidence is needed to clarify the role of IA thrombolysis in modern endovascular practice. (42/85; 49.4%)\t\nResults\nFrom February to May 2019, 106 responses were collected with an 80% completion rate. Of those, 104 respondents had completed at minimum questions 1 through 7 and were included in this analysis (Supplementary Table 1).\n\nClinical and Practice Background\nOf the 104 respondents, 80 (76.9%) were interventional neurologists, 16 (15.4%) interventional neuro-radiologists, and 8 (7.7%) were endovascular neurosurgeons (Supplementary Table 1). Most respondents had ≥5-years of neuro-interventional experience (80.8%). Almost half (49.0%) were in an academic practice, and 52.9% were in a Joint Commission certified comprehensive stroke center. On average, 42.3% performed more than 75 MTs per year. Only 23.1% had previous experience as a participating investigator in the Interventional Management of Stroke-III and/or the Prolyse in Acute Cerebral Thromboembolism II trial.\n\nIA Thrombolytic Use\nMost respondents (60.6%) used IA thrombolytics in their practice, of which 47.1% treated 1–5 cases/year with IA-rtPA (Table 1).\n\nHow IA Lytic Is Used\nOf those that use IA lytics, 60.4% indicated that they used IA-rtPA in all three different approaches: (1) for treating primary distal occlusion, (2) as rescue therapy, and/or (3) adjunctive therapy (Supplementary Figure 1).\n\nDosage and Location of Infusion\nThe average IA-rt-PA dosage was 3–5 mg among 35.9% and 6–10 mg among 32.1% of respondents (Table 1). 56.6% infuse IA-rtPA at a rate of 1 mg/min and 54.7% sometimes use microwire clot maceration with IA-rtPA.\n\nIn reference to where in relation to the clot should IA lytic be administered for distal M3/M4 occlusions, the majority of respondents (62.3%) would administer IA-rtPA proximal to the clot and 26.4% would administer within the clot itself (Table 1).\n\nMT Approaches\nWhen questioned regarding types of MT that were used in conjunction with IA-rt-PA (irrespective of the approach), 70.0% chose a single response, of which 51.4% answered aspiration plus stent-retriever (Table 1, Supplementary Figure 2).\n\nIA Lytic Criteria\nMost respondents (86.8%) chose a single response when asked which scenario they would not feel comfortable giving a patient IA-rtPA, with 56.5% indicating that they would feel comfortable in all scenarios (age >85 years, NIHSS >25, and IV rt-PA prior to MT) and 32.6% would not feel comfortable using IA-rtPA in patients treated with IV-rtPA (Supplementary Table 1, Supplementary Figure 3).\n\nThere was no consensus by respondents on an Alberta Stroke Program Early CT Score cut-off for use of IA-rtPA, with 20.8% answering 8–10, 17.0% 7–10, 35.9% 6–10, and 26.4% preferred no cut-off. The core infarct volume (on MR/CT perfusion) cut-off for not giving IA-rtPA varied; however, 60.4% answered either 51–70 ml (32.1%) or 71–100 ml (28.3%).\n\nApproximately half of the respondents feel that there should be no time limit for IA lytic administration with favorable imaging, while 30.2% indicted ≤6 h.\n\nImportantly, 84.9% did not have a standardized protocol for administering IA-rtPA.\n\nCase Presentations\nTwo case examples were provided to gauge respondents preferred treatment approaches for distal occlusions after MT (Supplementary Table 1).\n\nDistal Embolization, Post-MT, and IV-rtPA\nFor case example 1 (Figure 1), treatment preferences varied; however, the majority of respondents agreed that further treatment is necessary (78.9%).\n\nFigure 1 Case presentation #1. A 75-year-old with RICA T occlusions post-IV t-PA and MT with distal embolization into the right ACA A2. The MCA territory has completely recanalized; however, there is a subocclusive thrombus in the right pericallosal and callosmarginal divisions. Pie chart depicts the respondents' treatment preferences.\n\nDistal Embolization, Post-MT Without IV-tPA\nFor case example 2 (Figure 2), about half of the respondents (47.1%) would recommend no further treatment and 41.4% would treat with IA-rtPA only.\n\nFigure 2 Case presentation #2. A 65-year-old with right sided weakness and aphasia, NIHSS 18, last known well 8 h prior to presentation, ASPECTS 9, with a left M1 occlusion on head CTA. Post left MCA MT, distal embolization occurred into multiple M3 branches. Pie chart depicts the respondents' treatment preferences. A, aspiration only; S, stent-retriever only; A+S, aspiration and stent-retriever.\n\nIA Thrombolysis in Modern Endovascular Practice\nNew IA Lytics\nWhen asked if respondents would consider using IA tenecteplase for treatment of distal occlusions in a trial setting, 76.5% answered yes (Supplementary Table 1).\n\nFuture of IA Thrombolysis\nAlmost half (49.4%) of those surveyed believed that IA thrombolysis may have a role in modern endovascular practice, but more evidence is needed, while 37.6% agreed that IA thrombolysis has a role in current endovascular practice (Supplementary Table 1).\n\nImpact of Case Volume and Experience\nWhen stratifying the results by case volume or experience level, no difference was found in use of IA lytic; however, those with ≥10 years of experience were less enthusiastic about the future of IA lytic (p = 0.006) (Figure 3, Supplementary Tables 1, 2).\n\nFigure 3 Results stratified by years of experience.\n\nDiscussion\nTo date, little is known about the use of IA thrombolysis in the current era of endovascular stroke therapy. Recent studies after the landmark MT trials (5–10) have investigated IA-rtPA use in conjunction with MT (2–4); however, these studies were limited by their retrospective non-randomized nature, small sample size, and heterogeneous populations and techniques. Our study revealed that most respondents use IA thrombolysis in their current clinical practice; however, few implement standardized protocols for IA-rtPA administration.\n\nOur survey highlights the variability of IA-rt-PA use, with most respondents using IA lytic for primary distal occlusions, or RT for distal embolization and embolization into new territory after MT, and in different settings of MT, including aspiration and stent-retrievers. When presented with two different cases of distal occlusions after MT, there was no consensus on the preferred treatment approach. As distal vessel occlusions (DVO) may cause significant deficits depending on the eloquence of the affected branch or branches (11, 12), endovascular therapies, such as IA rt-PA, may be viable treatment options for these occlusions. A recent retrospective single center case study of DVO demonstrated an acceptable safety and reperfusion profile with endovascular therapy (52% treated with IA-rtPA) (13). Although newer devices have made MT in distal vessels possible, in cases of extreme tortuosity, IA thrombolytics may be preferable.\n\nAdditionally, we also found a wide-range of IA-rtPA dosing for anterior circulation LVOs and distal occlusions; however, more than half of survey respondents administered in the range of 3–10 mg with varying infusion rates. Recent MT trials, MR CLEAN, and ESCAPE, allowed the use of IA-rtPA (9, 10). MR CLEAN allowed for a maximum of dose of 90 mg (if IV-rtPA was not administered) and 30 mg (if IV-rtPA was administered) administered via micro-catheter at the level of occlusion. The ESCAPE Trial protocol recommended a maximum dose of 10 mg rtPA via micro-catheter for use as adjunctive therapy. Two retrospective studies reported dosing of IA rt-PA of up to 15 mg and <5 mg (3, 4). As there are no standardized dosing guidelines, prospective studies are warranted to determine the dosing threshold for IA-rtPA.\n\nCurrently, there are no established criteria for IA thrombolysis administration in the context of MT and results of our survey highlight the lack of consensus among MT practitioners. Less than 50% of respondents would feel comfortable administering IA-rtPA to those >85 years, NIHSS>25, or received IV-rt-PA prior to endovascular therapy and no clear consensus was reached for a cut-off regarding Alberta Stroke Program Early CT Score or time window. The above results further demonstrate the need for clinical studies to define the criteria for use of IA thrombolysis in endovascular therapy, including the optimal patient population.\n\nFuture of IA Thrombolysis\nRespondents believed that IA thrombolysis may have a place in modern endovascular practice, but more evidence is required to define its role. This was supported by the respondents' enthusiasm for enrolling in future IA lytic trials, including IA tenecteplase.\n\nLimitations\nOur study has several limitations, including the inherent limitations of survey research. As this survey was administered to SVIN members, results may not be inclusive of the practice patterns or opinions of other MT practitioners not affiliated with SVIN. For example, 76.9% of respondents were interventional neurologists and only 7.7% were endovascular neurosurgeons. As not all respondents answered all survey questions, it is possible that lack of response may have introduced selection bias into the survey results. Additionally, the small sample size may limit the interpretability and generalizability of this study.\n\nConclusion\nOur survey demonstrates that IA thrombolysis is widely used in current practice. These results support the need for further studies on IA thrombolysis in the context of MT and may serve as a guide for the design of future IA thrombolysis clinical studies.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/Supplementary Material.\n\nEthics Statement\nThis survey was classified as exempt human subject research by the University of Toledo institutional review board. As such, written informed consent was not required.\n\nAuthor Contributions\nAC, SZ, OZ, DH, MJ, and AJ participated in the design, analysis, drafting, and editing of the manuscript. HS participated in the analysis and critical review of the manuscript.\n\nConflict of Interest\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/fneur.2019.01195/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Zaidat OO Castonguay AC Linfante I Gupta R Martin CO Holloway WE . First pass effect: a new measure for stroke thrombectomy devices . Stroke . (2018 ) 49 :660 –6 . 10.1161/STROKEAHA.117.020315 29459390 \n2. Zaidi SF Castonguay AC Jumaa MA Malisch TW Linfante I Marden FA \nIntraarterial thrombolysis as rescue therapy for large vessel occlusions . Stroke . (2019 ) 50 :1003 –6 . 10.1161/STROKEAHA.118.024442 30791829 \n3. Yi TY Chen WH Wu YM Zhang MF Lin DL Lin XH . Adjuvant intra-arterial rt-pa injection at the initially deployed solitaire stent enhances the efficacy of mechanical thrombectomy in acute ischemic stroke . J Neurol Sci . (2018 ) 386 :69 –73 . 10.1016/j.jns.2018.01.012 29406970 \n4. Heiferman DM Li DD Pecoraro NC Smolenski AM Tsimpas A Ashley WW Jr . Intra-arterial alteplase thrombolysis during mechanical thrombectomy for acute ischemic stroke . J Stroke Cerebrovasc Dis . (2017 ) 26 :3004 –8 . 10.1016/j.jstrokecerebrovasdis.2017.07.031 28843804 \n5. Goyal M Menon BK van Zwam WH Dippel DW Mitchell PJ Demchuk AM . Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials . Lancet . (2016 ) 387 :1723 –1 . 10.1016/S0140-6736(16)00163-X 26898852 \n6. Saver JL Goyal M Bonafe A Diener HC Levy EI Pereira VM . Stent-retriever thrombectomy after intravenous t-pa vs . T-pa alone in stroke. N Engl J Med . (2015 ) 372 :2285 –95 . 10.1056/NEJMoa1415061 25882376 \n7. Campbell BC Mitchell PJ Investigators E-I \nEndovascular therapy for ischemic stroke . N Engl J Med . (2015 ) 372 :2365 –6 . 10.1056/NEJMoa1414792 26061843 \n8. Jovin TG Chamorro A Cobo E de Miquel MA Molina CA Rovira A . Thrombectomy within 8 hours after symptom onset in ischemic stroke . N Engl J Med . (2015 ) 372 :2296 –306 . 10.1056/NEJMoa1503780 25882510 \n9. Goyal M Demchuk AM Menon BK Eesa M Rempel JL Thornton J . Randomized assessment of rapid endovascular treatment of ischemic stroke . N Engl J Med . (2015 ) 372 :1019 –30 . 10.1056/NEJMoa1414905 25671798 \n10. Berkhemer OA Fransen PS Beumer D van den Berg LA Lingsma HF Yoo AJ . A randomized trial of intraarterial treatment for acute ischemic stroke . N Engl J Med . (2015 ) 372 :11 –20 . 10.1056/NEJMoa1411587 25517348 \n11. Kurre W Vorlaender K Aguilar-Perez M Schmid E Bazner H Henkes H . Frequency and relevance of anterior cerebral artery embolism caused by mechanical thrombectomy of middle cerebral artery occlusion . AJNR Am J Neuroradiol . (2013 ) 34 :1606 –11 . 10.3174/ajnr.A3462 23471019 \n12. King S Khatri P Carrozella J Spilker J Broderick J Hill M . Anterior cerebral artery emboli in combined intravenous and intra-arterial rtpa treatment of acute ischemic stroke in the IMS I and II trials . AJNR Am J Neuroradiol . (2007 ) 28 :1890 –4 . 10.3174/ajnr.A0702 17898199 \n13. Grossberg JA Rebello LC Haussen DC Bouslama M Bowen M Barreira CM . Beyond large vessel occlusion strokes: distal occlusion thrombectomy . Stroke . (2018 ) 49 :1662 –8 . 10.1161/STROKEAHA.118.020567 29915125\n\n",
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"title": "Insights Into Intra-arterial Thrombolysis in the Modern Era of Mechanical Thrombectomy.",
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"abstract": "Metastatic pancreatic adenocarcinoma (MPA) represents a highly lethal condition. Despite the improvements seen with FOLFIRINOX, there is no randomized data to guide treatment selection beyond this regimen. We aimed to evaluate the outcomes of patients with MPA progressing on FOLFIRINOX who were treated with Gemcitabine-based chemotherapy afterwards.\nWe included patients aged 18 years or older, treated for MPA with FOLFIRINOX in the first-line setting and who experienced disease progression, with Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and treated with at least one cycle of Gemcitabine-based chemotherapy in second or further lines of treatment. We used descriptive statistics to characterize the study population and Cox proportional-hazards models to describe factors associated with survival. As an exploratory analysis, we compared the outcomes of patients treated with single-agent Gemcitabine with those of patients undergoing Gemcitabine-based polychemotherapy.\nThe study population consisted of 42 patients. Median age was 59 years and 78.6% of patients presented ECOG 0-1. Thirty-three patients (78.6%) were treated with Gemcitabine-based chemotherapy in the second-line setting and 27 patients (64.3%) were treated with single-agent Gemcitabine. Objective response rate and disease control rate were 2.4% and 33.4%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were 2.9 and 5.5 months, respectively. Six-month PFS and OS rates were 19.2% and 46.2%, respectively. We observed no significant difference in OS according to the type of Gemcitabine-based chemotherapy, despite numerically improved disease control rate and PFS for those treated with Gemcitabine-based polychemotherapy. In multivariate analysis, ECOG 2 (vs. ECOG 0-1) was the only factor significantly associated with inferior PFS and OS.\na subgroup of patients with MPA derives benefit from treatment with Gemcitabine-based regimens after FOLFIRINOX. There is a suggestion that Gemcitabine-based combinations, in particular Gemcitabine plus Nab-Paclitaxel, provide superior outcomes compared to single-agent Gemcitabine. Additionally, treatment in this setting should be offered carefully to patients with ECOG 2, as they present shorter survival and increased risk of toxicity.",
"affiliations": "Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.;Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.;Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.;Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.;Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.;Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.;Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.",
"authors": "de Jesus|Victor Hugo Fonseca|VHF|;Camandaroba|Marcos Pedro Guedes|MPG|;Donadio|Mauro Daniel Spina|MDS|;Cabral|Audrey|A|;Muniz|Thiago Pimentel|TP|;de Moura Leite|Luciana|L|;Sant'Ana|Lucas Ferreira|LF|",
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"issue": "9(5)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "FOLFIRINOX; Gemcitabine; Metastatic; neoplasm; pancreatic",
"medline_ta": "J Gastrointest Oncol",
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"pubdate": "2018-10",
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"title": "Retrospective analysis of efficacy and safety of Gemcitabine-based chemotherapy in patients with metastatic pancreatic adenocarcinoma experiencing disease progression on FOLFIRINOX.",
"title_normalized": "retrospective analysis of efficacy and safety of gemcitabine based chemotherapy in patients with metastatic pancreatic adenocarcinoma experiencing disease progression on folfirinox"
}
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{
"abstract": "BACKGROUND\nFree-floating thrombus (FFT) of the cervical carotid artery is a rare but critical condition leading to stroke. The most common underlying pathology is atherosclerotic plaque; nonatherosclerotic pathologies are much rarer. Here we report a case of FFT associated with cervical carotid artery dissection that was successfully treated by surgical thromboendarterectomy.\n\n\nMETHODS\nA 51-year-old man presented with headache, pain in the left neck, and amaurosis fugax. Magnetic resonance angiography revealed mild stenosis in the bifurcation of the left carotid artery. The stenotic lesion was considered as a possible dissection because of the normal appearance of the vessel 2 years ago and its clinical presentation. Oral aspirin was initiated with the diagnosis of transient ischemic attack. Two weeks later, ultrasound was planned for further examination, which demonstrated a massive FFT with intramural hematoma in the lesion. Because FFT was present despite taking aspirin, surgical thromboendarterectomy was performed to prevent further ischemic events.\n\n\nRESULTS\nIntraoperative findings revealed that FFT was the thrombus protruding from the intramural hematoma caused by arterial dissection. After the whole dissected layer was removed, the residual lumen was reinforced by multiple tacking sutures to prevent recurrence of dissection. No further ischemic events and recurrence occurred during the 1-year of follow-up after the surgery.\n\n\nCONCLUSIONS\nWhen managing patients with carotid artery dissection, the formation of FFT should be considered as a possible critical feature. Surgical thromboendarterectomy with intimal tacking sutures might be an option for the treatment, ensuring immediate, preventive effects against the risk of cerebral embolism.",
"affiliations": "Department of Neurosurgery, Toyooka Hospital, Hyogo, Japan. Electronic address: [email protected].;Department of Neurosurgery, Toyooka Hospital, Hyogo, Japan.;Department of Neurosurgery, Toyooka Hospital, Hyogo, Japan.;Department of Neurosurgery, Kobe University Graduate School of Medicine, Hyogo, Japan.",
"authors": "Imahori|Taichiro|T|;Tanaka|Kazuhiro|K|;Arai|Atsushi|A|;Kohmura|Eiji|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2020.04.076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": "68()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000784:Aneurysm, Dissecting; D002340:Carotid Artery Diseases; D004691:Endarterectomy; D006801:Humans; D002546:Ischemic Attack, Transient; D008297:Male; D008875:Middle Aged; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "572.e9-572.e14",
"pmc": null,
"pmid": "32439523",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D059040:Video-Audio Media",
"references": null,
"title": "Surgical Thromboendarterectomy for Free-Floating Thrombus Associated with Cervical Carotid Artery Dissection: A Case Report.",
"title_normalized": "surgical thromboendarterectomy for free floating thrombus associated with cervical carotid artery dissection a case report"
}
|
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],
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] |
{
"abstract": "OBJECTIVE\nThe aim of this study was to evaluate the tolerability of adding OROS methylphenidate (MPH) to children who are partial responders to atomoxetine (ATMX) in the treatment of attention-deficit/hyperactivity disorder (ADHD).\n\n\nMETHODS\nThis was a two-phase, 7-week, open study in children aged 6-17 years. Phase 1 initiated ATMX for a minimum of 4 weeks. Phase 2 entered partial responders to ATMX and added OROS MPH to their regimen. Safety was assessed using blood pressure and heart rate measurements, electrocardiogram readings, AEs, laboratories, and ATMX levels.\n\n\nRESULTS\nFifty subjects who were partial responders to ATMX received the combination therapy, with 41 subjects completing the entire protocol. As reported elsewhere (Wilens et al., 2009 ), OROS MPH added to partial responders of ATMX was accompanied by a 40% reduction in the ADHD rating scale score and improvements in executive functioning. However, the combination of ATMX plus OROS MPH was associated with greater rates of insomnia, irritability, and loss of appetite compared to ATMX alone. A small significant increase in diastolic blood pressure was observed during adjunctive OROS MPH, with no clinically meaningful changes in electrocardiogram (ECG) parameters during the study. ATMX levels and liver function tests did not significantly change during the combination treatment.\n\n\nCONCLUSIONS\nAdjunct OROS MPH in ATMX partial responders yielded an additive adverse effect burden in this short-term study. Further controlled research with larger samples of children is warranted.",
"affiliations": "Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Harvard Medical School , Boston Massachusetts, USA.",
"authors": "Hammerness|Paul|P|;Georgiopoulos|Anna|A|;Doyle|Robert L|RL|;Utzinger|Linsey|L|;Schillinger|Mary|M|;Martelon|Marykate|M|;Brodziak|Kerry|K|;Biederman|Joseph|J|;Wilens|Timothy E|TE|",
"chemical_list": "D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2008.0126",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "19(5)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity; D001794:Blood Pressure; D000697:Central Nervous System Stimulants; D002648:Child; D003692:Delayed-Action Preparations; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008774:Methylphenidate; D011437:Propylamines",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "493-9",
"pmc": null,
"pmid": "19877973",
"pubdate": "2009-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16768642;19877972;14594346;10434498;12862507;10221637;10591283;16429085;17581453;16899230;11707061;17897473;14993578;15142400;18366245;16151689;11581440;10831022;18281409;11177062;16860138;16182674;16961428;18507848;19394037;3572779;16389216;14595084;11694667;12611822",
"title": "An open study of adjunct OROS-methylphenidate in children who are atomoxetine partial responders: II. Tolerability and pharmacokinetics.",
"title_normalized": "an open study of adjunct oros methylphenidate in children who are atomoxetine partial responders ii tolerability and pharmacokinetics"
}
|
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"transmissiondate": "20150821"
},
{
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"fulfillexpeditecriteria": "2",
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"reactionmeddrapt": "Anxiety",
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],
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"qualification": "1",
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},
"primarysourcecountry": "US",
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},
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},
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}
] |
{
"abstract": "Autoimmune hepatitis (AIH) in pregnancy can affect both fetal and maternal outcomes. Little is known regarding the fetal outcomes of AIH in pregnancy. The major risks include spontaneous abortions, fetal mortality, perinatal mortality and prematurity. Two common drugs used in the management of AIH, azathioprine and prednisone, may also be associated with adverse fetal outcomes. We present the case of perinatal focal intestinal perforation with a meconium pseudocyst in a preterm infant of a mother with autoimmune hepatitis on azathioprine and methylprednisone.",
"affiliations": "Department of Pediatrics, New York Methodist Hospital, Brooklyn, NY, USA.;Saint George's University School of Medicine, True Blue, Grenada.;Department of Pediatrics, New York Methodist Hospital, Brooklyn, NY, USA.;Department of Surgery, New York Methodist Hospital, Brooklyn, NY, USA.;Department of Pediatrics, New York Methodist Hospital, Brooklyn, NY, USA.",
"authors": "Charlagorla|P|P|;Sublett|S|S|;Sy|F|F|;Kessler|E|E|;Gad|A|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins; D007166:Immunosuppressive Agents; D000667:Ampicillin; D001379:Azathioprine",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/NPM-1471113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-4429",
"issue": "7(1)",
"journal": "Journal of neonatal-perinatal medicine",
"keywords": "Fetal intestinal perforation; autoimmune hepatitis; azathioprine; meconium peritonitis",
"medline_ta": "J Neonatal Perinatal Med",
"mesh_terms": "D000328:Adult; D000667:Ampicillin; D000900:Anti-Bacterial Agents; D001379:Azathioprine; D013293:Enterococcus faecalis; D005260:Female; D005839:Gentamicins; D016908:Gram-Positive Bacterial Infections; D019693:Hepatitis, Autoimmune; D006801:Humans; D007081:Ileostomy; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D007234:Infant, Premature; D007416:Intestinal Perforation; D007813:Laparotomy; D008297:Male; D008470:Meconium; D010538:Peritonitis; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D012307:Risk Factors; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "101468335",
"other_id": null,
"pages": "71-4",
"pmc": null,
"pmid": "24815708",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fetal intestinal perforation and meconium peritonitis associated with maternal autoimmune hepatitis.",
"title_normalized": "fetal intestinal perforation and meconium peritonitis associated with maternal autoimmune hepatitis"
}
|
[
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
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"drugdosagetext": "(MATERNAL DOSE: 7.5 MG)",
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{
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"activesubstancename": "AZATHIOPRINE"
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"drugdosagetext": "(MATERNAL DOSE: 100 MG)",
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],
"patientagegroup": "1",
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"reaction": [
{
"reactionmeddrapt": "Ileal perforation",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Enterococcal infection",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Meconium cyst",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Meconium abnormal",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ascites",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Breech presentation",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hydrops foetalis",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Use of accessory respiratory muscles",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Meconium peritonitis",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gastrointestinal haemorrhage",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal distension",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gastrointestinal sounds abnormal",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHARLAGORLA P, SUBLETT S, SY F, KESSLER E, GAD A. FETAL INTESTINAL PERFORATION AND MECONIUM PERITONITIS ASSOCIATED WITH MATERNAL AUTOIMMUNE HEPATITIS. JOURNAL OF NEONATAL-PERINATAL MEDICINE. 2014;7 (1):71-74",
"literaturereference_normalized": "fetal intestinal perforation and meconium peritonitis associated with maternal autoimmune hepatitis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20140708",
"receivedate": "20140708",
"receiver": {
"receiverorganization": "FDA",
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},
