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"abstract": "A 71-year-old man with advanced vocal cord carcinoma presented with severe airway obstruction. Therapeutic anticoagulation with enoxaparin complicated management. Failure of an oral awake bronchoscopic intubation was rescued by passing a guidewire through the working channel and threading an Arndt exchange catheter into the trachea under videoscopic vision. Ventilation with the Ventrain device lasting 40 minutes (15 L/min, inspiration/expiration 1:1, 15 breaths/min), during IV anesthesia with muscle paralysis, resulted in excellent blood gas values until placement of the tracheal cannula. This case report highlights the effectiveness of a novel ventilation technique that should be considered as back-up when bronchoscopic intubation fails.",
"affiliations": "From the Departments of Anesthesiology.;From the Departments of Anesthesiology.;Otorhinolaryngology, Antwerp University Hospital, Edegem, Belgium.;Otorhinolaryngology, Antwerp University Hospital, Edegem, Belgium.",
"authors": "Morrison|Stuart|S|;Aerts|Sophie|S|;Van Rompaey|Diane|D|;Vanderveken|Olivier|O|",
"chemical_list": "D017984:Enoxaparin",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000975",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "13(1)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000368:Aged; D000402:Airway Obstruction; D001999:Bronchoscopy; D057785:Catheters; D017984:Enoxaparin; D006801:Humans; D007442:Intubation, Intratracheal; D007822:Laryngeal Neoplasms; D008297:Male; D012121:Respiration, Artificial; D014827:Vocal Cords; D014851:Wakefulness",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "23-26",
"pmc": null,
"pmid": "30730309",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Failed Awake Intubation for Critical Airway Obstruction Rescued With the Ventrain Device and an Arndt Exchange Catheter: A Case Report.",
"title_normalized": "failed awake intubation for critical airway obstruction rescued with the ventrain device and an arndt exchange catheter a case report"
}
|
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"activesubstancename": "ENOXAPARIN SODIUM"
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"medicinalproduct": "ENOXAPARIN SODIUM."
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"patientagegroup": "6",
"patientonsetage": "71",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Dysphagia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
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{
"reactionmeddrapt": "Dyspnoea",
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{
"reactionmeddrapt": "Dysphonia",
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{
"reactionmeddrapt": "Tachypnoea",
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{
"reactionmeddrapt": "Obstructive airways disorder",
"reactionmeddraversionpt": "22.0",
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{
"reactionmeddrapt": "Chest discomfort",
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{
"reactionmeddrapt": "Stridor",
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"literaturereference": "MORRISON S, AERTS S, VAN RD, VANDERVEKEN O.. FAILED AWAKE INTUBATION FOR CRITICAL AIRWAY OBSTRUCTION RESCUED WITH THE VENTRAIN DEVICE AND AN ARNDT EXCHANGE CATHETER: A CASE REPORT. A+A PRACTICE. 2019?13(1):23-26.",
"literaturereference_normalized": "failed awake intubation for critical airway obstruction rescued with the ventrain device and an arndt exchange catheter a case report",
"qualification": "1",
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"receiptdate": "20190731",
"receivedate": "20190731",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
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"safetyreportid": 16653157,
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"sender": {
"senderorganization": "FDA-Public Use",
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
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"transmissiondate": "20191004"
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{
"abstract": "Timely use of Sacubitril/Valsartan has the potential to significantly improve cardiac function and dramatically reduce secondary mitral regurgitation (MR) severity even in patients presenting with acute decompensated heart failure (HF), not only in compensated chronic HF patients. The outstanding impact of echocardiography is obvious in monitoring improvement of cardiac function and MR severity in patients with HF with reduced ejection fraction (HFrEF).\nWe report a relevant case of an elderly patient who presented with acute decompensated HF and severe MR. He was symptomatic despite being on maximally tolerated doses of ACEI, beta-blockers, and diuretics. Left ventricular ejection fraction (LVEF) improved from 15% to 35% 2 weeks following initiation of Sacubitril/Valsartan during second HF hospitalization. There was a dramatic improvement of patient's symptoms from New York Heart Association (NYHA) Class IV to NYHA I. N-terminal pro B-type natriuretic peptide reduced from 9000 pg/mL to 800 pg/mL. Coronary angiography depicted three-vessel coronary artery disease. The patient was advised to undergo coronary artery bypass graft surgery with mitral valve repair, then followed by implantation of a cardiac resynchronization therapy-defibrillator device (CRT-D) if no LV function improvement is observed after revascularization. The electrocardiogram showed Q waves in inferior leads with QRSd ≥ 125 ms, hence a good candidate for CRT. Following an elective percutaneous coronary intervention, LVEF further improved to 50%. The patient became asymptomatic with preserved LVEF on follow-up for 18 months later.\nThis case report documents the swift echocardiographic and symptom improvement in a decompensated end-stage HF patient when Sacubitril/Valsartan initiated during acute setting.",
"affiliations": "Department of Cardiovascular Sciences, NMC Specialty Hospital, Cardiology Clinic, Al Ain, Postal code P.O. Box 84142,United Arab Emirates.;Department of Cardiovascular Sciences, NMC Specialty Hospital, Cardiology Clinic, Al Ain, Postal code P.O. Box 84142,United Arab Emirates.;Department of Cardiology, Mediclinic Al-Ain hospital,United Arab Emirates.;Department of Cardiology, University of Alexandria,Egypt.",
"authors": "Gerges|Fady|F|0000-0002-8813-119X;Komaranchath|Austin|A|;Al Bakshy|Faiz|F|0000-0002-7464-1391;Almaghraby|Abdallah|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytaa530",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytaa530\nytaa530\nCase Report\nAcademicSubjects/MED00200\nThe power of optimal medical therapy using angiotensin receptor-neprilysin inhibitor in acute decompensated heart failure, sparing a critical patient open-heart surgery with a device therapy: a case report\nhttp://orcid.org/0000-0002-8813-119X\nGerges Fady 1\nKomaranchath Austin 1\nhttp://orcid.org/0000-0002-7464-1391\nAl Bakshy Faiz 2\nAlmaghraby Abdallah 3\nAboumarie Hatem Soliman Handling Editor\nAbela Mark Editor\nBaghdasaryan Lilit Editor\nKurdi Hibba Editor\nJakstaite Aiste Monika Editor\n1 Department of Cardiovascular Sciences, NMC Specialty Hospital, Cardiology Clinic, Al Ain, Postal code P.O. Box 84142,United Arab Emirates\n2 Department of Cardiology, Mediclinic Al-Ain hospital,United Arab Emirates\n3 Department of Cardiology, University of Alexandria,Egypt\nCorresponding author. Tel: +971 3 7030300, Fax: +971 3 7030300, Email:[email protected],[email protected]\n2 2021\n29 12 2020\n29 12 2020\n5 2 ytaa53009 6 2020\n28 7 2020\n01 12 2020\n© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2020\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]\n\nAbstract\n\nBackground\n\nTimely use of Sacubitril/Valsartan has the potential to significantly improve cardiac function and dramatically reduce secondary mitral regurgitation (MR) severity even in patients presenting with acute decompensated heart failure (HF), not only in compensated chronic HF patients. The outstanding impact of echocardiography is obvious in monitoring improvement of cardiac function and MR severity in patients with HF with reduced ejection fraction (HFrEF).\n\nCase summary\n\nWe report a relevant case of an elderly patient who presented with acute decompensated HF and severe MR. He was symptomatic despite being on maximally tolerated doses of ACEI, beta-blockers, and diuretics. Left ventricular ejection fraction (LVEF) improved from 15% to 35% 2 weeks following initiation of Sacubitril/Valsartan during second HF hospitalization. There was a dramatic improvement of patient’s symptoms from New York Heart Association (NYHA) Class IV to NYHA I. N-terminal pro B-type natriuretic peptide reduced from 9000 pg/mL to 800 pg/mL. Coronary angiography depicted three-vessel coronary artery disease. The patient was advised to undergo coronary artery bypass graft surgery with mitral valve repair, then followed by implantation of a cardiac resynchronization therapy-defibrillator device (CRT-D) if no LV function improvement is observed after revascularization. The electrocardiogram showed Q waves in inferior leads with QRSd ≥ 125 ms, hence a good candidate for CRT. Following an elective percutaneous coronary intervention, LVEF further improved to 50%. The patient became asymptomatic with preserved LVEF on follow-up for 18 months later.\n\nDiscussion\n\nThis case report documents the swift echocardiographic and symptom improvement in a decompensated end-stage HF patient when Sacubitril/Valsartan initiated during acute setting.\n\nAngiotensin receptor-neprilysin inhibitor\nSacubitril/Valsartan\nCRT-D\nEchocardiography\nheart failure with reduced ejection fraction\nCoronary artery disease\nNT-proBNP\nCase report\n==== Body\nLearning points\n\nDramatic reduction in secondary mitral regurgitation severity is possible when using angiotensin receptor-neprilysin inhibitor even in patients with acute decompensated heart failure (HF).\n\nThe outstanding impact of multimodality imaging is obvious in monitoring the improvement of cardiac function and deciding for revascularization.\n\nIt is necessary to make a change in clinical practice to early implement this lifesaving therapy in acute decompensated HF patients.\n\nThere was an obvious role of Sacubitril/Valsartan in improving symptoms and New York Heart Association class with the dramatic swift improvement of left ventricular ejection fraction (LVEF) in acute decompensated HF with reduced ejection fraction patients when started during hospital admission and the acute setting.\n\nApart from the improvement of LV function, there is a significant reduction of secondary mitral regurgitation severity, pulmonary hypertension, and normalization of right ventricular function after starting Sacubitril/Valsartan.\n\nIntroduction\n\nSacubitril/Valsartan is a first-in-class combination of angiotensin receptor blocker (ARB) and neprilysin inhibitor. It is now recommended as the first line for the treatment of chronic heart failure with reduced ejection fraction (HFrEF). It is also recommended in cases that remain symptomatic despite optimal medical therapy.1\n\nCompared with enalapril, sacubitril/valsartan reduced the composite endpoint of cardiovascular death or HF hospitalization and is recommended as an alternative for angiotensin‐converting enzyme inhibitors (ACEI) and (ARB) in patients with HFrEF and New York Heart Association (NYHA) Class II–III symptoms.2,3\n\nTimeline\n\nTime intervals\tClinical status\tEcho findings\tTreatment\tInvestigations\t\nDay 1 of admission\tAcute decompensated CHF-dyspnoea New York Heart Association (NYHA) Class IV for the past 10 days\tSevere Bi-ventricular dysfunction. Left ventricular ejection fraction (LVEF) 15–20%, severe mitral regurgitation (MR), severe tricuspid regurgitation, severe pulmonary hypertension, right ventricular systolic pressure (RVSP) 70 mmHg. Frequent B-lines on lung us\tPrevious non-optimal medical treatment: bisoprolol 2.5 mg o.d. and ramipril 1.25 mg o.d. Bisoprolol stopped on admission.\tNT-pro BNP > 9000 pg/mL (normal <450 pg/mL for patients aged 75–99 years)\n\nCreatinine Cl. 45 mL/min (normal 107–139 mL/min), S. Potassium 3.8 mmol/L (normal 3.5–5.0 mmol/L),\n\nHaemoglobin 14 gm/dL (normal 13.8–17.2 g/dL)\n\n\t\nDay 5 of admission\tDyspnoea NYHA Class III after starting diuretics\tSame as before, however no B lines on lung us\tFurosemide infusion, aspirin 100 mg o.d., spironolactone 25 mg o.d., Ramipril 2.5 mg b.i.d., Rosuvastatin 20 mg o.d., Empagliflozin 10 mg o.d.\tCoronary angiogram: severe triple coronary artery disease\t\nDay 1 of discharge after 10 days of hospitalization\tDyspnoea NYHA Class II–III\tSame as before\tSame as before plus added on top carvedilol 6.25 mg b.i.d. (Bisoprolol 5 mg o.d. stopped due to hypotension). Discharged on Lasix 40 mg oral b.i.d.\t\t\nWeek 2 post-discharge (in outpatient clinic)\tRecurrent clinic visits due to dyspnoea NYHA Class III and poor effort tolerance\tMild LV function improvement to 25%\tEnalapril 5 mg bd, up-titrated carvedilol to 12.5 mg b.i.d., up-titrated spironolactone to 50 mg o.d.- received Lasix 40 mg IV bolus injection – Enalapril changed to Valsartan 160 mg o.d. due to ACEI intolerance\tNT-pro-BNP >6000 pg/ml\n\nCreatinine Cl. 47 ml/min, S. Potassium 4.2 mmol/L\n\n\t\nDay 1 of re-admission (4 weeks post-discharge)\tRecurrent hospitalization due to acute decompensated heart failure.\tSame as before\tSacubitril/Valsartan 24 mg/26 mg b.i.d. with 36 h wash-out period. Up titrated Furosemide to 80 mg b.i.d. Metoprolol 50 mg b.i.d. added on discharge due to hypotension with carvedilol.\t\t\nWeek 1 post-discharge after 2 weeks of 2nd hospitalization\tImprovement to dyspnoea NYHA class I–II\tLVEF improved to 35–40%, MR severity to Grade II, TR severity to Grade I. Marked RVSP reduction to 25 mmHg\tSacubitril/Valsartan dose then increased to 49 mg/51 mg BD\tNT-pro-BNP 800 pg/ml\t\nWeek 3 post-discharge\tAsymptomatic.\n\nImproved quality of life\n\n\t\tReduced Furosemide to 40 mg OD\tMyocardial perfusion scan: viable left anterior descending (LAD) and left circumflex (LCX)/optimal medical (OM) territories.\t\nWeek 5 post-discharge\n\n\tAsymptomatic.\n\nImproved quality of life\n\n\tLVEF 50%\tPercutaneous coronary intervention to LAD and LCX/OM arteries, angiotensin receptor-neprilysin inhibitor, Aspirin + Clopidogrel, Metoprolol 50 mg b.i.d., Empagliflozin 25 mg o.d., Rosuvastatin 20 mg o.d., stopped diuretics\tCreatinine Cl. 56 mL/min\t\nFollow-up visit 18 months later\tAsymptomatic\n\nImproved quality of life\n\n\tLVEF 50%\tSacubitril/Valsartan 49 mg/51 mg b.i.d., Metoprolol 50 mg b.i.d., Aspirin o.d., Empagliflozin 25 mg o.d., Rosuvastatin 20 mg o.d.\t\t\n\nCase presentation\n\nHerein, we describe a case report of a low body weight 74-year-old Asian male patient with a body mass index of 17.2 kg/m2 who presented with acute decompensated HF with both end-stage systolic and diastolic HF including right ventricular (RV) failure.\n\nHe is known to have type II diabetes mellitus, hypertension, and a previous presumed diagnosis of dilated cardiomyopathy (DCM) in another facility on non-optimal medical therapy (OMT) for the past 2 years.\n\nOn presentation, the patient was dyspnoeic (NYHA functional Class IV) for the previous 10 days.\n\nPhysical examination revealed wide-spread coarse inspiratory crepitations extending till mid-zonal area of both lungs with III/IV harsh systolic murmur and S3 gallop heard over the apex.\n\nVitals were as follows normal temperature, blood pressure 120/80 mmHg, heart rate 87 beats/minute, respiratory rate 30/minute, SpO2 at room air 90%.\n\nInitial work up included 2D echocardiography (Echo) which showed severe LV dysfunction with an estimated LVEF of 15–20% (Video 1), with global hypokinesia, apical and inferolateral wall akinesia, suggestive of ischaemic dilated cardiomyopathy. There was severe RV dysfunction with interventricular septal flattening in diastole suggesting RV volume overload (Video 2). There was also severe tricuspid regurgitation (TR) with high right ventricular systolic pressures (RVSP) of 70 mmHg suggesting severe pulmonary hypertension (PH). There was severe grade IV mitral regurgitation (MR) (Video 3) and Grade IV TR (Figure 1) with hepatic vein systolic flow reversal on pulsed wave Doppler (PWD) (Figure 2). Mitral regurgitation severity was quantified by a vena contracta area of 0.8 cm, an effective regurgitant orifice area (EROA) by proximal isovelocity surface area (PISA) method of 0.4 cm2, peak velocity of the MR jet of 5 m/s by continuous-wave Doppler, in addition to the presence of PH derived from TR jet velocity and a dominant early filling (E velocity 1.5 m/s) by PWD of mitral inflow.\n\nFigure 1 2D transthoracic echocardiogram with colour Doppler on admission, A4C view demonstrating severe grade IV TR and severe grade IV MR. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.\n\nFigure 2 Transthoracic echocardiogram with pulsed wave Doppler (PWD) interrogation across hepatic vein on admission illustrating hepatic vein systolic flow reversal due to severe TR. D wave, atrial diastole; S wave, ventricular systole; SR, systolic atrial flow reversal.\n\nFurthermore, there was a restrictive pattern Grade III diastolic dysfunction with elevated LV filling pressure by tissue Doppler imaging.\n\nLung ultrasound demonstrated frequent B-lines on both lungs denoting pulmonary interstitial oedema.\n\nThe patient was hospitalized and started on Frusemide infusion at a rate of 10 mg/h after an IV bolus dose of 40 mg, besides Spironolactone 25 mg o.d., Ramipril 1.25 mg o.d., Rosuvastatin 20 mg o.d., Empagliflozin 10 mg o.d., and Aspirin 100 mg o.d.\n\nElectrocardiogram showed a sinus rhythm with interventricular conduction delay and QRS duration ≥ 125 ms. Q waves seen in inferior leads (Figure 3).\n\nFigure 3 Baseline 12-leads electrocardiogram showing sinus rhythm with wide QRS complex and interventricular conduction delay with increased duration of QRS complex ≥ 125 ms. Q waves seen in inferior leads.\n\nChest X-ray showed signs of pulmonary congestion.\n\nN-terminal pro B-type natriuretic peptide (NT-proBNP) was over 9000 pg/mL (normal <450 pg/mL). Serum potassium 3.8 mmol/L (normal 3.5–5.0 mmol/L), serum sodium 141 mmol/L (normal 135–145 mmol/L), haemoglobin 14 g/dL (normal 13.8–17.2 g/dL), and creatinine clearance of 45 mL/min (normal 107–139 mL/min).\n\nConsequently, the patient improved on medical therapy. Coronary angiography (CAG) was done during hospitalization and revealed triple vessel disease with 90% diffuse tight lesions in proximal to mid-left anterior descending (LAD) artery, 90% significant lesion in both obtuse marginal (OM) branches of left circumflex (LCX) artery, and chronic total occlusion (CTO) of right coronary artery (RCA) with retrograde filling from the left system (Supplementary material online,Videos S1 andS2).\n\nIn view of severe MR, triple vessel disease and severe LV and RV dysfunction; accordingly we recommended coronary artery bypass graft (CABG) surgery combined with mitral valve repair (MVr), then followed by implantation of a cardiac resynchronization therapy defibrillator (CRT-D) device if no LV function improvement achieved after coronary revascularization.\n\nAwaiting myocardial viability stress test before revascularization and with efforts to improve LV function, we started maximally tolerated dose of ACEI using Ramipril 2.5 mg b.i.d., however, the patient developed mild hypotension with dizziness even with reducing diuretic dose from 40 mg b.i.d. to 20 mg b.i.d. of Frusemide. We then shifted the patient to Enalapril 5 mg b.i.d. that was stopped due to ACEI intolerance in the form of dry tickling cough. Eventually, we started valsartan with 80 mg o.d. then titrated to 160 mg o.d. Additionally, we had to change to different classes of beta-blockers. After hypotension with Bisoprolol 5 mg o.d. it was stopped and then the patient was started on Carvedilol 6.25 mg b.i.d. that resulted as well in hypotension after gradually increasing its dose to 12.5 mg b.i.d., with complaints of generalized weakness and fatigue. Finally, we shifted the patient on slowly increasing the dose of Metoprolol up to 50 mg b.i.d. with no resulting adverse effects. Patient was maintained as well on mineralocorticoid receptor antagonists (MRA) (Spironolactone 25 mg o.d.), sodium-glucose cotransporter-2 (SGLT-2) inhibitors (Empagliflozin 10 mg o.d.), aspirin 100 mg OD, and Furosemide 40 mg b.i.d.\n\nPatient could not financially afford Sacubitril/Valsartan.\n\nHe experienced recurrent hospitalization due to acute decompensated HF. After hospital discharge, the patient showed up every other day in the hospital for Furosemide injection to alleviate his HF symptoms.\n\nThree weeks later during a re-admission with heart failure, Sacubitril/Valsartan in a dose of 24 mg/26 mg PO b.i.d. was offered to the patient. A dramatic improvement in symptoms from NYHA Class IV to Class II was observed 5 days after starting Sacubitril/Valsartan. NYHA class also improved to NYHA I 2 weeks after treatment initiation. Following discharge, the patient was walking 4 km everyday with good exercise tolerance. N-terminal pro-B-type natriuretic peptide also decreased to 800 pg/mL after 2 weeks.\n\nScreening 2D echo on hospital discharge showed dramatic improvement of LVEF to 35–40% with significant reversal of LV remodelling. MR improved to Grade II (Figure 4,Supplementary material online,Video S3) and TR improved to Grade I (Supplementary material online,Video S4). Moreover, RVSP was reduced to 30 mmHg (Supplementary material online,Figure S1). Additionally, the diastolic function improved to Grade I (Supplementary material online,Figure S2).\n\nFigure 4 2D transthoracic echocardiogram, A2C view showing reduction of MR severity to grade II after 2 weeks of starting Sacubitril/Valsartan. LA, left atrium; LV, left ventricle.\n\nSacubitril/Valsartan dose was then increased to 49 mg/51 mg PO b.i.d. A myocardial perfusion scintigraphy scan 3 weeks later showed evidence of viable LAD and LCX/OM territories with non-viable RCA territory (Figure 5).\n\nFigure 5 Gated cardiac SPECT images after IV injection of Tc-Sestamibi for Regadenoson stress and rest studies showing almost absent tracer uptake in Apex, apical lateral, and infero-apical regions of left ventricle (LV) after stress. There is moderate to severe reduction of tracer uptake in the rest of the lateral and inferior wall. Perfusion to the anterior wall and septum is well preserved. Following re-distribution, there is improvement in the lateral, mid-inferior, infero-apical, and apical region of the LV with evidence of inducible myocardial ischemia (and hence a reversible defect) in the same previously mentioned territories. Possible partial thickness infarct in the apical lateral region and basal lateral wall with superimposed ischaemia was noted.\n\nWith the marked improvement in EF and MR severity following the initiation of angiotensin receptor-neprilysin inhibitor (ARNI), the revascularisation strategy was re-discussed with the team and the patient. Percutaneous coronary intervention was thought to be a better option in this scenario as the peri-operative risks associated with CABG were substantially lower in this elderly low body weight individual. There was also no surgical indication for MV intervention at this point. Elective PCI was successfully performed to the LAD and LCX/OM arteries (Supplementary material online,Videos S5 andS6), with the EF increasing to 50% on the follow-up Echo (Supplementary material online,Video S7). The patient subsequently reported improved exercise tolerance. The improved LVEF persisted during the 18 months follow-up period whilst on Sacubitril/Valsartan.