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"abstract": "A 59-year-old woman receiving methotrexate and tacrolimus for rheumatoid arthritis (RA) was referred to our hospital following bilateral ground-glass opacity observed in her chest X-ray and elevated serum KL-6. After methotrexate and tacrolimus cessation, shortness of breath developed and ground-glass opacity observed in the chest computed tomography rapidly worsened. Bronchoalveolar lavage showed increased lymphocytes, and trans-bronchial lung biopsy confirmed lymphocytic alveolitis. In addition, the patient had serum antibodies against Trichosporon asahii, a fungal pathogen. The mildew in her bathroom and washing machine which were the source of the fungus were removed, which resulted in no further relapse of the condition. In this patient's case, methotrexate and tacrolimus may have masked and suppressed summer-type hypersensitivity pneumonitis.",
"affiliations": "Department of Respiratory Medicine, Allergy and Clinical Immunology Nagoya City University Graduate School of Medical Sciences Nagoya Aichi Japan.;Department of Respiratory Medicine, Allergy and Clinical Immunology Nagoya City University Graduate School of Medical Sciences Nagoya Aichi Japan.;Department of Respiratory Medicine, Allergy and Clinical Immunology Nagoya City University Graduate School of Medical Sciences Nagoya Aichi Japan.;Department of Respiratory Medicine, Allergy and Clinical Immunology Nagoya City University Graduate School of Medical Sciences Nagoya Aichi Japan.",
"authors": "Ohkubo|Hirotsugu|H|;Okayama|Minami|M|;Fukumitsu|Kensuke|K|;Niimi|Akio|A|",
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"fulltext": "\n==== Front\nRespirol Case RepRespirol Case Rep10.1002/(ISSN)2051-3380RCR2Respirology Case Reports2051-3380John Wiley & Sons, Ltd Chichester, UK 10.1002/rcr2.194RCR2194Case ReportCase ReportsSummer‐type hypersensitivity pneumonitis in a patient with rheumatoid arthritis on methotrexate and tacrolimus Hypersensitivity pneumonitis with RAH. Ohkubo et al.Ohkubo Hirotsugu [email protected] \n1\nOkayama Minami \n1\nFukumitsu Kensuke \n1\nNiimi Akio \n1\n1 Department of Respiratory Medicine, Allergy and Clinical ImmunologyNagoya City University Graduate School of Medical SciencesNagoyaAichiJapan* Correspondence\n\nHirotsugu Ohkubo, Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho‐cho, Mizuho‐ku, Nagoya, Aichi 467‐8601, Japan. E‐mail: [email protected]\n13 10 2016 11 2016 4 6 10.1002/rcr2.v4.6e0019425 7 2016 16 9 2016 20 9 2016 © 2016 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of RespirologyThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.A 59‐year‐old woman receiving methotrexate and tacrolimus for rheumatoid arthritis (RA) was referred to our hospital following bilateral ground‐glass opacity observed in her chest X‐ray and elevated serum KL‐6. After methotrexate and tacrolimus cessation, shortness of breath developed and ground‐glass opacity observed in the chest computed tomography rapidly worsened. Bronchoalveolar lavage showed increased lymphocytes, and trans‐bronchial lung biopsy confirmed lymphocytic alveolitis. In addition, the patient had serum antibodies against Trichosporon asahii, a fungal pathogen. The mildew in her bathroom and washing machine which were the source of the fungus were removed, which resulted in no further relapse of the condition. In this patient's case, methotrexate and tacrolimus may have masked and suppressed summer‐type hypersensitivity pneumonitis.\n\nMethotrexaterheumatoid arthritissummer‐type hypersensitivity pneumonitistacrolimusKL‐6 source-schema-version-number2.0component-idrcr2194header-idrcr2194-hdr-0001cover-dateNovember 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:15.12.2016\n\n\nOhkubo , H. \n, \nOkayama , M. \n, \nFukumitsu , K. \n and \nNiimi , A. \n (2016 ) Summer‐type hypersensitivity pneumonitis in a patient with rheumatoid arthritis on methotrexate and tacrolimus, or something similar . Respirology Case Reports , 4 (6 ), e00194. doi: 10.1002/rcr2.194.\n\n\nAssociate Editor: Conroy Wong\n==== Body\nIntroduction\nSummer‐type hypersensitivity pneumonitis is the most prevalent form of hypersensitivity pneumonia in Japan 1. Summer‐type hypersensitivity pneumonitis is classically recognized as types III and IV hypersensitivity and is caused by repeated airborne exposure to Trichosporon asahii or Trichosporon mucoides during hot and humid summers 1, 2. Repeated exposure to airborne antigens induces formation of immune complexes with immunoglobulin G as well as complement activation. Particularly, alveolitis occurs via influx of CD4 and CD8 T lymphocytes, pro‐inflammatory cytokines, and mediators. Here we report a case of summer‐type hypersensitivity pneumonitis in a patient with rheumatoid arthritis (RA) during treatment with methotrexate and tacrolimus.\n\nCase Report\nA 59‐year‐old woman who had been receiving methotrexate (10 mg/week) and tacrolimus (2 mg/day) for treatment of RA for 2 years, was referred to our Division of Respiratory Medicine following observation of bilateral ground‐glass opacity in her chest X‐ray and an elevated serum KL‐6 of 1097 U/mL (normal, <500 U/mL) in mid‐June 2015. She had no history of smoking; however, mildew was found in her bathroom and washing machine. In addition, other rooms were cluttered and dirty. Chest computed tomography (CT) also showed diffuse ground‐glass opacities (Fig. 1A). Her resting percutaneous oxygen saturation was 96%. Differential diagnoses included Pneumocystis jirovecii pneumonia, cytomegalovirus infection, drug‐induced pneumonia, and acute interstitial pneumonia associated with RA. Although she did not wish to be admitted emergently, methotrexate and tacrolimus were discontinued because of the stable disease status of RA and the possibility of infection or drug‐induced pneumonia. However, she was admitted to our hospital 7 days later due to acute respiratory failure. Her resting and ambulatory percutaneous oxygen saturations were 91 and 78%, respectively. Fine crackles were audible in both lung bases. A subsequent chest CT showed worsening of ground‐glass opacity and appearance of consolidations (Fig. 1B). Bronchoscopy was performed, and the cell counts of bronchoalveolar lavage fluid from the right middle lobe were as follows: lymphocytes (76%), neutrophils (1%), eosinophils (2%), and macrophages (21%). Polymerase chain reaction results were negative for Mycobacterium tuberculosis, P. jirovecii, cytomegalovirus, Mycoplasma pneumoniae, and Legionella pneumoniae. Trans‐bronchial lung biopsy confirmed lymphocytic alveolitis. Serum antibody for T. asahii assessed using antigen‐captured enzyme‐linked immunosorbent assay was positive. High‐dose corticosteroid treatment was started with methylprednisolone (0.5 g on day 1 and 1.0 g on days 2 and 3). Her respiratory failure resolved immediately, and thus, the corticosteroid dose was rapidly tapered and stopped on postadmission day 15. Then, methotrexate and tacrolimus treatments were resumed. Since summer‐type hypersensitivity pneumonitis was suspected, the medical team encouraged her husband to remove all mildew from the bathroom; however, this was not completely accomplished. She came back to hospital after spending 4 days at home. Her serum KL‐6 level was marginally elevated to 703 U/mL as compared to the 636 U/mL value obtained before she returned home (Fig. 2). The medical team again encouraged further removal of mildew from the bathroom and cleaning of all rooms in her house. She was discharged on postadmission day 35. Upon returning home, her KL‐6 level slightly increased again, but then it decreased. Together, with these results and other clinical findings, including being positive for T. asahii antibody, the diagnosis of summer‐type hypersensitivity pneumonitis was made.\n\nFigure 1 Patient's chest computed tomography (CT) from her first visit to the Division of Respiratory Medicine, which revealed diffuse ground‐glass opacities in the lungs (A). Chest CT at 7 days after cessation of methotrexate and tacrolimus showed worsening of ground‐glass opacities and appearance of consolidations (B).\n\nFigure 2 Patient's clinical course. The KL‐6 serum levels decreased after admission but increased after the patient returned home. The KL‐6 serum level decreased again upon a second hospital admission and increased slightly after discharge. MTX, methotrexate; TAC, tacrolimus.\n\nDiscussion\nHerein, we presented a case of summer‐type hypersensitivity pneumonitis in an RA patient on a methotrexate and tacrolimus treatment regimen. Methotrexate inhibits enzymes involved in purine metabolism, leading to inhibition of T‐cell activation, intercellular adhesion molecule expression by T‐cells, and downregulation of B‐cells 3. Tacrolimus prevents dephosphorylation of nuclear factor of activated T‐cells (NFAT) via calcineurin inhibition 4. For our patient, pneumonitis worsened rapidly after cessation of methotrexate and tacrolimus. No symptoms of fever or granuloma formation in the lung tissue were observed in this patient. It is possible that we simply did not detect granulomata in this patient. However, in patients treated with immunosuppressive agents, granuloma development may not occur. Additionally, it was possible that methotrexate and tacrolimus masked and suppressed the progression of summer‐type hypersensitivity pneumonitis.\n\nFor the diagnosis of summer‐type hypersensitivity pneumonitis, antigen‐captured enzyme‐linked immunosorbent assay of serum T. asahii antibody is useful, of which the sensitivity and specificity are 87, and 96%, respectively 5. Our case fulfilled the diagnostic criteria of summer‐type hypersensitivity pneumonitis 1. We used a biomarker of interstitial pneumonia, KL‐6, to orchestrate a challenge test as well as to monitor disease progression. In our patient, KL‐6 decreased after corticosteroid treatment, and it increased after the challenge test.\n\nIn conclusion, we have reported a case of summer‐type hypersensitivity pneumonitis developed in a patient with RA treated with immunosuppressive agents. To the best of our knowledge, this is the first case of summer‐type hypersensitivity pneumonitis that worsened after withdrawal of immunosuppressive drugs. Thus, physicians must pay attention to the possibility of accidental suppression of summer‐type hypersensitivity pneumonitis by immunosuppressants.\n\nDisclosure Statements\nNo conflict of interest declared.\n\nAppropriate written informed consent was obtained for publication of this case report and accompanying images.\n==== Refs\nReferences\n1 \n\nAndo \nM \n, \nArima \nK \n, \nYoneda \nR \n, et al. 1991 \nJapanese summer‐type hypersensitivity pneumonitis. Geographic distribution, home environment, and clinical characteristics of 621 cases . Am. Rev. Respir. Dis. \n144 :765 –769 .1928946 \n2 \n\nBourke \nSJ \n, \nDalphin \nJC \n, \nBoyd \nG \n, et al. 2001 \nHypersensitivity pneumonitis: current concepts . Eur. Respir. J. \n32 :81s –92s .\n3 \n\nWessels \nJA \n, \nHuizinga \nTW \n, and \nGuchelaar \nHJ \n\n2008 \nRecent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis . Rheumatology (Oxford) \n47 :249 –255 .18045808 \n4 \n\nScott \nLJ \n, \nMcKeage \nK \n, \nKeam \nSJ \n, et al. 2003 \nTacrolimus: a further update of its use in the management of organ transplantation . Drugs \n63 :1247 –1297 .12790696 \n5 \n\nYoshizawa \nY \n, \nFuruie \nT \n, \nOtani \nY \n, et al. 2001 \nSymposium on molecular pathogenesis of respiratory diseases and its clinical implication. 3. Immunological lung disease – recent advances in the pathogenesis of hypersensitivity pneumonitis . Intern. Med. \n40 :164 –167 .11300156\n\n",
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"keywords": "KL‐6; Methotrexate; rheumatoid arthritis; summer‐type hypersensitivity pneumonitis; tacrolimus",
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"title": "Summer-type hypersensitivity pneumonitis in a patient with rheumatoid arthritis on methotrexate and tacrolimus.",
"title_normalized": "summer type hypersensitivity pneumonitis in a patient with rheumatoid arthritis on methotrexate and tacrolimus"
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"title": "Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment.",
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"literaturereference": "WILKINS E, COHEN C, TROTTIER B, ESSER S, SMITH D, HAAS B, ET AL.. PATIENT-REPORTED OUTCOMES IN THE SINGLE-TABLET REGIMEN (STAR) TRIAL OF RILPIVIRINE/EMTRICITABINE/TENOFOVIR DISOPROXIL FUMARATE VERSUS EFAVIRENZ/EMTRICITABINE/ TENOFOVIR DISOPROXIL FUMARATE IN ANTIRETROVIRAL TREATMENT-NAIVE ADULTS INFECTED WITH HIV-1 THROUGH 48 WEEKS OF TREATMENT. AIDS CARE. 2015?1-8",
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"abstract": "Delirium is considered as the most common complication afflicting hospitalized elderly patients, accompanied by high morbidity and mortality rate; and despite its high prevalence, it often remains unrecognized. Drug-induced delirium is a well-known entity with sedatives, narcotics and anticholinergics most often implicated in its causation. Delirium attributed to antibiotics, mainly cephalosporins and macrolids, has been infrequently reported, and until yet only seven cases of levofloxacin-induced delirium have been described in the medical literature. We describe another case of delirium associated with levofloxacin in an elderly patient who was hospitalized in our medical ward for pneumonia. The present case and the other cases previously reported should raise the awareness of physicians to this serious, underestimated, and underdiagnosed adverse effect of a commonly used antibiotic, levofloxacin.",
"affiliations": "Department of Internal Medicine A, Bnai Zion Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.;Department of Internal Medicine A, Bnai Zion Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.;Infectious Diseases Unit, Bnai Zion Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.;Department of Internal Medicine A, Bnai Zion Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.",
"authors": "Kogan|Yana|Y|;Elias|Nizar|N|;Paz|Alona|A|;Odeh|Majed|M|",
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"fulltext": "\n==== Front\nJ Clin Med ResJ Clin Med ResElmer PressJournal of Clinical Medicine Research1918-30031918-3011Elmer Press 10.14740/jocmr3538wCase ReportAcute Delirium Associated With Levofloxacin Levofloxacin-Induced DeliriumKogan Yana aElias Nizar aPaz Alona bOdeh Majed aca Department of Internal Medicine A, Bnai Zion Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israelb Infectious Diseases Unit, Bnai Zion Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israelc Corresponding Author: Majed Odeh, Department of Internal Medicine A, Bnai Zion Medical Center, Golomb Street 47, Haifa 31048, Israel. Email: [email protected] 2018 31 7 2018 10 9 725 727 10 7 2018 20 7 2018 Copyright 2018, Kogan et al.2018This 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.Delirium is considered as the most common complication afflicting hospitalized elderly patients, accompanied by high morbidity and mortality rate; and despite its high prevalence, it often remains unrecognized. Drug-induced delirium is a well-known entity with sedatives, narcotics and anticholinergics most often implicated in its causation. Delirium attributed to antibiotics, mainly cephalosporins and macrolids, has been infrequently reported, and until yet only seven cases of levofloxacin-induced delirium have been described in the medical literature. We describe another case of delirium associated with levofloxacin in an elderly patient who was hospitalized in our medical ward for pneumonia. The present case and the other cases previously reported should raise the awareness of physicians to this serious, underestimated, and underdiagnosed adverse effect of a commonly used antibiotic, levofloxacin.\n\nLevofloxacinQuinoloneFluoroquinoloneDelirium\n==== Body\nIntroduction\nDelirium, a term used to describe an acute confusional state, is defined as a relatively acute decline in cognition that fluctuates over hours or days. The hallmark of delirium is a deficit of attention, although all cognitive domains, including memory, executive function, visuospatial tasks, and language, are variably involved. Associated symptoms may include altered sleep-awake cycles, perceptual disturbances such as hallucinations or delusions; affect changes, and autonomic findings that include heart rate and blood pressure instability [1]. It is a result of multiple interacting predisposing and precipitating factors [1, 2]. The prevalence of delirium increases with age, and hospitalized elderly patients are particularly at risk to become acutely confused [1, 2]. The two most consistently identified risks for delirium are older age and baseline cognitive dysfunction [1]. It is considered as the most common complication afflicting hospitalized elderly patients; and despite its high prevalence, it often remains unrecognized, with a recent study estimating the rate of undetected delirium to be as high as 60% [3]. It can negatively affect outcomes by increasing length of stay, morbidity, and mortality, yet is often preventable and potentially reversible [3, 4].\n\nDrug-induced delirium is a well-known entity with sedatives, narcotics and anticholinergics most often implicated in its causation [1, 5]. Delirium attributed to antibiotics, mainly cephalosporins and macrolides, has been infrequently reported [6-8]. To the best of our knowledge, only seven cases of levofloxacin-induced delirium have been previously described in the medical literature [9-15], one of them from our medical ward [11]. We describe another case of delirium associated with levofloxacin in an elderly patient who was hospitalized in our medical ward for pneumonia.\n\nCase Report\nA 79-year-old woman was admitted to our medical ward for right lower lobe pneumonia accompanied by fever, non-productive cough and dyspnea for the last 3 days. Her other medical history included essential hypertension and hypercholesterolemia, for the last several years, well controlled by ramipril and simvastatin; and she was allergic to penicillin. She had no history of confusional state, and no any other documented disorder of the central nervous system (CNS).\n\nPhysical examination revealed a fully conscious and oriented woman, with normal informed bedside examination of her cognitive state. Her blood pressure was 136/80 mm Hg, heart rate 104 bpm, and body temperature 38.4 °C. No signs of meningeal irritation were observed. Examination of the lungs revealed fine inspiratory rales and decreased ventilation over the base of the right lung, as well as, diffuse bilateral rhonchi. Laboratory examinations revealed white blood cell count (WBC) of 24,200/mm3 with 84% neutrophils, hematocrit 39%, serum creatinine 0.9 mg/dL, urea 40 mg/dL sodium 138 mEq/L, potassium 4.3 mEq/L, C-reactive protein (CRP) 96 mg/L, arterial blood O2 saturation 90% on room air, and pCO2 41 mm Hg. The cheat X-ray film demonstrated a right lower lobe infiltrate.\n\nEmpiric treatment with oral levofloxacin, 750 mg daily, was started. Forty-eight h later the patient felt better, her body temperature decreased back to normal range, the heart rate and blood pressure were in the normal range, arterial blood O2 saturation increased to 96% on room air, WBC decreased to 15,100/mm3 and serum CRP level decreased to 24 mg/L. On the third day of hospitalization the patient became confused, irritable, and disoriented to time, place, and person. She had optic and acoustic hallucinations, and her attention capacity became impaired. The patient body temperature, heart rate and blood pressure were in the normal range, no dyspnea was observed, and her arterial blood O2 saturation was 97% on room air. Neurological examination revealed no signs of meningeal irritation and no lateralizing motor findings. Serum levels of electrolytes, including sodium, potassium, magnesium, and calcium were normal. Computerized tomography (CT) scan of the brain, and electroencephalogram (EEG) performed while the patient was awake, were unremarkable.\n\nThe diagnosis of delirium was made according to the American Psychiatric Association’s Diagnostic and Statistical Manual Mental Disorders (DMS IV); and was related to levofloxacin. Treatment with levofloxacin was stopped immediately after 3 days of administration, and treatment with azithromycin was started. Subsequently, the patient neurological condition gradually improved, and complete resolution of the delirium was documented 48 h after discontinuation of levofloxacin treatment. Upon discharge from our medical ward, she was referred to our outpatient medical clinic. Three weeks later a repeat chest X-ray film showed complete resolution of the pulmonary infiltrate, and informed bedside examination of her cognitive state was normal.\n\nDiscussion\nDelirium can be related to several predisposing factors, and in our patient the pneumonia itself with its accompanying febrile illness and hypoxemia, or drugs may have been involved [2]. The delirium developed on the third day of levofloxacin treatment, and was not associated to the initial severe phase of pneumonia. It developed while the patient was afebrile, with normal heart rate, blood pressure, and arterial oxygen saturation, and with no serum electrolyte disturbances or signs of dehydration. Except of the delirium itself, the neurological examination was essentially normal, brain CT and EEG did not reveal any significant abnormality, thus excluding a primary neurological disease. However, the patient is an elderly where this risk factor might predispose to the development of delirium induced by levofloxacin.\n\nDrug-induced delirium is a well-known entity with sedatives, narcotics and anticholinergics most often implicated in its causation [3, 5]. Delirium attributed to antibiotics, mainly cephalosporins and macrolids, has been infrequently reported [6-8], and until yet only seven cases of levofloxacin-induced delirium have been described in the medical literature [9-15], one of them from our medical ward [11].\n\nLevofloxacin is a third generation fluorinated quinolone antibiotic, the active levo stereoisomer of ofloxacin, having a broad spectrum of antibacterial activity against both gram-positive and gram-negative bacteria. It belongs to the group of new quinolone derivatives (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin, gatifloxacin and moxifloxacin). As with levofloxacin, delirium has rarely been reported in association with other quinolones [4, 16-20].\n\nThe mechanism behind fluoroquinolones-associated delirium is still not fully understood, but has been hypothesized to involve these antibiotics having N-methyl-D-aspartate (NMDA) agonist activity, as well as, acting partly as gamma-aminobutyric acid (GABA)-A receptor antagonism [4]. Flouoroquinolones may lower the seizure threshold by binding competitively to the GABA-A receptor [21, 22]. Non-convulsive status epilepticus (NCSE) is an epileptic condition often under-diagnosed, clinically manifested by an altered mental state, and associated with continuous or recurrent epileptic form discharge on EEG [22]. NCSE associated with the use of fluoroquinolones and manifesting as an acute confusional state has been reported [23]. Since the EEG of our patient did not show features of NCSE, this possible side effect of levofloxacin can be excluded. The complete resolution of the delirium shortly after discontinuation of levofloxacin treatment supports the association of our patient’s delirium to levofloxacin. Rechalenge with the drug was not done since it was considered unethical.\n\nIn conclusion, delirium is the most common complication afflicting hospitalized elderly patients, and can negatively affect outcomes by increasing length of stay at hospital, morbidity, and mortality; yet is often preventable and potentially reversible. Development of the delirium in our patient after starting treatment with levofloxacin, and its complete resolution shortly after discontinuation of the drug, in the absence of any other possible cause of delirium, supports the attribution of the delirium to levofloxacin. Although only seven cases of levofloxacin-induced delirium have been previously reported, since two cases including the present case were observed in one medical ward (ours), it indicates that this serious and potentially fatal levofloxacin-induced side effect is really under-estimated and under-diagnosed world-wide. Physicians should be aware to its occurrence in order to prevent significant morbidity and mortality accompanying this serious but potentially reversible CNS complication of levofloxacin.\n\nFunding\nThere was no funding support for this manuscript.\n\nConflict of Interest\nThe authors state that they have no conflict of interest.\n==== Refs\nReferences\n1 Josephson SA Miller BL Confusion and Delirium Kasper DL Fauci AS Hauser SL Longo DL Jameson JL Loscalzo J Harrison's Principles of Internal Medicine. 19th ed. New York McGraw-Hill 2015 166 170 \n2 Inouye SK Delirium in older persons N Engl J Med 2006 354 11 1157 1165 10.1056/NEJMra052321 16540616 \n3 Hshieh TT Inouye SK Oh ES Delirium in the Elderly Psychiatr Clin North Am 2018 41 1 1 17 10.1016/j.psc.2017.10.001 29412839 \n4 Sellick J Mergenhagen K Morris L Feuz L Horey A Risbood V Wojciechowski A et al Fluoroquinolone-Related Neuropsychiatric Events in Hospitalized Veterans Psychosomatics 2018 59 3 259 266 10.1016/j.psym.2017.11.001 29275962 \n5 Brown TM Drug-induced delirium Semin Clin Neuropsychiatry 2000 5 2 113 124 10837100 \n6 Chow KM Szeto CC Hui AC Wong TY Li PK Retrospective review of neurotoxicity induced by cefepime and ceftazidime Pharmacotherapy 2003 23 3 369 373 10.1592/phco.23.3.369.32100 12627936 \n7 Vicente de Vera C Garcia M Pifarre Teixido R Barbe F Delirium induced by clarithromycin in a patient with community-acquired pneumonia Eur Respir J 2006 28 3 671 672 10.1183/09031936.06.00039006 16946100 \n8 Mermelstein HT Clarithromycin-induced delirium in a general hospital Psychosomatics 1998 39 6 540 542 10.1016/S0033-3182(98)71287-3 9819955 \n9 Hakko E Mete B Ozaras R Tabak F Ozturk R Mert A Levofloxacin-induced delirium Clin Neurol Neurosurg 2005 107 2 158 159 10.1016/j.clineuro.2004.05.006 15708235 \n10 Kiangkitiwan B Doppalapudi A Fonder M Solberg K Bohner B Levofloxacin-induced delirium with psychotic features Gen Hosp Psychiatry 2008 30 4 381 383 10.1016/j.genhosppsych.2007.11.003 18585545 \n11 Slobodin G Elias N Zaygraikin N Sheikh-Ahmad M Sabetay S Weller B Odeh M Levofloxacin-induced delirium Neurol Sci 2009 30 2 159 161 10.1007/s10072-009-0027-9 19189043 \n12 Kocyigit I Dortdudak S Sipahioglu M Unal A Yucel HE Tokgoz B Eroglu E et al Levofloxacin-induced delirium: is it a dangerous drug in patients with renal dysfunction? Ren Fail 2012 34 5 634 636 10.3109/0886022X.2012.660855 22390219 \n13 Lertxundi U Palacios RH Gutierrez FC Domingo-Echaburu S Garcia MG Gomez CA Levofloxacin-induced delirium in a patient suffering from schizoaffective disorder and multiple sclerosis Curr Drug Saf 2013 8 3 199 200 10.2174/15748863113089990043 23914753 \n14 Raj V Murthy TV Levofloxacin induced delirium with psychotic features in a young patient Med J Armed Forces India 2013 69 4 404 405 10.1016/j.mjafi.2012.10.001 24600154 \n15 Ghoshal A Damani A Salins N Deodhar J Muckaden MA Management of levofloxacin induced anaphylaxis and acute delirium in a palliative care setting Indian J Palliat Care 2015 21 1 76 78 10.4103/0973-1075.150194 25709191 \n16 McDermott JL Gideonse N Campbell JW Acute delirium associated with ciprofloxacin administration in a hospitalized elderly patient J Am Geriatr Soc 1991 39 9 909 910 10.1111/j.1532-5415.1991.tb04459.x 1885866 \n17 Al-Ghamdi SM Reversible encephalopathy and delirium in patients with chronic renal failure who had received ciprofloxacin Saudi J Kidney Dis Transpl 2002 13 2 163 170 17660656 \n18 Fennig S Mauas L Ofloxacin-induced delirium J Clin Psychiatry 1992 53 4 137 138 1564051 \n19 Tasleem H Viswanathan R Moxifloxacin-induced delirium with hallucinations Psychosomatics 2011 52 5 472 474 10.1016/j.psym.2011.01.037 21907069 \n20 Sumner CL Elliott RL Delirium associated with gatifloxacin Psychosomatics 2003 44 1 85 86 10.1176/appi.psy.44.1.85 12515846 \n21 Ball P Mandell L Niki Y Tillotson G Comparative tolerability of the newer fluoroquinolone antibacterials Drug Saf 1999 21 5 407 421 10.2165/00002018-199921050-00005 10554054 \n22 Fernandez-Torre JL Levofloxacin-induced delirium: Diagnostic considerations Clin Neurol Neurosurg 2006 108 6 614 10.1016/j.clineuro.2005.03.004 16905436 \n23 Isaacson SH Carr J Rowan AJ Ciprofloxacin-induced complex partial status epilepticus manifesting as an acute confusional state Neurology 1993 43 8 1619 1621 10.1212/WNL.43.8.1619-a 8351027\n\n",
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"title": "Acute Delirium Associated With Levofloxacin.",
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{
"abstract": "The aim of the study was to investigate the efficacy and safety of trientine-dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight-based dosages on their clinical and biochemical outcome.\n\n\n\nWe retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight-based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg · kg-1 · day-1.\n\n\n\nMedian follow-up was 60 (5-60) months in the total study group. During TD therapy, nonceruloplasmin-bound copper was reduced from mean 1.53 (0.01-6.95) at baseline to 0.62 (0.01-4.57) μmol/l. 24h-urinary copper excretion diminished to 1.85 (0.8-9.6) μmol/day approximating the therapeutic goal of 1.6 μmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases).Investigations about weight-based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg · kg-1 · day-1, median follow-up 60 [9-60] months), whereas in group 2 (>20 mg · kg-1 · day-1, median follow-up 60 [14-60] months), it was 63.6%.\n\n\n\nTD proves to be an efficacious alternative chelating agent for children with WD. Weight-based dosages above the recommended 20 mg · kg-1 · day-1 may increase the rate of adverse effects in pediatric patients.",
"affiliations": "Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.;Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Center for Child and Adolescent Medicine, Division of Pediatric Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Center for Child and Adolescent Medicine, Division of Pediatric Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.;Center for Child and Adolescent Medicine, Division of Pediatric Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.",
"authors": "Mayr|Toni|T|;Ferenci|Peter|P|;Weiler|Markus|M|;Fichtner|Alexander|A|;Mehrabi|Arianeb|A|;Hoffmann|Georg Friedrich|GF|;Mohr|Isabelle|I|;Pfeiffenberger|Jan|J|;Weiss|Karl Heinz|KH|;Teufel-Schäfer|Ulrike|U|",
"chemical_list": "D002614:Chelating Agents; D003300:Copper; D014266:Trientine",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0000000000002902",
"fulltext": null,
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"issn_linking": "0277-2116",
"issue": "72(1)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D000293:Adolescent; D002614:Chelating Agents; D002648:Child; D003300:Copper; D006527:Hepatolenticular Degeneration; D006801:Humans; D012189:Retrospective Studies; D014266:Trientine",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "115-122",
"pmc": null,
"pmid": "32804908",
"pubdate": "2021-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Optimized Trientine-dihydrochloride Therapy in Pediatric Patients With Wilson Disease: Is Weight-based Dosing Justified?",
"title_normalized": "optimized trientine dihydrochloride therapy in pediatric patients with wilson disease is weight based dosing justified"
}
|
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{
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}
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{
"abstract": "Gestational gigantomastia is an uncommon condition characterized by abnormal and excessive growth of breast tissue during an otherwise uncomplicated pregnancy. Gestational gigantomastia may be accompanied by hypercalcemia, which in some cases has been associated with elevated serum levels of PTHrP. The source of the PTHrP in these cases has been suggested to be the enlarged breasts.\n\n\n\nTo describe the rapid resolution of hypercalcemia and normalization of serum PTHrP after elective termination of pregnancy, indicating that the placenta was the source of the PTHrP.\n\n\n\nA retrospective analysis of clinical and biochemical data over a 2-year interval and review of literature.\n\n\n\nAn academic medical center.\n\n\n\nA 33-year-old G8P4 female who presented at week 8 of pregnancy with gestational gigantomastia and subsequently developed marked hypercalcemia at week 13. Serum levels of PTH were suppressed but circulating PTHrP was elevated. There was no history of hypercalcemia or significant breast growth during previous pregnancies.\n\n\n\nHypercalcemia was poorly responsive to IV saline, prednisone, calcitonin, and cinacalcet. She requested termination of pregnancy at week 20.\n\n\n\nSerum levels of calcium, PTH, and PTHrP normalized within 48 hours of termination of pregnancy.\n\n\n\nThe rapid resolution of hypercalcemia after termination of pregnancy, despite persistent gigantomastia, provides evidence for a pathologic role of the placenta in the excess production of PTHrP, possibly through an as yet uncharacterized placenta-breast hormonal axis.",
"affiliations": "Department of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.",
"authors": "Modarressi|Taher|T|;Levine|Michael A|MA|;Tchou|Julia|J|;Khan|Amna N|AN|",
"chemical_list": "C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2018-01181",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "103(9)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000032:Abortion, Therapeutic; D000328:Adult; D001940:Breast; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D006984:Hypertrophy; D044162:Parathyroid Hormone-Related Protein; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "3124-3130",
"pmc": null,
"pmid": "30032172",
"pubdate": "2018-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gestational Gigantomastia Complicated by PTHrP-Mediated Hypercalcemia.",
"title_normalized": "gestational gigantomastia complicated by pthrp mediated hypercalcemia"
}
|
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{
"abstract": "Tacrolimus is a calcineurin inhibitor that has been used to prevent allograft rejection after organ transplantation. We report the case of a living-donor liver transplant recipient with breast cancer who received adjuvant chemotherapy at an appropriate relative dose intensity in spite of a decrease in the trough blood concentration of tacrolimus. The patient was a woman in her 50s who had undergone living-donor liver transplantation because of primary biliary cirrhosis and received maintenance therapy consisting of tacrolimus. She was diagnosed as having locally advanced breast cancer(ER and HER2 positive). After surgery, we administered 4 courses of EC followed by weekly administration of paclitaxel plus trastuzumab. During chemotherapy, although the trough blood concentration of tacrolimus was slightly decreased, neither severe adverse event nor allograft rejection was observed. Recently, organ transplantation outcomes have significantly improved as a result of the progress of immunosuppressive agents. However, the development of malignancies after transplantation is a serious problem.",
"affiliations": "Dept. of Breast Surgery, Japanese Red Cross Wakayama Medical Center.",
"authors": "Nakakimura|Tomomi|T|;Kotake|Takeshi|T|;Torii|Masae|M|;Lin|Xue|X|;Yoshibayashi|Hiroshi|H|",
"chemical_list": "D016559:Tacrolimus",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D019520:Living Donors; D008875:Middle Aged; D016559:Tacrolimus",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "83-85",
"pmc": null,
"pmid": "32381868",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Breast Cancer Treated with Adjuvant Chemotherapy in a Patient Receiving Tacrolimus Medication after Liver Transplantation.",
"title_normalized": "a case of breast cancer treated with adjuvant chemotherapy in a patient receiving tacrolimus medication after liver transplantation"
}
|
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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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"reaction": [
{
"reactionmeddrapt": "Neutrophil count decreased",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuropathy peripheral",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
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"literaturereference": "NAKAKIMURA T, TORII M, XUE LIN, ET AL A CASE OF BREAST CANCER TREATED WITH ADJUVANT CHEMOTHERAPY IN A PATIENT RECEIVING TACROLIMUS MEDICATION AFTER LIVER TRANSPLANTATION. JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY 2020?47 (1):83-85.",
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"qualification": "1",
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},
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},
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200713"
}
] |
{
"abstract": "Granulomatosis with polyangiitis (GPA), a vasculitis that most commonly affects small to medium-size vessels of the respiratory tract and kidneys, may also present with a wide array of skin findings. We present the case of a 12-year-old boy with pyoderma gangrenosum-like ulcerations on his lower extremity as the initial manifestation of GPA despite negative cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCAs). Although GPA is strongly associated with c-ANCA, c-ANCA may be negative on presentation. Thus clinical and pathologic clues must be relied upon when serologic confirmation is negative.",
"affiliations": "Philadelphia College of Medicine, Philadelphia, Pennsylvania.;Geisinger Health System, Danville, Pennsylvania.;Geisinger Health System, Danville, Pennsylvania.",
"authors": "Kass|Ashley|A|;Fagan|Jake D|JD|http://orcid.org/0000-0002-8992-866X;Long|Paul|P|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "34(5)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D019268:Antibodies, Antineutrophil Cytoplasmic; D002648:Child; D003937:Diagnosis, Differential; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D017511:Pyoderma Gangrenosum; D012867:Skin; D012883:Skin Ulcer",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e231-e234",
"pmc": null,
"pmid": "28884919",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Granulomatosis with Polyangiitis Presenting with Pyoderma Gangrenosum-Like Ulceration and Negative Cytoplasmic Antineutrophilic Cytoplasmic Antibodies in a Child.",
"title_normalized": "granulomatosis with polyangiitis presenting with pyoderma gangrenosum like ulceration and negative cytoplasmic antineutrophilic cytoplasmic antibodies in a child"
}
|
[
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-04017",
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"patient": {
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{
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},
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},
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},
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},
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"drugindication": "GRANULOMATOSIS WITH POLYANGIITIS",
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"medicinalproduct": "CLINDAMYCIN."
},
{
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"activesubstancename": "CYCLOSPORINE"
},
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"medicinalproduct": "CYCLOSPORINE."
},
{
"actiondrug": "1",
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"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
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"drugcharacterization": "1",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "080352",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "GRANULOMATOSIS WITH POLYANGIITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": null,
"patientonsetage": "12",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Granulomatosis with polyangiitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Diabetes mellitus",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KASS A,FAGAN J,LONG P. GRANULOMATOSIS WITH POLYANGIITIS PRESENTING WITH PYODERMA GANGRENOSUM?LIKE ULCERATION AND NEGATIVE CYTOPLASMIC ANTINEUTROPHILIC CYTOPLASMIC ANTIBODIES IN A CHILD. PEDIATRIC DERMATOLOGY 2017 SEP 01;34(5):231-234.",
"literaturereference_normalized": "granulomatosis with polyangiitis presenting with pyoderma gangrenosum like ulceration and negative cytoplasmic antineutrophilic cytoplasmic antibodies in a child",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20171024",
"receivedate": "20171024",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14119585,
"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": "The appearance of solid tumors und lymphomas during treatment with fingolimod was observed in studies and has been described in case reports.\n\n\n\nTo report a case of primary cutaneous CD30(+) anaplastic large-cell T-cell lymphoma during treatment of multiple sclerosis (MS) with fingolimod.\n\n\n\nCase study.\n\n\n\nOur patient developed a lymphoma a few weeks after initialization of therapy with fingolimod; 5 weeks after discontinuation of treatment the lesions resolved.\n\n\n\nCausality of fingolimod is indicated by the fact that the skin lesions appeared after commencement of treatment and resolved after discontinuation of therapy. This case serves as a reminder of the potential side effects of fingolimod.",
"affiliations": "Department of Dermatology and Venereology, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany [email protected].;Department of Dermatology and Venereology, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany.;Department of Pathology, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany.;Department of Neurology, University of Rostock, Rostock, Germany.;Department of Dermatology and Venereology, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany.",
"authors": "Papathemeli|Despoina|D|;Gräfe|Ronald|R|;Hildebrandt|Uwe|U|;Zettl|Uwe K|UK|;Ulrich|Jens|J|",
"chemical_list": "D007166:Immunosuppressive Agents; D017730:Ki-1 Antigen; D000068876:Fingolimod Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1177/1352458516645868",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "22(14)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Fingolimod; adverse side effects; lymphoma; multiple sclerosis; primary cutaneous CD30(+) anaplastic large-cell T-cell lymphoma; skin",
"medline_ta": "Mult Scler",
"mesh_terms": "D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D017730:Ki-1 Antigen; D017728:Lymphoma, Large-Cell, Anaplastic; D008875:Middle Aged; D009103:Multiple Sclerosis; D012878:Skin Neoplasms",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1888-1890",
"pmc": null,
"pmid": "27207455",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of a primary cutaneous CD30(+) anaplastic large-cell T-cell lymphoma during treatment of multiple sclerosis with fingolimod.",
"title_normalized": "development of a primary cutaneous cd30 anaplastic large cell t cell lymphoma during treatment of multiple sclerosis with fingolimod"
}
|
[
{
"companynumb": "PHHY2016DE057229",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
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"reactionmeddraversionpt": "19.0",
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},
{
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"reactionmeddraversionpt": "19.0",
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},
{
"reactionmeddrapt": "Facial paralysis",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin mass",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Paraparesis",
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},
{
"reactionmeddrapt": "Anaplastic large cell lymphoma T- and null-cell types",
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},
{
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},
{
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},
{
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},
{
"reactionmeddrapt": "Progressive multiple sclerosis",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intention tremor",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "PAPATHEMELI D, GRAFE R, HILDEBRANDT U, ZETTL KU, ULRICH J. DEVELOPMENT OF A PRIMARY CUTANEOUS CD30(+) ANAPLASTIC LARGE-CELL T-CELL LYMPHOMA DURING TREATMENT OF MULTIPLE SCLEROSIS WITH FINGOLIMOD. MULTIPLE SCLEROSIS JOURNAL. 2016;1-3",
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"qualification": "3",
"reportercountry": "DE"
},
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] |
{
"abstract": "We present a 63-year-old Japanese woman who had clinically unique symmetrical skin rashes on her lower face, inframammary area, back and extremities, with some pustules on the cheeks. Skin biopsy specimens showed typical findings of psoriasis, and Psoriasis Area and Severity Index score was 5.9. After the skin lesions were treated successfully with vitamin D3 ointment, pustules developed on the tips of the fingers and toes, with paronychial and subungual involvement. The pathology of the nail matrix was consistent with pustular psoriasis, and the patient was diagnosed with acrodermatitis continua of Hallopeau (ACH) following psoriasis with an unusual clinical presentation. ACH was well controlled with a low dose of cyclosporin. Our patient is a rare case chronologically affected by two diseases in the same category. We confirmed that ACH is a variant of pustular psoriasis, and believe that the patient could provide another clue to determining the entity of ACH.",
"affiliations": "Department of Dermatology, Mito Saiseikai General Hospital, Ibaraki, Japan.",
"authors": "Iijima|Shigeruko|S|;Okazaki|Yukiko|Y|;Watanabe|Shinya|S|;Maruyama|Yoko|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.12639",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "41(11)",
"journal": "The Journal of dermatology",
"keywords": "acrodermatitis continua of Hallopeau; cyclosporin; nail biopsy; pustular psoriasis; vitamin D3 ointment",
"medline_ta": "J Dermatol",
"mesh_terms": "D000169:Acrodermatitis; D005260:Female; D006801:Humans; D008875:Middle Aged; D011565:Psoriasis; D012867:Skin",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "1006-8",
"pmc": null,
"pmid": "25346303",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of acrodermatitis continua of Hallopeau following psoriasis with atypical clinical presentation.",
"title_normalized": "case of acrodermatitis continua of hallopeau following psoriasis with atypical clinical presentation"
}
|
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},
{
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{
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},
{
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}
],
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},
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] |
{
"abstract": "Most reports of drug induced meningitis in systemic lupus erythematosus (SLE) have implicated ibuprofen. We describe a 46-year-old woman with SLE who developed aseptic meningitis abruptly after ingesting trimethoprim-sulfamethoxasole (TMP-SMX). This patient had received TMP-SMX twice before; each was associated with increasingly severe reactions, whose relationship with the use of TMP-SMX became apparent only in retrospect. A history of medication use should be sought in all patients with meningitis who have an underlying autoimmune disorder.",
"affiliations": "Arthritis Service, Rancho Los Amigos Medical Center, Downey, CA.",
"authors": "Escalante|A|A|;Stimmler|M M|MM|",
"chemical_list": "D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "19(5)",
"journal": "The Journal of rheumatology",
"keywords": null,
"medline_ta": "J Rheumatol",
"mesh_terms": "D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008582:Meningitis, Aseptic; D008875:Middle Aged; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014552:Urinary Tract Infections",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "800-2",
"pmc": null,
"pmid": "1613713",
"pubdate": "1992-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trimethoprim-sulfamethoxasole induced meningitis in systemic lupus erythematosus.",
"title_normalized": "trimethoprim sulfamethoxasole induced meningitis in systemic lupus erythematosus"
}
|
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"abstract": "Heyde's syndrome was first proposed in 1958. It refers to gastrointestinal haemorrhage resulting from a combination of aortic stenosis with angiodysplasia. This report explores the case of a 93-year-old lady who was admitted to hospital following a neck of femur fracture. She suffered from multiple comorbidities including renal failure and congestive heart failure secondary to critical aortic stenosis. As an inpatient she suffered an exacerbation of both her heart and renal failure postoperatively. A week later she suffered from heavy upper gastro-intestinal bleeding, which failed to respond to pharmacological and endoscopic therapies as well as angiographic embolisation. The pathophysiology of Heyde's syndrome: an acquired von Willebrand deficiency syndrome has a much wider impact than was commonly thought, both in terms of how common it is and in how the association may be extrapolated to a wide range of bleeding disorders, rather than simply angiodysplasia associated gastrointestinal haemorrhage.",
"affiliations": "Department of Neurosciences, John Radcliffe Hospital, Oxford, Oxfordshire, UK. [email protected]",
"authors": "Ledingham|David|D|",
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"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D016888:Angiodysplasia; D001024:Aortic Valve Stenosis; D003937:Diagnosis, Differential; D003952:Diagnostic Imaging; D017809:Fatal Outcome; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D013577:Syndrome",
"nlm_unique_id": "101526291",
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"pages": null,
"pmc": null,
"pmid": "23605838",
"pubdate": "2013-04-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14631548;17259184;17150267;14571395;15494999;21364113;17184682;10830178;11957793;3499881;9306572;19276092",
"title": "Heyde's syndrome: exploring the link between aortic stenosis and an acquired bleeding disorder.",
"title_normalized": "heyde s syndrome exploring the link between aortic stenosis and an acquired bleeding disorder"
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"abstract": "Objective: We report two cases of atypical femoral fracture (AFF) in patients with cancer. Patients: Two patients, a 53-year-old woman with breast cancer and a 77-year-old man with prostate cancer, could not walk after being injured in a fall. They used bone-modifying agents (BMA) for the prevention of bone metastasis for three and four years, respectively. Results: Intramedullary nails were placed to fix the femoral fractures in each patient. Neither of them had pathological metastatic femoral fractures based on fracture site specimens; however, severe suppression of bone turnover at the fracture site was suspected. Both patients could ambulate with a T-cane and were free of hip pain after surgery. Radiographs showed no callus formation at the fracture site. Conclusion: Based on the two cases of AFF in patients with cancer related to BMA use, we should consider that the incidence of AFF may be associated with long-term BMA use.",
"affiliations": "Department of Orthopaedic Surgery, JA Toride Medical Center.;Department of Orthopaedic Surgery, JA Toride Medical Center.;Department of Orthopaedic Surgery, JA Toride Medical Center.;Department of Orthopaedic Surgery, JA Toride Medical Center.;Department of Orthopaedic Surgery, JA Toride Medical Center.",
"authors": "Fuchioka|Yusuke|Y|;Suzuki|Kohji|K|;Kimura|Hiroaki|H|;Furuoka|Hideto|H|;Tamura|Yuri|Y|",
"chemical_list": null,
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"fulltext": "\n==== Front\nJ Rural Med\nJ Rural Med\nJRM\nJournal of Rural Medicine : JRM\n1880-487X\n1880-4888\nThe Japanese Association of Rural Medicine\n\n2020-061\n10.2185/jrm.2020-061\nCase Report\nTwo cases of atypical femoral fracture in cancer patients administered with bone-modifying agents\nFuchioka Yusuke 1\nSuzuki Kohji 1\nKimura Hiroaki 1\nFuruoka Hideto 1\nTamura Yuri 1\n1 Department of Orthopaedic Surgery, JA Toride Medical Center\n01 7 2021\n7 2021\n16 3 170173\n09 12 2020\n16 3 2021\n©2021 The Japanese Association of Rural Medicine\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: http://creativecommons.org/licenses/by-nc-nd/4.0/）.\nObjective: We report two cases of atypical femoral fracture (AFF) in patients with cancer.\n\nPatients: Two patients, a 53-year-old woman with breast cancer and a 77-year-old man with prostate cancer, could not walk after being injured in a fall. They used bone-modifying agents (BMA) for the prevention of bone metastasis for three and four years, respectively.\n\nResults: Intramedullary nails were placed to fix the femoral fractures in each patient. Neither of them had pathological metastatic femoral fractures based on fracture site specimens; however, severe suppression of bone turnover at the fracture site was suspected. Both patients could ambulate with a T-cane and were free of hip pain after surgery. Radiographs showed no callus formation at the fracture site.\n\nConclusion: Based on the two cases of AFF in patients with cancer related to BMA use, we should consider that the incidence of AFF may be associated with long-term BMA use.\n\natypical femoral fracture\nbone-modifying agent\ncancer patients\nbone metastasis\n==== Body\nIntroduction\n\nRecently, an association between atypical femoral fracture (AFF) and bone-modifying agents (BMA), such as bisphosphonates and denosumab, has been established. These agents are used for the treatment of osteoporosis, and as the life expectancy of patients with cancer has increased, the incidence of AFF with long-term use of BMA is expected to increase1). We report two cases of AFF in patients with cancer who received long-term BMA therapy.\n\nThis case report was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from the patients for publication of this case report and any accompanying images.\n\nCase presentation\n\nCase 1\n\nA 53-year-old woman, who weighed 68 kg and was 168 cm tall, was treated with total surgical resection of invasive ductal carcinoma of the breast in December 2001. Immediately after the cancer surgery, she was treated with tamoxifen for three years and eight months before discontinuing the therapy because of liver dysfunction. In September 2009, she had lung metastasis and bone metastatic disease (thoracic and lumbar vertebrae) detected on bone scan, and she was treated with monthly intravenous (IV) zoledronate for three years. She received 41 doses of 4 mg IV infusion until she stopped in September 2012. The total amount of zoledronate administered to the patient was 164 mg. Next, she started treatment with denosumab, receiving a total of 27 doses of 120 mg subcutaneous injections, on a monthly basis for three years (a total dose of 3,240 mg).\n\nIn July 2015, she was unable to walk after being injured in a fall accompanied with severe pain in her right thigh. Radiography revealed a right femoral subtrochanteric transverse fracture and an area of focal thickening of the left femoral lateral cortex (Figure 1Figure 1 Subtrochanteric transverse fracture on the right side and one area of focal thickening in the left femoral lateral cortex.\n\n). On the fourth day after the injury, she underwent open reduction and internal fixation (ORIF) with an intramedullary nail (Figure 2Figure 2 We performed bilateral ORIF using intramedullary nails (Synthes PFNA nails®), the right side first and the left side seven days later.\n\n). The operative time was 2 h and 42 min, and the intraoperative blood loss was 530 g. After surgery, left hip pain worsened. On the seventh postoperative day, the patient underwent surgery on the left hip (Figure 2). The operative time was 53 min, and intraoperative blood loss was negligible. Surgery for the right hip pain revealed no pathological findings suggestive of bone metastasis. Laboratory data showed the following parameters: bone specific alkaline phosphatase (BAP) 4.1 μg/L (2.9–14.5), tartrete-resistant acid phosphatase 5b (TRACP-5b) 62 mU/dL (120–420), and type 1 procollagen N-terminal propeptide (P1NP) 12.3 μg/L (17.1–64.7). Dual energy X-ray absorptiometry (DEXA) showed 154% of the young adult mean (YAM) in the left femur and 141% of YAM in the lumbar spine.