\n\nDiscussion\n\nThis case demonstrates the tremendous effect of ARNI on LV function and reverse remodelling.\n\nIn 2016, the U.S. Food and Drug Administration (FDA) approved a new drug for the treatment of heart failure, the scientific evidence that has supported the approval of this new drug was mainly obtained from the results of the PARADIGM-HF trial which was a prospective comparison of ARNI with ACEI to determine the impact on mortality and morbidity in patients with heart failure.2\n\nThe PIONEER-HF trial by Velazquezet al. in 2019 showed that patients with acute decompensated heart failure treated with ARNI had a greater reduction in NT-proBNP levels compared to standard care.4\n\nMany case reports and case series reports have been published with similar observation of the improved ejection fraction after using ARNI, one of them was published by Pandeyet al in 2017 where he included 60 HFrEF individuals and noticed the improvement of their EF from 27.3% to 37.5% after a period of 1 year (P < 0.001).5\n\nIn the randomized controlled trial Pharmacological Reduction of Functional, Ischaemic Mitral Regurgitation (PRIME) sacubitril/valsartan treatment resulted in a greater reduction of MR associated with HF compared to valsartan alone.6\n\nConclusion\n\nAppropriate and timely use of Sacubitril/Valsartan has the potential to improve LV function even significantly and swiftly in patients with acute decompensated HF, not only in chronic HF patients.\n\nEchocardiography is the most useful tool in evaluating progress in a heart failure patient being optimized on medical therapy.\n\nLead author biography\n\nDr Fady Gerges, Cardiovascular imaging specialist and clinical cardiologist. His main areas of interests are TTE, TEE, cardiovascular CT and clinical cardiology. He has a master's degree in Cardiology and Critical Care Medicine. He has had international publications as the first Author in peer-reviewed journals . He has been a speaker and abstract presenter in International congresses. He is a regular reviewer in international peer-reviewed journals in both imaging and interventional cardiology. Editorial board member for the Internatonal Journal of the Cardiovascular Academy. He has EACVI Accreditation in adult TTE and Level 1 & 2 certification in Cardiovascular CT from SCCT, UK. He is the President of the medical Board of International Young Academy of Cardiology.\n\nSupplementary material\n\nSupplementary material is available atEuropean Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online asSupplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: none declared.\n\nFunding: none declared.\n\nSupplementary Material\n\nytaa530_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 PonikowskiP ,VoorsAA ,AnkerSD ,BuenoH ,RuttenFH ,van der MeerP, et al ;ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J 2016;37 :2129–2200.27206819\n2 McMurrayJJ ,PackerM ,DesaiAS ,GongJ ,LefkowitzMP ,RizkalaAR et al angiotensin-neprilysin inhibition versus enalapril in heart failure.N Engl J Med 2014;371 :993–1004.25176015\n3 YancyCW ,JessupM ,BozkurtB ,ButlerJ ,CaseyDEJr ,ColvinMM et al 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines and the Heart Failure Society of America.J Am Coll Cardiol 2016;68 :1476–1488.27216111\n4 VelazquezEJ ,MorrowDA ,DeVoreAD ,DuffyCI ,AmbrosyAP ,McCagueK et al Angiotensin-neprilysin inhibition in acute decompensated heart failure.N Engl J Med 2019;380 :539–548.30415601\n5 PandeyA ,ClarusS ,PandeyA ,VermaS. The impact of ARNI therapy on LV systolic function as measured by 2-D echocardiography: a 1 year case series.Can J Card 2017;33 :S161–S162. Volume issue supplement,\n6 KangD-H ,ParkS-J ,ShinS-H ,HongG-R ,LeeS ,KimM-S et al Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation.Circulation 2019;139 :1354–1365.30586756\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(2)",
"journal": "European heart journal. Case reports",
"keywords": "Angiotensin receptor-neprilysin inhibitor; CRT-D; Case report; Coronary artery disease; Echocardiography; NT-proBNP; Sacubitril/Valsartan; heart failure with reduced ejection fraction",
"medline_ta": "Eur Heart J Case Rep",
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"pmid": "33738400",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "30586756;30415601;27206819;27216111;25176015",
"title": "The power of optimal medical therapy using angiotensin receptor-neprilysin inhibitor in acute decompensated heart failure, sparing a critical patient open-heart surgery with a device therapy: a case report.",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "24.1",
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},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dizziness",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "Gerges F, Komaranchath A, Bakshy FA, Almaghraby A. The power of optimal medical therapy using angiotensin receptor-neprilysin inhibitor in acute decompensated heart failure, sparing a critical patient open-heart surgery with a device therapy: a case report. European heart journal-Case reports. 2021;5(2):1-8",
"literaturereference_normalized": "the power of optimal medical therapy using angiotensin receptor neprilysin inhibitor in acute decompensated heart failure sparing a critical patient open heart surgery with a device therapy a case report",
"qualification": "1",
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},
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"receiptdate": "20211109",
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},
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},
"serious": 2,
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"seriousnessdeath": 2,
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"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
}
] |
{
"abstract": "A 17-year-old woman had two admissions within five months for recurrent episodes of ventricular tachycardia in conjunction with a prolonged QT interval. On both occasions these were refractory to intravenous lidocaine and bretylium. During her first admission her dysrhythmia was controlled by repeated doses of intravenous propranolol; however, she required temporary overdrive transvenous pacing on her second admission. On both occasions when the low normal serum potassium was replaced and therapeutic levels of diphenylhydantoin and phenobarbital were obtained, the episodes of ventricular tachycardia subsided. This case illustrates the complexities inherent in making the diagnosis and in treating this syndrome, and should assist the emergency physician in treating this difficult and potentially fatal dysrhythmia.",
"affiliations": null,
"authors": "Parrish|C|C|;Wooster|W E|WE|;Braen|G R|GR|;Robertson|H D|HD|",
"chemical_list": "D010672:Phenytoin; D011433:Propranolol; D011188:Potassium; D010634:Phenobarbital",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(82)80240-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "11(3)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000293:Adolescent; D003937:Diagnosis, Differential; D004562:Electrocardiography; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D010138:Pacemaker, Artificial; D010634:Phenobarbital; D010672:Phenytoin; D011188:Potassium; D011433:Propranolol; D012640:Seizures; D013614:Tachycardia, Paroxysmal; D014693:Ventricular Fibrillation",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "143-6",
"pmc": null,
"pmid": "7065489",
"pubdate": "1982-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Les torsades des pointes.",
"title_normalized": "les torsades des pointes"
}
|
[
{
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{
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},
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"medicinalproduct": "PHENYTOIN."
},
{
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"activesubstancename": "PHENOBARBITAL"
},
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"drugdosagetext": "60 MG, 2X/DAY",
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"drugindication": "SEIZURE",
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"medicinalproduct": "PHENOBARBITAL."
}
],
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"reaction": [
{
"reactionmeddrapt": "Drug level below therapeutic",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PARRISH, C.. LES TORSADES DES POINTES. ANNALS OF EMERGENCY MEDICINE. 1982;11(3):143-6",
"literaturereference_normalized": "les torsades des pointes",
"qualification": "1",
"reportercountry": "US"
},
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},
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},
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"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Anemia is a common complication of hepatitis C (HCV), and antiviral treatment can further increase this risk. We present the case of a 59-year-old man with HCV treated with ribavirin and pegylated interferon alpha (INF-α) who presented with severe anemia. Two months after initiating treatment his hemoglobin dropped from 14.2 to 5.0 g/dL. There was no evidence of bleeding or hemolysis, and a bone marrow biopsy revealed pure red cell aplasia (PRCA). Evaluations for acute cytomegalovirus and parvovirus B19 were negative. There was no evidence of malignancy or thymoma. The INF-α and ribavirin treatment were determined to have caused the PRCA, and withdrawal of the medications led to PRCA remission. INF-α and ribavirin have become the standard treatment for HCV. While these medications offer a potential cure, they are often poorly tolerated due to frequent side effects including anemia. Patients who are receiving treatment with ribavirin and INF-α warrant close monitoring for development of anemia, and PRCA should be considered in all patients in whom reticulocytopenic anemia develops.",
"affiliations": "88th Medical Group, Department of Internal Medicine, Wright-Patterson Medical Center, 88th MDOS/SGOMI, 4881 Sugar Maple Drive, Wright-Patterson Air Force Base, OH, 45433, USA. [email protected].;88th Medical Group, Department of Internal Medicine, Wright-Patterson Medical Center, 88th MDOS/SGOMI, 4881 Sugar Maple Drive, Wright-Patterson Air Force Base, OH, 45433, USA.;88th Medical Group, Department of Internal Medicine, Wright-Patterson Medical Center, 88th MDOS/SGOMI, 4881 Sugar Maple Drive, Wright-Patterson Air Force Base, OH, 45433, USA.",
"authors": "Skabelund|Andrew J|AJ|;Hauser|Timothy R|TR|;Goist|Kevin J|KJ|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-011-0235-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "4(5)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Hepatitis C; Interferon; Pure red cell aplasia; Ribavirin",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "313-317",
"pmc": null,
"pmid": "26189631",
"pubdate": "2011-10",
"publication_types": "D016428:Journal Article",
"references": "8639856;18091373;9479876;12097253;20704699;14582000;8834023;6740667;3115335;18615552;19508613;15597025;16629641;20445419;15117326;10609785;9973647;16441367;16019474;15929778;4600198;15028837;10762306;19327582;11167735;8304314;15465516;11272289;9258213;12105843;14568226;8579062;17607592;12324553;8861276;11836661;10206512;3919781;19483404;14638354",
"title": "Pure red cell aplasia caused by ribavirin and interferon treatment.",
"title_normalized": "pure red cell aplasia caused by ribavirin and interferon treatment"
}
|
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},
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"medicinalproduct": "RIBAVIRIN."
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"medicinalproduct": "GABAPENTIN."
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"medicinalproduct": "NYSTATIN."
},
{
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},
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"abstract": "BACKGROUND\nGiant thoracic aortic aneurysms (TAA) are extremely uncommon, and there are only a few cases reported in the literature. Most patients presented with symptoms before the size of the aneurysm reached a magnitude >10 cm, and most of the reported cases were treated with open repair.\n\n\nMETHODS\nHere we report a 15 cm asymptomatic thoracic aortic aneurysm of a 72-year-old male patient, treated successfully with thoracic endovascular aortic repair (TEVAR). The patient was discharged asymptomatic on postoperative day 2.\n\n\nCONCLUSIONS\nOnly 20 case reports of giant TAAs were found in the literature, and this is the biggest TAA reported treated with TEVAR. This procedure is a promising treatment as morbidity and mortality is lower when compared with open aortic repair (OAR).\n\n\nCONCLUSIONS\nEven though there is limited documented experience, use of TEVAR seems a safe and promising option in the treatment of giant thoracic aneurysms as presented in this case.",
"affiliations": "Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Electronic address: [email protected].;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Electronic address: [email protected].;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Electronic address: [email protected].;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Electronic address: [email protected].;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Electronic address: [email protected].;Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Electronic address: [email protected].",
"authors": "González-Urquijo|Mauricio|M|;Dominguez-Porras|Victor A|VA|;Tellez-Martinez|Luis G|LG|;Lozano-Balderas|Gerardo|G|;Flores-Villalba|Eduardo|E|;Fabiani|Mario Alejandro|MA|",
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"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(18)30336-510.1016/j.ijscr.2018.08.036ArticleA case report of successful endovascular repair of a giant 15 cm diameter asymptomatic thoracic aortic aneurysm González-Urquijo Mauricio [email protected] Victor A. [email protected] Luis G. [email protected] Gerardo [email protected] Eduardo [email protected] Mario Alejandro [email protected]⁎Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud⁎ Corresponding author. [email protected] 8 2018 2018 25 8 2018 51 344 348 5 2 2018 6 8 2018 20 8 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• We report a 15 cm asymptomatic thoracic aortic aneurysm of a 72-year-old male patient, treated successfully with TEVAR.\n\n• Endovascular aortic repair is a safe and promising option in the treatment of giant thoracic aneurysms.\n\n• Giant thoracic aortic aneurysm is considered when widening of the aortic wall exceeds 10 cm in diameter.\n\n\n\nIntroduction\nGiant thoracic aortic aneurysms (TAA) are extremely uncommon, and there are only a few cases reported in the literature. Most patients presented with symptoms before the size of the aneurysm reached a magnitude >10 cm, and most of the reported cases were treated with open repair.\n\nPresentation of case\nHere we report a 15 cm asymptomatic thoracic aortic aneurysm of a 72-year-old male patient, treated successfully with thoracic endovascular aortic repair (TEVAR). The patient was discharged asymptomatic on postoperative day 2.\n\nDiscussion\nOnly 20 case reports of giant TAAs were found in the literature, and this is the biggest TAA reported treated with TEVAR. This procedure is a promising treatment as morbidity and mortality is lower when compared with open aortic repair (OAR).\n\nConclusion\nEven though there is limited documented experience, use of TEVAR seems a safe and promising option in the treatment of giant thoracic aneurysms as presented in this case.\n\nKeywords\nThoracic aortic aneurysmGiant thoracic aortic aneurysmEndovascular aortic repair\n==== Body\n1 Introduction\nThoracic aortic aneurysm (TAA) is defined as a loss of parallelism of the aortic walls, resulting in saccular, fusiform, or diffuse dilation, 1.5 times greater than the superjacent aorta [1]. Giant TAA is considered when widening exceeds 10 cm in diameter [2]. Thoracic aneurysms affect 10 of every 100,000 elderly adults, and are less common than their abdominal counterparts [3,4].\n\nWe present a case of a 72-year-old male presenting a 15 cm asymptomatic TAA, successfully treated by TEVAR. A review of the literature is also presented.\n\nThe work has been reported in line with the SCARE criteria [5].\n\n2 Presentation of case\nA 72-year-old male with no past history of smoking, and with medical history of hypertension, dyslipidemia and benign prostate hyperplasia treated with angiotensin-converting-enzyme inhibitor, atorvastatin, tamsulosin, and finasteride respectively, presented with a giant descending thoracic aortic aneurysm. Diagnosis was incidentally found after a CT-scan was performed for polycystic kidney disease. Tomography revealed an unruptured aortic aneurysm, affecting the distal part of the aortic arch and the descending aorta, with a maximum diameter of 15.6 cm (Fig. 1A, B). The patient didn’t have any mass effect manifestation such as dyspnea, cough, chest pain, or any other symptom. At that time, the patient underwent a laparoscopic left nephrectomy, which went unremarkable, at a small town 1000 miles away from our teaching hospital.Fig. 1 a) Coronal MPR CT image obtained with intravenous contrast in arterial phase shows a sacular aneurism of the descending aorta, with the presence of an intramural thrombus (arrows). There is no extravasation of the contrast media from the true lumen (arrowhead). b) Axial MPR image shows calcification of the aortic wall (arrowhead). The true lumen (arrowhead) measures 7.4 cm; the aneurysm measured in the perpendicular plane has a diameter of 15.6 cm.\n\nFig. 1\n\nThe patient arrived to our hospital two months after the kidney surgery. He had a complete cardiac assessment with no abnormalities in cardiac function, and serum creatinine of 0.9 mg/dl. No contraindications for surgery were presented, and TEVAR was performed. An open approach to the right common femoral artery was done under general anesthesia. A Medtronic-Valiant 34-30-200 thoracic endograft (Santa Rosa, CA Medtronic) was placed distally to the left subclavian artery and a Medtronic-Valiant 30-30-200 thoracic endograft (Santa Rosa, CA Medtronic) was positioned proximally to the origin of the celiac trunk, with 5 cm overlapping. No blood pressure reduction during deployment was needed, nor CSF drainage. An angiogram showed complete exclusion of the aneurysm without endoleaks (Fig. 2).Fig. 2 TEVAR (A) Invasive angiography depicts the thoracic aneurism before repair. There is no extravasation of the contrast. (B) Invasive angiography posterior the placement of two endoprothesis. There are no endoleaks.\n\nFig. 2\n\nPatient recovered satisfactorily and was discharged on postoperative day two. No complications were seen in the CT angiography at four-month follow-up (Fig. 3). At 24-month follow up the patient is doing well without complications.Fig. 3 CT angiogram at a four-month follow up. The endoprothesis is well positioned with no endoleaks.\n\nFig. 3\n\n3 Discussion\nMost TAAs occur in the ascending aorta followed by the descending thoracic aorta, and the aortic arch. The average age at the time of diagnosis is around the 60–70 years range [4,6,7]. Women with degenerative TAA have greater aneurysm growth rates than men, independently of body size or other clinical variables [7].\n\nPathophysiology of TAA formation involves the process of cystic medial necrosis, where focal degeneration of the elastic and muscle tissue within the tunica media of the aortic wall occurs. The aortic wall subsequently weakens and dilates as a result of the high pressure of intraluminal blood flow [6]. This definition differentiates an aneurysm from a false aneurysm, with the latter being a perivascular pulsatile hematoma secondary to a vessel injury often seen after endovascular procedures. A third type of aneurysm is the mycotic counterpart, which is defined by the presence of two or more of the following features: sepsis, positive blood culture, positive culture from the aneurysmal wall, or a characteristic radiological appearance [8]. Another type of aneurysm is the one following an acute event of aortic dissection.\n\nIn this case, the patient was diagnosed with hypertension 30 years before intervention, which constitutes the main risk factor predisposing for TAAs, aortic dissection and rupture, accounting for 50–60% of deaths. Patients with aneurysms greater than 10 cm have a 5-year survival of 15% [2,4,7]. In retrospect, our patient’s aneurysm should have been repaired first before performing the nephrectomy due to the high risk of rupture that it presented.\n\nSigns and symptoms that might present with a TAA include a diastolic murmur or, less often, patients may present with congestive heart failure. On the other hand, giant TAAs may suffer a local mass effect, such as compression of the trachea or mainstem bronchus, provoking fatigue, nausea, cough, dyspnea, wheezing, chest pain, or recurrent pneumonitis [1,6,9]. Additionally, typical symptoms of aortic rupture include the abrupt onset of severe pain in the chest, neck, back, and/or abdomen [6]. Aortoesophageal fistulaes (AEsFs), which have also been described as complications in giant TAA, are classified as being either primary or secondary. The first are the results of intrinsic disease, such as TAA, esophageal cancer, mediastinal tubercular infections, or incurred injury from foreign body ingestion, trauma or caustic erosions as from lye consumption, whereas the latter are communications between the esophagus and the repaired aorta. Chiari’s triad for this fatal disorder is composed of (1) midthoracic pain, (2) a sentinel hemorrhage event, and (3) delayed exsanguination after a symptom-free hiatus. Overall mortality with nonsurgical therapy is total, with surgical intervention mortality ranges from 30% to 80% [10,11].\n\nOur patient was diagnosed during evaluation for polycystic kidney disease. It is known that most patients with TAA are asymptomatic and diagnosis is made incidentally during image studies for additional reasons [1,2,6,9]. Contrast enhanced CT scan and MR angiography are the preferred image methods to assess aneurysms, being both the gold standard for diagnosis [1,6].\n\nPatients with aneurysms smaller than 6 cm are generally not candidates for surgery, unless they have symptoms or they present comorbidities, therefore they may be treated medically. Elective surgery may be carried out at a size of 5.5 cm for ascending and 6.5 cm for descending aortic aneurysms, repair is also suggested for patients with documented aneurysm growth of >1 cm per year. Propranolol has shown significantly slower rate of aortic dilatation, fewer aortic events, and lower mortality than treatment with non β -blocker therapy [6,9].\n\nTEVAR has been successfully performed under both general anesthesia (GA) and regional anesthesia (RA). The advantage of RA is that it allows the patient to remain awake, avoid tracheal intubation, and provide postoperative pain relief. Factors favoring GA include a endovascular repair with planned fenestrated or branched endografts, expecting a long technique duration; a need for debranching procedures or for aortic/iliac artery access and planned hemodynamic manipulations to create a immobile field during stent placement [12].\n\nThe most feared nonfatal complication in TAA’s repair is postoperative paraplegia secondary to interruption of the blood supply to the spinal cord [6]. The incidence of spinal cord ischemia (SCI) after TEVAR is generally less when compared to open aneurysm repair (OAR) but still occurs with a reported incidence of 0%–13%; this is because blood flow to the spinal cord via distal aortic branches is not compromised during TEVAR because there is no aortic cross-clamping [13].