\n\nShe received four units of packed red blood cell transfusions during hospitalization. Gradually, her bilateral hip pain decreased. Fourteen days after the surgery, the patient could stand while holding onto a handrail. She was transferred to another hospital for breast cancer treatment. Five months after surgery, she could walk assisted with a T-cane and was free of hip pain. Radiographs showed no displacement or callus formation at the fracture site (Figure 3Figure 3 Five months after surgery, radiographs showed no callus formation at the fracture site and no new fracture at the left side.\n\n). After bilateral surgery, the patient continued treatment with monthly denosumab.\n\nCase 2\n\nA 77-year-old man, weighing 78 kg and 161 cm tall, was diagnosed with prostate cancer in September 2010. Computed tomography (CT) revealed multiple bone metastases in the spine. The patient underwent treatment with docetaxel for seven years after hormone therapy for two years. In addition, he was treated with IV injections of 4 mg monthly zoledronate for bone metastasis in the spine due to prostate cancer between January 2015 and November 2019. The total dose of zoledronate administered was 192 mg.\n\nIn May 2020, he could not walk after being injured in a fall. He had been enduring thigh pain for several months. Radiographic examination revealed a subtrochanteric transverse fracture of the left femur (Figure 4Figure 4 Subtrochanteric transverse fracture on the left side with bilateral thickening of the cortex.\n\n). On the fourth day after the injury, he underwent ORIF with an intramedullary nail (Figure 5Figure 5 We performed ORIF with an intramedullary nail (Smith & Nephew InterTAN®).\n\n). The operative time was 1 h and 45 min, and intraoperative blood loss was 300 g. The patient did not receive any perioperative blood transfusion. Surgery for the left hip pain revealed no pathological findings suggestive of bone metastasis. Laboratory data showed the following parameters: BAP, 8.6 μg/L; TRACP-5b, 219 mU/dL; and P1NP, 55.7 μg/L. DEXA showed 105% of YAM in the right femur and 121% of YAM in the lumbar spine.\n\nRehabilitation was started on postoperative day 1. On postoperative day 22, the patient was transferred to a rehabilitation hospital. Five months after surgery, the patient could walk with a T-cane, and radiographs showed no callus formation at the fracture site (Figure 6Figure 6 Five months after surgery, radiographs showed only a very mild callus formation at the fracture site.\n\n).\n\nAfter AFF surgery, he received 120 mg of denosumab monthly. He died of pneumonia seven months after surgery.\n\nDiscussion\n\nThe American Society for Bone and Mineral Research defines the major clinical features of AFF as follows: 1) atraumatic or minimal trauma, 2) transverse or oblique fracture from the lesser trochanter to the supracondylar area, 3) a medial spike in a complete fracture or crack of only the lateral cortex in an incomplete fracture, 4) no comminution, and 5) periosteal or endosteal thickening of the lateral cortex. Minor features include cortical thickening, prodromal pain, and bilateral complete or incomplete fractures. Our patients had all the major features and several minor features of AFF2).\n\nThe optimal duration of the BMA exposure was not determined. However, the risk of AFF is higher with long-term BMA exposure than with short-term exposure, according to Dell et al3). Shane et al. reported that the risk of AFFs is 2 per 10,000 persons after two years of BMA use and 78 per 10,000 persons after eight years4). Schilcher et al. showed that the risk decreases by 70% per year after drug discontinuation5). In contrast, Puhaindran et al. reported that the incidence of AFF is not related to the doses of intravenous bisphosphonates or the duration of treatment6). In case 1, AFF likely developed due to the long-term use of both denosumab and zoledronate. Schilcher et al. showed that suppression of bone turnover by denosumab may lead to a high risk of AFF and reported a similar case of AFF with denosumab after zoledronate use7). In another study, AFF caused by denosumab was reported after the discontinuation of alendronate8). Case 2 had received intravenous zoledronate for five years, and he complained of thigh pain. Therefore, in this case, we believe that the use of both drugs was the cause of AFF. Dell et al. analyzed the records of a large health maintenance organization and identified 102 patients with AFFs who had been on oral bisphosphonates for a mean of five and a half years3).\n\nLockwood et al. reported that surgical treatment should be considered for incomplete fractures with thigh pain9). As exemplified by case 1, who had a complete fracture on the right side and an incomplete fracture on the left side, the operative time and intraoperative blood loss were lower, and the surgery was minimally invasive for the left side compared to the right side. Therefore, even if there is an incomplete fracture accompanied by prodromal thigh pain, surgical treatment may be considered. In cases 1 and 2, we believe that one of the main causes of the delayed union is an insufficient reduction of the fracture site, and it might have been better to use LIPUS10).\n\nWe think we should choose a middle or long nail with a large diameter to prevent nonunion of the fracture site. Isehuku et al. reported that sufficient reaming and insertion of an intramedullary nail with the largest possible diameter can help prevent nonunion11).\n\nAs in our patients, the life expectancy of patients with cancer has improved in recent years due to advances in medical care. Long-term BMA therapy is expected to prevent the pain caused by bone metastasis. Cakmak recommended radiographic evaluation of both femurs during long-term BMA treatment lasting over five years12). However, at present, AFF is not well recognized as a complication of long-term BMA use, except in the field of orthopedics. In the future, it will be necessary to disseminate knowledge regarding AFF and, at the same time, follow patients carefully, such that surgery can be performed before a complete fracture occurs.\n\nThis study had some limitations. First, there were only two patients, one with breast cancer and one with prostate cancer. Second, we could not confirm the bone union of the fracture site because the follow-up of these cases was only short-term.\n\nConclusion\n\nWe encountered two cases of AFF in patients with cancer related to BMA. We should consider that the incidence of AFF may be associated with long-term BMA use.\n==== Refs\nReferences\n\n1 Kaku T Oh Y Sato S et al . Incidence of atypical femoral fractures in the treatment of bone metastasis: an alert report. J Bone Oncol 2020; 23 : 100301. doi: 10.1016/j.jbo.2020.100301 32642421\n2 Shane E Burr D Abrahamsen B et al . 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. doi: 10.1002/jbmr.1998 23712442\n3 Dell RM Adams AL Greene DF et al . Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012; 27 : 2544–2550. doi: 10.1002/jbmr.1719 22836783\n4 Shane E Burr D Ebeling PR et al . American Society for Bone and Mineral ResearchAtypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010; 25 : 2267–2294. doi: 10.1002/jbmr.253 20842676\n5 Schilcher J Michaëlsson K Aspenberg P . Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011; 364 : 1728–1737. doi: 10.1056/NEJMoa1010650 21542743\n6 Puhaindran ME Farooki A Steensma MR et al . Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am 2011; 93 : 1235–1242. doi: 10.2106/JBJS.J.01199 21776577\n7 Schilcher J Aspenberg P . Atypical fracture of the femur in a patient using denosumab—a case report. Acta Orthop 2014; 85 : 6–7. doi: 10.3109/17453674.2014.885355 24460109\n8 Drampalos E Skarpas G Barbounakis N et al . Atypical femoral fractures bilaterally in a patient receiving denosumab. Acta Orthop 2014; 85 : 3–5. doi: 10.3109/17453674.2013.854668 24171686\n9 Lockwood M Banderudrappagari R Suva LJ et al . Atypical femoral fractures from bisphosphonate in cancer patients - Review. J Bone Oncol 2019; 18 : 100259. doi: 10.1016/j.jbo.2019.100259 31497503\n10 Jingushi S Mizuno K Matsushita T et al . Low-intensity pulsed ultrasound treatment for postoperative delayed union or nonunion of long bone fractures. J Orthop Sci 2007; 12 : 35–41. doi: 10.1007/s00776-006-1080-3 17260115\n11.Isehuku S Isawa R Koakutsu T et al . Effect of tightness of the reamed interlocking intramedullary nail on the fracture healing in femoral shaft fractures. Kossetu 2003; 25 : 258–261 (in Japanese, Abstract in English).\n12 Çakmak S Mahiroğulları M Keklikçi K et al . Bilateral low-energy sequential femoral shaft fractures in patients on long-term bisphosphonate therapy. Acta Orthop Traumatol Turc 2013; 47 : 162–172. doi: 10.3944/AOTT.2013.2934 23748615\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "16(3)",
"journal": "Journal of rural medicine : JRM",
"keywords": "atypical femoral fracture; bone metastasis; bone-modifying agent; cancer patients",
"medline_ta": "J Rural Med",
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"other_id": null,
"pages": "170-173",
"pmc": null,
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"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
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"title": "Two cases of atypical femoral fracture in cancer patients administered with bone-modifying agents.",
"title_normalized": "two cases of atypical femoral fracture in cancer patients administered with bone modifying agents"
}
|
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"literaturereference": "FUCHIOKA Y, SUZUKI K, KIMURA H, FURUOKA H, TAMURA Y. TWO CASES OF ATYPICAL FEMORAL FRACTURE IN CANCER PATIENTS ADMINISTERED WITH BONE?MODIFYING AGENTS. JOURNAL OF RURAL MEDICINE. 2021?16(3):170?173",
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{
"abstract": "Terbinafine is an antimicrobial agent commonly prescribed for fungal infections. Its side effect profile is generally benign, but there is limited evidence that it has the potential to cause rhabdomyolysis. Rhabdomyolysis is a potentially life-threatening condition caused by profound muscle injury. It has characteristic findings of muscle pain, weakness, and dark urine. When recognized early, patients with rhabdomyolysis can be managed conservatively with hydration and watchful monitoring. However, if treatments are delayed, or in severe cases of rhabdomyolysis, complications such as electrolyte abnormalities, acute kidney injury, and disseminated intravascular coagulation can develop.\nA previously healthy 22-year-old male presented with nausea, vomiting, and dark urine after taking terbinafine 250 mg daily for a tinea infection for 9 days. He developed severe rhabdomyolysis with a serum creatine kinase (CK) of >100 000 U/L as well as anuric acute kidney injury.\nThe clinical history combined with the diagnostic findings suggest acute kidney injury and rhabdomyolysis associated with terbinafine use.\nTerbinafine use was stopped immediately. The patient was started on intravenous fluids and bicarbonate drip. Hemodialysis was initiated to prevent further complications. After his CK level decreased and his clinical status stabilized, he was discharged home and continued to receive outpatient hemodialysis treatments.\nThe patient's kidney function returned to baseline after 1 month of outpatient hemodialysis treatments.\nIn this report, we present a case of rhabdomyolysis associated with terbinafine use that progressed to acute kidney injury requiring dialysis. Our case highlights a less known and severe side effect of this medication and emphasizes the importance of early recognition and treatment of rhabdomyolysis.",
"affiliations": "Schulich School of Medicine & Dentistry, Western University, Windsor, ON, Canada.;Schulich School of Medicine & Dentistry, Western University, Windsor, ON, Canada.",
"authors": "Zhou|Shijie|S|https://orcid.org/0000-0002-2080-5610;Bagga|Amit|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2054358120951371",
"fulltext": null,
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"issn_linking": "2054-3581",
"issue": "7()",
"journal": "Canadian journal of kidney health and disease",
"keywords": "acute kidney injury; hemodialysis; rhabdomyolysis; terbinafine",
"medline_ta": "Can J Kidney Health Dis",
"mesh_terms": null,
"nlm_unique_id": "101640242",
"other_id": null,
"pages": "2054358120951371",
"pmc": null,
"pmid": "33149920",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016441:Retracted Publication",
"references": "27381816;27301374;19841484;30581936;25829882;31198572;2229523;15774072;17198674;20407858;11898964;25043142;19571284;10906171;29778556",
"title": "Rhabdomyolysis and Acute Kidney Injury Associated With Terbinafine Use: A Case Report.",
"title_normalized": "rhabdomyolysis and acute kidney injury associated with terbinafine use a case report"
}
|
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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": "1"
},
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood bicarbonate decreased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood albumin decreased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myoglobin urine present",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
},
{
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},
{
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myalgia",
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"reactionoutcome": "1"
}
],
"summary": null
},
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{
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"reactionoutcome": "2"
},
{
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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": "1"
},
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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": "TERBINAFINE HYDROCHLORIDE."
}
],
"patientagegroup": "5",
"patientonsetage": "22",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZHOU S, BAGGA A. RHABDOMYOLYSIS AND ACUTE KIDNEY INJURY ASSOCIATED WITH TERBINAFINE USE: A CASE REPORT. CAN-J-KIDNEY-HEALTH-DIS 2020?7:NO PAGINATION.",
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"qualification": "3",
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},
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"receivedate": "20201127",
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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": "20210114"
},
{
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"occurcountry": "CA",
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{
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"activesubstancename": "DICLOFENAC"
},
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"drugindication": "PAIN IN EXTREMITY",
"drugintervaldosagedefinition": "804",
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},
{
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},
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"drugdosageform": null,
"drugdosagetext": "250 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TINEA INFECTION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "250",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TERBINAFINE HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": "22",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Calcium ionised decreased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood creatinine increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anuria",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood albumin decreased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myoglobin urine present",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypocalcaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myalgia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Urine output decreased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Aspartate aminotransferase increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood creatine phosphokinase increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood bicarbonate decreased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hyperphosphataemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Chromaturia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood phosphorus increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Fluid overload",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZHOU S AND BAGGA A.. RHABDOMYOLYSIS AND ACUTE KIDNEY INJURY ASSOCIATED WITH TERBINAFINE USE: A CASE REPORT. CANADIAN JOURNAL OF KIDNEY HEALTH AND DISEASE. 2020?7:1-5",
"literaturereference_normalized": "rhabdomyolysis and acute kidney injury associated with terbinafine use a case report",
"qualification": "3",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20201106",
"receivedate": "20201106",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18473136,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20210114"
},
{
"companynumb": "CA-ORCHID HEALTHCARE-2096223",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TERBINAFINE HYDROCHLORIDE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "078163",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TINEA INFECTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "250",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TERBINAFINE HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": "22",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatotoxicity",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ZHOU S, BAGGA A. RHABDOMYOLYSIS AND ACUTE KIDNEY INJURY ASSOCIATED WITH TERBINAFINE USE: A CASE REPORT. CAN J KIDNEY HEALTH DIS. 2020? 7: 1-5.",
"literaturereference_normalized": "rhabdomyolysis and acute kidney injury associated with terbinafine use a case report",
"qualification": "1",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20201124",
"receivedate": "20201124",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 18538142,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210114"
}
] |
{
"abstract": "The Fusarium species are one of the most common opportunistic fungal infections occurring in immunocompromised patients and are associated with high morbidity and mortality. Common sites of infection include blood, skin, nasal passages, lungs, bone, and other visceral organs. There is a paucity of literature on Fusarium infections in the brain, and the true nature and extent of central nervous system involvement is not well described. To the authors' knowledge, there have been no reported cases of Fusarium infection of the spine. The authors report the case of a man with acute myeloblastic leukemia and resultant pancytopenia who presented with fungal sinusitis, upper- and lower-extremity weakness, and cardiopulmonary arrest. Imaging studies revealed a spinal cervical intramedullary ring-enhancing lesion. Because of the progressive nature of his symptoms, neurosurgical intervention involving a C2-3 laminectomy and drainage of the lesion was performed. Intraoperative cultures and histopathology results were positive for Fusarium species and, along with intraoperative findings, were consistent with a fungus ball. The patient was placed on a regimen of intravenous and intrathecal antifungal therapy. Unfortunately, his clinical condition declined postoperatively, and he ultimately died of disseminated infection.",
"affiliations": "Departments of1Neurosurgery and.;3Pathology, Roswell Park Comprehensive Cancer Center, Buffalo; and.;Departments of1Neurosurgery and.",
"authors": "Agyei|Justice O|JO|;Qiu|Jingxin|J|;Fabiano|Andrew J|AJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-5646",
"issue": "31(3)",
"journal": "Journal of neurosurgery. Spine",
"keywords": "AML = acute myeloblastic leukemia; Fusarium infection; Fusarium species; SIMA = spinal intramedullary abscess; intramedullary spinal cord; spinal cord fungus ball",
"medline_ta": "J Neurosurg Spine",
"mesh_terms": "D000038:Abscess; D017809:Fatal Outcome; D005670:Fusarium; D006801:Humans; D016867:Immunocompromised Host; D007796:Laminectomy; D008297:Male; D019635:Neurosurgical Procedures; D013116:Spinal Cord; D013131:Spine; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101223545",
"other_id": null,
"pages": "440-446",
"pmc": null,
"pmid": "31075770",
"pubdate": "2019-05-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fusarium species intramedullary spinal cord fungus ball: case report.",
"title_normalized": "fusarium species intramedullary spinal cord fungus ball case report"
}
|
[
{
"companynumb": "US-FRESENIUS KABI-FK201910981",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "040583",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "UNKNOWN",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "UNKNOWN",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "23",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fusarium infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Eye abscess",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardio-respiratory arrest",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Spinal cord infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "AGYEI J, QIU J, FABIANO A. FUSARIUM SPECIES INTRAMEDULLARY SPINAL CORD FUNGUS BALL: CASE REPORT. JOURNAL OF NEUROSURGERY-SPINE. 2019 SEP?31 (3):440-446.",
"literaturereference_normalized": "fusarium species intramedullary spinal cord fungus ball case report",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20191009",
"receivedate": "20191009",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16898574,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "We describe an infant male of Cambodian background who has typical craniofacial features of mycophenolate mofetil (MMF) embryopathy and a complex congenital heart defect (CHD) (double outlet right ventricle, mitral atresia, pulmonic stenosis, and total anomalous pulmonary venous return). Together with four case reports and the 20 patients included in two recent reviews, we report 24 (19 affected, five normal) patients with this pattern of anomalies. Eight (33%) have a CHD, most commonly, conotruncal or aortic arch defects (6/8, 75%). This would support the hypothesis that disturbance of cranial neural crest migration occurs in exposed infants, and may predict which additional anomalies will be observed in the future. We also attempted to score the severity of the facial anomalies in each MMF patient using a system created by plastic surgeons for patients with hemifacial microsomia. This classification had modest utility in comparing severity and correlating facial to extracranial defects. The findings are viewed with caution because of the preliminary methodology. Finally, since several exposed infants have been reported to be minimally affected, we remind clinicians to be sensitive to the potential mild expression of the effects of this teratogen. This awareness may influence clinical management of apparently normal MMF-exposed individuals.",
"affiliations": "Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA. [email protected]",
"authors": "Lin|Angela E|AE|;Singh|Kathryn E|KE|;Strauss|Arthur|A|;Nguyen|Son|S|;Rawson|Kristyn|K|;Kimonis|Virginia E|VE|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.33934",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "155A(4)",
"journal": "American journal of medical genetics. Part A",
"keywords": null,
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D005145:Face; D005260:Female; D005315:Fetal Diseases; D006330:Heart Defects, Congenital; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D010641:Phenotype; D011247:Pregnancy",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "748-56",
"pmc": null,
"pmid": "21594997",
"pubdate": "2011-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "An additional patient with mycophenolate mofetil embryopathy: cardiac and facial analyses.",
"title_normalized": "an additional patient with mycophenolate mofetil embryopathy cardiac and facial analyses"
}
|
[
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP010929",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": "90055",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"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": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Craniofacial deformity",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mitral valve atresia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Heart disease congenital",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anomalous pulmonary venous connection",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Double outlet right ventricle",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pulmonary valve stenosis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LIN AE, SINGH KE, STRAUSS A, NGUYEN S, RAWSON K, KIMONIS VE. AN ADDITIONAL PATIENT WITH MYCOPHENOLATE MOFETIL EMBRYOPATHY: CARDIAC AND FACIAL ANALYSES.. AM J MED GENET A.. 2011?A(4):748?56",
"literaturereference_normalized": "an additional patient with mycophenolate mofetil embryopathy cardiac and facial analyses",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180714",
"receivedate": "20180714",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15146140,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 1,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20181010"
}
] |
{
"abstract": "Concurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC) is a risk factor for oral candidiasis (OC). As Candida spp. are highly virulent, we conducted a retrospective study to determine whether OC increases the severity of dysphagia related to mucositis in HNC patients.\nWe retrospectively analyzed the cases of consecutive patients with carcinomas of the oral cavity, pharynx, and larynx who underwent CCRT containing cisplatin (CDDP) at our hospital. The diagnosis of OC was based on gross mucosal appearance. We performed a multivariate analysis to determine whether OC was associated with the development of grade 3 dysphagia in the Radiation Therapy Oncology Group (RTOG) Acute Toxicity Criteria. The maximum of the daily opioid doses was compared between the patients with and without OC.\nWe identified 138 HNC patients. OC was observed in 51 patients (37%). By the time of their OC diagnosis, 19 (37%) had already developed grade 3 dysphagia. Among the 30 patients receiving antifungal therapy, 12 (40%) showed clinical deterioration. In the multivariate analysis, OC was independently associated with grade 3 dysphagia (OR 2.75; 95%CI 1.22-6.23; p = 0.015). The patients with OC required significantly higher morphine-equivalent doses of opioids (45 vs. 30 mg/day; p = 0.029).\nCandida infection causes refractory dysphagia. It is worth investigating whether antifungal prophylaxis reduces severe dysphagia related to candidiasis.",
"affiliations": "Department of Radiation Oncology, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japan.;Departments of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.;Department of Otolaryngology Head and Neck Surgery, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japan.;Department of Oral Radiology, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japan.;Departments of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.;Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.;Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.;Department of Radiation Oncology, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japan.;Department of Radiation Oncology, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japan.;Department of Radiologic Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Chuo-ku, Niigata 951-8518, Japan.;Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.;Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.;Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.;Department of Radiologic Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Chuo-ku, Niigata 951-8518, Japan.;Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.",