\n\nCerebrospinal fluid drainage (CFD) has proven that its useful in preventing SCI [14]. For many years, we performed this preoperative measure in cases with long endovascular coverage, until systematic reviews failed to show that CFD prevents SCI in TEVAR [15]. Furthermore, many complications related to CFD have been reported [16,17]. Now, our strategy is more selective, and we only perform preoperative CFD in patients with high risk of developing SCI [18].\n\nOnly 20 case reports of giant TAAs were found in the literature and detailed in Table 1. The average age was of 67.5 years (28–88). The mean diameter of aneurysm was 12 cm (10–16 cm). Sixteen (80%) patients reported symptoms. Thirteen (65%) of the patients were treated with open approach, and six (30%) patients were not operated on and only one (5%) of the patients was successfully treated with TEVAR. This case to our knowledge is the largest thoracic aneurysm treated with TEVAR.Table 1 Aortic giant thoracic aneurysms reported in the english literature (>10 cm in transverse diameter).\n\nTable 1Age (yrs), Sex\tReference\tSize (transverse diameter), Location\tPresentation\tComorbidities and risk factors\tType of repair\tOutcome\t\n75, F\tRefaat et al.\t10 cm, ascending\tDyspnea and impaired consciousness\tNone\tNon-surgical.\tRecovers short-term. unknown long-term\t\n63, M\tWang et al.\t10.3 cm aortic arch\tCough, hoarseness and dyspnea for more than 1 week\tNone\tNon-surgical\tDies same day\t\n61, M\tEnriquéz-Puga et al.\t11.3 cm, ascending (root)\tDyspnea and chest pain\taortic prosthesis\tOpen repair. Bentall procedure,\tDischarged POD 8\t\n28, M\tGöncü et al.\t16 cm, ascending\tasymptomatic\taortic valve prosthesis\tOpen repair. Hemashiel woven graft 34 mm\tDischarge POD 10\t\n70, M\tPhilippakis\t10cm\tback pain\tHypertensive\tTEVAR. Medtronic Valiant Captvia 36 mm × 200 mm\tDischarged POD 3\t\n76, F\tLamrani et al.\t11 cm, decending\tDyspnea, cardiac insufficiency\tRenal failure and cardiac insufficiency\tNon-surgical\tUnknown\t\n75, M\tGarrido et al.\t15 cm, arch\tCardio-vocal syndrome: dysphonia, dysphagia, dyspnea, chest pain\tsmoker, hypertensive, CKD, COPD\tOpen repair\tUnknown\t\n77, F\tJmaa-Hela et al.\t13.97 cm, ascending (root)\tDyspnea\tNone\tOpen repair Bentall procedure\tDies same day\t\n78, F\tJ.Adekanmi et al.\t10.2 cm, ascending\tDyspnea\tHypertension, aortic valve calcification,\tNon-surgical\tDies 12 days after evaluation\t\n33, M\tShah et al.\t13 cm, ascending\tAsymptomatic\tMarfan syndrome\tOpen repair, Bentall procedure.\tDischarged POD 7\t\n76, M\tTomey et al.\t11.5 cm, ascending\tDyspnea, presyncope; aortitis and atherosclerosis\tSyphilis.\tOpen repair\tDies in OR\t\n76, M\tRajab et al.\t11.4 cm\nascending\tDyspnea and leg swelling.\tSyphilis\tOpen repair\tUnknown\t\n39, M\tTopcuoglu et al.\t15 cm, descending\tlumbalgia, nausea, fatigue\tHypertension, aortic coarctation\tOpen repair, dacron graft 16 mm\tDischarged POD 8\t\n85, F\tKampitakis et al.\t14.8 cm, descending\tdypsnea, dysphagia,\tHypertension, rheumatoid arthritis\tNon-surgical\tUnknown\t\n88, F\tOkura et al.\t10.5 cm, ascending\tAsymptomatic.\tNone\tNon-surgical\tDies 3 months later of pulmonary embolism\t\n66, M\tFatimi et al.\t11 cm, ascending\tDyspnea\taortic valve regurgitation, mitral valve regurgitant\tOpen repair\tDischarged POD 8\t\n64, M\tPietrzyk et al.\t10.5 cm, ascending and aortic arch.\tDyspnea\tNYHA III, permanent AF, CKD, DM2, AAA repair 10 years earlier\tOpen repair\tDies same day.\t\n72, M\tMoutakiallah et al.\t11 cm, ascending\tDyspnea, ortopnea, SVCS\tHeart failure\tOpen repair\tDischarged POD 21\t\n82, F\tCeresa et al.\t11 cm, ascending and aortic arch\tAcute chest pain\tHypertension, Diabetes\tOpen repair, tubular graft 30 mm\tDischarged POD 14\t\nUnknown\tSansone et al.\t13 cm, ascending\tAsymptomatic\tPast history of aortic valve replacement\tOpen repair, dacron graft 34 mm\tUnknown\t\nSVCS: Superior Vena Cava Syndrome. POD: Post Operative Day. AF: atrial fibrillation. AAA: Aortic Abdominal Aneurysm. CKD: Chronic Kidney Disease. DM2: Diabetes Mellitus Type II.\n\n\n\n4 Conclusion\nTEVAR is an emergent therapy to successfully treat TAAs. Morbidity and mortality has been reportedly decreasing by this surgical approach. Even though there is limited documented experience, use of TEVAR seems a safe and promising option in the treatment of giant thoracic aneurysms as presented in this case. There is still a lot of work to do regarding minimally invasive vascular procedures, since this may play an important role on the future of vascular surgery.\n\nConflicts of interest\nNone.\n\nFunding\nNone.\n\nEthical approval\nEthical approval has been exempted by our institution, Tecnologico de Monterrey.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nAlejandro Fabiani: He is a senior vascular surgeon. He is the one who performed the surgery. He wrote the presentation of case, and helped with the final edition.\n\nEduardo Flores Villalba: He is a surgery professor. He helped organized the manuscript, and helped with the final edition.\n\nGerardo Lozano Balderas: He is a vascular attending. He checked the manuscript and helped with the outline of the paper.\n\nMauricio Gonzalez- Urquijo: He is a second year general surgery resident. He was the leader of the work, he design the case report. He recollected data, and wrote the manuscript.\n\nLuis Gerardo Tellez: He is a senior radiology resident. He helped obtain the images and descriptions of them. He helped write the manuscript.\n\nVictor Dominguez: He is a senior medican student. He conducted a systematic review of cases reports of TAa >10 cm, and contributed with the table summarizing each one of them.\n\nRegistration of research studies\nNA.\n\nGuarantor\nMauricio González-Urquijo.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nAcknowledgment\nRodrigo González-Urquijo M.D.\n==== Refs\nReferences\n1 Lamrani M.Y.A. Idrissi M. Moujoudi M.E.L. Kamaoui I. Maâroufi M. Houssaini N.S. Tizniti S. Giant aneurysm of the thoracic aorta. Answer to January e-quid Diagn. Interv. Imaging 93 2012 212 215 22421288 \n2 Okura T. Giant Unruptured Aneurysm of the Thoracic Aorta Angiology 50 10 1999 865 869 10535727 \n3 Makaroun M.S. Dillavou E.D. Kee S.T. Sicard G. Bavaria J. Williams D. Cambria R.P. Scott R. From the Society for Vascular Surgery Endovascular Treatment of Thoracic Aortic Aneurysms: Results of the Phase II Multicenter Trial of the GORE TAG Thoracic Endoprosthesis 2001 1 9 \n4 Clouse W.D. Hallett J.W. Jr. Schaff H.V. Gayari M.M. Ilstrup D.M. Melton L.J. III Improved prognosis of thoracic aortic aneurysms JAMA 280 1998 1926 9851478 \n5 Agha R.A. Fowler A.J. Saeta A. Barai I. Rajmohan S. Orgill D.P. The SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565 \n6 Isselbacher E.M. Contemporary Reviews in Cardiovascular Medicine Thoracic and Abdominal Aortic Aneurysms 2005 816 828 \n7 Cheung K. Boodhwani M. Chan K. Beauchesne L. Dick A. Coutinho T. Thoracic aortic aneurysm growth: role of sex and aneurysm etiology J. Am. Heart Assoc. 6 2017 e003792 \n8 Jaffer U. Gibbs R. Mycotic thoracoabdominal aneurysms Ann. Cardiothorac. Surg. 1 2012 417 425 23977531 \n9 Findeiss L.K. Cody M.E. Endovascular Repair of Thoracic Aortic Aneurysms vol. 1 2011 107 117 \n10 Simão E. Tozzi F.L. Otochi P. Magalhães E. De Tolosa C. Ricardo C. Neves B. Fortes F. Paulo S. Aortoesophageal fistula caused by aneurysm of the thoracic aorta: successful surgical treatment, case report, and literature review J. Vasc. Surg. 30 1999 1150 1157 10587402 \n11 Jonker F.H.W. Heijmen R. Trimarchi S. Acute management of aortobronchial and aortoesophageal fistulas using thoracic endovascular aortic repair J. Vasc. Surg. 50 2009 999 1004 19481408 \n12 Nicolaou G. Ismail M. Thoracic endovascular aortic repair: update on indications and guidelines Anesthesiol. Clin. 31 2013 451 478 23711653 \n13 Feezor R.J. Lee W.A. Strategies for detection and prevention of spinal cord ischemia during TEVAR Semin. Vasc. Surg. 22 2009 187 192 19765530 \n14 Hnath J.C. Mehta M. Taggert J.B. Sternbach Y. Roddy S.P. Kreienberg P.B. Ozsvath K.J. Chang B.B. Shah D.M. Iii R.C.D. Strategies to improve spinal cord ischemia in endovascular thoracic aortic repair: outcomes of a prospective cerebrospinal fluid drainage protocol J. Vasc. Surg. 48 2008 836 840 18723308 \n15 Wong C.S. Healy D. Canning C. Coffey J.C. Boyle J.R. Walsh S.R. Kingdom U. A systematic review of spinal cord injury and cerebrospinal fluid drainage after thoracic aortic endografting J. Vasc. Surg. 56 2012 1438 1447 22884456 \n16 Cheung A.T. Pochettino A. Guvakov D.V. Weiss S.J. Shanmugan S. Bavaria J.E. Safety of lumbar drains in thoracic aortic operations performed with extracorporeal circulation Ann. Thorac. Surg. 76 2003 1190 1197 14530010 \n17 Wynn M.M. Mell M.W. Tefera G. Hoch J.R. Acher C.W. Complications of spinal fluid drainage in thoracoabdominal aortic aneurysm repair: a report of 486 patients treated from 1987 to 2008 J. Vasc. Surg. 49 2009 29 35 18951749 \n18 Fabiani A. Prevención y manejo de la isquemia medular en la cirugía de la aorta torácica vascular y endovascular Cirugía La Aorta Torácica 2010 211 214\n\n",
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"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15480083,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190205"
}
] |
{
"abstract": "Esomeprazole is the S-isomer of omeprazole and is used to treat stomach acid-related diseases. Most data regarding the safety of esomeprazole during pregnancy are derived from studies on omeprazole, and the data characterizing esomeprazole transfer across the placenta and excretion into breast milk are limited. In this report, we discuss the safety of esomeprazole with reference to drug concentrations in maternal and neonatal blood and breast milk. After the patient provided informed consent, esomeprazole concentrations in maternal serum, breast milk, cord blood, and infant's serum were measured after 10 mg of maternal oral esomeprazole administration. A 34-year-old female diagnosed with rheumatoid arthritis received esomeprazole before and during pregnancy and lactation. The esomeprazole concentration in cord blood was 40% of the level in maternal serum. At 12 hours after delivery (23.2 hours after dose), omeprazole was not detected in the infant's serum. In breast milk, esomeprazole concentrations at 0.7, 4.0, and 8.2 hours after the last dose were 10.5, 19.6, and 3.0 ng/mL, respectively, and esomeprazole was not detected at 10 hours after maternal administration. The calculated daily infant dose of esomeprazole through breast milk was 0.003 mg/[kg·day]. The infant demonstrated normal developmental progress and no detectable drug-related adverse effects. Exposure to esomeprazole through placenta and breast milk was not clinically relevant in the infant. Further studies are needed to evaluate any harmful effects after exposure to esomeprazole in utero or during breastfeeding after esomeprazole treatment.",
"affiliations": "Department of Pharmacy, National Center for Child Health and Development, Tokyo, Japan.;Japan Drug Information Institute in Pregnancy, National Center for Child Health and Development, Tokyo, Japan.;Department of Pharmacy, National Center for Child Health and Development, Tokyo, Japan.;Department of Pharmacy, National Center for Child Health and Development, Tokyo, Japan.;Division of Maternal Medicine, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Division of Obstetrics, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Department of Pharmacy, National Center for Child Health and Development, Tokyo, Japan.;Division of Obstetrics, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Japan Drug Information Institute in Pregnancy, National Center for Child Health and Development, Tokyo, Japan.",
"authors": "Saito|Jumpei|J|;Yakuwa|Naho|N|;Sandaiji|Noriko|N|;Kawasaki|Hiroyo|H|;Kaneko|Kayoko|K|;Suzuki|Tomo|T|;Yamatani|Akimasa|A|;Sago|Haruhiko|H|;Murashima|Atsuko|A|",
"chemical_list": "D064098:Esomeprazole",
"country": "United States",
"delete": false,
"doi": "10.1089/bfm.2020.0175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-8253",
"issue": "15(9)",
"journal": "Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine",
"keywords": "breastfeeding; esomeprazole; infant; omeprazole; placental transfer",
"medline_ta": "Breastfeed Med",
"mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D001942:Breast Feeding; D064098:Esomeprazole; D005260:Female; D005312:Fetal Blood; D006801:Humans; D007231:Infant, Newborn; D007774:Lactation; D008895:Milk, Human; D011247:Pregnancy",
"nlm_unique_id": "101260777",
"other_id": null,
"pages": "598-601",
"pmc": null,
"pmid": "32635742",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Esomeprazole During Pregnancy and Lactation: Esomeprazole Levels in Maternal Serum, Cord Blood, Breast Milk, and the Infant's Serum.",
"title_normalized": "esomeprazole during pregnancy and lactation esomeprazole levels in maternal serum cord blood breast milk and the infant s serum"
}
|
[
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2020-03873",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE MAGNESIUM"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "208333",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MILLIGRAM, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugseparatedosagenumb": "1",
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"medicinalproduct": "ESOMEPRAZOLE MAGNESIUM."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "2.5 MILLIGRAM",
"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": "2.5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISOLONE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB"
},
"drugadditional": null,
"drugadministrationroute": "058",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "200 MILLIGRAM, BIWEEKLY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CERTOLIZUMAB"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 GRAM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugstructuredosageunit": "002",
"drugtreatmentduration": null,
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"medicinalproduct": "SULFASALAZINE."
}
],
"patientagegroup": null,
"patientonsetage": "34",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": "60",
"reaction": [
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAITO J, YAKUWA N, SANDAIJI N, KAWASAKI H ET AL. ESOMEPRAZOLE DURING PREGNANCY AND LACTATION: ESOMEPRAZOLE LEVELS IN MATERNAL SERUM, CORD BLOOD, BREAST MILK, AND THE INFANT^S SERUM. BREASTFEEDING MEDICINE. 2020?UNK:UNK",
"literaturereference_normalized": "esomeprazole during pregnancy and lactation esomeprazole levels in maternal serum cord blood breast milk and the infant s serum",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200817",
"receivedate": "20200817",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18155679,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20201103"
}
] |
{
"abstract": "Obsessive-compulsive symptoms are prevalent, manifold, and sometimes insidious in patients with schizophrenia. In this case study, we reported an intractable headache that bears a close relationship with obsessive-compulsive symptoms in a schizophrenia patient. In a series of treatments, the headache was miraculously susceptible to haloperidol treatment.",
"affiliations": "Nanjing Meishan Hospital, Nanjing, China.;Nanjing Meishan Hospital, Nanjing, China.",
"authors": "Yuan|Hsinsung|H|https://orcid.org/0000-0001-6736-0885;Liu|Junjun|J|https://orcid.org/0000-0003-0701-8070",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/8824204",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X 2090-6838 Hindawi \n\n10.1155/2020/8824204\nCase Report\nAn Obsessive-Compulsive Symptom-Related Headache in a Patient with Schizophrenia\nhttps://orcid.org/0000-0001-6736-0885Yuan Hsinsung [email protected] https://orcid.org/0000-0003-0701-8070Liu Junjun Nanjing Meishan Hospital, Nanjing, China\nAcademic Editor: Liliana Dell'Osso\n\n\n2020 \n10 10 2020 \n2020 88242048 4 2020 25 8 2020 5 10 2020 Copyright © 2020 Hsinsung Yuan and Junjun Liu.2020This 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.Obsessive-compulsive symptoms are prevalent, manifold, and sometimes insidious in patients with schizophrenia. In this case study, we reported an intractable headache that bears a close relationship with obsessive-compulsive symptoms in a schizophrenia patient. In a series of treatments, the headache was miraculously susceptible to haloperidol treatment.\n\nNanjing Department of HealthYKK16241YKK17246\n==== Body\n1. Case\nA 52-year-old woman with a 9-year history of schizophrenia presented with a persistent headache and depression after she was mauled by five people 2 months ago, with the left side of the top of her head hit by a crabstick and no disturbance of consciousness after the attack. She had two head MRI scans after the hit, but all of them showed negative results. The woman presented argumentative hallucinations and paranoid delusions 9 years ago. She was diagnosed with schizophrenia and was then treated with 600 mg quetiapine daily. The treatment was effective, and quetiapine was maintained at a dosage of 200 mg daily. During these 9 years, she sometimes heard some people talking about her, but even if she heard this, she thought these voices had nothing to do with her. She worked as a cleaner during these years. She has been hard-working and self-disciplined. The hallucinations increased in both frequency and intensity 6 months ago, and she could constantly hear her neighbours and people from nearby villages commenting on her. Two months ago, a white dog and a yellow dog were fighting in front of her house, and then her neighbour shouted at these dogs. At that time, the patient was dressed in yellow, and she thought her neighbour was shouting at her, so she went to fight her neighbour; then, the neighbour's family came out and mauled her. As an outpatient, she had taken 15 mg olanzapine daily, 10 mg aripiprazole daily, and 100 mg sertraline daily during the following two months, but her headache had worsened.\n\nWhen the patient came to the inpatient ward, she was kempt but made passive contact, talked little, and avoided eye contact with psychiatrists; her only complaint was a severe and unbearable headache. Her thoughts were consistent and logical, but her reaction was slow. She could hear several different kinds of auditory hallucinations. The first was a kind of functional auditory hallucination triggered by whispering, barking, or car noises, and these whispers could present as argumentative swearing. The second was a kind of primary auditory hallucination, which could occur without any sign, and it could be combined with a persecutory delusion in which she thought there were people nearby talking about her. The third kind of functional hallucination was that when she talked with psychiatrists, she could hear psychiatrists swearing at her at the same time as the real psychiatrists' voice. The fourth kind of hallucination was a psycho-hallucination that stemmed from her brain. These voices often commented on her or presented themselves as the fifth form and broadcasted her thoughts, which coincided with the dilution of the diffusion of her thoughts. When she heard the commenting and criticizing voice, thoughts of guilt came to her mind. When thoughts of guilt emerged, she denied them and swore against them in her mind, but she could not avoid these thoughts. Every time she swore against these people, she felt shameful and repentant because she believed that speaking ill of others was immoral; she then was angry with herself, and her headache then appeared. When she lived in the hospital, she often wandered around the garden, which she said could relieve her headache because she could verify that nobody was talking about her in the garden. She had insomnia because the auditory hallucinations were too loud to allow her to sleep, and in the early morning, the auditory hallucinations interrupted her sleep.\n\nShe did not smoke, did not drink alcohol, and denied the use of illicit drugs. No parental relative was reported to have a diagnosis of mental disorder. There was no comorbid physical illness. The patient only completed 3 years of elementary education. She quit her studies because her family could not afford her tuition fee, and she was required to work to support her family; however, she could read and write. She had been obedient and forbearing since she was a child. She was married at 24 years of age in an arranged marriage. Her first child was a daughter, so she gave birth to a son one year later because of patriarchal culture. However, owing to the one-child policy, she had to pay a large amount of forfeit, and it took her 10 years to repay the debt. Unfortunately, her son accidentally drowned at 7 years old. After her son died, she had an episode of depression. At that time, she had feelings of sorrow and self-condemnation. She laid on the bed every day and quit her job because she heard many colleagues talking about her. She was diagnosed with major depressive disorder, but she did not take medicine, and her depression subsided 6 months later. During these 14 years, she had not shown any sign of mood or psychotic symptoms, and her symptoms during these 9 years was not closely related to the context of her son. She did not avoid to talk about her son, and her son's death no longer bothers her. There was no obvious manic episode in her life.\n\nOn examination, her head MRI scan was normal. Her blood count, liver function, kidney function, thyroid function, and infectious disease portfolio were normal. Her Hamilton Anxiety Scale (HAMA) was 23, and her 17 items of Hamilton Depression Rating Scale (HAMD-17) was 24. We conducted drug-gene testing, which showed that her CYP2D was ∗10/∗41 and her FKBP genes were GG (rs4713916) and CC (rs1360780), which implied that venlafaxine might not be effective.\n\n2. Discussion\nSchizophrenia is regarded as a disorder with hypoalgesia [1–4]. However, headache has been regarded as a widely reported symptom of schizophrenia [5–9]. Studies have shown that 57% of schizophrenia patients suffer from headache, but most of these patients cannot be classified as having any kind of headache in the International Classification of Headache Disorders (ICHD); furthermore, these headaches are not related to any social, demographic, and biological factors, including whether participants adhere to their treatment [10]. Furthermore, it remains controversial whether headaches are a manifestation of mental symptoms or a sign of physical injury [11]. After she was hit two months ago, she presented a variety of symptoms amongst headache and depression. The depressive episode during these two months might be related to the acute stress condition. However, she was not physically injured by that incident, so it was possibly that acute stress condition was owing to her delusion. In this case, we present a headache that is closely related to obsessive-compulsory symptoms in schizophrenia.\n\nIn patients with psychotic symptoms, depression, obsessive-compulsory symptoms, and headache, we have to differentiate schizoaffective disorder and bipolar disorder. In this case, though the woman's medication had been maintaining at a low dosage and she had presented depression and headache in this episode; she had been having residue persistent paranoid auditory hallucination during the last nine years, with a flat mood without comorbid personality disorder. Even in this episode, her hallucination has already been worsening 6 months ago and she presented a formal thought disorder in that she considered her neighbour was shouting at her. According to ICD-10, the patient's psychotic symptoms have been persistent and worsened 6 months ago, but the depression has only presented since 2 months ago; the patient did not meet the criteria of schizoaffective disorder. However, according to ICD-11, the diagnoses of schizophrenia and schizoaffective disorder are intended to apply to the current period of illness, so she could meet the criteria of schizoaffective disorder under the ICD-11 criteria.\n\nSome case studies have reported that mood stabilizers [12] and olanzapine [13] were associated with alleviating headache in schizophrenia. We used 1000 mg sodium valproate daily to decrease her agitation with regard to her headache, which often occurred when she was agitated, and it was also reported that this drug is helpful for both headache and functional hallucination in schizophrenia. After using this drug, the patients' headache and agitation were slightly alleviated, but the headache still persisted after one week of medication, with no improvement in obsessive self-accusatory thoughts.\n\nObsessive-compulsive symptoms (OCS) in schizophrenia are common but challenging to manage. Twenty-five percent of schizophrenia patients present OCS [14–18], and it is arguable that clozapine, one of the most effective medications in schizophrenia, could worsen the symptoms [19]. In contrast, it has been reported that OCS in schizophrenia could be relieved faster than OCS in OCD [20]. In this patient, the usage of olanzapine slightly alleviated auditory hallucinations, but after the hallucinations ceased, the headache remained and even worsened. We found that the headache was closely connected with a series of obsessive self-accusatory thoughts and agitated reactions, which could be obfuscated with depression and potentially lead psychiatrists to add clozapine.\n\nWe found that the patient's silence and avoidance were evidenced not through her negative symptoms and depression but rather through her endurance of her anger and agitation. In regard to her working performance before hospitalization, her negative symptoms did not appear to progress, so we tapered off the ineffective aripiprazole treatment. Although olanzapine could alleviate OCS in schizophrenia [21], to alleviate her obsessive thoughts, we started the treatment of haloperidol; haloperidol and amisulpride are the two main drugs used to control OCS in schizophrenia [22]. With regard to the genetic results, venlafaxine was not suitable for this patient, and we used escitalopram to address the OCS and sad mood [23]. One week after the usage of 2 mg haloperidol and 10 mg escitalopram daily, all auditory hallucinations and delusions disappeared, and the obsessive self-accusatory thoughts and headaches disappeared.\n\nCompared with depression in affective disorder, depression in schizophrenia is characterized by self-accusatory thoughts, thoughts of guilt, hypochondriasis, and delusions, rather than hypodynamics in MDD [24]. In the case of this patient, she denied feeling lethargic, had obvious agitation, and worked very hard during the peak of her depression. It must be stated that her self-accusation is a form of obsessive-compulsive symptoms, but regarding personality traits, she avoided people, talked less to hide her agitation, and probably even developed a reaction mechanism, namely, somatization, which is a psychoanalytic term; somatization often develops in Chinese women in rural areas. If her depression and negative symptoms were recognized, the use of aripiprazole and a relatively large dosage of an antidepressant, or even clozapine, would worsen her compulsive symptoms and agitation.\n\n3. Patient Outcome\nAfter the addition of 1000 mg sodium valproate daily and the reduction of her dosage of antidepressants to alleviate her agitation, her headache was slightly alleviated, and she reported that her feelings of anger and agitation were significantly reduced. However, after one month, she still had many auditory hallucinations, as well as obsessive thoughts of self-accusation, and she still compulsively swore at them. She reported that when she saw other people, including psychiatrists, their images would reflect in her brain, and she could not dismiss these images. Then, we changed aripiprazole to 2 mg haloperidol per day and stopped venlafaxine to alleviate OCS. All her psychotic and obsessive-compulsive symptoms rapidly resolved over the next week; she said she no longer heard any auditory hallucinations arguing about or commenting on her. She denied being able to see another person's image, her thoughts were no longer broadcasting, and her depressive mood and headache disappeared. At the same time, her HAMA score was 2, her HAMD-17 score was 2, and she was discharged from our hospital. One month after her discharge, the patient relapsed due to a mild obsessive thought and secondary depression, in which she felt her boss was not satisfied with her work; she then felt remorseful, so we increased her dosage of haloperidol to 4 mg per day. Three months, six months, and one year later, most of the patient's symptoms were in remission, with some auditory hallucination persisting, but she could address them. She has kept taking 1000 mg sodium valproate daily, 4 mg haloperidol per daily, and 15 mg olanzapine daily. She maintains the ability to work and maintains an acceptable quality of life.\n\nAcknowledgments\nThis study was supported by the Clinical Medicine Development Funding of Nanjing Department of Health (Nos. YKK17246 and YKK16241).\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n==== Refs\n1 Potvin S. Marchand S. Hypoalgesia in schizophrenia is independent of antipsychotic drugs: a systematic quantitative review of experimental studies Pain 2008 138 1 70 78 10.1016/j.pain.2007.11.007 2-s2.0-79955653707 18160219 \n2 Engels G. Francke A. L. van Meijel B. Clinical pain in schizophrenia: a systematic review The Journal of Pain 2014 15 5 457 467 10.1016/j.jpain.2013.11.005 2-s2.0-84899969811 24365324 \n3 Bonnot O. Anderson G. M. Cohen D. Willer J. C. Tordjman S. Are patients with schizophrenia insensitive to pain? A reconsideration of the question The Clinical Journal of Pain 2009 25 3 244 252 10.1097/AJP.0b013e318192be97 2-s2.0-60649109675 19333176 \n4 Brooks J. M. Blake J. Sánchez J. Self-reported pain intensity and depressive symptoms among community-dwelling older adults with schizophrenia spectrum disorders Community Mental Health Journal 2019 55 8 1298 1304 10.1007/s10597-019-00403-x 2-s2.0-85071144085 31098766 \n5 Gittleson N. L. Psychiatric Headache: A clinical study Journal of Mental Science 1961 107 448 403 416 10.1192/bjp.107.448.403 13705792 \n6 Hinterhuber Der kopfschmerz, ein initial symptom schizophrener erkrankungen Münchener Medizinische Wochenschrift 1975 117 1521 1522 810681 \n7 TF M. N. Helmchen H. Henn F. Perinatal factors in the development of schiziphrenia Biological Perspectives of schizophrenia 1987 Chichester John Wiley and Sons 125 138 \n8 Varsamis J. Adamson J. D. Somatic symptoms in schizophrenia Canadian Psychiatric Association Journal 1976 21 1 1 6 1268796 \n9 Watson G. D. Chandarana P. C. Merskey H. Relationships between pain and schizophrenia The British Journal of Psychiatry 1981 138 1 33 36 10.1192/bjp.138.1.33 2-s2.0-0019350446 7272636 \n10 Connaughton J. Wand B. Prevalence, characteristics and management of headache experienced by people with schizophrenia and schizoaffective disorder: a cross sectional cohort study Australasian Psychiatry 2017 25 4 381 384 10.1177/1039856217695703 2-s2.0-85027181566 28747114 \n11 Lake A. E. III Rains J. C. Penzien D. B. Lipchik G. L. Headache and psychiatric comorbidity: historical context, clinical implications, and research relevance Headache 2005 45 5 493 506 10.1111/j.1526-4610.2005.05101.x 2-s2.0-18944366140 15953266 \n12 Lévesque M. Potvin S. Marchand S. Pain perception in schizophrenia: evidence of a specific pain response profile Pain Medicine 2012 13 12 1571 1579 10.1111/j.1526-4637.2012.01505.x 2-s2.0-84871383539 23170852 \n13 Silberstein S. D. Peres M. F. P. Hopkins M. M. Shechter A. L. Young W. B. Rozen T. D. Olanzapine in the treatment of refractory migraine and chronic daily headache Headache 2002 42 6 515 518 10.1046/j.1526-4610.2002.02126.x 2-s2.0-0036617585 12167140 \n14 Schirmbeck F. Zink M. Comorbid obsessive-compulsive symptoms in schizophrenia: contributions of pharmacological and genetic factors Frontiers in Pharmacology 2013 4 p. 99 10.3389/fphar.2013.00099 2-s2.0-84881619853 \n15 Zink M. Comorbid obsessive-compulsive symptoms in schizophrenia: insight into pathomechanisms facilitates treatment Advances in Medicine 2014 2014 18 317980 10.1155/2014/317980 26556409 \n16 Meier S. M. Petersen L. Pedersen M. G. Obsessive-compulsive disorder as a risk factor for schizophrenia: a nationwide study JAMA Psychiatry 2014 71 11 1215 1221 10.1001/jamapsychiatry.2014.1011 2-s2.0-84923700273 25188738 \n17 Cheng Y. F. Chen V. C. H. Yang Y. H. Chen K. J. Lee Y. C. Lu M. L. Risk of schizophrenia among people with obsessive-compulsive disorder: a nationwide population-based cohort study Schizophrenia Research 2019 209 58 63 10.1016/j.schres.2019.05.024 2-s2.0-85066104017 31133461 \n18 du Montcel C. T. Pelissolo A. Schürhoff F. Pignon B. Obsessive-compulsive symptoms in schizophrenia: an up-to-date review of literature Current Psychiatry Reports 2019 21 8 p. 64 10.1007/s11920-019-1051-y 2-s2.0-85068558832 \n19 Leung J. G. Palmer B. A. Psychosis or obsessions? Clozapine Associated with Worsening Obsessive-Compulsive Symptoms Case Reports in Psychiatry. 2016 2016, article 2180748 5 10.1155/2016/2180748 27313938 \n20 Poletti M. Raballo A. Obsessively thinking through the schizophrenia spectrum: disentangling pseudo-obsessive schizophrenia from OCD Schizophrenia Research 2019 212 232 233 10.1016/j.schres.2019.08.014 2-s2.0-85072968133 31421971 \n21 de Berardis D. Vellante F. Fornaro M. Rapid improvement of obsessive-compulsive disorder associated with schizophrenia with cariprazine add-on in a subject under paliperidone long-acting injection: a case report International Clinical Psychopharmacology 2020 35 2 113 118 10.1097/YIC.0000000000000284 2-s2.0-85070987029 32004167 \n22 Wu T. H. Chiu C. C. Chen P. Y. Obsessive-compulsive symptoms in patients with schizophrenia: relationships with olanzapine pharmacological parameters, psychopathology, and quality of life Psychiatry Research 2019 276 1 5 10.1016/j.psychres.2019.03.007 2-s2.0-85064078521 30981095 \n23 Hwang M. Y. Kim S. W. Yum S. Y. Opler L. A. Management of schizophrenia with obsessive-compulsive features The Psychiatric Clinics of North America 2009 32 4 835 851 10.1016/j.psc.2009.08.002 2-s2.0-70450270895 19944887 \n24 Rubin-Kahana D. S. Shelef A. Weizman A. The effectiveness of high-dose escitalopram in the treatment of patients suffering from schizophrenia with comorbid obsessive-compulsive disorder: an open-label study International Clinical Psychopharmacology 2019 34 4 179 183 10.1097/YIC.0000000000000266 2-s2.0-85067270136 31058717\n\n",
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"title": "An Obsessive-Compulsive Symptom-Related Headache in a Patient with Schizophrenia.",
"title_normalized": "an obsessive compulsive symptom related headache in a patient with schizophrenia"
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"abstract": "Spontaneous splenic rupture is a rare entity that requires high index of suspicion for diagnosis. Usually, it occurs due to underlying pathology that could be inflammatory, neoplastic or infectious. However, there are also cases of spontaneous splenic rupture in a normal-sized spleen without obvious pathologic process. In our case, the patient suffered a spontaneous splenic rupture 1 week after laparoscopic appendectomy due to acute appendicitis. Histopathologic examination revealed a normal-sized spleen without any obvious pathology. In our patient, we did not found any explanation for a spontaneous splenic rupture, besides her primary inflammatory condition.",
"affiliations": "Department of Abdominal Surgery, University Medical Centre Ljubljana; Department of Surgery, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1104 Ljubljana, Slovenia.",
"authors": "Janez|Jurij|J|",
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"fulltext": "\n==== Front\nJ Minim Access Surg\nJ Minim Access Surg\nJMAS\nJournal of Minimal Access Surgery\n0972-9941 1998-3921 Wolters Kluwer - Medknow India \n\n32503960\nJMAS-16-269\n10.4103/jmas.JMAS_1_20\nUnusual Case\nSpontaneous splenic rupture 1 week after laparoscopic appendectomy due to acute appendicitis\nJanež Jurij 12 1 Department of Abdominal Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia\n2 Department of Surgery, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1104 Ljubljana, Slovenia\nAddress for correspondence: Dr. Jurij Janež, Department of Abdominal Surgery, University Medical Centre Ljubljana, Zaloška Cesta 7, 1525 Ljubljana, Slovenia. E-mail: [email protected]\nJul-Sep 2020 \n05 6 2020 \n16 3 269 270\n02 1 2020 16 1 2020 Copyright: © 2020 Journal of Minimal Access Surgery2020This 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.Spontaneous splenic rupture is a rare entity that requires high index of suspicion for diagnosis. Usually, it occurs due to underlying pathology that could be inflammatory, neoplastic or infectious. However, there are also cases of spontaneous splenic rupture in a normal-sized spleen without obvious pathologic process. In our case, the patient suffered a spontaneous splenic rupture 1 week after laparoscopic appendectomy due to acute appendicitis. Histopathologic examination revealed a normal-sized spleen without any obvious pathology. In our patient, we did not found any explanation for a spontaneous splenic rupture, besides her primary inflammatory condition.\n\nAppendectomyatraumatic splenic rupturehaemorrhagic shocksplenectomyurgent surgery\n==== Body\nINTRODUCTION\nSplenic rupture usually follows blunt or rarely penetrant abdominal trauma, but there are also cases of spontaneous atraumatic splenic rupture. Most frequent causes of spontaneous splenic rupture are haematologic and malignant diseases or infectious diseases.[1] There are also some rare cases of spontaneous splenic rupture, described in the literature, such as ectopic pregnancy in the spleen.[2] This paper presents an unusual case of spontaneous atraumatic splenic rupture in a patient, who underwent laparoscopic appendectomy due to acute perforated appendicitis and diffuse peritonitis. The spontaneous splenic rupture occurred 7 days after laparoscopic appendectomy and presented with haemorrhagic shock. The urgent surgery and splenectomy were necessary.\n\nCASE REPORT\nA 60-year-old female patient was referred to the emergency unit due to lower abdominal pain, which lasted for the past 4 days. She had elevated body temperature, ranging between 38°C and 39°C. The laboratory tests showed elevated inflammatory parameters (leucocytes 19 × 109/L and C-reactive protein 400 mg/L). Abdominal ultrasound (US) showed fluid collection (9 cm × 4 cm × 4 cm) in the Douglas pouch and signs of acute sigmoid diverticulitis with suspected perforation. Because US diagnosis was not completely reliable, abdominal computed tomography (CT) was performed. CT showed signs of appendicitis with perforation. The patient underwent emergency surgery. Laparoscopy was performed that confirmed acute appendicitis with perforation and pelvic abscess. Laparoscopic appendectomy was performed and pelvic abscess was evacuated and abdominal drain was inserted. At the beginning, the post-operative course was uneventful. Due to perforated appendicitis, the antibiotic therapy with gentamicin and metronidazole was prolonged. The inflammatory parameters started to decrease. She started to eat normal food, and she passed stool spontaneously. On the 5th post-operative day, the abdominal drain was removed. On the 7th post-operative day, the patient suddenly started to feel nausea, and she complained about abdominal pain. She was pale, tachycardic and hypotensive. Urgent abdominal US was performed that showed large perisplenic haematoma with suspected splenic rupture. She underwent emergency exploratory laparotomy. Splenic rupture with perisplenic haematoma was found. Splenectomy and haemostasis were performed, the haematoma was evacuated and abdominal drain was inserted. The abdominal drain was removed 2 day after surgery. Because elevated inflammatory parameters persisted despite antibiotic treatment, the abdominal US was repeated 7 days after the second surgery. Haematoma was seen in the left sub-phrenic space, which was evacuated with percutaneous drainage under US guidance. The rest of the post-operative course was uneventful. Thirteen days after the second surgery, the patient was discharged from hospital.\n\nDISCUSSION\nSpontaneous splenic rupture is otherwise rare condition, which most often occurs in patients with a haematologic or other malignant disease. Other causes of spontaneous splenic rupture are also known, such as infectious mononucleosis and ectopic pregnancy. Generally speaking, around 93% of spontaneous splenic rupture is attributed to pathologic causes and the remaining 7% is due to idiopathic causes.[3] The following are six major causes of non-traumatic splenic rupture: neoplasm (30%), infectious (30%), inflammatory disease (15%), medication and medical treatment (10%), mechanical causes (7%) and idiopathic (7%).[4] The pathogenesis of atraumatic splenic rupture is not well understood. Splenomegaly is present in almost all patients (~95%), although the rupture of normal spleens (both in size and underlying histology) has been reported.[5] In our case, spontaneous splenic rupture occurred 1 week after laparoscopic appendectomy, and according to our knowledge, this is the first such case, reported in the literature. The removed spleen was sent to histopathologic examination that revealed a normal-sized spleen without any evident pathology that would explain the sudden rupture. The surgical procedure was confined to the lower abdomen, and no surgical manoeuvres were performed in the left sub-phrenic space near the spleen that could explain a possible accidental splenic trauma during surgery. In our patient, we did not find any explanation for a spontaneous splenic rupture, besides her primary inflammatory condition. Our patient had a septic condition with high inflammatory parameters due to perforated acute appendicitis, and that septic condition was the probable cause of delayed spontaneous splenic rupture.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Dessie A Binder W Spontaneous rupture of the spleen due to infectious mononucleosis R I Med J (2013) 2017 100 33 5 \n2 Wu BQ Zhu F Jiang Y Sun DL Case of spontaneous splenic rupture caused by ectopic pregnancy in the spleen J Obstet Gynaecol Res 2017 43 1778 80 28762583 \n3 Weaver H Kumar V Spencer K Maatouk M Malik S Spontaneous splenic rupture: A rare life-threatening condition; diagnosed early and managed successfully Am J Case Rep 2013 14 13 5 23569554 \n4 Kocael PC Simsek O Bilgin IA Tutar O Saribeyoglu K Pekmezci S Characteristics of patients with spontaneous splenic rupture Int Surg 2014 99 714 8 25437576 \n5 Maria V Saad AM Fardellas I Spontaneous spleen rupture in a teenager: An uncommon cause of acute abdomen Case Rep Med 2013 2013 675372 23710190\n\n",
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"other_id": null,
"pages": "269-270",
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"pubdate": "2020",
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"title": "Spontaneous splenic rupture 1 week after laparoscopic appendectomy due to acute appendicitis.",
"title_normalized": "spontaneous splenic rupture 1 week after laparoscopic appendectomy due to acute appendicitis"
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"abstract": "OBJECTIVE\nTo explore the clinical efficacy and safety of EPOCH±R followed by DICE±R regimen for primary breast diffuse large B-cell lymphoma.\n\n\nMETHODS\nForty-three patients with primary breast diffuse large B-cell lymphoma were admitted in our hosptial from January 2000 to April 2016. Among them 24 patients were treated with CHOP±R regimen, 19 patients were treated with EPOCH±R followed by DICE±R regimen. The clinical efficacy, survival rate and adverse effects were observed and compared between them.\n\n\nRESULTS\nThe complete rate in EPOCH±R followed by DICE±R regimen group was higher than that in the CHOP±R group (84.2% vs 70.8%), and the relapsed rate was lower in EPOCH±R followed by DICE±R regimen group than that in the CHOP±R group (6.25% vs 35.3%). Progression-free survival (PFS) and overall survival (OS) rates of 5 years after diagnosis in the EPOCH±R followed by DICE±R group were significantly higher as compared with that in CHOP±R group (PFS, 75% vs 47.4%, P=0.035; OS, 73.3% vs 45.2%, P= 0.043). Treatment-related hematologic adverse events were more serious in the EPOCH±R followed by DICE±R group(63.2% vs 25%). However, these adverse events were controlled and no treatment-related deaths were observed. Multivariate analysis showed that age (P=0.008; 95% CI, 0.026 to 0.579), radiotherapy (P=0.045; 95% CI, 1.028 to 14.719) and LDH level (P=0.007; 95% CI, 0.017 to 0.531) were independent prognostic factors for 5 year overall survival.\n\n\nCONCLUSIONS\nEPOCH±R followed by DICE±R regimen is an effective and safe treatment regimen for PB-DLBCL. Prognostic factors for survival are age, LDH level and radiotherapy.",
"affiliations": "Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Institute of Hematology, Zhengzhou 450008, Henan Province , China.;Department of Hematology, Zhejiang Taizhou Central Hospital, Taizhou 31800, Zhejiang Province, China.;Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Institute of Hematology, Zhengzhou 450008, Henan Province , China.;Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Institute of Hematology, Zhengzhou 450008, Henan Province , China.;Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Institute of Hematology, Zhengzhou 450008, Henan Province , China. E-mail: [email protected].;Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Institute of Hematology, Zhengzhou 450008, Henan Province , China.;Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Institute of Hematology, Zhengzhou 450008, Henan Province , China.",
"authors": "Dong|Li-Hua|LH|;Chen|Jian-Lin|JL|;Gao|Xue|X|;Li|Gang-Ping|GP|;Li|Yu-Fu|YF|;Song|Yong-Ping|YP|;Wei|Xu-Dong|XD|",
"chemical_list": "D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
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"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101084424",
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"title": "Clinical Efficacy of EPOCH±R Followed by DICE±R Regimen for Primary Breast Diffuse Large B-Cell Lymphoma.",
"title_normalized": "clinical efficacy of epoch r followed by dice r regimen for primary breast diffuse large b cell lymphoma"
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{
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"reactionoutcome": "6"
},
{
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},
{
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},
{