"authors": "Saito|Hirotake|H|;Shodo|Ryusuke|R|;Yamazaki|Keisuke|K|;Katsura|Kouji|K|;Ueki|Yushi|Y|;Nakano|Toshimichi|T|;Oshikane|Tomoya|T|;Yamana|Nobuko|N|;Tanabe|Satoshi|S|;Utsunomiya|Satoru|S|;Ohta|Atsushi|A|;Abe|Eisuke|E|;Kaidu|Motoki|M|;Sasamoto|Ryuta|R|;Aoyama|Hidefumi|H|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ctro.2019.10.006",
"fulltext": "\n==== Front\nClin Transl Radiat OncolClin Transl Radiat OncolClinical and Translational Radiation Oncology2405-6308Elsevier S2405-6308(19)30106-510.1016/j.ctro.2019.10.006ArticleThe association between oral candidiasis and severity of chemoradiotherapy-induced dysphagia in head and neck cancer patients: A retrospective cohort study Saito Hirotake [email protected]⁎Shodo Ryusuke bYamazaki Keisuke cKatsura Kouji dUeki Yushi bNakano Toshimichi eOshikane Tomoya eYamana Nobuko aTanabe Satoshi aUtsunomiya Satoru fOhta Atsushi eAbe Eisuke eKaidu Motoki eSasamoto Ryuta fAoyama Hidefumi ea Department of Radiation Oncology, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japanb Departments of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japanc Department of Otolaryngology Head and Neck Surgery, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japand Department of Oral Radiology, Niigata University Medical and Dental Hospital, 1-754 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8520, Japane Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japanf Department of Radiologic Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Chuo-ku, Niigata 951-8518, Japan⁎ Corresponding author. [email protected] 10 2019 1 2020 31 10 2019 20 13 18 27 6 2019 21 10 2019 26 10 2019 © 2019 The Author(s)2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Oral candidiasis (OC) aggravated dysphagia in chemoradiation for HNC.\n\n• OC patients required higher doses of opioids.\n\n• Early diagnosis of chemoradiation-associated OC seems difficult.\n\n• Antifungal prophylaxis may reduce the severity of mucositis and dysphagia.\n\n\n\nBackground and purpose\nConcurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC) is a risk factor for oral candidiasis (OC). As Candida spp. are highly virulent, we conducted a retrospective study to determine whether OC increases the severity of dysphagia related to mucositis in HNC patients.\n\nPatients and methods\nWe retrospectively analyzed the cases of consecutive patients with carcinomas of the oral cavity, pharynx, and larynx who underwent CCRT containing cisplatin (CDDP) at our hospital. The diagnosis of OC was based on gross mucosal appearance. We performed a multivariate analysis to determine whether OC was associated with the development of grade 3 dysphagia in the Radiation Therapy Oncology Group (RTOG) Acute Toxicity Criteria. The maximum of the daily opioid doses was compared between the patients with and without OC.\n\nResults\nWe identified 138 HNC patients. OC was observed in 51 patients (37%). By the time of their OC diagnosis, 19 (37%) had already developed grade 3 dysphagia. Among the 30 patients receiving antifungal therapy, 12 (40%) showed clinical deterioration. In the multivariate analysis, OC was independently associated with grade 3 dysphagia (OR 2.75; 95%CI 1.22–6.23; p = 0.015). The patients with OC required significantly higher morphine-equivalent doses of opioids (45 vs. 30 mg/day; p = 0.029).\n\nConclusion\nCandida infection causes refractory dysphagia. It is worth investigating whether antifungal prophylaxis reduces severe dysphagia related to candidiasis.\n\nKeywords\nHead and neck cancerDysphagiaCandidiasis\n==== Body\n1 Introduction\nThe standard curative approach for locally advanced head and neck cancer (HNC) is concomitant chemotherapy containing cisplatin (CDDP) and radiotherapy (RT) (CCRT; concurrent chemoradiotherapy) [1], [2]. One of the most frequent adverse events in CCRT for HNC is severe dysphagia related to mucositis [3], [4]. CCRT-associated dysphagia is detrimental to the patients’ quality of life and increases the need for nutritional support, and >50% of the HNC patients undergoing CCRT require either enteral or parenteral nutrition (PN) [5], [6]. Several approaches to the prevention of dysphagia have been explored, including intensity-modulated RT (IMRT) to reduce the dose to the pharyngeal constrictors, and de-escalated CCRT regimens [7], [8], [9]. However, these approaches are not recognized as standard treatments. It is crucial to elucidate the pathophysiology of CCRT-associated dysphagia and to establish an effective prophylactic approach [10].\n\nCandida spp. colonize the upper aerodigestive tract in 70% of HNC patients [11], [12]. Under physiological conditions, the virulence of Candida spp. is suppressed by mucosal epithelium and T cells [13], whereas the breakdown of the mucosal barrier leads to opportunistic candidiasis. Invasive candidiasis is associated with high morbidity and mortality rates [14]. It has thus been speculated that mucosal candidiasis causes oropharyngeal dysfunction in HNC patients undergoing CCRT. Busetto et al. conducted a prospective cohort study (MIR; Mycosis in Radiotherapy) and analyzed the relationship between the development of oral candidiasis (OC) and various toxicity outcomes in HNC patients undergoing curative RT [15]. They reported that among the patients with OC, the incidences of high-grade mucositis and dysphagia were significantly increased compared to the patients without OC.\n\nSeveral studies have investigated OC in HNC patients undergoing RT [11], [15], [16], [17]. These reports, which were written before CDDP-based CCRT had become a common practice, suffer from the heterogeneity of concomitant chemotherapy. The concomitant administration of RT and CDDP synergistically causes severe mucosal damage [18] and is thought to aggravate the symptoms of OC. We conducted the present study to elucidate (1) the severity of dysphagia associated with OC, (2) the impact of OC on the magnitude of dysphagia and the pain caused by mucositis, and (3) the response to antifungal agents among HNC patients undergoing CDDP-based CCRT.\n\n2 Patients and methods\n2.1 Eligible patients\nConsecutive patients with carcinomas of the oral cavity, nasopharynx, oropharynx, hypopharynx, or larynx who were treated at our radiation oncology department during the 7+-year period between January 2011 and May 2018 were identified through an institutional cancer registry. The inclusion criteria were: (1) undergoing curative CCRT containing CDDP, and (2) being capable of oral intake at the start of the CCRT. Staging was done according to the 7th version of the American Joint Committee on Cancer (AJCC) TNM Classification. The patients' concurrent chemotherapy regimen was either (a) 5-fluorouracil (5FU) 700 mg/m2 on days 1–5 and 29–33, plus CDDP 70 mg/m2 on days 1 and 29, or (b) CDDP 80 mg/m2 on days 1, 22, and 43. In general, we administered the CDDP + 5FU regimen from 2011 to 2014, and we administered the CDDP regimen in 2015 or later as concomitant chemotherapy.\n\nAll patients underwent CT simulation and 70 Gy in 35 once-daily fractions of RT delivered with 4–10 MV linear accelerators. The details of the dose prescription were 44–46 Gy to the elective regional nodes and 70 Gy to the gross tumor volume. The nasopharyngeal cancer patients treated in 2013 or later underwent IMRT, and the other patients underwent 3D conformal RT. The maximal dose to the spinal cord was kept at <50 Gy. In the IMRT planning, the mean dose to the parotid glands was kept at ≤25 Gy. No thresholds were set for the dose to the pharyngeal constrictors.\n\nWe used an opt-out approach in which eligible HNC patients and their family members were advised to contact the researchers only if they declined to be included in the study [19]. The study was approved by the institutional review board of our hospital (no. 2018–0127).\n\n2.2 Data collection\nAll patients were hospitalized for the entire period from the start of their CCRT until their recovery of oral intake. Otolaryngologists examined the oropharyngeal mucosa with a fiberoptic scope 2×/week. Specialist dentists or dental hygienists provided oral care 1×/week. Acetaminophen and long-acting and short-acting opioids were prescribed based on the severity of the pain caused by mucositis [20]. The diagnosis of OC was based on the gross mucosal appearance, and mycological confirmation was not mandatory [15], [21]. It was left to each physician’s judgement whether to initiate antifungal treatment. Both topical and systemic antifungal agents were used [22].\n\nA radiation oncologist (SH) reviewed all of the patients' medical charts. The severity of dysphagia was graded according to the Radiation Therapy Oncology Group (RTOG) Acute Toxicity Criteria [23]. At our institution, the use of a specific mucositis severity scale is not mandatory; we used the opioid dose as a surrogate for the severity of the pain caused by mucositis. The maximal daily dose of long-acting opioids was converted into the intravenous morphine-equivalent dose [24], [25]. In the patients who developed OC, the RTOG grade of dysphagia was recorded at the time of OC diagnosis. The patients' responses to antifungal agents was judged retrospectively: “deterioration” corresponded to the worsening of mucosal lesions, the increase in opioid doses, or the initiation of nutritional therapy within 14 days of antifungal treatment [26], and “improvement” corresponded to the complete or partial resolution of symptoms without deterioration. The other responses were classified as “indistinguishable”.\n\n2.3 Statistical analyses\nWe first used Fisher's exact test to investigate the relationships between the development of OC and various clinical factors including age, gender, chemotherapy, performance status (PS), primary site, presence of diabetes mellitus (DM), and stage. We tested the hypothesis that OC is associated with grade 3 dysphagia by performing both univariate and multivariate analyses. The associations of grade 3 dysphagia with clinical factors including the development of OC were tested with Fisher's exact test. The variables that showed relative significance (p < 0.10) in the univariate analysis were included in the binary logistic regression model [27]. The morphine-equivalent doses of opioids were compared between the patients with and without OC (Mann-Whitney U test). P-values < 0.05 were considered significant. All analyses were performed with EZR ver. 1.35, a graphical user interface for R statistical software [28].\n\n3 Results\nWe identified 471 consecutive HNC patients, and 138 met the inclusion criteria (Fig. A1). There were no significant differences in the baseline patient demographics between the group of patients treated with RT + 5FU + CDDP (n = 50) and the group of patients treated with RT + CDDP (n = 88) (Table 1). The median follow-up period for all patients, which was calculated from the first day of CCRT, was 26.1 months. All eligible patients were hospitalized throughout their CCRT, and the complete medical chart was available for all patients. Ninety-two patients (67%) required either PN or tube feeding and were judged as having developed grade 3 dysphagia.Table 1 Baseline characteristics of the HNC patients (n = 138).\n\n\tCDDP + RT\tCDDP + 5FU + RT\tp\t\n\tn = 88\tn = 50\t\t\nAge (median, range)\t65 (37–78)\t66 (32–78)\t0.635\t\nGender\t\t\t\n Male\t77 (88%)\t46 (92%)\t0.572\t\n Female\t11 (12%)\t4 (8%)\t\t\nHistology\t\t\t\n SqCC\t88 (100%)\t49 (98%)\t0.362\t\n AC\t0\t1 (2%)\t\t\nPrimary site\t\t\t\n Hypopharynx\t35 (40%)\t17 (34%)\t0.9\t\n Larynx\t8 (9%)\t4 (8%)\t\t\n Nasopharynx\t17 (19%)\t13 (26%)\t\t\n Oral cavity\t3 (3%)\t2 (4%)\t\t\n Oropharynx\t25 (28%)\t14 (28%)\t\t\nStage\t\t\t\t\n II\t11 (12%)\t13 (26%)\t0.033\t\n III\t29 (33%)\t8 (16%)\t\t\n IV\t48 (55%)\t29 (58%)\t\t\nECOG PS\t\t\t\n 0\t7 (8%)\t2 (4%)\t0.771\t\n 1\t79 (90%)\t47 (94%)\t\t\n 2\t2 (2%)\t1 (2%)\t\t\nRT techniques\t\t\t\n 3DCRT\t71 (81%)\t44 (88%)\t0.345\t\n IMRT\t17 (19%)\t6 (12%)\t\t\nDose (Gy; median, range)\t70 (66–70)\t70 (60–70)\t0.653\t\nYOT\t\t\n 2011\t0\t14 (28%)\tNA\t\n 2012\t0\t7 (14%)\t\t\n 2013\t6 (7%)\t8 (16%)\t\t\n 2014\t3 (3%)\t11 (22%)\t\t\n 2015\t13 (15%)\t7 (14%)\t\t\n 2017\t29 (33%)\t1 (2%)\t\t\n 2018\t7 (8%)\t0\t\t\nAbbreviations; HNC = head and neck cancer, CDDP = cisplatin, RT = radiotherapy, 5FU = 5-fluorouracil, SqCC = squamous cell carcinoma, AC = adenocarcinoma, ECOG = Eastern Cooperative Oncology Group, PS = Performance Status, 3DCRT = 3D conformal radiotherapy, IMRT = intensity-modulated radiotherapy, YOT = year of treatment.\n\n\n\nOC was observed in 51 patients (37%). Fifty patients were diagnosed with pseudomembranous OC, and one patient was diagnosed with hyperplastic OC. No patients were diagnosed with erythematous OC. Mycological culture tests using oral swabs were performed in eight patients, and C. albicans was recovered from all specimens. The median cumulative dose at the time of OC diagnosis was 38 Gy (range 6–70 Gy). These patients were diagnosed with OC at a median of CCRT day 29 (range 5–83). There were no significant differences in the incidence of OC by the primary site, stage, age, or chemotherapy (Table 2).Table 2 Univariate analysis of the association between OC and clinical factors.\n\n\tDevelopment of OC\t\t\n\tNo\tYes\tp\t\nChemotherapy\t\t0.587\t\n CDDP\t57\t31\t\t\n CDDP + 5FU\t30\t20\t\t\nGender\t\t\t0.411\t\n Male\t79\t44\t\t\n Female\t8\t7\t\t\nAge\t\t\t0.161\t\n ≤65\t47\t21\t\t\n ≥66\t40\t30\t\t\nPrimary site\t\t0.275\t\n Hypopharynx\t35\t17\t\t\n Larynx\t9\t3\t\t\n Nasopharynx\t21\t9\t\t\n Oral cavity\t3\t2\t\t\n Oropharynx\t19\t20\t\t\nECOG PS\t\t\t0.545\t\n 0\t5\t4\t\t\n 1\t81\t45\t\t\n 2\t1\t2\t\t\nRT techniques\t\t1\t\n 3DCRT\t72\t43\t\t\n IMRT\t15\t8\t\t\nStage\t\t\t0.697\t\n II\t17\t7\t\t\n III\t22\t15\t\t\n IV\t48\t29\t\t\nYOT\t\t\t1\t\n 2011–2015\t43\t26\t\t\n 2016–2018\t44\t25\t\t\nDM\t\t\t\t\n No\t72\t45\t0.47\t\n Yes\t15\t6\t\t\nAbbreviations; OC = oral candidiasis, CDDP = cisplatin, RT = radiotherapy, 5FU = 5-fluorouracil, ECOG = Eastern Cooperative Oncology Group, PS = Performance Status, 3DCRT = 3D conformal radiotherapy, IMRT = intensity-modulated radiotherapy, YOT = year of treatment, DM = diabetes mellitus.\n\n\n\nThe RTOG grade of dysphagia at the time of OC diagnosis was grade 0–1 in 11 patients (22%), grade 2 in 21 patients (41%), and grade 3 in 19 patients (37%). Among the 32 patients whose dysphagia grade was 0–2 at the time of OC diagnosis, 21 patients (66%) developed grade 3 dysphagia. Topical antifungal agents were administered in 28 patients. Two patients underwent systemic azole therapy; one patient received 200 mg/day of itraconazole syrup for 7 days, and the other received 200 mg/day of intravenous fluconazole for 13 days. The topical agents failed to improve the symptoms of OC in 10 patients (36%), and the systemic azoles failed in both patients (100%). Five of the 28 patients receiving topical agents showed an improvement of symptoms.\n\nThe patients with OC developed grade 3 dysphagia significantly more frequently compared to the patients without OC (78% vs. 60%, p = 0.026) (Table 3). Similarly, the stage II patients tended to have a higher incidence of grade 3 dysphagia compared to the stage III patients (83% vs. 54%, Bonferroni-adjusted p = 0.081). In the multivariate analysis, OC alone was independently associated with grade 3 dysphagia (OR 2.75, 95%CI 1.22–6.23, p = 0.015) (Table 4).Table 3 Univariate analysis of the association between grade 3 dysphagia and clinical factors.\n\n\tDysphagia grade\t\t\n\t1–2\t3\tp\t\nChemotherapy\t\t\t0.352\t\n CDDP\t32\t56\t\t\n CDDP + 5FU\t14\t36\t\t\nGender\t\t\t0.385\t\n Male\t43\t80\t\t\n Female\t3\t12\t\t\nAge\t\t\t0.37\t\n ≤65\t20\t48\t\t\n ≥66\t26\t44\t\t\nOC\t\t\t0.0264\t\n No\t35\t52\t\t\n Yes\t11\t40\t\t\nPrimary site\t\t0.349\t\n Hypopharynx\t14\t38\t\t\n Larynx\t6\t6\t\t\n Nasopharynx\t11\t19\t\t\n Oral cavity\t3\t2\t\t\n Oropharynx\t12\t27\t\t\nECOG PS\t\t\t0.673\t\n 0\t3\t6\t\t\n 1\t43\t83\t\t\n 2\t0\t3\t\t\nRT techniques\t\t1\t\n 3DCRT\t38\t77\t\t\n IMRT\t8\t15\t\t\nStage\t\t\t0.061\t\n II\t4\t20\t\t\n III\t17\t20\t\t\n IV\t25\t52\t\t\nYOT\t\t\t1\t\n 2011–2015\t23\t46\t\t\n 2016–2018\t23\t46\t\t\nAbbreviations; CDDP = cisplatin, RT = radiotherapy, 5FU = 5-fluorouracil, OC = oral candidiasis, ECOG = Eastern Cooperative Oncology Group, PS = Performance Status, 3DCRT = 3D conformal radiotherapy, IMRT = intensity-modulated radiotherapy, YOT = year of treatment.\n\nTable 4 Multivariate logistic regression analysis of grade 3 dysphagia.\n\nVariable\tOR (95%CI)\tp\t\nOC\t2.75 (1.22–6.23)\t0.015\t\nStage\t\t\t\n IV\tReference\t\t\n II\t2.68 (0.81–8.83)\t0.11\t\n III\t0.53 (0.23–1.22)\t0.14\t\nAbbreviations; OC = oral candidiasis.\n\n\n\nWe drew the histogram of the maximum of daily morphine-equivalent doses of opioids for the OC group and the non-OC group, respectively. The opioid dose peak was observed in the 40–60 mg interval in the OC group, whereas the peak was observed in the 0–20 mg and 40–60 mg intervals in the non-OC group (Fig. 1). Thirty-five patients in the non-OC group required ≥40 mg morphine-equivalent dose of opioids. The patients with OC required significantly higher morphine-equivalent doses of opioids (45 vs. 30 mg/day; p = 0.029). One patient developed sepsis and OC, but the association between sepsis and OC is unclear.Fig. 1 Histogram of morphine-equivalent of the maximum of daily opioid doses in the OC and non-OC groups.\n\n\n\n4 Discussion\nThe results of the present study demonstrated that the development of oral candidiasis (OC) during CDDP-based CCRT aggravates the pain and dysphagia related to mucositis. These findings are consistent with the results of the prospective MIR Study by Busetto et al. [15]. It thus appears that Candida infection is not only the consequence of chemoradiation-induced mucositis; rather, it is also one of the aggravating factors of mucositis and dysphagia. Based on the findings of the latest high-quality molecular biological study of the peptide toxin of C. albicans\n[29], it is obvious that Candida spp. vigorously destroy the mucosa and aggravate dysphagia secondary to radiation-induced mucositis.\n\nWe also observed that by the time of the recognition of mucosal lesions of OC, more than one-third of the patients had developed high-grade dysphagia, which makes the early diagnosis of OC difficult. Another obstacle to the early detection of OC may be the presence of erythematous candidiasis. Formerly called “antibiotic sore tongue,” erythematous candidiasis is characterized by localized mucosal hyperemia and associated pain [30]. These lesions are generally more difficult to recognize compared to pseudomembranous OC [31], [32]. In our present patient cohort, the incidence of OC was 37%, which was disproportionately lower compared to the Candida colonization rate of 70% [11], [12]. The histogram analysis revealed that 35 patients (25% of the entire cohort) experienced severe pain without typical pseudomembranous lesions of OC. We suspect that some of these patients might have developed “undiagnosed” erythematous candidiasis.\n\nOC associated with cytotoxic chemotherapy or RT is refractory to antifungal treatment. In the guidelines provided by the Infectious Diseases Society of America, topical antifungal agents including miconazole gel are recommended for mild OC, whereas systemic fluconazole or itraconazole is recommended for moderate to severe OC [22]. In the OC associated with HIV infection, systemic fluconazole or itraconazole provides the complete cure of symptoms in 80%–90% of the cases [26], [33], [34], [35]. In the OC associated with cytotoxic chemotherapy or RT, the clinical cure rate falls to 45%–75% [36], [37] (Table 5).Table 5 Treatment outcomes of OC in precedent clinical trials.\n\nPatients\tDrug\tDaily dose (mg)\tDuration (days)\tClinical cure rate (%)\tAuthor and publication year\tReference No.\t\nAIDS\tFluconazole\t100\t14\t82.5\tVazquez et al. 2006\t[26]\t\nAIDS\tFluconazole\t100\t14\t87\tGraybill et al. 1998\t[33]\t\n\tItraconazole\t200\t14\t97\t\t\t\n\tItraconazole\t200\t7\t86\t\t\t\nAIDS\tFluconazole\t150\t14\t95.5\tHamza et al. 2008\t[34]\t\nAIDS\tFluconazole\t100\t14\t87\tPons et al. 1997\t[35]\t\nRT for HNC\tMiconazole MAT\t50\t14\t52.5\tBensadoun et al. 2008\t[36]\t\n\tMiconazole gel\t500\t14\t45.4\t\t\t\nMalignant tumor\tFluconazole\t100\t10\t74\tOude Lashof et al. 2004\t[37]\t\n\tItraconazole\t200\t15\t62\t\t\t\nCCRT for HNC\tFluconazole\t200\t13\t0\tPresent study\t\t\n\tItraconazole\t200\t7\t0\t\t\t\nAbbreviations; AIDS = acquired immunodeficiency syndrome, RT = radiotherapy, HNC = head and neck cancer, OC = oral candidiasis, MAT = mucoadhesive tablet, CCRT = concurrent chemoradiotherapy.\n\n\n\nWe propose a biological hypothesis to explain how CCRT-associated OC causes refractory dysphagia in HNC patients. Combined RT and CDDP disrupt the mucosal barrier, thus facilitating Candida infection [13]. The aspartyl proteinases and cytotoxic peptides secreted by C. albicans destroy the desmosomes and plasma membranes of the mucosal epithelium and aggravate mucositis [29], [38], [39]. The inflammatory processes involve the submucosal pharyngeal constrictors and lead to severe dysphagia [40]. It is difficult to restore the function of the mucosa and pharyngeal constrictors with antifungal treatment initiated upon the onset of OC, because the physiological wound healing capacities are severely impaired during and after CCRT.\n\nFor these reasons, CCRT-associated OC is difficult to detect at the early stage of infection, and antifungal prophylaxis seems to be efficacious. In a nonrandomized prospective trial by Nicolatou-Galitis et al., the prophylactic administration of fluconazole during RT for various head and neck malignancies reduced the incidence of severe mucositis compared to the control group [41]. Rao et al. published a similar report about their retrospective analysis [17]. However, mucositis-associated dysphagia and pain were not evaluated in these studies. A prospective trial is necessary to determine whether antifungal prophylaxis reduces the severity of pain and dysphagia related to mucositis in HNC patients.\n\nThe present study has several limitations. First, the study dealt with a small cohort with heterogenous characteristics and treatment details (different primary tumor sites, IMRT vs. 3DCRT, differing doses to pharyngeal constrictors, etc.) We performed a multivariate analysis to reduce these biases. Second, the patients' daily medical charts generally lack microbiological data. Third, the response to antifungal treatment was not mentioned in the medical charts and was judged retrospectively. Nevertheless, it was clear that both two patients treated with systemic azole therapy showed clinical failure, which implies the refractoriness of chemoradiation-associated OC. Despite these limitations, we consider that our study revealed clinically relevant information, and our findings pose an important question that should be addressed in a prospective trial; i.e., whether antifungal prophylaxis reduces the severity of pain and dysphagia related to mucositis in HNC patients.\n\n5 Conclusions\nCandida infection aggravated the severity of pain and dysphagia related to mucositis during CCRT for head and neck cancer. One-third of the patients with OC in our cohort had already developed high-grade dysphagia by the time of their diagnosis of OC. CCRT-associated OC was refractory to antifungal treatment. As the early diagnosis of OC is difficult, it is worth investigating whether antifungal prophylaxis reduces the severity of dysphagia related to candidiasis.\n\nFunding support\nThe present work was supported by a grant from the Japanese Society for Promotion of Science KAKENHI, grant #19K17262.\n\nDeclaration of Competing Interest\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAppendix\nFig. A1.Fig. A1 CONSORT diagram. Abbreviations; RT = radiotherapy, CDDP = cisplatin, 5FU = 5-fluorouracil.\n==== Refs\nReferences\n1 Lacas B. Bourhis J. Overgaard J. Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis Lancet Oncol 18 9 2017 1221 1237 28757375 \n2 Pignon J.P. le Maitre A. Maillard E. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients Radiother Oncol 92 1 2009 4 14 19446902 \n3 Nguyen N.P. Moltz C.C. Frank C. Dysphagia following chemoradiation for locally advanced head and neck cancer Ann Oncol 15 3 2004 383 388 14998839 \n4 Rosenthal D.I. Lewin J.S. Eisbruch A. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer J Clin Oncol 24 17 2006 2636 2643 16763277 \n5 Gillison M.L. Trotti A.M. Harris J. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial Lancet 393 10166 2018 40 50 30449625 \n6 Noronha V. Joshi A. Patil V.M. Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial J Clin Oncol 36 11 2018 1064 1072 29220295 \n7 Chen A.M. Felix C. Wang P.C. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study Lancet Oncol 18 6 2017 803 811 28434660 \n8 Feng F.Y. Kim H.M. Lyden T.H. Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in patients with oropharyngeal cancer: clinical and functional results J Clin Oncol 28 16 2010 2732 2738 20421546 \n9 Mesia R. Taberna M. HPV-related oropharyngeal carcinoma de-escalation protocols Lancet Oncol 18 6 2017 704 705 28434659 \n10 Greco E. Simic T. Ringash J. Dysphagia Treatment for Patients With Head and Neck Cancer Undergoing Radiation Therapy: A Meta-analysis Review Int J Radiat Oncol Biol Phys 101 2 2018 421 444 29726363 \n11 Dahiya M.C. Redding S.W. Dahiya R.S. Oropharyngeal candidiasis caused by non-albicans yeast in patients receiving external beam radiotherapy for head-and-neck cancer Int J Radiat Oncol Biol Phys 57 1 2003 79 83 12909218 \n12 Redding S.W. Zellars R.C. Kirkpatrick W.R. Epidemiology of oropharyngeal Candida colonization and infection in patients receiving radiation for head and neck cancer J Clin Microbiol 37 12 1999 3896 3900 10565903 \n13 Netea M.G. Joosten L.A. van der Meer J.W. Immune defence against Candida fungal infections Nat Rev Immunol 15 10 2015 630 642 26388329 \n14 Brown G.D. Denning D.W. Gow N.A. Hidden killers: human fungal infections Sci Transl Med 4 165 2012 165rv13 \n15 Busetto M. Fusco V. Corbella F. Predictive factors for oropharyngeal mycosis during radiochemotherapy for head and neck carcinoma and consequences on treatment duration. Results of mycosis in radiotherapy (MIR): a prospective longitudinal study Radiother Oncol 109 2 2013 303 310 23932151 \n16 Gligorov J. Bastit L. Gervais H. Prevalence and treatment management of oropharyngeal candidiasis in cancer patients: results of the French CANDIDOSCOPE study Int J Radiat Oncol Biol Phys 80 2 2011 532 539 20594986 \n17 Rao N.G. Han G. Greene J.N. Effect of prophylactic fluconazole on oral mucositis and candidiasis during radiation therapy for head-and-neck cancer Pract Radiat Oncol 3 3 2013 229 233 24674369 \n18 Sanguineti G. Sormani M.P. Marur S. Effect of radiotherapy and chemotherapy on the risk of mucositis during intensity-modulated radiation therapy for oropharyngeal cancer Int J Radiat Oncol Biol Phys 83 1 2012 235 242 22104358 \n19 Lacey R.J. Wilkie R. Wynne-Jones G. Evidence for strategies that improve recruitment and retention of adults aged 65 years and over in randomised trials and observational studies: a systematic review Age Ageing 46 6 2017 895 903 28481964 \n20 Zenda S. Matsuura K. Tachibana H. Multicenter phase II study of an opioid-based pain control program for head and neck cancer patients receiving chemoradiotherapy Radiother Oncol 101 3 2011 410 414 22001102 \n21 Farah C.S. Lynch N. McCullough M.J. Oral fungal infections: an update for the general practitioner Aust Dent J 55 Suppl 1 2010 48 54 20553244 \n22 Pappas P.G. Kauffman C.A. Andes D.R. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America Clin Infect Dis 62 4 2016 e1 e50 26679628 \n23 Cox J.D. Stetz J. Pajak T.F. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) Int J Radiat Oncol Biol Phys 31 5 1995 1341 1346 7713792 \n24 Le Q.T. Kim H.E. Schneider C.J. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study J Clin Oncol 29 20 2011 2808 2814 21670453 \n25 Elting L.S. Cooksley C.D. Chambers M.S. 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An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis Eur J Cancer 40 9 2004 1314 1319 15177489 \n38 Naglik J.R. Challacombe S.J. Hube B. Candida albicans secreted aspartyl proteinases in virulence and pathogenesis Microbiol Mol Biol Rev 67 3 2003 400 428 12966142 \n39 Reichart P.A. Philipsen H.P. Schmidt-Westhausen A. Pseudomembranous oral candidiasis in HIV infection: ultrastructural findings J Oral Pathol Med 24 6 1995 276 281 7562665 \n40 Popovtzer A. Cao Y. Feng F.Y. Anatomical changes in the pharyngeal constrictors after chemo-irradiation of head and neck cancer and their dose-effect relationships: MRI-based study Radiother Oncol 93 3 2009 510 515 19520446 \n41 Nicolatou-Galitis O. Velegraki A. Sotiropoulou-Lontou A. Effect of fluconazole antifungal prophylaxis on oral mucositis in head and neck cancer patients receiving radiotherapy Support Care Cancer 14 1 2006 44 51 15947956\n\n",
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"title": "The association between oral candidiasis and severity of chemoradiotherapy-induced dysphagia in head and neck cancer patients: A retrospective cohort study.",
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"abstract": "An 81-year-old woman with chronic kidney disease was on enoxaparin (1 mg/kg subcutaneously two times a day) for 4 months to manage pulmonary embolism. While admitted for diagnostic evaluation of frequent falls, transient ischaemic attacks and pain management, she developed vomiting, diarrhoea, melena and hypotension. Her estimated glomerular filtration rate decreased from an admission value of 34 mL/min/1.73 m2 to 13 mL/min/1.73 m2. CT scan showed retroperitoneal haematoma. She was placed in intensive care and stabilised with aggressive fluid replacement, blood transfusion, and discontinuation of enoxaparin and concomitant aspirin. We attribute this major bleeding to enoxaparin use in an elderly woman with chronic kidney disease and concomitant aspirin intake. We will review reported cases of enoxaparin-associated retroperitoneal haematoma. We suggest that enoxaparin be used with caution in elderly patients with chronic kidney disease, and stress that treatment monitoring and reversal may not be readily available.",
"affiliations": "Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada.;Department of Family Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada.;Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada.;Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada.",
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{
"abstract": "Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela.",
"affiliations": null,
"authors": "Mengual-Moreno|Edgardo|E|;Lizarzábal-García|Maribel|M|;Ruiz-Soler|María|M|;Silva-Suarez|Niniveth|N|;Andrade-Bellido|Raúl|R|;Lucena-González|Maribel|M|;Bessone|Fernando|F|;Hernández|Nelia|N|;Sánchez|Adriana|A|;Medina-Cáliz|Inmaculada|I|",
"chemical_list": null,
"country": "Venezuela",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0535-5133",
"issue": "56(1)",
"journal": "Investigacion clinica",
"keywords": null,
"medline_ta": "Invest Clin",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012017:Referral and Consultation; D014687:Venezuela; D055815:Young Adult",
"nlm_unique_id": "0421531",
"other_id": null,
"pages": "3-12",
"pmc": null,
"pmid": "25920181",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela.",
"title_normalized": "case reports of drug induced liver injury in a reference hospital of zulia state venezuela"
}
|
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"abstract": "A 24-year-old male patient seropositive for the human immunodeficiency virus with Burkitt's Leukemia was treated successfully with aggressive systemic chemotherapy and central nervous system prophylaxis. He presented with a leukocyte count of 68,900/microliter with 33% L3 lymphoblasts, massive hepatosplenomegaly, generalized lymphadenopathy, a lactic dehydrogenase level of 9105 IU/l, creatinine level of 5.8 mg/dl, and a uric acid level of 43.5 mg/dl. Hemodialysis, intrathecal methotrexate, hydrocortisone and cytosine arabinoside, and fractionated doses of cyclophosphamide followed by vincristine and doxorubicin were promptly instituted. He received eight subsequent courses of chemotherapy consisting of either methotrexate with leucovorin rescue and high dose, continuous infusion cytosine arabinoside or cyclophosphamide, vincristine, and methotrexate with leucovorin. There was marked hematologic toxicity resulting from this treatment. However, the patient was alive and in complete remission more than 6 years from diagnosis. This paper demonstrated that it is possible to successfully treat a patient who is HIV-1 antibody positive with poor prognosis Burkitt's Leukemia. Further studies need to be undertaken to define the least toxic, most effective therapy for this disease.",
"affiliations": "Department of Medicine, University of Miami School of Medicine, Florida.",
"authors": "Greenberg|A L|AL|;Droller|D G|DG|",
"chemical_list": "D003561:Cytarabine; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D006854:Hydrocortisone; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(19940815)74:4<1261::aid-cncr2820740413>3.0.co;2-b",
"fulltext": null,
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"issn_linking": "0008-543X",
"issue": "74(4)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003561:Cytarabine; D004317:Doxorubicin; D006679:HIV Seropositivity; D006801:Humans; D006854:Hydrocortisone; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D008727:Methotrexate; D012074:Remission Induction; D006435:Renal Dialysis; D014750:Vincristine",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "1261-4",
"pmc": null,
"pmid": "8055447",
"pubdate": "1994-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of a patient with seropositive human immunodeficiency virus with high risk Burkitt's leukemia.",
"title_normalized": "successful treatment of a patient with seropositive human immunodeficiency virus with high risk burkitt s leukemia"
}
|
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{
"abstract": "Plaque psoriasis affects children and adults, but treatment options for paediatric psoriasis are limited.\n\n\n\nTo evaluate the efficacy and safety of ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, for moderate-to-severe paediatric psoriasis.\n\n\n\nIn a randomized, double-blind, placebo-controlled, phase III study (IXORA-PEDS), patients aged 6 to < 18 years with moderate-to-severe plaque psoriasis were randomized 2 : 1 to weight-based dosing of IXE every 4 weeks (IXE Q4W, n = 115) or placebo (n = 56) through week 12, followed by open-label IXE Q4W. Coprimary endpoints were the proportions of patients at week 12 achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and those achieving a static Physician's Global Assessment score of 0 or 1 (sPGA 0,1).\n\n\n\nIXE was superior (P < 0·001) to placebo for both coprimary endpoints of PASI 75 (IXE Q4W, 89%; placebo, 25%) and sPGA (0,1) (IXE Q4W, 81%; placebo, 11%). IXE was also superior for all gated secondary endpoints, including PASI 75 and sPGA (0,1) at week 4, improvement in itch, and complete skin clearance. IXE Q4W provided significant (P < 0·001) improvements vs. placebo in quality of life and clearance of scalp and genital psoriasis. Responses at week 12 were sustained or further improved through week 48. Through week 12, 45% (placebo) and 56% (IXE) of patients reported treatment-emergent adverse events. One serious adverse event was reported (IXE), one patient discontinued due to an adverse event (placebo) and no deaths were reported.\n\n\n\nIXE was superior to placebo in the treatment of moderate-to-severe paediatric psoriasis, and the safety profile was generally consistent with that observed in adults. What is already known about this topic? Paediatric psoriasis affects approximately 1% of children and can negatively impact health-related quality of life. Treatment options for paediatric psoriasis are typically limited to off-label treatments and approved systemic biologics. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for moderate-to-severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate-to-severe paediatric psoriasis. What does this study add? Ixekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health-related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate-to-severe plaque psoriasis. The safety profile of ixekizumab was generally consistent with that seen in adults. Ixekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin-17A antagonist) for the treatment of moderate-to-severe paediatric psoriasis. Plain language summary available online.",
"affiliations": "Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Dermatology, Radboud University Medical Center, Nijmegen, the Netherlands.;Psoriahue, Buenos Aires, Argentina.;Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ, USA.;Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Frankfurt am Main, Germany.;Mindful Dermatology and Modern Research Associates, Dallas, TX, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;Eli Lilly and Company, Indianapolis, IN, USA.;K Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada.",
"authors": "Paller|A S|AS|0000-0001-6187-6549;Seyger|M M B|MMB|;Alejandro Magariños|G|G|;Bagel|J|J|;Pinter|A|A|0000-0002-1330-1502;Cather|J|J|;Keller|S|S|;Rodriguez Capriles|C|C|;Gontijo Lima|R|R|;Gallo|G|G|;Little|C A|CA|;Edson-Heredia|E|E|0000-0002-3187-331X;Li|L|L|;Xu|W|W|;Papp|K|K|0000-0001-9557-3642;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; C549079:ixekizumab; D000068800:Etanercept",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.19147",
"fulltext": "\n==== Front\nBr J Dermatol\nBr. J. Dermatol\n10.1111/(ISSN)1365-2133\nBJD\nThe British Journal of Dermatology\n0007-0963 1365-2133 John Wiley and Sons Inc. Hoboken \n\n10.1111/bjd.19147\nBJD19147\nClinical Trial\nOriginal Articles\nClinical Trial\nEfficacy and safety of ixekizumab in a phase III, randomized, double‐blind, placebo‐controlled study in paediatric patients with moderate‐to‐severe plaque psoriasis (IXORA‐PEDS)†\n\nPaller et al.Paller A.S. https://orcid.org/0000-0001-6187-6549\n1\[email protected] Seyger M.M.B. \n2\n Alejandro Magariños G. \n3\n Bagel J. \n4\n Pinter A. https://orcid.org/0000-0002-1330-1502\n5\n Cather J. \n6\n Keller S. \n7\n Rodriguez Capriles C. \n7\n Gontijo Lima R. \n7\n Gallo G. \n7\n Little C.A. \n7\n Edson‐Heredia E. https://orcid.org/0000-0002-3187-331X\n7\n Li L. \n7\n Xu W. \n7\n Papp K. https://orcid.org/0000-0001-9557-3642\n8\n the IXORA‐PEDS study group \n1 \nDepartment of Dermatology\nNorthwestern University Feinberg School of Medicine\nChicago\nIL\nUSA\n\n\n2 \nDepartment of Dermatology\nRadboud University Medical Center\nNijmegen\nthe Netherlands\n\n\n3 \nPsoriahue\nBuenos Aires\nArgentina\n\n\n4 \nPsoriasis Treatment Center of Central New Jersey\nEast Windsor\nNJ\nUSA\n\n\n5 \nDepartment of Dermatology, Venereology and Allergology\nUniversity Hospital Frankfurt\nFrankfurt am Main\nGermany\n\n\n6 \nMindful Dermatology and Modern Research Associates\nDallas\nTX\nUSA\n\n\n7 \nEli Lilly and Company\nIndianapolis\nIN\nUSA\n\n\n8 \nK Papp Clinical Research and Probity Medical Research\nWaterloo\nON\nCanada\n\n* \nCorrespondence\n\nAmy Paller\n\nEmail: [email protected]\n\n15 6 2020 \n8 2020 \n183 2 10.1111/bjd.v183.2231 241\n12 4 2020 © ? 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of DermatologistsThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Summary\nBackground\nPlaque psoriasis affects children and adults, but treatment options for paediatric psoriasis are limited.\n\nObjectives\nTo evaluate the efficacy and safety of ixekizumab (IXE), a high‐affinity monoclonal antibody that selectively targets interleukin‐17A, for moderate‐to‐severe paediatric psoriasis.\n\nMethods\nIn a randomized, double‐blind, placebo‐controlled, phase III study (IXORA‐PEDS), patients aged 6 to < 18 years with moderate‐to‐severe plaque psoriasis were randomized 2 : 1 to weight‐based dosing of IXE every 4 weeks (IXE Q4W, n = 115) or placebo (n = 56) through week 12, followed by open‐label IXE Q4W. Coprimary endpoints were the proportions of patients at week 12 achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and those achieving a static Physician's Global Assessment score of 0 or 1 (sPGA 0,1).\n\nResults\n\nIXE was superior (P < 0·001) to placebo for both coprimary endpoints of PASI 75 (IXE Q4W, 89%; placebo, 25%) and sPGA (0,1) (IXE Q4W, 81%; placebo, 11%). IXE was also superior for all gated secondary endpoints, including PASI 75 and sPGA (0,1) at week 4, improvement in itch, and complete skin clearance. IXE Q4W provided significant (P < 0·001) improvements vs. placebo in quality of life and clearance of scalp and genital psoriasis. Responses at week 12 were sustained or further improved through week 48. Through week 12, 45% (placebo) and 56% (IXE) of patients reported treatment‐emergent adverse events. One serious adverse event was reported (IXE), one patient discontinued due to an adverse event (placebo) and no deaths were reported.\n\nConclusions\n\nIXE was superior to placebo in the treatment of moderate‐to‐severe paediatric psoriasis, and the safety profile was generally consistent with that observed in adults.\n\n\nWhat is already known about this topic?\n\n\n\nPaediatric psoriasis affects approximately 1% of children and can negatively impact health‐related quality of life.\n\nTreatment options for paediatric psoriasis are typically limited to off‐label treatments and approved systemic biologics.\n\nIxekizumab, a high‐affinity monoclonal antibody that selectively targets interleukin‐17A, is approved for moderate‐to‐severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate‐to‐severe paediatric psoriasis.\n\n\n\n\n\nWhat does this study add?\n\n\n\nIxekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health‐related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate‐to‐severe plaque psoriasis.\n\nThe safety profile of ixekizumab was generally consistent with that seen in adults.\n\nIxekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin‐17A antagonist) for the treatment of moderate‐to‐severe paediatric psoriasis.\n\n\n\n\n\nPlain language summary available online\n\nEli Lilly and Company 10.13039/100004312 source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020\nFunding sources Eli Lilly and Company (Indianapolis, IN, USA) was involved in the study design, data collection, data analysis, data interpretation, manuscript preparation and publication decisions. All authors had full access to all data in the study and had final responsibility for the decision to submit for publication.\n\n\nConflicts of interest statements are listed in Appendix \n\n1\n.\n\nA list of study investigators is provided in Appendix S1 (see Supporting Information).\n\n† \nPlain language summary available online\n==== Body\nPaediatric plaque psoriasis affects approximately 1% of children and adolescents, and is estimated to occur first before 20 years of age in 35–50% of adults with plaque psoriasis.1, 2, 3 Paediatric psoriasis can be associated with reduced quality of life and a higher incidence of multiple comorbidities, including psoriatic arthritis, obesity, diabetes, Crohn's disease, ulcerative colitis and psychiatric comorbidities.4 Thus, early recognition and treatment of paediatric psoriasis are important for overall health and quality of life.\n\nAs there have been few clinical studies of paediatric psoriasis, treatment options are limited and often used off‐label. Topical therapies comprise first‐line treatment, followed by phototherapy for moderate‐to‐severe paediatric psoriasis.5 Systemic treatments are recommended for moderate‐to‐severe paediatric psoriasis recalcitrant to topical therapies.5, 6 Nonbiologic systemic treatments such as methotrexate or ciclosporin are used, but they may not be well tolerated or provide adequate efficacy.5, 6\n\n\nIxekizumab (IXE) is a high‐affinity monoclonal antibody that selectively targets interleukin‐(IL)‐17A. The objective of this study was to evaluate the efficacy and safety of IXE for moderate‐to‐severe plaque psoriasis in paediatric patients aged 6 to < 18 years. Prior to the current study, two tumour necrosis factor inhibitors (etanercept and adalimumab) and one IL‐12/23 antagonist (ustekinumab) were approved for paediatric psoriasis.7 Based on the findings from this study, IXE was recently approved by the US Food and Drug Administration (FDA) for moderate‐to‐severe paediatric psoriasis in addition to previously approved indications for adult patients with moderate‐to‐severe plaque psoriasis, active psoriatic arthritis and ankylosing spondylitis.\n\nPatients and methods\nPatients\nStudy participants were 6 to < 18 years of age and had moderate‐to‐severe plaque psoriasis, defined as Psoriasis Area and Severity Index (PASI) ≥ 12, static Physician's Global Assessment (sPGA) ≥ 3 and psoriasis‐affected body surface area ≥ 10% at screening and baseline. They were also candidates for phototherapy or systemic therapy or their psoriasis was not adequately controlled by topical therapies as determined by the investigator. Patients with pustular, erythrodermic and/or guttate forms of plaque psoriasis or drug‐induced psoriasis, or with clinical and/or laboratory evidence of untreated latent or active tuberculosis were excluded. Appendix S2 (see Supporting Information) provides complete eligibility criteria.\n\nStudy design\nIXORA‐PEDS is a 108‐week multicentre, double‐blind, randomized, placebo‐controlled, phase III study examining the efficacy and safety of IXE vs. placebo in paediatric patients with moderate‐to‐severe plaque psoriasis. During a 12‐week double‐blind treatment period, patients were randomized 2 : 1 to subcutaneous IXE every 4 weeks (Q4W) or placebo, administered according to baseline weight categories of > 50 kg, 25–50 kg and < 25 kg (Table S1; see Supporting Information). As part of a European Union protocol addendum, an etanercept reference arm was included in IXORA‐PEDS to demonstrate the efficacy of IXE in the context of an approved therapy for paediatric psoriasis. At the time of trial commencement, etanercept was approved only for severe psoriasis in paediatric patients in the European Union. Therefore, patients with severe psoriasis (PASI ≥ 20 or sPGA ≥ 4) at baseline in countries where etanercept is approved only for severe paediatric psoriasis were eligible for inclusion in the protocol addendum. These patients were randomized 2 : 2 : 1 to IXE Q4W, open‐label etanercept (0·8 mg kg−1 every 1 week, not exceeding 50 mg per dose) or placebo until approximately 75 patients were randomized. Efficacy assessments were conducted by blinded assessors to minimize potential bias in assessments of patients receiving open‐label etanercept.\n\nPatients completing the double‐blind treatment period entered a 48‐week open‐label maintenance period (week 12 to week 60), during which patients initially randomized to IXE Q4W or placebo received IXE Q4W and patients initially randomized to etanercept received IXE Q4W after an 8‐week washout period.\n\nEnrolment for IXORA‐PEDS occurred between 17 April 2017 and 13 November 2018. At the time of publication of this report, the study is currently ongoing. IXORA‐PEDS (ClinicalTrials.gov: NCT03073200) was conducted in accordance with the ethical principles of the Declaration of Helsinki. The study was approved by the ethical review board at each participating site. A parent or legal guardian provided written informed consent and the patient provided written assent prior to conduct of study assessments, examinations or procedures. Appendix S3 (see Supporting Information) provides additional details on the study design.\n\nOutcomes\nThe prespecified coprimary objectives of the study were to assess whether IXE Q4W was superior to placebo at week 12 as measured by the proportions of patients achieving ≥ 75% improvement from baseline in PASI (PASI 75) and an sPGA score of 0 or 1 [sPGA (0,1)]. The prespecified gated secondary objectives were to assess whether IXE Q4W was superior to placebo at week 12, as measured by the proportion of patients achieving PASI 90, an sPGA score of 0 [sPGA (0)], PASI 100 and ≥ 4‐point improvement from baseline in the Itch Numerical Rating Scale (Itch NRS ≥ 4, in patients with baseline score ≥ 4); as well as PASI 75 and sPGA (0,1) at week 4. Other prespecified secondary outcomes included a 0 or 1 score on the Children's Dermatology Life Quality Index (CDLQI, patients aged 6–16 years) or Dermatology Life Quality Index (DLQI, patients aged ≥ 17 years), a score of 0 or 1 on the Patient's Global Assessment of Disease Severity [PatGA (0,1)], a Nail Psoriasis Severity Index score of 0 (NAPSI = 0, in patients with baseline NAPSI > 0), a Psoriasis Scalp Severity Index score of 0 (PSSI = 0, in patients with baseline PSSI > 0), 100% improvement from baseline in the Palmoplantar Psoriasis Area and Severity Index (PPASI 100, in patients with baseline PPASI > 0), clearance of genital psoriasis (in patients with baseline genital psoriasis), mean change from baseline in Itch NRS, and mean change from baseline in NAPSI, PSSI and PPASI for patients with baseline NAPSI > 0, PSSI > 0 and PPASI > 0, respectively. Appendixes S4 and S5 (see Supporting Information) provide further details on the objectives and outcomes.\n\nSafety outcomes included assessments of adverse events (AEs) – including treatment‐emergent AEs (TEAEs), serious AEs (SAEs) and AEs of special interest – laboratory tests and vital signs. Data on suspected inflammatory bowel disease (IBD) were adjudicated by an external clinical events committee. Appendixes S3 and S6 (see Supporting Information) provide details on antidrug antibody assays and safety outcomes.\n\nStatistical analyses\nA gated multiple testing strategy was implemented for the primary and major secondary objectives to control the family‐wise type I error rate at a two‐sided α‐level of 0·05. To assess whether IXE Q4W was superior to placebo, the primary and gated secondary endpoints were tested sequentially. If any test was not successful, all subsequent tests were not tested.\n\nAnalyses are provided for the week 12 and week 48 database locks. Efficacy analyses during the double‐blind treatment period were performed on all randomized patients according to the initially assigned treatment. Efficacy was also summarized using descriptive statistics for all patients randomized to IXE at week 0 who received IXE throughout their study participation up to week 48. Additional efficacy analyses were performed according to the initially assigned treatment on all randomized patients with severe psoriasis in countries where etanercept was approved for severe psoriasis. Efficacy was also analysed according to baseline weight category (< 25 kg, ≥ 25 kg to ≤ 50 kg and > 50 kg).\n\nTreatment group comparisons for categorical outcomes were performed using Fisher's exact test with nonresponder imputation for handling of missing data. Continuous outcomes were analysed using a mixed model for repeated‐measures analysis, including treatment, region, baseline sPGA score, baseline weight category, baseline value, visit, treatment‐by‐visit and baseline‐by‐visit interactions as fixed factors. Type III tests for the least‐squares means were used for statistical comparisons. Table S2 (see Supporting Information) lists the number of patients with nonmissing data at each postbaseline visit through week 48.\n\nSafety was summarized using descriptive statistics. Safety analyses during the double‐blind treatment period were performed on all randomized patients who took at least one dose of double‐blind study treatment according to the initially assigned treatment. Safety was also summarized up to the week 48 interim database lock for the all‐IXE safety population, defined as all patients who received at least one dose of IXE, including patients initially randomized to placebo or etanercept. Additional safety analyses were conducted in all randomized patients in etanercept‐approved countries who took at least one dose of double‐blind study treatment according to the initially assigned treatment.\n\nAnalyses of antidrug antibodies were conducted on all evaluable patients in the all‐IXE safety population. Patients with treatment‐emergent antidrug antibodies (TE‐ADAs) were classified as having low, moderate or high titre if their last titre value within the baseline or postbaseline period was < 1 : 160, ≥ 1 : 160 to < 1 : 1280, or ≥ 1 : 1280, respectively. Appendix S7 (see Supporting Information) provides additional information on the statistical analyses.\n\nResults\nOf 199 patients screened, 171 (86%) were randomized to placebo (n = 56) or IXE Q4W (n = 115); 53 (95%) and 113 (98%), respectively, completed the double‐blind treatment period (Figure 1). Overall, 166 patients entered the maintenance period and 89% (152 of 171) completed week 48. Three (placebo) and two (IXE Q4W) patients discontinued during the double‐blind treatment period and 14 discontinued during the maintenance period. Figure S1 (see Supporting Information) presents a flow diagram for patients with severe psoriasis in etanercept‐approved countries.\n\nFigure 1 Patient flow diagram through Week 48 of IXORA‐PEDS. Q4W, every 4 weeks.\n\nThe baseline demographics and disease characteristics were similar between treatment arms (Table 1; and Table S3; see Supporting Information). The mean ± SD age was 13·5 ± 3·04 years (range 6–17), 58% (n = 99) of patients were female, and most (84%, n = 140) were of white race. Most patients (73%, n = 125) weighed > 50 kg, 25% (n = 43) weighed ≥ 25 and ≤ 50 kg, and 2% (n = 3) weighed < 25 kg. The mean ± SD duration of psoriasis symptoms was 4·7 ± 3·17 years and the mean ± SD PASI score was 19·7 ± 7·65. Baseline nail (NAPSI > 0), scalp (PSSI > 0), palmoplantar (PPASI > 0) and genital psoriasis were present for 27% (n = 46), 89% (n = 152), 15% (n = 26) and 32% (n = 55) of patients, respectively. Most patients (72%, n = 123) had baseline Itch NRS ≥ 4 and all patients (n = 171) had baseline PatGA > 0. The mean ± SD DLQI and CLDQI scores were 9·4 ± 4·92 and 8·1 ± 5·30, respectively.\n\nTable 1 Baseline characteristics\n\n\tPlacebo (n = 56)\tIXE Q4W (n = 115)\t\nAge (years), mean ± SD\t13·1 ± 2·79\t13·7 ± 3·14\t\nFemale sex\t36 (64)\t63 (55)\t\nWhite racea\n\t45 (85)\t95 (83)\t\nWeight (kg), mean ± SD\t60·3 ± 20·33\t63·9 ± 24·94\t\n< 25 kg\t1 (2)\t2 (2)\t\n≥ 25 kg and ≤ 50 kg\t14 (25)\t29 (25)\t\n> 50 kg\t41 (73)\t84 (73)\t\nBMI (kg m−2), mean ± SD\t23·5 ± 5·57\t24·1 ± 6·77\t\nDuration of psoriasis since diagnosis (years), mean ± SD\t4·7 ± 3·01\t4·7 ± 3·26\t\nPrior psoriasis treatment\t\t\t\nNonbiologic systemic\t15 (27)\t39 (34)\t\nBiologic\t2 (4)\t5 (4)\t\nPhototherapy\t13 (23)\t25 (22)\t\nInvolved BSA (%), mean ± SD\t27·1 ± 17·27\t27·1 ± 18·55\t\nsPGA score, mean ± SD\t3·5 ± 0·6\t3·6 ± 0·6\t\nsPGA = 3\t31 (55)\t57 (50)\t\nsPGA = 4\t21 (38)\t51 (44)\t\nsPGA = 5\t4 (7)\t7 (6)\t\nPASI, mean ± SD\t19·7 ± 8·01\t19·8 ± 7·51\t\nNAPSI, mean ± SDb\n\t24·5 ± 20·86\t33·9 ± 29·52\t\nNAPSI > 0\t12 (21)\t34 (30)\t\nPSSI, mean ± SDc\n\t29·7 ± 17·24\t27·3 ± 17·01\t\nPSSI > 0\t50 (89)\t102 (89)\t\nPPASI, mean ± SDd\n\t15·4 ± 21·08\t8·2 ± 8·67\t\nPPASI > 0\t9 (16)\t17 (15)\t\nItch NRS, mean ± SD\t5·0 ± 2·47\t5·4 ± 2·75\t\nItch NRS ≥ 4\t40 (71)\t83 (72)\t\nCDLQI, mean ± SDe\n\t7·4 ± 4·78\t8·5 ± 5·54\t\nDLQI, mean ± SDf\n\t10·2 ± 5·42\t9·3 ± 4·90\t\nPatGA, mean ± SD\t3·5 ± 0·97\t3·6 ± 1·08\t\nPatGA > 0\t56 (100)\t115 (100)\t\nGenital psoriasis present\t14 (25)\t41 (36)\t\nUnless otherwise specified, data are presented as n (%). Values are reported as observed. Unless otherwise indicated, there were no missing values in the baseline characteristics. BMI, body mass index; BSA, body surface area; CDLQI, Children's Dermatology Life Quality Index; DLQI, Dermatology Life Quality Index; IXE, ixekizumab; NAPSI, Nail Psoriasis Severity Index; NRS, numerical rating scale; PASI, Psoriasis Area and Severity Index; PatGA, Patient's Global Assessment of Disease Severity; PPASI, Palmoplantar Psoriasis Area and Severity Index; PSSI, Psoriasis Scalp Severity Index; Q4W, every 4 weeks; sPGA, static Physician's Global Assessment. aNumber of patients with nonmissing values: placebo, n = 53; IXE Q4W, n = 114. bAssessed for patients with nail psoriasis at baseline (as reported by the investigator). Number of patients with non‐missing values: placebo, n = 13; IXE Q4W, n = 34. cAssessed for patients with scalp psoriasis at baseline (as reported by the investigator). Number of patients with non‐missing values: placebo, n = 50; IXE Q4W, n = 103. dAssessed for patients with palmoplantar psoriasis at baseline (as reported by the investigator). Number of patients with non‐missing values: placebo, n = 9; IXE Q4W, n = 18. eAssessed in patients 6–16 years of age. Number of patients with nonmissing values: placebo, n = 48; IXE Q4W, n = 86. fAssessed in patients ≥ 17 years of age. Number of patients with nonmissing values: placebo, n = 6; IXE Q4W, n = 26.