"reactionmeddrapt": "Hypokalaemia",
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"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DONG L, CHEN J, GAO X, LI G, LI Y, SONG Y AND WEI X. CLINICAL EFFICACY OF EPOCH +/- R FOLLOWED BY DICE +/- R REGIMEN FOR PRIMARY BREAST DIFFUSE LARGE B-CELL LYMPHOMA. JOURNAL OF EXPERIMENTAL HEMATOLOGY 2017?25 (3):766-771.",
"literaturereference_normalized": "clinical efficacy of epoch r followed by dice r regimen for primary breast diffuse large b cell lymphoma",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20190211",
"receivedate": "20190211",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 15945718,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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"transmissiondate": "20190417"
}
] |
{
"abstract": "Future fertility is a concern for many young breast cancer survivors. Secondary amenorrhea occurs frequently during or soon after oncologic treatment. Return of menstruation and serum biomarkers are not absolute predictors of future fertility. We report a case of a 28 year old gravida 0 with recurrent Stage IIB invasive ductal breast carcinoma who managed to conceive twice despite showing clinical and biochemical signs of decreased ovarian reserve following treatment with chemotherapy and radiation. This case illustrates the potential for fertility in a patient with breast cancer despite chemotherapy-related amenorrhea and undetectable anti-Müllerian hormone levels. It exemplifies the imprecise nature of all clinical tests used to predict future fertility in breast cancer patients post-treatment. It should remind all providers to be careful in basing recommendations for childbearing on these surrogate endpoints.",
"affiliations": "Department of Obstetrics and Gynecology Columbia University Medical Center 622 W 168th St. PH-16 10032 New York NY USA.;Department of Medicine Columbia University Medical Center 622 W 168th St. PH-8 10032 New York NY USA.;Department of Obstetrics and Gynecology Columbia University Medical Center 622 W 168th St. PH-16 10032 New York NY USA.;Department of Obstetrics and Gynecology Columbia University Medical Center 622 W 168th St. PH-16 10032 New York NY USA.",
"authors": "Mahany|Erica B|EB|;Hershman|Dawn L|DL|;Sauer|Mark V|MV|;Choi|Janet M|JM|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12522-012-0133-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1445-5781",
"issue": "12(1)",
"journal": "Reproductive medicine and biology",
"keywords": "Breast neoplasms; Chemoradiotherapy; Fertility; Ovarian function tests; Pregnancy",
"medline_ta": "Reprod Med Biol",
"mesh_terms": null,
"nlm_unique_id": "101213278",
"other_id": null,
"pages": "35-38",
"pmc": null,
"pmid": "29699128",
"pubdate": "2013-01",
"publication_types": "D002363:Case Reports",
"references": "19918920;16820385;18080443;20602496;16720842;15824416;12973836;8141209;16476708;20187091;21411023;19409543;21326118;19691088;16134178;17061039;14745861;17158581;21221981",
"title": "Pregnancy despite ovarian insufficiency in a patient with breast cancer.",
"title_normalized": "pregnancy despite ovarian insufficiency in a patient with breast cancer"
}
|
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"abstract": "OBJECTIVE\nTo study an alternative strategy for the treatment of radial artery occlusion (RAO) using balloon angioplasty and intrathrombus administration of abciximab.\n\n\nBACKGROUND\nRAO is a well-described complication of transradial procedures. The optimal method to restore the patency of the radial artery following its occlusion remains unclear. Spontaneous recanalization can occur in some patients and systemic anticoagulation can be recommended but is often unsuccessful.\n\n\nMETHODS\nA retrospective review of all patients in our database from 2009 to 2013 with RAO who underwent treatment with balloon angioplasty and intra-arterial abciximab administered directly at the site of occlusion.\n\n\nRESULTS\nFour patients with symptomatic RAO following transradial catheterization were treated with balloon angioplasty and a 90-second intrathrombus infusion of abciximab. All procedures were successful and patency was documented the following day with duplex sonography and again at follow-up (mean 189 days). The patients also remained free of symptoms at follow-up. The fifth patient was treated with balloon angioplasty alone. This patient suffered symptomatic reocclusion of the radial artery.\n\n\nCONCLUSIONS\nBalloon angioplasty and intrathrombus administration of abciximab via a catheter appears to be a safe, effective, and durable technique for reestablishing the patency of an occluded radial artery following transradial catheterization. Larger studies are needed to confirm our findings and establish the role for this technique in an algorithm for treatment of RAO.",
"affiliations": "Indiana University Health Cardiology, Indianapolis, Indiana.",
"authors": "Jaradat|Ziad|Z|;Basir|Babar|B|;Revtyak|George|G|",
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"abstract": "Status asthmaticus is a life-threatening disorder that can manifest in dangerous levels of hypercapnia and acidosis. The use of extracorporeal carbon dioxide removal (ECCO2R) has been used successfully to control pH and PaCO2 in patients with acute severe asthma. The present report describes the use of this technology in near-fatal asthma with brain death, and awaiting organ harvest. The ProLUNG® system consists of a veno-venous hemoperfusion circuit with an artificial lung polymethylpentene membrane coated with phosphorylcholine with a surface of 1.81 m2. The system can reach a blood flow of 450 ml/min trough a double-lumen central venous catheter (13.0 Fr) placed in femoral, subclavian or jugular vein. The platform is provided with automated management of airflow and VCO2 monitoring during treatment. The patient was maintained on extracorporeal treatment ensuring stable arterial pH control and PaCO2 control. In acute status asthmaticus, complicated with cardiac arrest, mini-invasive ECCO2R was an effective method of controlling pH and PaCO2, for optimizing hemodynamic and aerobic metabolism and for performing protective ventilation for an optimal organ donor preservation until the organ harvest occurs.",
"affiliations": "International Renal Research Institute of Vicenza, Vicenza, Italy.;International Renal Research Institute of Vicenza, Vicenza, Italy.;International Renal Research Institute of Vicenza, Vicenza, Italy.",
"authors": "De Rosa|Silvia|S|;Golino|Gianlorenzo|G|;Ronco|Claudio|C|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30391-010.1016/j.rmcr.2020.101010101010Case ReportExtracorporeal carbon dioxide removal in heart-beating donor with acute severe asthma: A case report De Rosa Silvia [email protected]∗Golino Gianlorenzo abcRonco Claudio adea International Renal Research Institute of Vicenza, Vicenza, Italyb Department of Anesthesiology and Intensive Care, San Bortolo Hospital, Vicenza, Italyc Department of Medicine – DIMED, Section of Anesthesiology and Intensive Care Medicine, University of Padova, Padova, Italyd Department of Nephrology, Dialysis and Transplantation and International Renal Research Institute of Vicenza, San Bortolo Hospital, Vicenza, Italye Department of Medicine, University of Padova, Padova, Italy∗ Corresponding author. Department of Anesthesiology and Intensive Care Medicine, AULSS 8 Berica, San Bortolo Hospital, Viale Rodolfi 37, 36100, Vicenza, Veneto, Italy. [email protected] 1 2020 2020 28 1 2020 29 1010105 12 2019 25 1 2020 25 1 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/).Status asthmaticus is a life-threatening disorder that can manifest in dangerous levels of hypercapnia and acidosis. The use of extracorporeal carbon dioxide removal (ECCO2R) has been used successfully to control pH and PaCO2 in patients with acute severe asthma. The present report describes the use of this technology in near-fatal asthma with brain death, and awaiting organ harvest.\n\nThe ProLUNG® system consists of a veno-venous hemoperfusion circuit with an artificial lung polymethylpentene membrane coated with phosphorylcholine with a surface of 1.81 m2. The system can reach a blood flow of 450 ml/min trough a double-lumen central venous catheter (13.0 Fr) placed in femoral, subclavian or jugular vein. The platform is provided with automated management of airflow and VCO2 monitoring during treatment.\n\nThe patient was maintained on extracorporeal treatment ensuring stable arterial pH control and PaCO2 control.\n\nIn acute status asthmaticus, complicated with cardiac arrest, mini-invasive ECCO2R was an effective method of controlling pH and PaCO2, for optimizing hemodynamic and aerobic metabolism and for performing protective ventilation for an optimal organ donor preservation until the organ harvest occurs.\n\nKeywords\nAcute hypercapnic respiratory failureExtracorporeal carbon dioxide removalHypercapniaNear-fatal asthmaRespiratory dialysisStatus asthmaticus\n==== Body\n1 Introduction\nStatus asthmaticus is a life-threatening disorder that can manifest in dangerous levels of hypercapnia and acidosis, with a significant mortality and morbidity [1]. Peripheral tissue perfusion and oxygenation depend on various factors, including inspired oxygen concentration, arterial oxygen tension [2], hemoglobin concentration [3], cardiac output [4], local perfusion [5] and the autonomous response to stress in pain [6]. Different concentrations of carbon dioxide can alter some of these parameters. Mechanical ventilation (MV) can cause increased air trapping and hyperinflation, predisposing the lungs to barotraumas [7,8]. Although with well-defined indications, extracorporeal membrane oxygenation (ECMO) is generally recommended in the setting of potentially reversible cardiopulmonary failure poorly responsive to maximal conventional medical [8]. Since hypercarbia rather than hypoxemia is the primary abnormality in asthmaticus status, the use of extracorporeal carbon dioxide removal (ECCO2R) must also be given consideration. ECCO2R is a partial respiratory support technique that, based on the use of an extracorporeal circuit with a gas-exchanging membrane, achieves a relevant CO2 clearance directly from the blood, at a blood flow in the range of 0.4–1 L/min [[9], [10], [11]]. Interestingly, the concept of mini-invasive ECCO2R, where a proper design of the artificial lung can ensure a clinically relevant CO2 removal amount at a blood flow around 400 ml/min using a double lumen venous-venous vascular access between 12 and 14 Fr, like the ones commonly used for continuous renal replacement therapies.\n\nNowadays, ECCO2R systems are proposed as respiratory support for recovery, or to facilitate protective ventilation [9]. The present case report describes the use of mini-invasive ECCO2R in a near-fatal asthma patient with brain death awaiting organ harvest.\n\n2 Case report\nA 51 year-old male was admitted to the hospital after collapse and respiratory arrest. He had a medical history of bronchial asthma for 3 years duration and was currently taking inhaled corticosteroids with a long acting beta-2 agonist (budesonide/formoterol) and short acting beta-2 agonist (Salbutamol), as needed. His past medical history was significant for allergic reactions to levofloxacin and ceftriaxone. His parents reported that, during the last 10 days, he had more frequent dyspnea episodes, and a poor medication adherence. During the course of his work in the tannery, he fell unconscious as a result of cardiac arrest. The cardiac arrest was witnessed firstly by volunteers, then by an advanced cardiac life support team hat immediately started advanced cardiopulmonary resuscitation (first return of spontaneous circulation achieved in 40’). After successful resuscitation with standard cardiopulmonary resuscitation with chest compressions and epinephrine, he was transferred to the Shock Room. On admission, SaO2 96%, heart rate 105 b.p.m., blood pressure 60/40 mmHg, normal heart sounds with no additional murmurs, and his chest was positive on auscultation for end-expiratory wheezing. There was no elevation of cardiac enzymes. His electrocardiography was unremarkable. Echocardiography was performed, which also showed no abnormalities. In the absence of any cardiac abnormalities, his case was managed as exacerbation of bronchial asthma. At admission, the patient was unresponsive with a Glasgow Coma Scale of 3 (E1VtM1) weakly preserved brainstem reflexes. Initial arterial blood gas showed pH 6.76, PaCO2 132.4 mmHg, PaO2 89.4 mmHg, Bicarbonate 18.5 mmol/L, Base Excess −18.3.\n\nHe failed to respond to nebulized salbutamol and therapeutic doses of intravenous aminophylline, magnesium sulfate, and steroids. MV was attempted in accordance with general principles of ventilation for severe acute asthma: sedation and analgesia, neuromuscular blocking drugs, low respiratory rate, prolonged expiratory time, and low extrinsic positive end-expiratory pressure. Intrinsic positive end-expiratory pressure (PEEP) (PEEPi) was 14 cmH2O. Fig. 1 shows the pressure–time waveform on the volume preset ventilation mode. However, the patient remained hypercapnic and acidotic. We started a target controlled inhalative sedation with Sevofluorane through Mirus™ system (Pall Medical, Dreieich, Germany) with etSEVO of 2%. After 2 hrs of ventilation and Sevoflurane, PaCO2 had reached 71.7 mm Hg with pH of 7.08.Fig. 1 The pressure–time waveform on the volume preset ventilation mode.\n\nChanges in the pressure–time waveform secondary to the presence of bronchospasm with associated gas trapping or Similar degree of increase in both PIP and Pplat.\n\nPIP indicates peak inspiratory pressure; Pplat, plateau pressure, PEEP, positive end-expiratory pressure.\n\nFig. 1\n\nBecause of the failure of this trial of MV to control the PaCO2 and arterial pH, it was decided to reduce PaCO2 with the ProLUNG® (Estor SpA, Pero, Italy). The ProLUNG® system consists of a veno-venous hemoperfusion circuit with a gas exchanger device (surface of 1.81 m2 of polymethylpentene membrane coated with phosphorylcholine). Anticoagulation was performed with continuous administration of low dosage of Heparin (7.5 IU/kg/h). The veno-venous CO2 removal (VVCO2R) relies on a peristaltic pump to drive blood flow through the system.\n\nUnder ultrasound guidance, a 13.0 Fr double lumen catheter was inserted into the right femoral vein using the Seldinger technique. The system was primed with saline and Heparin and attached to the vascular catheter. Blood was then gently released into the ProLUNG circuit, with an initial flow of 400 mL/min through the catheter. The patient was maintained on this system with adequate control of the PaCO2 and arterial pH. After two hours, this produced a corresponding fall in PaCO2 to 42.7 mm Hg and pH 7.24. Fig. 2 shows changes in pH, PaCO2, vasoactive inotropic score and lactate before and after ProLUNG. Unresponsive mydriasis was also noted (Right Eye 4.7 mm with 1% of reactivity to the light stimulus, Left Eye 5.2 mm with 0% of reactivity to the light stimulus). A first electroencephalogram (EEG) showed no status epilepticus and slow activity. Twenty-four hours later, brainstem reflexes disappeared. Second EEG was flat. VVCO2R was stopped after 30 hours to determine the absence of brain-stem reflexes (included hypercapnia testing). The patient was pronounced brain dead, and the family agreed to organ donation. Both kidneys, the liver and pancreas were recovered and subsequently transplanted into 4 recipients.Fig. 2 Arterial pH, paCO2, Vasoactive Inotropic Score and Lactate before and after VVCO2R.\n\nFig. 2\n\n3 Discussion\nA substantial percentage of 4% of acute asthma exacerbation requires admission to intensive care and one third of these patients require endotracheal intubation and MV [12,13]. Risk factors for NFA requiring MV include a younger age at presentation, poor compliance with prescribed therapy, poor outpatient follow-up, more than three emergency department visits in the preceding year, recent hospital admission, a prior episode of NFA and prior MV [14]. In the present case report, the patient had poor compliance with prescribed therapy and poor follow-up. The significant heart-lung interaction present in patients with asthma causes hemodynamic instability. An increase in intrathoracic pressure secondary to gas trapping (dynamic hyperinflation) can lead to an acute increase in pulmonary vascular resistance and right heart pressure, with impaired venous return, right ventricular preload of the right ventricular afterload and then left ventricular diastolic volume and cardiac output [15]. In our patient, when we selected the mode of ventilation, we considered the degree of underlying airway resistance and the presence of gas trapping, alveolar hyperinflation and permissive hypercapnia. On ventilator waveform, the airflow resistance was indicated by elevated peak inspiratory pressure together with an increase in peak inspiratory pressure to plateau pressure gradient. Plateu pressure (Pplat) was high. Although plateau pressure is a reflection of lung compliance or alveolar pressure and pathophysiology of asthma does not directly involve the alveoli, an increase in Pplat would suggest the presence of either worsening bronchospasm with associated gas trapping or an expanding pneumothorax [[16], [17], [18]]. Gas trapping, also described as PEEPi, auto-PEEP, dynamic hyperinflation, or expiratory airflow obstruction, should be quantified by measuring the total volume of exhaled gas during a 20- to 40-s period of apnea (end-inspiratory lung volume) [19]. We determined the presence of PEEPi by real time analysis of ventilator waveform graphics. We observed increase in pressure above the set PEEP after initiating an end-expiratory hold maneuver with the patient paralyzed. The difference between this and the set PEEP was the PEEPi, that in our case was 14 cmH20. In presence of a further worsening of hypercapnia, despite the MV, nebulized salbutamol, therapeutic doses of intravenous aminophylline, magnesium sulfate, and steroids, the use of modified extracorporeal membrane oxygenation (ECMO) techniques such as extracorporeal carbon dioxide removal (ECCO2 R) was taken in consideration. In literature, ECMO is generally recommended in the setting of potentially reversible cardiopulmonary failure that is poorly responsive to maximal conventional medical treatment. However, although literature is confined to a few case reports [20,21], a recent review of the multicenter International Extracorporeal Life Support Organization registry by Mikkelsen and colleagues [22] documented that status asthmaticus was the primary indication for ECMO in 24 of 1257 adult patients included in the registry. A total of 20 (83.3%) patients with asthma survived to hospital discharge, whereas only 50.8% of patients with other causes of respiratory failure (odds ratio 4.86) survived therapy. Extracorporeal carbon dioxide removal, when compared to ECMO, is less invasive, requires a single venous catheter and a lower blood flow rate. MacDonnell et al. reported the first use of ECCO2R as an adjunct to IMV for refractory asthma [23]. Subsequently, Brenner et al. reported two patients with refractory status asthmaticus managed with ECCO2R, emphasizing the challenges in managing patients with distinct asthma exacerbation phenotypes, the use of modern extracorporeal technology and a new perspective of the role of ECCO2R for status asthmaticus [24]. Sakai et al. [25], Elliot et al. [26], Jung et al. [27] reported cases of successful treatment with ECCO2R for status asthmaticus. Despite our interventions aimed at improving the patient's ventilation, unfortunately our patient suffered a brain death, so our objective shifted towards preserving the organs of the potential donor, limiting the harmful effects of hypercapnia. Brain death diagnosis and donor care are becoming important for patients awaiting organ transplants due to organ failure. However, in patients with brain death with cardiorespiratory insufficiency, such as acute myocardial infarction and acute respiratory distress syndrome, it is difficult to protect donor organs not only from ischemic damage but also from damage related to high CO2 levels. Particularly, hypercarbia leads to cerebral ischemia, brain edema, and increased ICP mutually resulting in a vicious cycle. The vasodilatation effect of increased PaCO2 also affects systemic vasculature, thus causing hypotension. Several studies have shown that the most frequent complication of apnea testing, as high as 39%, is hypotension [26,27], as a result of peripheral vasodilatation, acidosis, and the cardio-depressant effects of CO2. The harmful apnea test consists in the disconnection of the patient from the ventilator to let the PaCO2 rise at least 20 mmHg above the baseline, while oxygenation is preserved via a catheter down the endotracheal tube delivering 100% O2 [28]. This apnea test is harmful because the hypercarbia that results can bring the cerebral blood flow below the critical level of 10–15 ml/100 g/min, below which the irreversible damage of the brain tissue occurs [29]. Extracorporeal carbon dioxide removal could be an useful therapeutic tool. In our case brain death occurred, and we continued with ECCO2 R for its organ‐preserving role. The treatment was discontinued for procedure for Clinical Assessment of Brain Death and in order to perform apnea test.\n\n4 Conclusion\nIn status asmaticus complicated with cardiac arrest, veno-venous extracorporeal carbon dioxide removal was an effective method of controlling pH and PaCO2, to optimize hemodynamic and aerobic metabolism and to perform a protective ventilation for an optimal preservation in organ donor until organ harvest.\n\nStatement of ethics\nThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The patient gave his consent for publication of the report.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAuthors' contributions\nSDR and GG wrote the first draft of the manuscript and provided revisions; CR critically revised the manuscript. All the authors read and approved the final version of the manuscript.\n\nDeclaration of competing interest\nThe authors do not have any conflicts of interest to disclose.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgement\nNone.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2020.101010.\n==== Refs\nReferences\n1 McFadden E.R. Jr. Acute severe asthma Am. J. Respir. Crit. Care Med. 168 2003 740 759 14522812 \n2 Greif R. Akça O. Horn E.P. Kurz A. Sessler D.I. Outcomes Research Group Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection N. Engl. J. Med. 342 3 2000 Jan 20 161 167 10639541 \n3 Gosain A. Rabkin J. Reymond J.P. Jensen J.A. Hunt T.K. Upton R.A. Tissue oxygen tension and other indicators of blood loss or organ perfusion during graded hemorrhage Surgery 109 4 1991 Apr 523 532 2008657 \n4 Shoemaker W. Appel P. Kram H. Oxygen transport measurements to evaluate tissue perfusion and titrate therapy: dobutamine and dopamine effects Crit. Care Med. 19 1991 672 688 2026030 \n5 Ikeda T. Tayefeh F. Sessler D.I. Kurz A. Plattner O. Petschnigg B. Local radiant heating increases subcutaneous oxygen tension Am. J. Surg. 175 1998 33 37 9445236 \n6 Akça O. Melischek M. Scheck T. Hellwagner K. Arkiliç C.F. Kurz A. Postoperative pain and subcutaneous oxygen tension Lancet 354 1999 41 42 10406365 \n7 Oddo M. Feihl F. Schaller M.D. Perret C. Management of mechanical ventilation in acute severe asthma: practical aspects Intensive Care Med. 32 4 2006 Apr 501 510 16552615 \n8 Laher A.E. Buchanan S.K. Mechanically ventilating the severe asthmatic J. Intensive Care Med. 33 9 2018 Sep 491 501 29105540 \n9 Barrett N.A. Camporota L. The evolving role and practical application of extracorporeal carbon dioxide removal in critical care Crit. Care Resusc. 