\n\nJohn Wiley & Sons, LtdThe coprimary and all gated secondary objectives were achieved. IXE was superior to placebo for both coprimary endpoints of PASI 75 (IXE Q4W: 89%, placebo: 25%, P < 0·001) and sPGA (0,1) (IXE Q4W: 81%, placebo: 11%, P < 0·001) at week 12 (Figure 2 and Table 2). IXE was superior to placebo at week 12 for the gated secondary endpoints of PASI 90 (IXE Q4W: 78%, placebo: 5%, P < 0·001), sPGA (0) (IXE Q4W: 52%, placebo: 2%, P < 0·001), PASI 100 (IXE Q4W: 50%, placebo: 2%, P < 0·001) and Itch NRS ≥ 4 (IXE Q4W: 71%, placebo: 20%, P < 0·001) (Figure 3 and Table 2); and at week 4 for PASI 75 (IXE Q4W: 54%, placebo: 9%, P < 0·001) and sPGA (0,1) (IXE Q4W: 48%, placebo: 7%, P < 0·001) (Figure 2).\n\nFigure 2 Proportions of patients achieving (a) ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and (b) static Physician's Global Assessment score of 0 or 1 [sPGA (0,1)] for up to 48 weeks of treatment with ixekizumab (nonresponder imputation). Ixekizumab vs. placebo P‐values during the 12‐week double‐blind treatment period are indicated as *P < 0·05, ‡P < 0·001. Error bars indicate 95% confidence intervals. Analyses of PASI 75 and sPGA (0,1) at week 12 (coprimary endpoints) and at week 4 (gated secondary endpoints) were included in the gated multiple testing strategy. Analyses at other timepoints were not adjusted for multiplicity.\n\nTable 2 Efficacy outcomes at weeks 12 and 48\n\n\tWeek 12\tWeek 48\t\nPlacebo (n = 56)\tIXE Q4W (n = 115)\tIXE Q4W vs. placebo\tIXE Q4W (n = 115)\t\nResponse n (%)\tResponse n (%)\t\nP‐value\tDifference vs. placebo (95% CI)\tResponse n (%)\t\nPASI 50\t21 (38)\t106 (92)\t< 0·001\t54·7% (41·1–68·3)\t106 (92)\t\nPASI 75\t14 (25)\t102 (89)\t< 0·001\t63·7% (51·0–76·4)\t103 (90)\t\nPASI 90\t3 (5)\t90 (78)\t< 0·001\t72·9% (63·3–82·5)\t95 (83)\t\nPASI 100\t1 (2)\t57 (50)\t< 0·001\t47·8% (38·0–57·6)\t63 (55)\t\nsPGA 0 or 1\t6 (11)\t93 (81)\t< 0·001\t70·2% (59·3–81·0)\t93 (81)\t\nsPGA 0\t1 (2)\t60 (52) \t< 0·001\t50·4% (40·6–60·2)\t65 (57)\t\nItch NRS ≥ 4a\n\t8 (20)\t59 (71)\t< 0·001\t51·1% (35·3–66·9)\t65 (78)\t\nCDLQI/DLQI 0 or 1b\n\t13 (23)\t74 (64)\t< 0·001\t41·1% (27·0–55·2)\t87 (76)\t\nPatGA 0 or 1\t9 (16)\t91 (79)\t< 0·001\t63·1% (50·9–75·2)\t99 (86)\t\nNAPSI = 0c\n\t0\t6 (18)\t0·317\t17·6% (4·8–30·5)\t17 (50)\t\nPSSI = 0d\n\t8 (16)\t70 (69)\t< 0·001\t52·6% (39·1–66·2)\t75 (74)\t\nPPASI 100e\n\t1 (11)\t8 (47)\t0·098\t35·9% (4·6–67·3)\t13 (76)\t\nClearance of genital psoriasisf\n\t5 (36)\t35 (85)\t< 0·001\t49·7% (22·3–77·0)\t37 (90)\t\n\tResponse, LSM CFB ± SD\tResponse, LSM CFB ± SD\t\nP‐value\tDifference vs. placebo, LSM difference ± SE\tResponse, LSM CFB ± SE\t\nItch NRS\t−0·43 ± 0·44\t−3·15 ± 0·40\t< 0·001\t−2·72 ± 0·33\t−3·46 ± 0·40\t\nNAPSIc\n\t0·17 ± 5·33\t−16·87 ± 3·11\t0·005\t−17·04 ± 5·75\t−31·17 ± 2·18\t\nPSSId\n\t−12·28 ± 2·57\t−27·64 ± 2·32\t< 0·001\t−15·36 ± 1·68\t−25·72 ± 1·30\t\nPPASIe\n\t6·89 ± 3·38\t−5·11 ± 2·15\t0·006\t−12·01 ± 3·85\t−9·04 ± 0·26\t\nUnless otherwise specified, values are presented as the number of responders (%). Categorical outcomes: Fisher's exact test with nonresponder imputation for handling missing data. Continuous outcomes: mixed model for repeated‐measures analysis. Type III tests for least‐squares means (LSMs) was used for treatment group comparisons. CDLQI, Children's Dermatology Life Quality Index; CFB, change from baseline; DLQI, Dermatology Life Quality Index; IXE, ixekizumab; NAPSI, Nail Psoriasis Severity Index; NRS, numerical rating scale; PASI, Psoriasis Area and Severity Index; PatGA, Patient's Global Assessment of Disease Severity; PPASI, Palmoplantar Psoriasis Area and Severity Index; PSSI, Psoriasis Scalp Severity Index; Q4W, every 4 weeks; sPGA, static Physician's Global Assessment. aAssessed for patients with baseline itch NRS ≥ 4. Placebo, n = 40; IXE Q4W, n = 83. bCDLQI was assessed for patients 6–16 years of age. DLQI was assessed for patients ≥ 17 years of age. cAssessed for patients with baseline NAPSI > 0. Placebo, n = 12; IXE Q4W, n = 34. dAssessed for patients with baseline PSSI > 0. Placebo, n = 50; IXE Q4W, n = 102. eAssessed for patients with baseline PPASI > 0. Placebo, n = 9; IXE Q4W, n = 17. fAssessed for patients with genital psoriasis at baseline.\n\nJohn Wiley & Sons, LtdFigure 3 Proportions of patients achieving (a) ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90); (b) static Physician's Global Assessment score of 0 [sPGA (0)]; (c) PASI 100 and (d) ≥ 4‐point improvement from baseline in itch numerical rating scale (Itch NRS) for up to 48 weeks of treatment with ixekizumab (nonresponder imputation). Ixekizumab vs. placebo P‐values during the 12‐week double‐blind treatment period are indicated as †P < 0·01, ‡P < 0·001. Error bars indicate 95% confidence intervals. Analyses of PASI 90, sPGA (0), PASI 100 and Itch NRS ≥ 4 at week 12 (gated secondary endpoints) were included in the gated multiple testing strategy. Analyses at other timepoints were not adjusted for multiplicity.\n\nSignificantly (P < 0·001) more patients achieved PASI 50 at week 12 with IXE Q4W (92%) than with placebo (38%) (Table 2), with significant differences as early as week 1 (IXE Q4W: 36%, placebo: 7%, P < 0·001). IXE provided significant improvements over placebo as early as week 1 for PASI 75 (P = 0·032) and Itch NRS ≥ 4 (P = 0·008), and as early as week 4 (P < 0·001) for PASI 90, PASI 100, sPGA (0,1) and sPGA (0) (Figures 2 and 3). In patients with severe psoriasis in etanercept‐approved countries, IXE resulted in significantly greater response than etanercept for PASI 90 (IXE Q4W: 76%, etanercept: 40%, P = 0·003), PASI 100 (IXE Q4W: 61%, etanercept: 53%, P < 0·001) and sPGA 0 (IXE Q4W: 63%, etanercept: 17%, P < 0·001). Responses with IXE Q4W were numerically greater than with etanercept for PASI 75 (IXE Q4W: 84%, etanercept: 63%, P = 0·089) and sPGA (0,1) (IXE Q4W: 76%, etanercept: 53%, P = 0·070), but were not statistically significant (Table 3; and Figure S2; see Supporting Information).\n\nTable 3 Efficacy outcomes at week 12 in patients with severe psoriasis in etanercept‐approved countries\n\n\tPlacebo (n = 19)\tETN (n = 30)\tIXE Q4W (n = 38)\tIXE Q4W vs. ETN\t\nResponse\tResponse\tResponse\t\nP‐value\tDifference IXE vs. ETN (95% CI)\t\nPASI 75\t5 (26)\t19 (63)\t32 (84)\t0·089\t20·9% (0·1–41·7)\t\nPASI 90\t0\t12 (40)\t29 (76)\t0·003\t36·3% (14·2–58·5)\t\nPASI 100\t0\t5 (17)\t23 (61)\t< 0·001\t43·9% (23·4–64·3)\t\nsPGA 0 or 1\t1 (5)\t16 (53)\t29 (76)\t0·070\t23·0% (0·6–45·4)\t\nsPGA 0\t0\t5 (17)\t24 (63)\t< 0·001\t46·5% (26·2–66·8)\t\nValues are presented as the number of responders (%). Fisher's exact test with nonresponder imputation was used to handle missing data. CI, confidence interval; ETN, etanercept; IXE, ixekizumab; PASI, Psoriasis Area and Severity Index; Q4W, every 4 weeks; sPGA, static Physician's Global Assessment.\n\nJohn Wiley & Sons, LtdCDLQI/DLQI (0,1) and PatGA (0,1) responses at week 12 were significantly (P < 0·001) greater with IXE than with placebo (Table 2). At week 12, significantly more patients with IXE than with placebo achieved clearance of baseline scalp (PSSI = 0, P < 0·001) and genital psoriasis (P < 0·001). IXE Q4W resulted in a significantly greater mean change from baseline than placebo at week 12 for Itch NRS (P < 0·001), NAPSI (P = 0·005), PSSI (P < 0·001) and PPASI (P = 0·006).\n\nResponses at week 12 were sustained or further improved through week 48 (Figures 2 and 3 and Table 2). For patients initially randomized to IXE Q4W, responses at week 48 were 92% (PASI 50), 90% (PASI 75), 83% (PASI 90), 55% (PASI 100), 81% [sPGA (0,1)], 57% [sPGA (0)] and 78% (Itch NRS ≥ 4). Sustained or additional improvements through week 48 were observed for CDLQI/DLQI (0,1), PatGA (0,1) and clearance of nail, scalp, palmoplantar or genital psoriasis.\n\nIn analyses by baseline weight, IXE resulted in significantly greater responses than placebo at week 12 for PASI 75, PASI 90, PASI 100, sPGA (0,1) and sPGA (0) in the subgroups of ≥ 25 kg to ≤ 50 kg and > 50 kg, and responses with IXE Q4W were numerically similar between these two subgroups (Table S4; see Supporting Information). Statistical comparisons of responses in patients with baseline weight < 25 kg were limited due to the small number of patients in this category (placebo: n = 1, IXE Q4W: n = 2). Both patients receiving IXE Q4W achieved PASI 75 and one (50%) achieved PASI 90, PASI 100, sPGA (0,1) and sPGA (0) at week 12; the patient receiving placebo achieved none of these endpoints.\n\nDuring the double‐blind treatment period, TEAEs were reported in 64 (56%) and 25 (45%) patients receiving IXE Q4W and placebo, respectively; no TEAEs were severe (Table 4). One (1%) SAE (IXE Q4W) was reported and one (2%) patient (placebo) discontinued due to an AE. In the all‐IXE safety population, TEAEs occurred in 161 (82%) patients; nine (5%) were severe. Thirteen patients (7%) reported SAEs (Table S5; see Supporting Information) and three (2%) discontinued due to an AE (two with Crohn's disease and one with pityriasis rubra pilaris). In the etanercept arm, 13 patients (43%) reported TEAEs (two severe, 7%), one (3%) SAE was reported, and there were no discontinuations due to AEs (Table S6; see Supporting Information). No deaths were reported.\n\nTable 4 Summary of adverse events\n\n\tSafety populationa (double‐blind treatment period)\tAll‐IXE safety populationb (all treatment periods)\t\nPlacebo (n = 56)\tIXE Q4W (n = 115)\tIXE Q4W (n = 196)\t\nPatient‐years of exposure\t26·9\t12·9\t253·9\t\nTreatment‐emergent adverse events\t25 (45)\t64 (56)\t161 (82)\t\nMild\t16 (29)\t47 (41)\t80 (41)\t\nModerate\t9 (16)\t17 (15)\t72 (37)\t\nSevere\t0\t0\t9 (5)\t\nDiscontinuation due to adverse event\t1 (2)\t0\t3 (2)\t\nSerious adverse events\t0\t1 (1)\t13 (7)\t\nDeaths\t0\t0\t0\t\nAdverse events of special interest\t\t\t\t\nInfections\t14 (25)\t37 (32)\t129 (66)\t\nSerious infections\t0\t0\t2 (1)\t\nOpportunistic infections\t0\t0\t0\t\nInjection‐site reactions\t1 (2)\t14 (12)\t39 (20)\t\nAllergic reactions/hypersensitivty\t1 (2)\t6 (5)\t16 (8)\t\nPotential anaphylaxis\t0\t0\t0\t\nCytopenia\t0\t1 (1)\t3 (2)\t\nHepatic\t0\t0\t4 (2)\t\nMalignancies\t0\t0\t0\t\nDepression\t0\t1 (1)\t6 (3)\t\nInterstitial lung disease\t0\t0\t0\t\nIBD\t0\t1 (1)\t4 (2)\t\nCrohn's disease\t0\t1 (1)\t4 (2)\t\nUlcerative colitis\t0\t0\t0\t\nThe data are presented as n (%). (Except patient‐years of exposure.) IBD, inflammatory bowel disease; IXE, ixekizumab; Q4W, every 4 weeks. aIncludes all randomized patients who took at least one dose of double‐blind study treatment according to the treatment to which they were assigned. bIncludes all patients who received at least one dose of IXE, including those randomized to placebo or etanercept at week 0 who received open‐label IXE Q4W during the maintenance period.\n\nJohn Wiley & Sons, LtdDuring the double‐blind treatment period, treatment‐emergent infections were reported in 37 (32%) patients receiving IXE Q4W and 14 (25%) receiving placebo; no serious infections were reported. In the all‐IXE safety population, 129 (66%) patients reported treatment‐emergent infections; one (1%) was severe (pharyngitis). Two (1%) patients reported serious infections (one acute otitis media and one tonsillitis) and no opportunistic infections were reported. In the etanercept arm, six (20%) infection‐related TEAEs were reported and there were no serious infections.\n\nDuring the double‐blind treatment period, 14 (12%) patients receiving IXE Q4W and one (2%) receiving placebo reported injection‐site reactions. In the all‐IXE safety population, 39 (20%) patients reported injection‐site reactions. There were no injection‐site‐related SAEs, and one severe injection‐site reaction (injection‐site pain) was reported. Safety related to depression, allergic reaction or hypersensitivity, cytopenia, and hepatic events is summarized in Table 4; none of which were SAEs. There were no TEAEs of grade 3 or 4 cytopenia reported and there were no reports of anaphylaxis, malignancies, or interstitial lung disease.\n\nOne patient receiving IXE Q4W reported an AE of diarrhoea during the double‐blind treatment period. This patient also reported intestinal inflammatory disease and abdominal pain at study day 1. The patient discontinued due to the AE of intestinal inflammatory disease and the case was adjudicated as probable Crohn's disease. Three patients reported TEAEs of IBD (adjudicated as probable Crohn's disease) during the maintenance period, each of whom reported SAEs and discontinued from the study. These discontinuations were due to withdrawal by patient (n = 1), AE of Crohn's disease (n = 1) and physician decision because of suspected IBD (n = 1). One of these patients reported autoimmune comorbidities of atopic dermatitis, alopecia areata and psoriatic arthritis. Appendix S8 (see Supporting Information) provides additional details regarding safety.\n\nOf 194 evaluable patients, 53 (27%) were TE‐ADA positive; 29 (15%) were low titre, 22 (11%) were moderate titre and two (1%) were high titre. Neutralizing antidrug antibodies were detected in five (3%) evaluable patients. The presence of TE‐ADAs had no impact on efficacy regardless of neutralizing antibody status, and there were no consistent temporal relationships between the presence of TE‐ADAs and the occurrence of injection‐site reactions or allergic reaction or hypersensitivity TEAEs.\n\nDiscussion\nIXE was superior to placebo for both coprimary endpoints and all gated secondary endpoints. Significant improvements in skin and itch were observed as early as week 1 and persisted through week 48. Itch affects many paediatric patients with psoriasis and has a high impact on quality of life.8, 9 In IXORA‐PEDS, nearly 75% of patients reported Itch NRS ≥ 4 at baseline. IXE provided clinically meaningful improvements in itch for nearly 80% of patients by week 48. IXE also provided significant improvements over placebo at week 12 in health‐related quality of life and clearance of scalp and genital psoriasis. Responses with IXE were generally consistent across weight subgroups, although analysis in patients with baseline weight < 25 kg was limited by the small sample size.\n\nMost AEs were mild to moderate in severity, SAEs occurred in < 7% of patients, < 2% of patients discontinued due to AEs, and no deaths occurred. Serious infections were reported in approximately 1% of patients, but there were no discontinuations due to infection‐related TEAEs. Crohn's disease was reported in one patient during the double‐blind treatment period and in three patients during the maintenance period, each adjudicated as probable Crohn's disease.\n\nPASI 75 was achieved by 89% of patients receiving IXE Q4W at week 12, a result consistent with the phase III UNCOVER‐1 (89%), UNCOVER‐2 (90%) and UNCOVER‐3 studies (87%) in adult patients with moderate‐to‐severe psoriasis.10, 11 PASI 75 responses persisted through week 48 (90%), which was greater than week 60 responses in UNCOVER‐3 (83%).10 More patients achieved complete skin clearance (PASI 100) with IXE at week 12 in IXORA‐PEDS (50%) than in UNCOVER‐3 (38%), but responses were similar between IXORA‐PEDS (55%) at week 48 and UNCOVER‐3 (55%) at week 60. Placebo responses in IXORA‐PEDS were greater than those observed in adults in the UNCOVER studies. At week 12, PASI 75 was achieved by 25% of paediatric patients receiving placebo in IXORA‐PEDS, compared with 3·9% (UNCOVER‐1), 2·4% (UNCOVER‐2) and 7·3% (UNCOVER‐3) in adult patients.10, 11 These findings are consistent with conclusions from reviews and meta‐analyses of clinical trials, in which placebo response rates in paediatric populations are generally higher than in adult populations.12 The placebo effect observed in IXORA‐PEDS was considerably lower for more stringent endpoints such as PASI 90 (5%) and PASI 100 (2%) at week 12, which was similar to placebo responses observed in adults (PASI 90: UNCOVER‐1, 0·5%; UNCOVER‐2, 0·6%; UNCOVER‐3, 3·1%; PASI 100: UNCOVER‐1, 0%; UNCOVER‐2, 0·6%; UNCOVER‐3, 0%).10, 11\n\n\nIXE was recently approved by the FDA for moderate‐to‐severe psoriasis in patients aged ≥ 6 years and is the first biologic therapy approved for paediatric psoriasis that targets IL‐17A. Other biologic therapies approved for paediatric psoriasis include two tumour necrosis factor inhibitors (etanercept and adalimumab) and the IL‐12/23 antagonist, ustekinumab. PASI 75 was achieved by 57% (week 12) and 58% of patients (week 16) in phase III studies of etanercept (0·8 mg kg−1) and adalimumab (0·8 mg kg−1) for paediatric psoriasis, respectively.13, 14 In adolescent patients (aged 12–17 years) with moderate‐to‐severe psoriasis, PASI 75 response at week 12 was achieved by 81% of patients receiving ustekinumab.15\n\n\nApproved use of these treatments differs across geographies, ages and severities. The FDA approved etanercept and ustekinumab in patients ≥ 4 and ≥ 12 years old, respectively, for moderate‐to‐severe plaque psoriasis but has not approved adalimumab for paediatric psoriasis. The European Medicines Agency approved etanercept and adalimumab in patients with severe psoriasis who are ≥ 6 and ≥ 4 years old, respectively, and ustekinumab for moderate‐to‐severe psoriasis in patients ≥ 6 years old. This study suggests that IXE may be an additional and efficacious treatment option for paediatric patients with moderate‐to‐severe plaque psoriasis.\n\nA strength of IXORA‐PEDS is enrolment of a geographically diverse population. IXE was administered on site during study visits to ensure consistent dosing and administration in paediatric patients. IXE provided consistent efficacy across weight subgroups; however, analysis of patients with baseline weight < 25 kg was limited to a small sample size of three patients. IXE Q4W showed significantly greater skin improvements [PASI 90, PASI 100 and sPGA (0)] compared with etanercept, although this comparison was for patients with severe psoriasis in etanercept‐approved countries outside the USA. Limitations of this comparison include a small patient number and the comparison of double‐blind IXE Q4W vs. open‐label etanercept. However, the outcomes assessors were blinded to treatment assignments to minimize potential bias.\n\nIn conclusion, IXE provided rapid, statistically significant and clinically meaningful improvements over placebo in skin, itch and health‐related quality of life that persisted for up to 48 weeks in paediatric patients with moderate‐to‐severe plaque psoriasis. The safety profile of IXE was generally consistent with that in adults with moderate‐to‐severe plaque psoriasis. Thus, IXE may be an additional therapeutic option for moderate‐to‐severe paediatric psoriasis.\n\nSupporting information\n\nAppendix S1 List of IXORA‐PEDS investigators.\n\n\nAppendix S2 Inclusion and exclusion criteria.\n\n\nAppendix S3 Study design.\n\n\nAppendix S4 List of all study endpoints in IXORA‐PEDS.\n\n\nAppendix S5 Description of efficacy outcomes.\n\n\nAppendix S6 Additional details regarding safety outcomes.\n\n\nAppendix S7 Statistical analyses.\n\n\nAppendix S8 Safety results.\n\n\nFigure S1 Trial profile for patients with severe paediatric psoriasis in etanercept‐approved countries.\n\n\nFigure S2 Efficacy outcomes in patients with severe paediatric psoriasis in etanercept‐approved countries.\n\n\nTable S1 Dosing of study drug through week 48 of IXORA‐PEDS.\n\n\nTable S2 Number of patients with nonmissing data at each postbaseline visit through Week 48.\n\n\nTable S3 Baseline demographics and disease characteristics in patients with severe paediatric psoriasis in etanercept‐approved countries.\n\n\nTable S4 Psoriasis Area and Severity Index and static Physician's Global Assessment responses by weight category.\n\n\nTable S5 Serious adverse events.\n\n\nTable S6 Safety through week 12 in patients with severe paediatric psoriasis in etanercept‐approved countries. \n\nClick here for additional data file.\n\n Acknowledgments\nThe authors thank Clinton C. Bertram, PhD, an employee of Eli Lilly and Company, for writing and editorial support.\n\nAppendix 1 Conflicts of interest. A.S.P. has been an investigator for AbbVie, Eli Lilly and Company, Exicure, Galderma, Incyte, Janssen, Novartis, Palvella and Regeneron; and has been a consultant with honoraria from AbbVie, Almirall, Asana, Boehringer Ingelheim, Castle Creek, Dermira, Eli Lilly and Company, Exicure, Forte, Galderma, Janssen, LEO Pharma, LifeMax, MEDACorp, Novartis, Pierre Fabre, Regeneron, Sanofi Genzyme and Sol‐Gel. M.M.B.S. has received grants from or has been involved in clinical trials with AbbVie, Celgene, Eli Lilly and Company, Janssen, LEO Pharma and Pfizer; and has served as a consultant for AbbVie, Eli Lilly and Company, Janssen, LEO Pharma and Pfizer; fees were paid directly to the institution. G.A.M. has received honoraria and/or grants as a speaker, advisor or investigator for AbbVie, Amgen, Biogen, Boehringer Ingelheim, Eli Lilly and Company, Janssen Cilag, Novartis, Pfizer and Sanofi Genzyme. J.B. has been a speaker, consultant or investigator for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, LEO Pharma, Novartis, Ortho Dermatologics and Sun Pharma. A.P. has been an investigator, speaker and/or advisor for AbbVie, Almirall‐Hermal, Amgen, Biogen Idec, Biontec, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galderma, GSK, Hexal, Janssen, LEO Pharma, MC2, Medac, Merck Serono, Mitsubishi, MSD, Novartis, Pascoe, Pfizer, Tigercat Pharma, Regeneron, Roche, Sandoz Biopharmaceuticals, Sanofi Genzyme, Schering‐Plough and UCB Pharma. J.C. has been an investigator, speaker, consultant and/or advisory board member for AbbVie, Amgen, Arena, Brickell Biotech, Bristol Myers Squibb, Celgene, ChemoCentryx, Eli Lilly and Company, Galderma, Janssen, Menlo, Regeneron, Sun Pharma and UCB. S.K., C.R.C., R.G.L., G.G., C.A.L., E.E.H., L.L. and W.X. are employees of and own stock in Eli Lilly and Company. K.P. has received honoraria, grants and/or research funding as a speaker, investigator, advisory board member, data safety monitoring board member and/or consultant for AbbVie, Akros, Amgen, Anacor, Arcutis, Astellas Pharma US, Bausch Health, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Can‐Fite Biopharma, Celgene Corporation, Coherus, Dermira, Dow Pharmaceuticals, Eli Lilly and Company, Evelo, Galapagos, Galderma, Genentech, Gilead, GSK, Janssen, Kyowa Hakko Kirin Pharma, LEO Pharma, MedImmune, Meiji Seika Pharma, Merck (MSD), Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche Laboratories, Sanofi Genzyme, Takeda Pharmaceuticals and UCB.\n\nAppendix 2 Author contributions. A.S.P. contributed to the study design, data acquisition, data interpretation and critical revision of the manuscript. M.M.B.S. and K.P. contributed to data acquisition, data interpretation and critical revision of the manuscript. G.A.M. contributed to the study design, data interpretation and critical revision of the manuscript. J.B. and A.P. contributed to data analysis, data interpretation and critical revision of the manuscript. J.C., G.G., C.A.L. and E.E.H. contributed to data interpretation and critical revision of the manuscript. S.K., C.R.C. and R.G.L. contributed to the study design, data interpretation and critical revision of the manuscript. L.L. and W.X. contributed to the study design, data analysis, data interpretation and critical revision of the manuscript. All authors provided approval of the final manuscript for submission and publication.\n==== Refs\nReferences\n1 \n\nDe Jager \nME \n, \nVan de Kerkhof \nPC \n, \nDe Jong \nEM \n\net al\nEpidemiology and prescribed treatments in childhood psoriasis: a survey among medical professionals\n. J Dermatolog Treat \n2009 ; 20 :254 –8\n.19418330 \n2 \n\nGelfand \nJM \n, \nWeinstein \nR \n, \nPorter \nSB \n\net al\nPrevalence and treatment of psoriasis in the United Kingdom: a population‐based study\n. Arch Dermatol \n2005 ; 141 :1537 –41\n.16365254 \n3 \n\nNapolitano \nM \n, \nMegna \nM \n, \nBalato \nA \n\net al\nSystemic treatment of pediatric psoriasis: a review\n. Dermatol Ther (Heidelb) \n2016 ; 6 :125 –42\n.27085539 \n4 \n\nPaller \nAS \n, \nSchenfeld \nJ \n, \nAccortt \nNA \n\net al\nA retrospective cohort study to evaluate the development of comorbidities, including psychiatric comorbidities, among a pediatric psoriasis population\n. Pediatr Dermatol \n2019 ; 36 :290 –7\n.30791141 \n5 \n\nMenter \nA \n, \nCordoro \nKM \n, \nDavis \nDMR \n\net al\nJoint American Academy of Dermatology‐National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis in pediatric patients\n. J Am Acad Dermatol \n2020 ; 82 :161 –201\n.31703821 \n6 \n\nBronckers \nIM \n, \nPaller \nAS \n, \nvan Geel \nMJ \n\net al\nPsoriasis in children and adolescents: diagnosis, management and comorbidities\n. Paediatr Drugs \n2015 ; 17 :373 –84\n.26072040 \n7 \n\nCline \nA \n, \nBartos \nGJ \n, \nStrowd \nLC \n\net al\nBiologic treatment options for pediatric psoriasis and atopic dermatitis\n. Children (Basel) \n2019 ; 6 :E103 .31514420 \n8 \n\nOostveen \nAM \n, \nde Jager \nME \n, \nvan de Kerkhof \nPC \n\net al\nThe influence of treatments in daily clinical practice on the Children's Dermatology Life Quality Index in juvenile psoriasis: a longitudinal study from the Child‐CAPTURE patient registry\n. Br J Dermatol \n2012 ; 167 :145 –9\n.22616669 \n9 \n\nvan Geel \nMJ \n, \nMaatkamp \nM \n, \nOostveen \nAM \n\net al\nComparison of the Dermatology Life Quality Index and the Children's Dermatology Life Quality Index in assessment of quality of life in patients with psoriasis aged 16–17 years\n. Br J Dermatol \n2016 ; 174 :152 –7\n.26361284 \n10 \n\nGordon \nKB \n, \nBlauvelt \nA \n, \nPapp \nKA \n\net al\nPhase 3 trials of ixekizumab in moderate‐to‐severe plaque psoriasis\n. N Engl J Med \n2016 ; 375 :345 –56\n.27299809 \n11 \n\nGriffiths \nCE \n, \nReich \nK \n, \nLebwohl \nM \n\net al\nComparison of ixekizumab with etanercept or placebo in moderate‐to‐severe psoriasis (UNCOVER‐2 and UNCOVER‐3): results from two phase 3 randomised trials\n. Lancet \n2015 ; 386 :541 –51\n.26072109 \n12 \n\nWeimer \nK \n, \nGulewitsch \nMD \n, \nSchlarb \nAA \n\net al\nPlacebo effects in children: a review\n. Pediatr Res \n2013 ; 74 :96 –102\n.23598811 \n13 \n\nPaller \nAS \n, \nSiegfried \nEC \n, \nLangley \nRG \n\net al\nEtanercept treatment for children and adolescents with plaque psoriasis\n. N Engl J Med \n2008 ; 358 :241 –51\n.18199863 \n14 \n\nPapp \nK \n, \nThaci \nD \n, \nMarcoux \nD \n\net al\nEfficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double‐blind, phase 3 trial\n. Lancet \n2017 ; 390 :40 –9\n.28478975 \n15 \n\nLandells \nI \n, \nMarano \nC \n, \nHsu \nMC \n\net al\nUstekinumab in adolescent patients age 12 to 17 years with moderate‐to‐severe plaque psoriasis: results of the randomized phase 3 CADMUS study\n. J Am Acad Dermatol \n2015 ; 73 :594 –603\n.26259989\n\n",
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"title": "Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).",
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"abstract": "A 68-year-old woman presenting with anorexia and epigastric pain was diagnosed with metastatic pancreatic cancer and idiopathic thrombocytopenic purpura(ITP). Chemotherapy was initiated with S-1. Subsequently, gemcitabine was administered in combination with prednisolone. Her platelets returned to normal after the treatment with steroids and chemotherapy, but the treatment could not be withdrawn completely. Pancreatic cancer presenting as idiopathic thrombocytopenic purpura has rarely been reported in the literature. Here, we present our experience and discuss a case of pancreatic cancer complicated with ITP.",