19 Suppl 1 2017 62 67 31 29084503 \n10 Camporota L. Barrett N. Current applications for the use of extracorporeal carbon dioxide removal in critically ill patients BioMed Res. Int. 2016 2016 9781695 26966691 \n11 Baker A. Richardson D. Craig G. Extracorporeal carbon dioxide removal (ECCO2R) in respiratory failure: an overview, and where next? J. Intensive Care Soc. 13 2012 232 237 \n12 Pendergraft T.B. Stanford R.H. Beasley R. Stempel D.A. Roberts C. McLaughlin T. Rates and characteristics of intensive care unit admissions and intubations among asthma-related hospitalizations Ann. Allergy Asthma Immunol. 93 1 2004 29 35 15281469 \n13 McFadden E.R. Acute severe asthma Am. J. Respir. Crit. Care Med. 168 7 2003 740 759 14522812 \n14 Cherpanath T.G.V. Lagrand W.K. Schultz M.J. Groeneveld A.B.J. Cardiopulmonary interactions during mechanical ventilation in critically ill patients Neth. Heart J. 21 4 2013 166 172 23460128 \n15 Rafanan A. Ventilator waveforms: interpretation [ published online August 12, 2014] http://www.apsresp.org/pdf/esap/esap-201408-lectures/gp-2-1.pdf \n16 Nagarjuna M. Ventilator waveform analysis [ published online July 19, 2016] http://www.indiachest.org/wp-content/uploads/2016/07/Ventilator-waveform-analysis_nagarjuna_2012.pdf \n17 Williams T.J. Tuxen D.V. Scheinkestel C.D. Czarny D. Bowes G. Risk factors for morbidity in mechanically ventilated patients with acute severe asthma Am. Rev. Respir. Dis. 146 3 1992 607 615 1519836 \n18 Chang C. Yates D. Use of early extra-corporeal membrane oxygenation (ECMO) for severe refractory status asthmaticus J. Med. Cases 2 3 2011 124 126 \n19 Alzeer A.H. Al Otair H.A. Khurshid S.M. Badrawy S.E.I. Bakir B.M. A case of near fatal asthma: the role of ECMO as rescue therapy Ann. Thorac. Med. 10 2 2015 143 145 25829967 \n20 Mikkelsen M.E. Woo Y.J. Sager J.S. Fuchs B.D. Christie J.D. Outcomes using extracorporeal life support for adult respiratory failure due to status asthmaticus Am. Soc. Artif. Intern. Organs J. 55 1 2009 47 52 \n21 MacDonnell K.F. Moon H.S. Sekar T.S. Ahluwalia M.P. Extracorporeal membrane oxygenator support in a case of severe status asthmaticus Ann. Thorac. Surg. 31 2 1981 Feb 171 175 7458488 \n22 Brenner K. Abrams D.C. Agerstrand C.L. Brodie D. Extracorporeal carbon dioxide removal for refractory status asthmaticus: experience in distinct exacerbation phenotypes Perfusion 29 1 2014 Jan 26 28 23842616 \n23 Sakai M. Ohteki H. Doi K. Narita Y. Clinical use of extracorporeal lung assist for a patient in status asthmaticus Ann. Thorac. Surg. 62 3 1996 Sep 885 887 8784029 \n24 Elliot S.C. Paramasivam K. Oram J. Bodenham A.R. Howell S.J. Mallick A. Pumpless extracorporeal carbon dioxide removal for life-threatening asthma Crit. Care Med. 35 3 2007 Mar 945 948 17255862 \n25 Jung C. Lauten A. Pfeifer R. Pumpless extracorporeal lung assist for the treatment of severe refractory status asthmaticus J. Asthma 48 2011 111 113 21039186 \n26 Goudreau J.L. Wijdicks E.F. Emery S.F. Complications during apnea testing in the determination of brain death: predisposing factors Neurology 55 7 2000 Oct 10 1045 1048 11061269 \n27 Saposnik G. Rizzo G. Vega A. Sabbatiello R. Deluca J.L. Problems associated with the apnea test in the diagnosis of brain death Neurol. India 52 3 2004 Sep 342 345 15472423 \n28 Joffe A.R. Anton N.R. Duff J.P. The apnea test: rationale, confounders, and criticism J. Child Neurol. 25 11 2010 Nov 1435 1443 20460247 \n29 Galli Coimbra Cicero Are “brain dead” (or “brain-stem dead'‘) patients neurologically recoverable? De Mattei Roberto Byrne Paul A. Finis Vitae: “Brain Death” Is Not True Death 2009 Life Guardian Foundation Oregon, Ohio 313–78\n\n",
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"pmid": "32042585",
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"references": "29084503;21039186;10639541;29105540;19092662;20460247;8784029;15472423;2008657;9445236;11061269;25829967;2026030;26966691;17255862;23460128;14522812;16552615;7458488;23842616;15281469;10406365;1519836",
"title": "Extracorporeal carbon dioxide removal in heart-beating donor with acute severe asthma: A case report.",
"title_normalized": "extracorporeal carbon dioxide removal in heart beating donor with acute severe asthma a case report"
}
|
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}
] |
{
"abstract": "A case of addiction to Diazepam is reported. Severe withdrawal symptoms such as tremulousness, irritability, increased psychomotor activity, generalized muscle cramps, photophobia, retro-orbital pains and insomnia are described. Visual hallucinations, illusions, and paranoid features are also present in this case. Detoxification and management were accomplished by gradual withdrawal and the addition of another tranquilizer, anticonvulsant and muscle relaxant. The author reviews other such reports of abuse and addiction in the literature which call for wide recognition of the addictive properties of Diazepam and for restrictions on its indiscriminate prescription by physicians.",
"affiliations": null,
"authors": "Agrawal|P|P|",
"chemical_list": "D003975:Diazepam",
"country": "Canada",
"delete": false,
"doi": "10.1177/070674377802300106",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-4824",
"issue": "23(1)",
"journal": "Canadian Psychiatric Association journal",
"keywords": null,
"medline_ta": "Can Psychiatr Assoc J",
"mesh_terms": "D000328:Adult; D017109:Akathisia, Drug-Induced; D003975:Diazepam; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders",
"nlm_unique_id": "0414266",
"other_id": null,
"pages": "35-7",
"pmc": null,
"pmid": "638930",
"pubdate": "1978-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diazepam addiction: a case report.",
"title_normalized": "diazepam addiction a case report"
}
|
[
{
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"occurcountry": "US",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "OVER A PERIOD OF THREE WEEKS SHE STARTED TO INCREASE THE DOSE INDISCRIMINATELY AND WAS TAKING UP TO",
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},
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},
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"drugdosagetext": "ON THE 5TH DAY OF TREATMENT OF WITHDRAWAL SYNDROME AND STOPPED ABRUPTLY",
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{
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},
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"drugdosagetext": "THEN RAPIDLY INCREASED IT TO 240 MG PER DAY FOR A TWO-WEEK PERIOD",
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},
{
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"activesubstancename": "DIAZEPAM"
},
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"drugdosagetext": "PLAN WAS TO DECREASE DIAZEPAM BY 10 MG/DAY",
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},
{
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},
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"drugindication": "BACK PAIN",
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],
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"patientonsetage": "30",
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"reaction": [
{
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Electrocardiogram abnormal",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug dependence",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Haemoglobin decreased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
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"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20191009",
"receivedate": "20191009",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
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"transmissiondate": "20200122"
}
] |
{
"abstract": "We report FK506-induced neurotoxicity in 14 of 44 consecutive patients following orthoptic liver transplantation. In 10 of these 14 patients, postural hand tremors were found in the first weeks following surgery, transient apraxia of speech in 3, and generalized tonic-clonic seizures were noted in 2 patients. Other manifestations included nightmares, agitation, and acute delirium. Reduction of the FK506 dose resulted in resolution of symptoms, but in 1 patient mild speech difficulties and in 3 patients a fine tremor remained. Blood and plasma levels of FK506 were similar in patients with and without neurotoxicity. FK506 neurotoxicity in patients with liver transplantation commonly results in transient neurological manifestations. The incidence of neurotoxicity in FK506 is dramatically reduced in maintenance doses of 0.075 mg/kg twice a day.",
"affiliations": "Department of Neurology (Critical Care Neurology), Mayo Clinic, Rochester, MN 55905.",
"authors": "Wijdicks|E F|EF|;Wiesner|R H|RH|;Dahlke|L J|LJ|;Krom|R A|RA|",
"chemical_list": "D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/ana.410350422",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-5134",
"issue": "35(4)",
"journal": "Annals of neurology",
"keywords": null,
"medline_ta": "Ann Neurol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D016559:Tacrolimus",
"nlm_unique_id": "7707449",
"other_id": null,
"pages": "498-501",
"pmc": null,
"pmid": "7512320",
"pubdate": "1994-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "FK506-induced neurotoxicity in liver transplantation.",
"title_normalized": "fk506 induced neurotoxicity in liver transplantation"
}
|
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{
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{
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"activesubstancename": "TACROLIMUS"
},
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"drugindication": "IMMUNOSUPPRESSION",
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"medicinalproduct": "TACROLIMUS."
},
{
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"abstract": "This study aimed to describe the clinical findings and management of eyes affected by uveal effusion syndrome.\n\n\n\nWe retrospectively evaluated the charts of 13 eyes of 8 consecutive patients diagnosed with uveal effusion syndrome attending the Ophthalmology Unit of the University Hospitals Leuven, Belgium, between 2007 and 2018. The presenting features, investigations, management, and outcomes were analyzed for each case.\n\n\n\nCataract surgery was the predisposing factor for uveal effusion in 6 eyes, 2 bilateral uveal effusions (4 eyes) were considered to be medication-induced, and in 3 eyes, the uveal effusion was described as idiopathic. Fundus examination of 5 of 13 eyes showed bullous choroidal detachment, treated with pars plana vitrectomy with superotemporal sclerectomy or transscleral punction. Fundoscopy showed uveal effusion without serous retinal detachment in 3 eyes. Serous retinal detachment accompanied by uveal swelling was observed in 3 eyes and the 2 remaining eyes presented with uveal swelling only. The 8 nonbullous choroidal detachments were treated in a conservative way. A rapid resolution of subretinal fluid and uveal effusion was observed in all cases.\n\n\n\nA conservative approach with acetazolamide treatment or just observation was used in our case series in choroidal detachment without substantial visual loss if, over time, slow improvement was documented. However, further studies are needed to verify the effectiveness of the reported therapy.",
"affiliations": "Department of Ophthalmology, University Hospitals Leuven.;Department of Ophthalmology, University Hospitals Leuven.;Department of Ophthalmology, University Hospitals Leuven.;Department of Ophthalmology, University Hospitals Leuven.;Department of Ophthalmology, University Hospitals Leuven.;Department of Ophthalmology, University Hospitals Leuven.",
"authors": "Claeys|Emilie|E|;Stalmans|Peter|P|;Van Calster|Joachim|J|;Casteels|Ingele|I|;Stalmans|Ingeborg|I|;Vandewalle|Evelien|E|",
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"issue": "29(10)",
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"nlm_unique_id": "9300903",
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"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
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"title": "A Retrospective Case Series of Uveal Effusion Syndrome.",
"title_normalized": "a retrospective case series of uveal effusion syndrome"
}
|
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},
{
"reactionmeddrapt": "Vision blurred",
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"literaturereference": "CLAEYS E., STALMANS P., VAN CALSTER J., CASTEELS I., STALMANS I., VANDEWALLE E.. A RETROSPECTIVE CASE SERIES OF UVEAL EFFUSION SYNDROME. JOURNAL OF GLAUCOMA. 2020?UNK:UNK",
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{
"abstract": "We describe two fatal cases of low dose methotrexate (MTX) toxicity in patients with psoriasis, emphasizing the factors that exacerbate MTX toxicity. The first patient was a 50-year-old male of psoriasis on intermittent treatment with MTX. After a treatment-free period of six months, he had self-medication of MTX along with analgesic for joint pain for one week which followed ulceration of the lesions, bone marrow suppression, and eventually death. The second patient was a 37-year-old male of psoriasis, who has taken MTX one week earlier without prior investigations. He had painful ulcerated skin lesions and bone marrow suppression. On investigations, he showed high creatinine level and atrophied, nonfunctioning right kidney on ultrasonography. In spite of dialysis, he succumbed to death. MTX is safe and effective if monitored properly, but inadvertent use may lead to even death also. Prior workup and proper counseling regarding the drug interactions as well as self-medication should be enforced.",
"affiliations": "Department of Skin & VD, Government Medical College & New Civil Hospital, Surat, Gujarat 395001, India.;Department of Skin & VD, Government Medical College & New Civil Hospital, Surat, Gujarat 395001, India.;Department of Skin & VD, Government Medical College & New Civil Hospital, Surat, Gujarat 395001, India.;Department of Skin & VD, GMERS Medical College & General Hospital, Gotri 202, Wings Ville 41, Arunoday Society, Alkapuri, Vadodara, Gujarat 390001, India.;Department of Skin & VD, Government Medical College & New Civil Hospital, Surat, Gujarat 395001, India.",
"authors": "Jariwala|Pankti|P|;Kumar|Vinay|V|;Kothari|Khyati|K|;Thakkar|Sejal|S|;Umrigar|Dipak Dayabhai|DD|",
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"fulltext": "\n==== Front\nCase Rep Dermatol MedCase Rep Dermatol MedCRIDMCase Reports in Dermatological Medicine2090-64632090-6471Hindawi Publishing Corporation 10.1155/2014/946716Case ReportAcute Methotrexate Toxicity: A Fatal Condition in Two Cases of Psoriasis Jariwala Pankti \n1\nKumar Vinay \n1\nKothari Khyati \n1\nThakkar Sejal \n2\n*Umrigar Dipak Dayabhai \n1\n1Department of Skin & VD, Government Medical College & New Civil Hospital, Surat, Gujarat 395001, India2Department of Skin & VD, GMERS Medical College & General Hospital, Gotri 202, Wings Ville 41, Arunoday Society, Alkapuri, Vadodara, Gujarat 390001, India*Sejal Thakkar: [email protected] Editor: Jeung-Hoon Lee\n\n2014 8 9 2014 2014 9467167 7 2014 27 8 2014 Copyright © 2014 Pankti Jariwala et al.2014This 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.We describe two fatal cases of low dose methotrexate (MTX) toxicity in patients with psoriasis, emphasizing the factors that exacerbate MTX toxicity. The first patient was a 50-year-old male of psoriasis on intermittent treatment with MTX. After a treatment-free period of six months, he had self-medication of MTX along with analgesic for joint pain for one week which followed ulceration of the lesions, bone marrow suppression, and eventually death. The second patient was a 37-year-old male of psoriasis, who has taken MTX one week earlier without prior investigations. He had painful ulcerated skin lesions and bone marrow suppression. On investigations, he showed high creatinine level and atrophied, nonfunctioning right kidney on ultrasonography. In spite of dialysis, he succumbed to death. MTX is safe and effective if monitored properly, but inadvertent use may lead to even death also. Prior workup and proper counseling regarding the drug interactions as well as self-medication should be enforced.\n==== Body\n1. Introduction\nMethotrexate (MTX), when used in low doses, has anti-inflammatory and immunosuppressive action. Low dose MTX is an effective and safe treatment for psoriasis being used for more than 50 years [1]. Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration [2]. It is also affected by concomitant ingestion of certain drugs which are protein bound like nonsteroidal anti-inflammatory drugs (NSAIDs), sulfonamides, and barbiturates. This demands careful monitoring of renal function tests and blood counts, along with carefully looking for mucosal lesions or ulcerations in skin to identify acute MTX toxicity. Failure to adhere to guidelines may lead to severe toxicity, even death. There are few publications mentioning adverse reactions of MTX, but very few are there mentioning fatality because of such a safe drug. Here, we report two cases that died of MTX toxicity because of just not abiding by the standard protocol.\n\n2. Case Reports\n2.1. Case 1\nA 50-year-old male presented with generalized skin lesions with ulcerations along with erosions over lips and oral cavity and difficulty in swallowing for 2 days. He also had fever with chills.\n\nHe was a known case of psoriasis for 5 years, on MTX (7.5 mg) once weekly for two years. He was under remission and stopped MTX six months earlier. He had aggravation of lesions along with knee joint pains for two weeks. He took oral MTX (7.5 mg/day) daily for one week along with some pain killers by himself. After two days he developed ulcerations over existing lesions along with erosions on lips and oral cavity (Figure 1).\n\nThe patient was conscious with body temperature 103°F, pulse rate 120/minute, and normal respiration and blood pressure. Cutaneous examination revealed generalized multiple annular ulcerated plaques with mucosal erosions. On admission, investigations showed myelosuppression (Hb 6.7 gms, WBC 1200, and 69,000 platelet count) with normal renal and liver profile.\n\nPatient was diagnosed as a case of acute MTX toxicity and treated with intravenous antibiotics and leucovorin and neukine (GM-CSF) injection subcutaneously. He was investigated periodically which showed persistent myelosuppression which was worsening day by day. He was supported with packed cell volume and platelet transfusions. On the fifth day, he was transferred to the intensive care unit for better monitoring. His platelet count increased to 45000/mm3 and WBCs to 1300/mm3 on the 10th day. His liver function deteriorated with bilirubin 8.1 grams on the 10th day. Unfortunately, he expired due to acute respiratory failure after six hours of onset on the 10th day.\n\n2.2. Case 2\nA 37-year-old male, a known case of psoriasis, presented with complaint of reduced oral intake due to painful lesions in the oral cavity, along with fever and chills for three days. He also complained of pain with ulceration in the existing lesions. On careful history taking, it was revealed that he took an unknown amount of oral MTX one week back without prior investigations.\n\nOn examination, he was conscious but febrile with 102°F temperature with normal vitals. Cutaneous examination showed ulcerated and necrotic psoriatic plaques with erythema and tenderness. There were few new pustules on chest and face (Figure 2). He also had crusting and fissuring of the lips along with erosions in oral cavity. On admission, investigations suggested bone marrow suppression (hemoglobin 8.2 grams, WBC 1600 cells/mm3, and platelet count 1,06,000 cells/mm3) and altered renal functions (blood urea 72 and creatinine level 4.8).\n\nBased on the clinical and laboratory findings, he was diagnosed having MTX toxicity and was covered with broad spectrum empirical antibiotics and injectable leucovorin. Sodium bicarbonate was added to aid in the excretion of drug by alkalinization of the urine and was hydrated aggressively. Despite aggressive therapy, there was gradual worsening with odynophagia/dysphagia and the blood counts still falling with no improvement in the renal functions. The patient was transferred to medicine ward. He was given platelet transfusions and taken for dialysis for two days, during which he succumbed to death.\n\n3. Discussion\nLow dose MTX in psoriasis rarely produces toxicity, and most of such cases occur due to failure to adhere to the recommended guidelines [1]. The risk of toxicity is greater if additional methotrexate is administered sooner than the usual scheduled weekly dose [3]. In the first case, it was a self-administration of the higher, consecutive dose which acted as a precipitating factor.\n\nMTX toxicity has its impact on skin, gastrointestinal mucosa, liver, kidneys, and bone marrow. Ulcerations in skin due to MTX toxicity are restricted to the psoriatic plaques probably because of higher uptake of methotrexate by the hyperproliferative psoriatic plaques than normal skin [4]. Both of the cases presented with ulceration on existing plaques of psoriasis.\n\nPancytopenia due to MTX is attributed to the patients with renal dysfunction, presence of infection, folic acid deficiency, hypoalbuminemia, concomitant use of drugs such as trimethoprim, and advanced age [5]. Both of our patients had mucositis along with myelosuppression as a presenting feature of MTX toxicity. The probable cause of myelosuppression in the first patient could be advanced age, concomitant use of NSAID, and inadvertent use of MTX dose, while, in the second patient, it was renal dysfunction which was not picked up before initiation of the treatment.\n\nDrugs can increase the risk of methotrexate toxicity either by decreasing renal elimination of methotrexate (aminoglycosides, cyclosporine, nonsteroidal anti-inflammatory agents, sulfonamides, probenecid, salicylates, penicillins, colchicines, cisplatin, and other renotoxic drugs) or by displacing methotrexate from protein binding sites in the plasma (salicylates, probenecid, sulfonamides, barbiturates, phenytoin, retinoids, sulfonylureas, and tetracyclines). NSAID taken for joint pain had contributed to the MTX toxicity in the first case.\n\nUnfortunately, we could not measure the drug level of MTX because of lack of facility. But the common feature in both of them was inadvertent dosage of MTX which is the major contributory factor for the toxicity.\n\nIt is a must to avoid self-administration of such drugs. There should be proper counseling of the patient for not taking the drugs on their own without consulting a dermatologist as well as not to combine with any other drug without taking doctors' consent. Selling such drugs without prescription should be banned.\n\nThe second case had consumed MTX without following the standard investigative as well as therapeutic protocol. Already compromised renal functions were missed out and impairment in renal clearance could have played a role in MTX toxicity. Prior workup is mandatory for MTX which is otherwise really safe and effective in cases of psoriasis.\n\nKey Messages\nPretreatment investigations are a must if MTX is to be prescribed. Proper monitoring and strict avoidance of self-administration of MTX are mandatory. Coadministration of the drugs like NSAIDs should be judicious.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Ulceration over psoriatic lesions with crusting on lips (Case 1).\n\nFigure 2 Pustules on face with mucositis in oral cavity (Case 2).\n==== Refs\n1 Roenigk HH Jr. Maibach HI Weinstein GD Use of methotrexate in psoriasis Archives of Dermatology 1972 105 3 363 365 2-s2.0-0015302347 5012144 \n2 Olsen EA The pharmacology of methotrexate Journal of the American Academy of Dermatology 1993 25 300 318 \n3 Bleyer WA Methotrexate: clinical pharmacology, current status and therapeutic guidelines Cancer Treatment Reviews 1977 4 2 87 101 2-s2.0-0017394305 329989 \n4 Kaplan DL Olsen EA Erosion of psoriatic plaques after chronic methotrexate administration International Journal of Dermatology 1988 27 1 59 62 2-s2.0-0023902184 3346128 \n5 Gutierrez-Ureña S Molina JF Garcia CO Cuellar ML Espinoza LR Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis Arthritis and Rheumatism 1996 39 272 276 8849378\n\n",
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"title": "Acute methotrexate toxicity: a fatal condition in two cases of psoriasis.",
"title_normalized": "acute methotrexate toxicity a fatal condition in two cases of psoriasis"
}
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}
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},
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"literaturereference": "JARIWALA P, KUMAR V, KOTHARI K, THAKKAR S, UMRIGAR DD. ACUTE METHOTREXATE TOXICITY: A FATAL CONDITION IN TWO CASES OF PSORIASIS. CASE REP DERMATOL MED. 2014;2014:946716.",
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},
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{
"abstract": "BACKGROUND\nCutaneous lymphoma diagnosed after anti-tumor necrosis factor-α therapy (anti-TNF-α) has been reported in the literature, yet a clear link between both events remains elusive.\n\n\nOBJECTIVE\nTo review our experience with cutaneous lymphoma diagnosed during or after the use of anti-TNF-α therapies.\n\n\nMETHODS\nThis is a multicenter retrospective study and a literature review.\n\n\nRESULTS\nA total of 22 cases, including 20 cutaneous T-cell lymphomas (CTCLs) and 2 cutaneous B-cell lymphomas, were identified. In the CTCL group, 75% of the patients received an anti-TNF-α agent for a presumed inflammatory skin condition. Mycosis fungoides and Sézary syndrome were the most common subtypes of CTCL diagnosed. Advanced disease (stage IIB to IVA) was commonly seen at time of diagnosis and required aggressive therapy, including stem cell transplant in 3 patients; 2 patients in whom cutaneous B-cell lymphomas was diagnosed had an indolent course. A total of 31 cases were gathered from a literature search.\n\n\nCONCLUSIONS\nThis is a retrospective study.\n\n\nCONCLUSIONS\nOur findings suggest that the disease of most of the identified patients was misdiagnosed as psoriasis or eczema; therefore, a comprehensive morphologic and molecular review of skin biopsy specimens and peripheral blood samples should be considered before initiation of anti-TNF-α therapy in patients with poorly defined dermatitis or atypical presentations of psoriasis.",
"affiliations": "Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Department of Dermatology, University of Texas Southwestern, Dallas, Texas.;Department of Dermatology, University of Texas Southwestern, Dallas, Texas.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Division of Dermatology, City of Hope Comprehensive Cancer Center, Duarte, California; Beckman Research Institute, Duarte, California.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.;Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Division of Dermatology, City of Hope Comprehensive Cancer Center, Duarte, California; Beckman Research Institute, Duarte, California.;Division of Dermatology, City of Hope Comprehensive Cancer Center, Duarte, California; Beckman Research Institute, Duarte, California.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address: [email protected].",
"authors": "Martinez-Escala|Maria Estela|ME|;Posligua|Alba L|AL|;Wickless|Heather|H|;Rutherford|Audrey|A|;Sable|Kimberly A|KA|;Rubio-Gonzalez|Belen|B|;Zhou|Xiaolong A|XA|;Kaplan|Jason B|JB|;Pro|Barbara|B|;Choi|Jaehyuk|J|;Querfeld|Christiane|C|;Rosen|Steven T|ST|;Guitart|Joan|J|",
"chemical_list": "D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaad.2017.12.068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "78(6)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "anti–tumor necrosis factor-α agents; cutaneous lymphoma; immunosuppression; large cell transformation; psoriasiform dermatitis; spongiotic dermatitis",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D016208:Databases, Factual; D057210:Delayed Diagnosis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides; D011379:Prognosis; D012189:Retrospective Studies; D012751:Sezary Syndrome; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "1068-1076",
"pmc": null,
"pmid": "29307643",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "25354264;19647103;21057746;21261674;19153359;19997706;23975254;16741509;19222452;16705109;25840730;17033176;27502891;17763616;23911677;12771475;15096373;19828563;19119122;27051683;19620563;23257839;28709694;17263820;26676102;12890213;15389210;22115382;19192017;26479768;16029354;21910704;19620564;25639382;27438209;16507211;22321651",
"title": "Progression of undiagnosed cutaneous lymphoma after anti-tumor necrosis factor-alpha therapy.",
"title_normalized": "progression of undiagnosed cutaneous lymphoma after anti tumor necrosis factor alpha therapy"
}
|
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{
"abstract": "BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking.\n\n\n\nWe analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score.\n\n\n\nPresumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease.\n\n\n\nUncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.",
"affiliations": "Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.;Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.;Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Woman's and Child's Health, University Hospital of Padova, Padua, Italy.;Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Woman's and Child's Health, University Hospital of Padova, Padua, Italy.;Hanover Medical School, Hanover, Germany.;Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany.;Department of Pediatric Nephrology, University Children's Hospital, Hamburg, Germany.;University Children's Hospital, Tübingen, Germany.;Pediatric Nephrology and Renal Transplant Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy.;Pediatric Nephrology, Pediatrics II, University Children's Hospital Essen, Essen, Germany.;Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Cologne, Germany.;Temple Street Children's University Hospital, Dublin, Ireland.;Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Olga Children's Hospital, Clinic of Stuttgart, Stuttgart, Germany.;1st Pediatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria.;Pediatric Nephrology Unit, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, Turin, Italy.;Hacettepe University Faculty of Medicine, Department of Pediatric Nephrology, Ankara, Turkey.;Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.;Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.;Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.;Institute of Medical Biometry and Informatics, University of Heidelberg, Germany.;Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.;Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland.;Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.",
"authors": "Höcker|Britta|B|;Schneble|Lukas|L|;Murer|Luisa|L|;Carraro|Andrea|A|;Pape|Lars|L|;Kranz|Birgitta|B|;Oh|Jun|J|;Zirngibl|Matthias|M|;Dello Strologo|Luca|L|;Büscher|Anja|A|;Weber|Lutz T|LT|;Awan|Atif|A|;Pohl|Martin|M|;Bald|Martin|M|;Printza|Nikoleta|N|;Rusai|Krisztina|K|;Peruzzi|Licia|L|;Topaloglu|Rezan|R|;Fichtner|Alexander|A|;Krupka|Kai|K|;Köster|Lennart|L|;Bruckner|Thomas|T|;Schnitzler|Paul|P|;Hirsch|Hans H|HH|;Tönshoff|Burkhard|B|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000002414",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "103(6)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000998:Antiviral Agents; D001739:BK Virus; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007674:Kidney Diseases; D016030:Kidney Transplantation; D008137:Longitudinal Studies; D008297:Male; D009894:Opportunistic Infections; D027601:Polyomavirus Infections; D012042:Registries; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014412:Tumor Virus Infections; D019562:Viral Load; D014779:Virus Replication",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "1224-1233",
"pmc": null,
"pmid": "30130322",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study.",
"title_normalized": "epidemiology of and risk factors for bk polyomavirus replication and nephropathy in pediatric renal transplant recipients an international certain registry study"
}
|
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{
"abstract": "Background. Cerebral hyperperfusion syndrome (CHS), a rare complication after cerebral revascularization, is a well-described phenomenon after carotid endarterectomy or carotid artery stenting. However, the imaging evidence of CHS after intravenous tissue plasminogen activator (iv tPA) for acute ischemic stroke (AIS) has not been reported. Case Report. Four patients were determined to have manifestations of CHS with clinical deterioration after treatment with iv tPA, including one patient who developed seizure, one patient who had a deviation of the eyes toward lesion with worsened mental status, and two patients who developed worsened hemiparesis. In all four patients, postthrombolysis head CT examinations were negative for hemorrhage; CT angiogram showed patent cervical and intracranial arterial vasculature; CT perfusion imaging revealed hyperperfusion with increased relative cerebral blood flow and relative cerebral blood volume and decreased mean transit time along with decreased time to peak in the clinically related artery territory. Vascular dilation was also noted in three of these four cases. Conclusions. CHS should be considered in patients with clinical deterioration after iv tPA and imaging negative for hemorrhage. Cerebral angiogram and perfusion studies can be useful in diagnosing CHS thereby helping with further management.",
"affiliations": "Department of Neurology, Saint Louis University, Saint Louis, MO 63110, USA.;Department of Neurology, Saint Louis University, Saint Louis, MO 63110, USA.;Department of Radiology, Saint Louis University, Saint Louis, MO 63110, USA.;Department of Radiology, Saint Louis University, Saint Louis, MO 63110, USA.",
"authors": "Zhang|Yi|Y|;Kumar|Abhay|A|0000-0002-6966-0918;Tezel|John B|JB|0000-0002-9495-3632;Zhou|Yihua|Y|0000-0003-0172-4628",
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"doi": "10.1155/2016/8725494",
"fulltext": "\n==== Front\nCase Rep Neurol MedCase Rep Neurol MedCRINMCase Reports in Neurological Medicine2090-66682090-6676Hindawi Publishing Corporation 10.1155/2016/8725494Case ReportImaging Evidence for Cerebral Hyperperfusion Syndrome after Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke Zhang Yi \n1\nhttp://orcid.org/0000-0002-6966-0918Kumar Abhay \n1\nhttp://orcid.org/0000-0002-9495-3632Tezel John B. \n2\nhttp://orcid.org/0000-0003-0172-4628Zhou Yihua \n2\n\n*\n1Department of Neurology, Saint Louis University, Saint Louis, MO 63110, USA2Department of Radiology, Saint Louis University, Saint Louis, MO 63110, USA*Yihua Zhou: [email protected] Editor: Isabella Laura Simone\n\n2016 3 5 2016 2016 872549413 1 2016 27 3 2016 19 4 2016 Copyright © 2016 Yi Zhang et al.2016This 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.\nBackground. Cerebral hyperperfusion syndrome (CHS), a rare complication after cerebral revascularization, is a well-described phenomenon after carotid endarterectomy or carotid artery stenting. However, the imaging evidence of CHS after intravenous tissue plasminogen activator (iv tPA) for acute ischemic stroke (AIS) has not been reported. Case Report. Four patients were determined to have manifestations of CHS with clinical deterioration after treatment with iv tPA, including one patient who developed seizure, one patient who had a deviation of the eyes toward lesion with worsened mental status, and two patients who developed worsened hemiparesis. In all four patients, postthrombolysis head CT examinations were negative for hemorrhage; CT angiogram showed patent cervical and intracranial arterial vasculature; CT perfusion imaging revealed hyperperfusion with increased relative cerebral blood flow and relative cerebral blood volume and decreased mean transit time along with decreased time to peak in the clinically related artery territory. Vascular dilation was also noted in three of these four cases. Conclusions. CHS should be considered in patients with clinical deterioration after iv tPA and imaging negative for hemorrhage. Cerebral angiogram and perfusion studies can be useful in diagnosing CHS thereby helping with further management.\n==== Body\n1. Introduction\nCerebral hyperperfusion syndrome (CHS) is a rare but expected complication after carotid endarterectomy or carotid artery stenting. Incidence of CHS is 1–3% after carotid endarterectomy [1]. CHS after iv tPA in patients with acute ischemic stroke (AIS) has also been recognized [2, 3]. However, radiographic evidence of CHS has not been described. We present this case series with imaging evidence of cerebral hyperperfusion after iv tPA treatment for AIS.\n\n2. Case Report\nWe reviewed a total of 772 CT perfusion (CTP) studies performed in our hospital from July 2009 to October 2015 to identify AIS patients who developed CHS after intravenous thrombolysis treatment. CTP hyperperfusion was characterized by increased relative cerebral blood flow (rCBF) and relative cerebral blood volume (rCBV) and decreased mean transit time (MTT) along with decreased time to peak (TTP) in the clinically related artery territory. Cerebral hyperperfusion syndrome was characterized by focal neurological deficit or seizures developing after cerebral revascularization. Revascularization was confirmed by CT angiogram (CTA). The study was approved by our Institutional Review Board.\n\nWe identified four cases of CHS after iv tPA for AIS (Table 1).\n\n\nCase 1 . \nA 61-year-old Caucasian male with history of chronic lymphocytic leukemia in remission and recurrent sinusitis was found in his garage with right-sided weakness. Examination at the local hospital 2 hours after the onset of the symptoms was significant for aphasia and right hemiplegia. Computed tomography of the head suggested a hyperdense left middle cerebral artery (MCA). He was given iv tPA three hours after onset of the symptoms and then transferred to our hospital for further management. His blood pressure was 157/82 mmHg. En route, the patient developed one seizure-like episode with sudden onset jerking movements of all extremities. Upon arrival, he was mute, confused, and agitated; however he was able to move the four extremities symmetrically. His National Institutes of Health Stroke Scale (NIHSS) was 9. The patient underwent CTA and CTP in anticipation of mechanical thrombectomy upon arrival. Instead, CTA showed patent cervical and intracranial arterial vasculature and a dilated left MCA while CTP revealed an increased rCBF and rCBV in the left middle cerebral artery (MCA) territory as well as a decreased MTT and TTP (Figure 1). MRI of the brain performed the following day demonstrated a large acute MCA territory infarct (Figure 2). Further workup revealed evidence of vegetation on the anterior and posterior mitral valve leaflets, likely the source of emboli. The patient was empirically treated with antibiotics for infective endocarditis. He was discharged to a rehabilitation facility on hospital day 6 with NIHSS 2. At the 3-month follow-up visit, the patient's right-sided weakness had resolved although aphasia persisted.\n\n\n\n\n\nCase 2 . \nAn 82-year-old Caucasian male with history of prostate cancer status after prostatectomy, hypertension, and atrial fibrillation developed sudden onset right upper extremity weakness and dysarthria. His warfarin was discontinued a week before for a right knee partial arthroplasty done two days prior to stroke onset. NIHSS was 9 at the local emergency department for which he received iv tPA and was then transferred to our hospital. The patient's blood pressure was 133/62 mmHg. His dysarthria resolved after iv tPA although his right upper extremity strength got worse on hospital day 2. A stat CTA showed no evidence of vessel occlusion but demonstrated dilated left MCA branches. CTP revealed hyperperfusion of the left MCA territory while noncontrast CT showed a left basal ganglia infarct. The patient also had urinary tract infection at admission, which was treated with antibiotics. The patient remained stable thereafter and improved with an NIHSS of 7 at the time of discharge.\n\n\n\n\n\nCase 3 . \nA 92-year-old male with history of atrial fibrillation and colon cancer developed right-sided weakness, global aphasia, and confusion. His NIHSS was 23. The patient received iv tPA. The patient's right-sided weakness worsened immediately following the infusion. His blood pressure was 143/76 mmHg. He underwent CTA and CTP, which demonstrated increased cerebral blood perfusion involving the left MCA territory. Noncontrast CT head 24 hours after thrombolysis showed infarction of a cortical area of the left parietal lobe. The patient had bright red blood per rectum one time. His vital signs and hemoglobin had been normal until hospital day 2 when he developed acute myocardial infarction. The family decided on palliative care, considering the patient's preexisting illness and age. The patient was deceased on hospital day 9.\n\n\n\n\n\nCase 4 . \nA 65-year-old female with history of hypertension, deep venous thrombosis, and colitis developed right-sided weakness and expressive aphasia. She was brought to the local hospital. She was awake and could not respond appropriately. Her NIHSS was 20. Stat CT head revealed a hyperdense left MCA. The patient received iv tPA and subsequently was transferred to our hospital. Her blood pressure was 136/79 mmHg. En route, the patient developed a deviation of the eyes toward the left. She became less arousable. The patient became mute upon arrival. A stat CTA showed patent cervical and intracranial arterial vasculature and a dilated left MCA branch. CTP revealed large area of hyperperfusion on the left hemisphere. Follow-up MRI of the brain performed the following day demonstrated a large acute left MCA territory infarct, which matched the large hyperperfusion area seen on the CTP. During the hospitalization, strength on the right side improved significantly, although global aphasia remained. The patient was discharged to an acute rehabilitation facility at day 5 with NIHSS 10.\n\n\n\n\n3. Discussion\nIn this case series, we present 4 cases of CHS with radiographic evidence after iv tPA treatment for AIS. CTA and CTP examinations after iv tPA treatment demonstrated recanalization and dilation (in three of the four cases) of the affected intracranial arteries as well as increased perfusion to the regions of the infarcted brain. Therefore, in patients with clinical deterioration after iv tPA treatment of acute ischemic stroke, cerebral CTA and CTP examinations may be helpful to diagnose cerebral hyperperfusion syndrome and provide evidence to guide further management.\n\nCerebral hyperperfusion syndrome is a rare complication following rapid revascularization. The likely pathophysiology is impaired cerebral autoregulation leading to increased cerebral blood flow, above the metabolic demands of brain tissue [4]. However, knowledge of CHS remains limited. Preexisting disease, such as chronic hypoperfusion from artery stenosis, infection, and chronic inflammatory disease, as well as expression of genes might affect cerebral myogenic, metabolic, or neurogenic regulation. Deficits are usually cortical which may be new or may represent worsening of a preexisting neurological deficit. In the study, three of the four cases had cortical infarction. Seizures may present as focal or generalized, depending on the affected cortical area [5]. One case had generalized seizure.\n\nCerebral hyperperfusion syndrome is a clinical syndrome of reperfusion injury which can occur in numerous ways including activation of endothelium, excess production of oxygen free radicals, inflammatory responses and leukocyte recruitment, increase in cytokine production, and edema formation [6]. There is disruption of the blood-brain barrier (BBB) through the release of neutrophil-derived oxidants and proteolytic enzymes. Two of the four cases in this study had active infectious disease during thrombolysis. One case had chronic colitis. Hyperperfusion initializes an inflammatory cascade, resulting in the deterioration of salvageable penumbra [7]. Infection appears to be an important trigger that precedes ischemic strokes and can bring about irreversible injury through a range of potential mechanisms. Preexisting infection in our patients may be a contributing factor for the development of CHS.\n\nInterestingly, three of the four cases in the study had history of cancer, which may have contributed to impaired cerebral autoregulation. Tumor endothelial cells often lose their normal barrier function. Changes in endothelial shape result in intercellular gaps or holes that leak fluid, blood, and fibrin into the surrounding tissue [8]. The vascular endothelium is a dynamic cellular “organ” that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. Tumor blood vessels have irregular diameters, are fragile and leaky, and have abnormal blood flow [9]. The pathophysiology of cerebral autoregulation in patients with cancer history needs further investigation.\n\nOur case series is limited by the lack of angiographic and perfusion studies prior to thrombolysis, although the presence of hyperdense MCA sign (as in Cases 1 and 4), sudden onset of focal neurological deficits, and high NIHSS suggest large vessel involvement. We were also not able to assess cerebral autoregulation based on the autoregulation index to monitor cerebral blood flow regulation. This would require a more specialized setting to do so. All four cases presented with a left hemisphere stroke. This might be due to reporting bias. A patient with a right hemisphere stroke commonly has neglect, which might mask the clinical deterioration.\n\nA main concern for clinical deterioration following tPA administration has been hemorrhagic transformation which can be evaluated with a noncontrasted head CT. One study showed that early neurological deterioration without clear mechanism affected 7% of the patients with acute stroke [10]. We believe some of these cases may be due to CHS, which is currently underrecognized and may also be delayed in onset as what happened in Case 2. The true incidence of CHS may thus be underreported as well given lack of angiographic and perfusion studies in the post-tPA administration setting. Therefore, when clinical deterioration following iv tPA cannot be simply explained by other obvious reasons such as hemorrhage, CHS should be considered. In addition, early clinical deterioration (or deterioration after improvement) can occur in ischemic stroke patients who have not received iv tPA treatment, which could be attributed to a number of reasons, including hemorrhagic transformation, internal herniation due to mass effect, and ventricular entrapment. However, as early spontaneous thrombolysis can occur, early clinical deterioration can potentially be due to CHS, when other causes are not apparent.