"affiliations": "Dept. of Pharmacy, Mitsui Memorial Hospital.",
"authors": "Sudo|Sho|S|;Miura|Atsushi|A|;Mae|Junnosuke|J|;Takada|Yuto|Y|;Naritomi|Takuma|T|;Sogabe|Naomi|N|",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D010190:Pancreatic Neoplasms; D011239:Prednisolone; D016553:Purpura, Thrombocytopenic, Idiopathic",
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"title": "Pancreatic Cancer Complicated with Idiopathic Thrombocytopenic Purpura and Treated with Chemotherapy-A Case Report.",
"title_normalized": "pancreatic cancer complicated with idiopathic thrombocytopenic purpura and treated with chemotherapy a case report"
}
|
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"literaturereference": "SUDO S, MIURA A, MAE J, TAKADA Y, NARITOMI T, SOGABE N. PANCREATIC CANCER COMPLICATED WITH IDIOPATHIC THROMBOCYTOPENIC PURPURA AND TREATED WITH CHEMOTHERAPY?A CASE REPORT. GAN TO KAGAKU RYOHO. 2020?47(12):1723?1725",
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{
"abstract": "Solid organ transplant recipients are at increased risk of malignancy. Pediatric transplant recipients particularly have a potentially higher risk given the young age of immunosuppression initiation. Posttransplant malignancies are the main cause of death in 5%-16% of liver transplantation patients. The frequency of de novo malignancies in pediatric liver transplant recipients has been reported to be 13%. Synovial sarcoma is a malignant mesenchymal neoplasm that has not been previously reported after liver transplantation. We report the case of an adolescent liver transplant recipient who was diagnosed with synovial sarcoma 14 years after liver transplantation.",
"affiliations": "Pediatric Liver Center, Children's Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.;Children's Hospital Colorado and Department of Pathology, University of Colorado School of Medicine, Aurora, CO.;Children's Hospital Colorado and Department of Pathology, University of Colorado School of Medicine, Aurora, CO.;Children's Hospital Colorado and Department of Orthopedics, University of Colorado School of Medicine, Aurora, CO.;Pediatric Liver Center, Children's Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.",
"authors": "Jaramillo|Catalina|C|;Gilani|Ahmed|A|;Haag|Mary|M|;Donaldson|Nathan|N|;Mack|Cara|C|",
"chemical_list": null,
"country": "United States",
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"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JACGCRJACGCRJAC9ACG Case Reports Journal2326-3253Wolters Kluwer Maryland, MD ACGCR-19-028610.14309/crj.000000000000009100016Case ReportLiverSynovial Cell Sarcoma in an Adolescent Liver Transplant Recipient Jaramillo Catalina MD1Gilani Ahmed MD, PhD2Haag Mary PhD2Donaldson Nathan DO3Mack Cara MD11 Pediatric Liver Center, Children's Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO2 Children's Hospital Colorado and Department of Pathology, University of Colorado School of Medicine, Aurora, CO3 Children's Hospital Colorado and Department of Orthopedics, University of Colorado School of Medicine, Aurora, COCorrespondence: Catalina Jaramillo, MD, Pediatric Liver Center, Children's Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, 13123 East 16th Ave, Box 290, Aurora, CO 80045 ([email protected]).16 5 2019 5 2019 6 5 e0009113 11 2018 28 2 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.ABSTRACT\nSolid organ transplant recipients are at increased risk of malignancy. Pediatric transplant recipients particularly have a potentially higher risk given the young age of immunosuppression initiation. Posttransplant malignancies are the main cause of death in 5%–16% of liver transplantation patients. The frequency of de novo malignancies in pediatric liver transplant recipients has been reported to be 13%. Synovial sarcoma is a malignant mesenchymal neoplasm that has not been previously reported after liver transplantation. We report the case of an adolescent liver transplant recipient who was diagnosed with synovial sarcoma 14 years after liver transplantation.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nMalignancy is a well-recognized complication in solid organ transplant recipients, with a 2–4 fold increase in risk.1 This risk is due to exposure to chronic, lifelong immunosuppression.1,2 Pediatric transplant recipients have a higher risk of malignancy given the young age of immunosuppression initiation and may often require re-transplantation which results in additional immunosuppressive therapy.3 Pediatric solid organ transplant recipients can have 30 times greater cancer incidence compared with the general population.3 Posttransplant malignancies are the cause of death in 5%–16% of liver transplantation patients. De novo malignancy frequency in pediatric liver transplant (LTX) recipients is 13%, with posttransplant lymphoproliferative disease most frequently diagnosed (53%) and mean time to diagnosis of 35 months.4 Synovial sarcoma is a malignant mesenchymal neoplasm that occurs predominantly in older children/young adults and can occur at almost any anatomic site.5 It accounts for 5%–10% of all childhood/adult soft-tissue sarcomas.5,6 Although soft-tissue sarcomas have previously been described in the post-LTX population, synovial sarcoma has not been previously reported after LTX.1,3 We report the first case of an adolescent male diagnosed with synovial sarcoma 14 years after LTX.\n\nCASE REPORT\nA 15-year-old white male with a history of biliary atresia, polysplenia syndrome, and primary ciliary dyskinesia, who underwent LTX at 1 year of age, presented with intermittent right ankle pain and tenderness for 3 years. He was seen by multiple providers, had unrevealing ankle radiographs, and was treated with physical therapy on at least 2 occasions. Due to the persistence of the pain, a noncontrast magnetic resonance imaging (MRI) was performed, which demonstrated what was thought to represent a benign ganglion cyst. After 2 attempts at the aspiration of the ganglion cyst which were unsuccessful, he was referred to a local orthopedic surgeon. He underwent excision of the ganglion cyst measuring 2.7 × 2 × 1.2 cm. Histopathologic examination revealed a spindle cell neoplasm with positive immunohistochemical staining for transducin-like enhancer of split 1 (TLE1), a protein specific to synovial sarcoma (Figure 1). This was confirmed by the presence of the chromosomal translocation t(X;18)(p11;q11) (Figure 2). Several margins were positive for the tumor. The patient was referred to Pediatric Orthopedic Oncology at our institution for further management. A chest computed tomography scan was negative for pulmonary metastasis, and therefore, management required only local control measures. After discussion of this case at the Solid Tumor Board, 2 therapeutic options were offered: limb salvage with tumor bed resection, free-flap coverage, and whole-foot radiation, or below the knee amputation. Given that whole-foot radiation would likely result in irreversible nerve damage and paralysis, the patient and his family decided to proceed with amputation. Pathology specimens from the amputated limb did not reveal residual tumor, and right inguinal sentinel lymph node biopsies were negative for metastasis.\n\nFigure 1. Positive immunohistochemical staining for transducin-like enhancer of split 1 (TLE1) of the tumor.\n\nFigure 2. Interphase fluorescent in situ hybridization using a dual color showing a break apart translocation assay for the SS18 locus at 18q11, where the presence of an SS18 rearrangement is noted with a split signal pattern (red split from green—arrows). The asterisk indicates a normal signal pattern of 2 fusions in the lower left of the panel.\n\nAt the time of amputation, the patient also underwent a liver biopsy to reassess for immune tolerance. A liver biopsy performed 1 year before was normal. In the first 3 years after LTX, he was weaned off steroids by 7 months and his tacrolimus troughs initially ranged from 6 to 12 ng/mL, followed by a downtrend to 2–7 ng/mL during his third-year post-LTX. Afterward, he was on very minimal immunosuppression, with tacrolimus troughs ranging from undetectable to 3 ng/mL on a dose of 0.5 mg twice daily. His posttransplant course had been unremarkable without any episodes of rejection and only an episode of cholangitis 3 years post-LTX. His liver biopsy showed minimal periportal lymphocytes (within normal range) and no fibrosis. He was taken off tacrolimus, and he remains immunotolerant with normal liver enzymes.\n\nDISCUSSION\nPatients receiving solid organ transplants at a young age are at increased risk of malignancy, which is related to chronic immunosuppression in immune-naive patients at risk of oncogenic viruses.3 A recent cohort study reported a 10-fold risk of cancer in pediatric LTX recipients compared with the general population, with an absolute cancer risk of 3–7 cases per 100 patients during a 10-year follow-up, with a cumulative incidence of 2% at 10 years posttransplant and 22% at 25 years posttransplant.7 Pediatric patients most commonly had non-Hodgkin's lymphoma, and only one case of soft-tissue malignancy was described.7 Another study reported a case of liver sarcoma in a pediatric LTX recipient.4\n\nOur patient is the first described case in the literature of synovial sarcoma occurring in solid organ transplantation. Synovial sarcoma is the most common non-rhabdomyosarcoma soft-tissue sarcoma in childhood and adolescence. Although 30% occur in patients younger than 20 years, it is rare below the age of 10 years.5 There is a slight male predilection. Up to 70% of cases present in the extremities (lower > upper), and it most commonly metastasizes to the lungs.8 This tumor is slow growing and presents within deep soft tissues, and in more than 50% of cases, it is associated with pain/tenderness. Symptoms can last from a few years to as many as 20 years.5 Whereas most lesions tend to be greater than 5 cm in diameter, distally located lesions tend to be smaller, which can be confused with benign pathologies, as in the case presented here.5 Synovial sarcoma is considered a high-grade, aggressive sarcoma, with 5- and 10-year survival rates of approximately 60% and 50%, respectively.5 Metastatic disease is more common in adults (up to 50%).9 Risk stratification based on tumor characteristics puts patients into low-risk groups (age <25 years, tumor size <5 cm, and no histologic evidence of poorly differentiated tumor) with 88% disease-free survival and high-risk groups (age ≥25 years, tumor size ≥5 cm, and poorly differentiated tumor) with 18% disease-free survival.10\n\nOur patient presented with 3 years of symptoms, tumor location in the lower extremity, a lesion that was <5 cm, and no lung metastases, consistent with low-risk stratification. It is unclear whether the low-dose chronic immunosuppression post-LTX led to impairment in immune-mediated tumor surveillance. However, because the patient had normal liver tests for over 10 years and normal liver histology, immune tolerance of the liver allograft was likely, and he was safely weaned off all immunosuppression. The original MRI performed without contrast led to the erroneous description of an ankle cyst early on. In LTX recipients, musculoskeletal abnormalities such as pain or soft-tissue masses should warrant heightened surveillance. Practitioners should have a low threshold to pursue further imaging, such as MRI with contrast, as well as early referral to a pediatric orthopedic oncologist to exclude potential neoplasms.\n\nDISCLOSURES\nAuthor contributions: C. Jaramillo contributed to conception and design, acquisition, and analysis and interpretation of data; drafted the manuscript; critically revised the manuscript for important intellectual content; and gave final approval. A. Gilani contributed to acquisition editing of images/figures included in the manuscript as well as conception and design and analysis and interpretation of data, critically revised the manuscript for important intellectual content, and gave final approval. M. Haag contributed to acquisition editing of images/figures included in the manuscript, critically revised the manuscript for important intellectual content, and gave final approval. N. Donaldson contributed to analysis and interpretation of data, critically revised the manuscript for important intellectual content, and gave final approval. C. Mack contributed to conception and design and analysis and interpretation of data, critically revised the manuscript for important intellectual content, and gave final approval. C. Jaramillo is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Engels EA Pfeiffer RM Fraumeni JF Jr \nSpectrum of cancer risk among US solid organ transplant recipients . JAMA \n2011 ;306 :1891 –901 .22045767 \n2. Nordin A Aberg F Pukkala E \nDecreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades . Am J Transpl \n2018 ;18 :952 –63 .\n3. Kitchlu A Dixon S Dirk JS \nElevated risk of cancer following solid organ transplant in childhood: A population-based cohort study . Transplantation \n2018 ;103 :588 –96 .\n4. Karakoyun M Onen S Baran M \nPost-transplant malignancies in pediatric liver transplant recipients: Experience of two centers in Turkey . Turk J Gastroenterol \n2018 ;29 :87 –91 .\n5. Thway K Fisher C \nSynovial sarcoma: Defining features and diagnostic evolution . Ann Diagn Pathol \n2014 ;18 :369 –80 .25438927 \n6. Andrassy RJ Okcu MF Despa S \nSynovial sarcoma in children: Surgical lessons from a single institution and review of the literature . J Am Coll Surg \n2001 ;192 :305 –13 .11245372 \n7. Aberg F Isoniemi H Pukkala E \nCancer after liver transplantation in children and young adults—A population-based study from four Nordic countries . Liver Transpl \n2018 ;24 :1252 –9 .30120902 \n8. Nielsen TO Poulin NM Ladanyi M \nSynovial sarcoma: Recent discoveries as a roadmap to new avenues for therapy . Cancer Discov \n2015 ;5 :124 –34 .25614489 \n9. Lagarde P Przybyl J Brulard C \nChromosome instability accounts for reverse metastatic outcomes of pediatric and adult synovial sarcomas . J Clin Oncol \n2013 ;31 :608 –15 .23319690 \n10. Bergh P Meis-Kindblom JM Gherlinzoni F \nSynovial sarcoma: Identification of low and high risk groups . Cancer \n1999 ;85 :2596 –607 .10375108\n\n",
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{
"abstract": "OBJECTIVE\nWe evaluated the anti-tumor activity and safety of cisplatin with irinotecan (IP) induction chemotherapy followed by chemoradiotherapy with etoposide/cisplatin (EP).\n\n\nMETHODS\nInduction chemotherapy consisted of irinotecan i.v. and cisplatin i.v. and was administered on day 1 and day 8 of each cycle. Patients underwent two cycles of chemotherapy with a 3-week interval. In the absence of progressive disease, 66 Gy radiation was administered concurrently with etoposide on days 1 to 5 and 29 to 33, as well as with cisplatin on day 1, 8, 29, and 36.\n\n\nRESULTS\nTwenty patients were enrolled between July 2007 and December 2009. This study was closed prematurely due to lack of efficacy in induction chemotherapy. The overall response rate was 45% [95% confidence interval (CI), 25 to 65%], which did not meet the upper limit for first stage rejection of the treatment. The rates of 3-year progression-free survival and overall survival were 17.1% (95% CI, 0 to 36.8%) and 25% (95% CI, 0.2 to 49.8%), respectively. The primary toxicities included neutropenia, diarrhea and fatigue.\n\n\nCONCLUSIONS\nThis study failed to demonstrate a benefit for induction chemotherapy which was characterized by suboptimal antitumor activity and was poorly tolerated, with excess treatment-related toxicity.",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University, 50 Yonseiro, Seodaemoon-gu, Seoul 120-752, Korea.",
"authors": "Chang|Hyun|H|;Kim|Se Hyun|SH|;Cho|Byoung Chul|BC|;Yoon|Sang Hyun|SH|;Kim|Hye Ryun|HR|;Lee|Chang Geol|CG|;Kim|Joo Hang|JH|",
"chemical_list": "D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin",
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{
"abstract": "Studies of HCV reinfection following direct-acting antiviral (DAA) therapy among PWID have been limited by short follow-up and small case numbers. This study evaluated the incidence of HCV reinfection following successful DAA therapy among people attending an inner-city community health centre in Victoria, Canada.\n\n\n\nIn this observational study, participants treated with DAA therapy between November 2014 and December 31, 2019 were included. Retrospective chart review was performed to assess demographics, recent injecting drug use at treatment initiation (previous six months), opioid agonist treatment (OAT), and HIV. Endpoints included sustained virologic response (SVR), HCV reinfection, and mortality.\n\n\n\nOf 482 participants initiating DAA treatment, 30% were female, 46% were receiving OAT, 49% had recent injection drug use, 15% had HIV/HCV coinfection, and 22% had cirrhosis. Treatment completion was 97% (468/482; 12 discontinued therapy, and 2 died during treatment). SVR was 87% (418/482). Outcomes among those who completed treatment but did not achieve SVR (n=53), included loss to follow-up (n=11), HCV RNA for SVR testing not completed (n=18), viral relapse (n=6), reinfection (n=5) and viral recurrence (n=5, unable to distinguish viral relapse from reinfection), and death (n=7). The rate of HCV reinfection was 3.6/100 person-years (95% confidence interval [CI] 2.4-5.5; 22 cases; 602 person-years follow-up). Factors associated with an increased risk of HCV reinfection included recent injection drug use (adjusted relative risk [aRR] 8.55, 95% CI 1.98-36.96) and HIV co-infection (aRR 2.35, 95% CI 1.01-5.44). Fifty-five people died (overdose, n=19) during (n=2) or following (n=53) therapy (7.4/100 person-years; 95% CI 5.6-9.6).\n\n\n\nThis study demonstrates ongoing reinfection among a marginalized population at an inner-city community health centre, with higher rates among those with HIV and recent injecting drug use. The rates of reinfection and mortality highlight the importance of integrating HCV care with strategies to address drug-related harms.",
"affiliations": "Cool Aid Community Health Centre, Victoria, Canada. Electronic address: [email protected].;The Kirby Institute, UNSW Sydney, Sydney, Australia.;Cool Aid Community Health Centre, Victoria, Canada.;Cool Aid Community Health Centre, Victoria, Canada.;Cool Aid Community Health Centre, Victoria, Canada.;Cool Aid Community Health Centre, Victoria, Canada.;Cool Aid Community Health Centre, Victoria, Canada.;Cool Aid Community Health Centre, Victoria, Canada.;The Kirby Institute, UNSW Sydney, Sydney, Australia.;Cool Aid Community Health Centre, Victoria, Canada.",
"authors": "Selfridge|Marion|M|;Cunningham|Evan B|EB|;Barnett|Tamara|T|;Drost|Anne|A|;Gray-Schleihauf|Christianne|C|;Guarasci|Kellie|K|;Lundgren|Karen|K|;Milne|Roz|R|;Grebely|Jason|J|;Fraser|Chris|C|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.drugpo.2021.103418",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0955-3959",
"issue": "96()",
"journal": "The International journal on drug policy",
"keywords": "DAA; Drug use; HIV; Hepatitis C; PWID; Re-infection",
"medline_ta": "Int J Drug Policy",
"mesh_terms": "D000998:Antiviral Agents; D002170:Canada; D003151:Community Health Centers; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C; D019698:Hepatitis C, Chronic; D006801:Humans; D000084063:Reinfection; D012189:Retrospective Studies; D015819:Substance Abuse, Intravenous",
"nlm_unique_id": "9014759",
"other_id": null,
"pages": "103418",
"pmc": null,
"pmid": "34538704",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reinfection following successful direct-acting antiviral therapy for HCV infection among people attending an inner-city community health centre in Victoria, Canada.",
"title_normalized": "reinfection following successful direct acting antiviral therapy for hcv infection among people attending an inner city community health centre in victoria canada"
}
|
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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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] |
{
"abstract": "The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance. The purpose of this review is to summarize current understanding of etiological factors including emerging evidence on the role of infectious agents, factors associated with therapeutic resistance and therapeutic options.\nThe unique aspect of PanCA is \"desmoplasia\", a process that involves proliferation of stromal fibroblasts and collagen deposition in and around the filtrating cancer. Recent studies have identified pancreatic stellate cells (PSCs) as a potential source of such desmoplasia. Biphasic interactions between PSCs and cancer cells, endothelial cells, and/or myeloid derived suppressor cells in the tumor microenvironment contribute to pancreatic carcinogenesis.\nWe summarize limitations of current therapeutic approaches and potential strategies to overcome these limitations using natural products including botanicals as adjuvant/neo-adjuvant for effective management of PanCA.",
"affiliations": "Department of Urology, The University of Texas Health Science Center, San Antonio, TX.;Department of Urology, The University of Texas Health Science Center, San Antonio, TX.;Department of Urology, The University of Texas Health Science Center, San Antonio, TX.;Department of Surgery, The University of Texas Health Science Center, San Antonio, TX.;Department of Urology, The University of Texas Health Science Center, San Antonio, TX.;Department of Urology, The University of Texas Health Science Center, San Antonio, TX.",
"authors": "Muñoz|Amanda R|AR|;Chakravarthy|Divya|D|;Gong|Jingjing|J|;Halff|Glenn A|GA|;Ghosh|Rita|R|;Kumar|Addanki P|AP|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40495-017-0112-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2198-641X",
"issue": "3(6)",
"journal": "Current pharmacology reports",
"keywords": "Chemotherapy; Gemcitabine; Natural products; Pancreatic cancer",
"medline_ta": "Curr Pharmacol Rep",
"mesh_terms": null,
"nlm_unique_id": "101649562",
"other_id": null,
"pages": "396-408",
"pmc": null,
"pmid": "29404265",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "25220842;24855007;23907428;24742583;16054982;27073726;1999720;3965101;28335509;15849724;25573338;22104574;25977074;26690340;24136929;26423282;21561347;21058202;23770008;22162234;28055103;23622135;25638248;24131140;26904541;16632103;22806689;22119354;26804739;24856585;26222906;27657339;26159697;3099992;26747091;20383573;27956793;26226900;22330678;18628464;27208550;21304978;27149201;18333087;25700304;24520096;19806144;25726049;26133769;22695133;22971992;24796733;25502106;26125317;26830752;25773752;24856586;22232209;26240291;20919528;21994333;28067628;22237781;25356972;25089377;22444872;28255158;23981573;22898636;8218880;27160474;22896693;26261723;22530568;23622141;23543271;27280632;3394699;25207767;24189415;28089829;26106858;7122019;25091797;20859741;25017900;24561061;28073890;17452677;17764494;27488376;25824606;27538405;23079587;24285690;23407481;26909576;26571462;9196156;20107864;25557080;22710569;27610015;27845339;25057164",
"title": "Pancreatic cancer: Current status and Challenges.",
"title_normalized": "pancreatic cancer current status and challenges"
}
|
[
{
"companynumb": "US-CIPLA LTD.-2017US21268",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": null,
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"drugauthorizationnumb": "078759",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "INFUSION",
"drugdosagetext": "1000 MG/M2, WEEKLY FOR 7 OF 8 WEEKS (CYCLE 1)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "GEMCITABINE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MUNOZ AR, CHAKRAVARTHY D, GONG J, HALFF GA, GHOSH R, KUMAR AP. PANCREATIC CANCER: CURRENT STATUS AND CHALLENGES. CURR PHARMACOL REP. 2017",
"literaturereference_normalized": "pancreatic cancer current status and challenges",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20171129",
"receivedate": "20171129",
"receiver": {
"receiverorganization": "FDA",
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},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180321"
}
] |
{
"abstract": "We report the first patient with pleuroparenchymal fibroelastosis (PPFE) to undergo living donor bilateral lobar lung transplantation. The patient was diagnosed with secondary PPFE as a late complication of chemotherapy that included high-dose cyclophosphamide for mature B-cell lymphocytic leukemia. Although the patient maintained complete remission, dry cough and back pain appeared 8 years after the chemotherapy. He had repeated bilateral pneumothoraces, and his respiratory condition gradually deteriorated because of progressive pleural thickening and parenchymal fibrosis. He underwent living-donor bilateral lobar lung transplantation with an inverse transplant on the left side.",
"affiliations": "Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: [email protected].;Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Cardiovascular Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.",
"authors": "Hata|Atsushi|A|;Nakajima|Takahiro|T|;Yoshida|Shigetoshi|S|;Kinoshita|Taku|T|;Terada|Jiro|J|;Tatsumi|Koichiro|K|;Matsumiya|Goro|G|;Date|Hiroshi|H|;Yoshino|Ichiro|I|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "101(5)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D006801:Humans; D015448:Leukemia, B-Cell; D019520:Living Donors; D016040:Lung Transplantation; D008297:Male; D010995:Pleural Diseases; D011658:Pulmonary Fibrosis",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "1970-2",
"pmc": null,
"pmid": "27106430",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Living Donor Lung Transplantation for Pleuroparenchymal Fibroelastosis.",
"title_normalized": "living donor lung transplantation for pleuroparenchymal fibroelastosis"
}
|
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},
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},
{
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"activesubstancename": "CYTARABINE"
},
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},
{
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},
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},
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},
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"medicinalproduct": "PIRARUBICIN"
},
{
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},
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"medicinalproduct": "VINCRISTINE (UNKNOWN)"
},
{
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"activesubstancename": "CYCLOPHOSPHAMIDE"
},
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"medicinalproduct": "CYCLOPHOSPHAMIDE."
},
{
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"activesubstancename": "ETOPOSIDE"
},
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"medicinalproduct": "ETOPOSIDE (UNKNOWN)"
},
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"activesubstancename": "CYTARABINE"
},
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],
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"reaction": [
{
"reactionmeddrapt": "Pulmonary fibrosis",
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},
{
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{
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "HATA?A, NAKAJIMA?T, YOSHIDA?S, KINOSHITA?T, TERADA?J, TATSUMI?K ET AL. LIVING DONOR LUNG TRANSPLANTATION FOR PLEUROPARENCHYMAL FIBROELASTOSIS. ANNALS OF THORACIC SURGERY. 2016; 101(5): 1970-1972.",
"literaturereference_normalized": "living donor lung transplantation for pleuroparenchymal fibroelastosis",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20160620",
"receivedate": "20160620",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12479095,
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"sender": {
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},
"serious": 1,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160815"
}
] |
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