\n\n4. Conclusion\nThe report provides imaging evidence of hyperperfusion in patients with CHS after iv tPA for acute cerebral infarction. Therefore, cerebral CTA and CTP studies should be considered to confirm the presence of cerebral hyperperfusion in patients with clinical deterioration after tPA treatment for acute stroke.\n\nCompeting Interests\nThe authors declare that there are no competing interests regarding this paper.\n\nFigure 1 Hyperperfusion on computed tomography perfusion and the dilation of the left middle cerebral artery and its branches on CT angiogram after iv tPA treatment: (a) increased cerebral blood volume; (b) shortened time to peak; (c) increased cerebral blood flow; (d) shortened mean transit time.\n\nFigure 2 Hyperdense middle cerebral artery on the initial CT prior to intravenous tissue plasminogen activator (a). Diffusion-weighted magnetic resonance imaging (b). Apparent diffusion coefficient (c) confirms acute infarction in the left MCA territory.\n\nTable 1 Four cases of cerebral hyperperfusion syndrome after intravenous tPA for acute ischemic stroke.\n\n \tAge\tSex\tStroke symptoms\tPMH\tNIHSS (onset)\ttPA dose\tCHS symptoms\tNIHSS (D/C) \tInfarct area\t\nCase 1\t61\tM\tAphasia, right hemiplegia\tCLL\t9\t90 mg\tSeizure \t2\tCortical \t\nCase 2\t82\tM\tDysarthria, right hemiplegia \tProstate cancer. HTN, Afib \t9\t70 mg \tWorsening hemiplegia \t7\tBasal ganglia \t\nCase 3\t92\tM\tAphasia, right hemiplegia, confusion\tColon cancer, Afib \t23\t74 mg\tWorsening hemiplegia \tDeceased\tCortical \t\nCase 4\t65\tF\tAphasia, right hemiplegia \tHTN, DVT, colitis \t20\t90 mg\tEyes deviation, confusion \t10\tCortical \t\nPMH: past medical history; NIHSS: NIH stroke scale; CHS: cerebral hyperperfusion syndrome; D/C: at discharge time; M: male; F: female; CLL: chronic lymphocytic leukemia; HTN: hypertension; Afib: atrial fibrillation; DVT: deep vein thrombosis.\n==== Refs\n1 Lieb M. Shah U. Hines G. L. Cerebral hyperperfusion syndrome after carotid intervention: a review Cardiology in Review 2012 20 2 84 89 10.1097/crd.0b013e318237eef8 2-s2.0-84857366025 22183061 \n2 Lau C.-I. Lien L.-M. Chen W.-H. Brainstem hyperperfusion syndrome after intravenous thrombolysis: a case report Journal of Neuroimaging 2011 21 3 277 279 10.1111/j.1552-6569.2010.00469.x 2-s2.0-79959716970 20331500 \n3 Backhaus R. Boy S. Fuchs K. Ulrich B. Schuierer G. Schlachetzki F. Hyperperfusion syndrome after MCA embolectomy—a rare complication? American Journal of Case Reports 2013 14 513 517 10.12659/ajcr.889672 2-s2.0-84888583366 24340127 \n4 Paulson O. B. Strandgaard S. Edvinsson L. Cerebral autoregulation Cerebrovascular and Brain Metabolism Reviews 1990 2 2 161 192 2-s2.0-0025437969 2201348 \n5 Sundt T. M. Jr. Sharbrough F. W. Piepgras D. G. Kearns T. P. Messick J. M. Jr. O'Fallon W. M. Correlation of cerebral blood flow and electroencephalographic changes during carotid endarterectomy: with results of surgery and hemodynamics of cerebral ischemia Mayo Clinic Proceedings 1981 56 9 533 543 2-s2.0-0019820832 7266064 \n6 Khatri R. McKinney A. M. Swenson B. Janardhan V. Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke Neurology 2012 79 13 S52 S57 10.1212/wnl.0b013e3182697e70 2-s2.0-84867525361 23008413 \n7 Emsley H. C. Hopkins S. J. Acute ischaemic stroke and infection: recent and emerging concepts The Lancet Neurology 2008 7 4 341 353 10.1016/S1474-4422(08)70061-9 2-s2.0-40749120506 18339349 \n8 Hashizume H. Baluk P. Morikawa S. Openings between defective endothelial cells explain tumor vessel leakiness American Journal of Pathology 2000 156 4 1363 1380 10.1016/S0002-9440(10)65006-7 2-s2.0-0033839080 10751361 \n9 Dudley A. C. Tumor endothelial cells Cold Spring Harbor Perspectives in Medicine 2012 2 3 a006536 2-s2.0-84881250967 \n10 Seners P. Turc G. Tisserand M. Unexplained early neurological deterioration after intravenous thrombolysis: incidence, predictors, and associated factors Stroke 2014 45 7 2004 2009 10.1161/strokeaha.114.005426 2-s2.0-84903796166 24876087\n\n",
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"abstract": "BACKGROUND\nPeritoneal metastases are often reported in several abdominal tumors. Peritoneal diffusion from extra-abdominal tumors is thought to be rare. Lung cancer is one of the most common cancers in the world with early metastases and it is associated with poor prognosis in advanced stages. Peritoneal metastases from lung cancer are uncommon and the real mechanism of its diffusion to the peritoneum is unknown. However, its clinical behavior is similar to any other peritoneal metastasis from abdominal tumors.\n\n\nMETHODS\nWe present two Caucasian patients (a 44-year-old man and a 59-year-old man) with bowel obstruction from peritoneal metastases from non-small cell lung cancer who successfully underwent emergency cytoreductive surgery and had a good prognosis and survival.\n\n\nCONCLUSIONS\nIn our patients with isolated peritoneal metastases from lung cancer, cytoreduction showed good prognosis with acceptable morbidity. This treatment option might be considered in highly selected cases to improve survival. Strict follow-up is mandatory to allow early diagnosis of peritoneal diffusion.",
"affiliations": "Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Via Lancisi 2, 00155, Rome, Italy. [email protected].;Department of Surgery, Tor Vergata University of Rome, Viale Oxford 81, 00133, Rome, Italy.;Department of Surgery, Tor Vergata University of Rome, Viale Oxford 81, 00133, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Via Lancisi 2, 00155, Rome, Italy.;Department of Surgery, Tor Vergata University of Rome, Viale Oxford 81, 00133, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Via Lancisi 2, 00155, Rome, Italy.;Department of Surgery \"Pietro Valdoni\", \"Sapienza\" University of Rome, Via Lancisi 2, 00155, Rome, Italy.",
"authors": "Sibio|Simone|S|http://orcid.org/0000-0002-5694-951X;Sica|Giuseppe Sigismondo|GS|;Di Carlo|Sara|S|;Cardi|Maurizio|M|;Di Giorgio|Alessandra|A|;Sollazzo|Bianca Maria|BM|;Sammartino|Paolo|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2178-5",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 217810.1186/s13256-019-2178-5Case ReportSurgical treatment of intraperitoneal metastases from lung cancer: two case reports and a review of the literature http://orcid.org/0000-0002-5694-951XSibio Simone +39 06 [email protected] 1Sica Giuseppe Sigismondo [email protected] 2Di Carlo Sara [email protected] 2Cardi Maurizio [email protected] 1Di Giorgio Alessandra [email protected] 2Sollazzo Bianca Maria [email protected] 1Sammartino Paolo [email protected] 11 grid.7841.aDepartment of Surgery “Pietro Valdoni”, “Sapienza” University of Rome, Via Lancisi 2, 00155 Rome, Italy 2 0000 0001 2300 0941grid.6530.0Department of Surgery, Tor Vergata University of Rome, Viale Oxford 81, 00133 Rome, Italy 21 8 2019 21 8 2019 2019 13 26227 11 2018 27 6 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPeritoneal metastases are often reported in several abdominal tumors. Peritoneal diffusion from extra-abdominal tumors is thought to be rare. Lung cancer is one of the most common cancers in the world with early metastases and it is associated with poor prognosis in advanced stages. Peritoneal metastases from lung cancer are uncommon and the real mechanism of its diffusion to the peritoneum is unknown. However, its clinical behavior is similar to any other peritoneal metastasis from abdominal tumors.\n\nCase presentation\nWe present two Caucasian patients (a 44-year-old man and a 59-year-old man) with bowel obstruction from peritoneal metastases from non-small cell lung cancer who successfully underwent emergency cytoreductive surgery and had a good prognosis and survival.\n\nConclusions\nIn our patients with isolated peritoneal metastases from lung cancer, cytoreduction showed good prognosis with acceptable morbidity. This treatment option might be considered in highly selected cases to improve survival. Strict follow-up is mandatory to allow early diagnosis of peritoneal diffusion.\n\nKeywords\nLung cancerPeritoneal metastasesCytoreductive surgeryeuropean society of degenerative diseases1issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe occurrence of peritoneal metastases represents the clinical final stage of several tumors: most commonly ovarian, colorectal, gastric cancers, and, less frequently, appendix cancer. In recent years, the inclusion of cytoreductive surgery, alone or associated with locoregional chemotherapy, in the treatment strategy of some of these conditions has increased (peritoneal metastases from ovarian cancer or primary peritoneal malignancies), whereas its application remains mainly investigational in other conditions (gastric, colorectal, endometrial, and breast cancers) [1, 2].\n\nLung cancer is one of the most common cancers worldwide. It is the leading cause of death from cancer; diagnosis is often made at an advanced stage when metastases have already spread to the other lung, to the liver, to the brain, to the bone, and to adrenal glands [3].\n\nFew reports are available in the literature about patients with peritoneal metastases from lung cancer [4–6]. Despite any treatment, overall survival for these patients is very poor, with reported rates of 9 months in a recent series [5].\n\nWe describe two cases of diffused peritoneal metastases from lung cancer who underwent emergency cytoreductive surgery for bowel occlusion and had an unexpectedly good prognosis and long-term survival.\n\nCases presentation\nPatient 1\nIn March 2013, a 44-year-old Caucasian man, a non-smoker of tobacco, was referred to our department as an emergency with 3 days’ history of bowel obstruction. His family history was negative for cancer. His past medical history included a right pneumonectomy in 2009 for a T2, N1, M0 G3, stage IIB lung adenocarcinoma. Immunohistochemistry was positive for cytokeratin 7 and negative for thyroid transcription factor 1 (TTF-1), caudal type homeobox transcription factor 2 (CDX2), cytokeratin 20, protein S100, thyroglobulin, the anti-melanosome clone, human melanoma black 45 (HMB-45), and the anti-melanoma, melanoma antigen recognized by T cells 1 (MART-1). After surgery, he underwent four cycles of adjuvant chemotherapy with cisplatin (100 mg/m2) and paclitaxel (175 mg/m2); he then received two cycles of gemcitabine (1000 mg/m2) after the fourth cycle of cisplatin and paclitaxel for a grade 4 toxicity to paclitaxel. On admission in our department, he was off any treatment, and 1 month previously he had negative magnetic resonance imaging (MRI) for brain metastases. His vital signs were normal. Performance status assessed by the Eastern Cooperative Oncologic Group (ECOG) [7] was 1. He had been vomiting and his bowel had been obstructed for 24 hours. A clinical examination revealed a tender distended abdomen. Blood tests were normal except for neutrophilic leukocytosis: white blood cells (WBC) 14,000/mm3. Neuron-specific enolase and cytokeratin-19 fragment (CYFRA 21-1) levels were normal (respectively 121 ng/ml and < 3 ng/ml). A total body contrast-enhanced computed tomography (CT) scan showed a distended large bowel with air-fluid levels and multiple neoplastic implants involving the right colon, greater omentum, spleen, and the sigmoid colon, ranging from 0.5 to 10 cm. (Fig. 1). No other pathological findings were disclosed and a chest examination was negative except for the outcomes of the previous thoracic surgery (Fig. 2).Fig. 1 Coronal two-dimensional image showing huge implants (arrows) of peritoneal metastases located near colonic splenic flexure providing a compression of the lumen and in Morison pouch between right kidney and right liver\n\nFig. 2 Axial two-dimensional image obtained after intravenous administration of iodinated contrast agent, showing outcomes of right pneumonectomy (arrow)\n\n\n\nConsidering his young age, the absence of lung recurrence and of any other distant metastasis, palliative surgery was considered in order to treat bowel obstruction. At laparotomy there was no ascites, and three gross neoplastic implants were found in the greater omentum, right colonic flexure, transverse colon, and left colon. Extensive cytoreductive surgery was performed and surgical procedures included subtotal colectomy with ileosigmoid anastomosis, splenectomy, and greater omentectomy (Figs. 3 and 4). At the end of the procedure no residual macroscopic disease was left, reaching a completeness of cytoreduction score (CCS) of 0.Fig. 3 Intraoperative picture showing gross neoplastic implants on greater omentum, transverse colon, and left colon (arrows)\n\nFig. 4 Final surgical specimen showing gross neoplastic implants involving right side of colon, transverse colon, left colon, greater omentum, and splenic flexure (arrows)\n\n\n\nPathology showed complete infiltration of the colonic wall and spleen by adenocarcinoma nodules with lymph node metastases in the mesocolon.\n\nImmunohistochemistry evaluation showed the same staining as the previous lung adenocarcinoma, confirming the lung origin of the peritoneal metastases.\n\nHis postoperative course was complicated by fever (38.5 °C) and dyspnea on postoperative day 9. A chest X-ray showed a “ground glass” picture of left lung and bloodstream and expectorate cultures were positive for Candida albicans species. Intravenously administered anidulafungin treatment was started with rapid improvement of our patient’s general condition and gradual resolution of sepsis. He was discharged on postoperative day 20 and subsequently he underwent six cycles of adjuvant chemotherapy with cisplatin (100 mg/m2). Considering the previous toxicity to paclitaxel no other drug was used. A follow-up protocol included clinical evaluation (1 month after surgery, then every 3 months), blood tests with tumor marker levels every 3 months, and total body CT scan 1 month after surgery, then every 3 months for the first year and every 6 months for the next 2 years. Yearly, a brain MRI was scheduled. He was alive and disease free 3 years after surgery. In September 2016 he was lost to follow-up.\n\nPatient 2\nIn September 2011, a 59-year-old Caucasian man, a heavy tobacco smoker, presented to our department as an emergency with abdominal pain and vomiting. His past medical history included a left upper lobectomy for a T1N1M0, G3 stage IIB lung adenocarcinoma (3 years before) followed by six cycles of systemic chemotherapy (carboplatin + paclitaxel 175 mg/m2). His family history was positive for cancer (a 39-year-old brother died of colon cancer). Two days before admission, abdominal distension and bowel obstruction occurred and progressively worsened. His WBC count was 18,000/mm3. A total body CT scan showed a large mass involving the distal ileal loops with obstruction and distension of the proximal bowel, with a small amount of ascites in his pelvis.\n\nHe underwent explorative laparoscopy that confirmed the CT scan findings, showing no other peritoneal seeding. Ascites was taken for cytological examination, and a laparoscopic ileocolic resection with ileotransverse anastomosis was performed, reaching a CCS of 0. His postoperative course was uneventful and he was discharged on postoperative day 4. Pathology confirmed the diagnosis of metastasis from adenocarcinoma; ascites was found to be negative for neoplastic cells. At immunohistochemistry, cancer cells were positive for cytokeratin 7 and TTF-1 confirming the origin of peritoneal metastases from the lung cancer. He was followed by medical oncologists and, due to his poor general condition, he underwent a second-line adjuvant chemotherapy with gemcitabine only (1000 mg/m2). He was disease free for 2 years. Subsequently, brain metastases occurred and in February 2014 he died (Table 1).Table 1 Key features of the patients\n\n\tPatient 1\tPatient 2\t\nAge (years)\t44\t59\t\nSex\tM\tM\t\nPrimary lung cancer\tT2 N1 M0 NSCLC\tT1 N1 M0 NSCLC\t\nPrevious thoracic surgery\tRight pneumonectomy\tLeft upper lobectomy\t\nPrevious adjuvant chemotherapy\tFour cycles intravenously administered 100 mg/m2 cisplatin + 175 mg/m2 Taxol (paclitaxel) and Two cycles intravenously administered 1000 mg/m2 gemcitabine\tSix cycles intravenously administered carboplatin + 175 mg/m2 paclitaxel\t\nClinical presentation\tBowel obstruction\tBowel obstruction\t\nSurgical procedure\tSubtotal colectomy, splenectomy, omentectomy\tLaparoscopic ileocolic resection\t\nCCS\t0 (no residual disease)\t0 (no residual disease)\t\nAdjuvant chemo\tSix cycles intravenously administered 100 mg/m2 cisplatin\tIntravenously administered 1000 mg/m2 gemcitabine\t\nFollow-up\tAlive disease free\tDied brain metastases\t\nSurvival (months)\t36\t25\t\nCCScompleteness of cytoreduction score, M male, NSCLC non-small cell lung carcinoma\n\n\n\nDiscussion\nOverall median survival in metastatic lung cancer is very poor. In recent studies it ranged between 3 and 12 months, depending on type of treatment [8]. Peritoneal metastases from extra-abdominal cancers are rare and have a poor prognosis. In a recent large population study by Flanagan et al., the overall incidence rate of peritoneal metastases from extra-abdominal cancers was 9%, mostly originating from breast cancer (40.8%), followed by lung cancer (25.6%), and melanoma (9.5%) [5]. Satoh et al. reported a rate of 1.2% of peritoneal metastases complicating the clinical course of advanced lung cancer [9], while in other autopsy series this rate was found to be 12% [10]. Therefore, it could be argued that a number of cases of peritoneal metastases remains undiagnosed or unreported in patients with lung cancer. A few studies reported isolated bowel metastases from non-small cell lung carcinoma (NSCLC) with very poor prognosis [4, 9, 10] and some others described the peritoneal diffusion of pleural mesothelioma [11, 12].\n\nIn gastrointestinal tumors, peritoneal metastases generally arise either from direct invasion of the bowel wall or from cancer cells spilled by surgical manipulation [13]. These mechanisms are not applicable to lung cancer. In stage IV lung cancer, pleural metastases at diagnosis are significantly associated with subsequent peritoneal spread, whereas no association between oncogene status and peritoneal disease has been reported [6]. Pleural serosa infiltration might eventually explain the peritoneal seeding, but this mechanism could not be considered in our cases since our patients had no pleural disease.\n\nAccording to the two most recent systematic reviews, bowel obstruction is the most frequent clinical presentation although bleeding and perforation are also reported [14, 15]. CT and positron emission tomography (PET) scans are useful tools for diagnosis in the late stages, while CT scan sensitivity is low at the early stage of peritoneal diffusion. In most patients, the time interval between primary lung cancer and peritoneal metastases ranges from 2 months to 4 years. The most frequent histology is NSCLC, with large cell cancer and adenocarcinoma being the most common subtypes. The prognosis for patients with peritoneal metastases from lung cancer is very poor regardless of the treatment, with a median survival rate of 2 to 4 months. In a recent review, Balla et al. found two cases of peritoneal metastases out of a sample of 91 patients with lung cancer with gastrointestinal metastases: the disparity with autopsy series suggests that most cases are asymptomatic or unreported [16, 17]. Emergency surgery for bowel obstruction and extra-abdominal metastases, found in up to 60% of patients [11, 12], could be the main reasons for the poor prognosis. However, the patients reported in this study had an unexpected good outcome despite their emergency presentation and the presence of diffused peritoneal involvement in one of them. They reached, respectively, 3-year and 2-year disease-free survival and one of them is currently alive. The absence of extra-abdominal metastases might perhaps explain the unexpected long survival. However, our results suggest that a combined approach (surgery and chemotherapy) could be advocated in selected patients with peritoneal metastases from lung cancer with some survival advantages compared to standard treatment. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in unconventional indications is occasionally reported in experienced tertiary centers [2], most frequently from rare ovarian cancers, sarcoma, or neuroendocrine tumors, and, more rarely, from gastrointestinal stromal tumor (GIST), hepatocellular and cholangiocarcinoma and desmoplastic small round cell tumors. The gap existing between the small reported series data and the incidence rates in autopsy series could suggest that in most cases peritoneal metastases from lung cancer remain clinically silent [16]. Our results on these two patients might help in stimulating more awareness of this condition and in suggesting a strict follow-up: in fact, early diagnosis of peritoneal diffusion, which is probably often underrated, could allow a radical cytoreductive surgery providing some advantages to survival.\n\nConsidering the behavior of lung cancer, in particular, its tendency to early metastases because of its continuous dynamic state and large blood and lymphatic supply that spreads a large amount of neoplastic cells directly in the bloodstream [18], the association of a strict follow-up and focused imaging techniques could help to identify selected cases to be treated, avoiding emergency “salvage” treatments that are difficult to perform even in dedicated centers.\n\nHigh postoperative morbidity should be carefully considered when an extensive surgical treatment is planned on a patient with an advanced oncological stage. In our small series of two patients no major complications were observed, and maximal cytoreduction and HIPEC should not be discarded a priori as a treatment option. Further studies on this specific subset of patients could better clarify indications and limits.\n\nConclusions\nIn our patients with isolated peritoneal metastases from lung cancer, cytoreduction showed good prognosis with acceptable morbidity. Although resection is the standard of care in bowel obstructions, this treatment option might be considered even in an elective stetting in highly selected cases to improve survival. Strict clinical and imaging diagnostic follow-up should be performed in these patients, and a peritoneal diffusion of the tumor should be anticipated and investigated.\n\nAbbreviations\nCCSCompleteness of cytoreduction score\n\nCDX2Caudal type homeobox transcription factor 2\n\nCTComputed tomography\n\nCYFRA 21-1Cytokeratin-19 fragment\n\nECOGEastern Cooperative Oncologic Group\n\nGISTGastrointestinal stromal tumor\n\nHIPECHyperthermic intraperitoneal chemotherapy\n\nHMB-45Human melanoma black 45\n\nMART-1Melanoma antigen recognized by T cells 1\n\nMRIMagnetic resonance imaging\n\nNSCLCNon-small cell lung carcinoma\n\nPETPositron emission tomography\n\nTTF-1Thyroid transcription factor 1\n\nWBCWhite blood cells\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthors’ contributions\nSS and GS designed the study and they were the surgeons who operated on the patients. BMS, SDC, MC, and ADG collected data and wrote the paper. PS critically revised and finally approved the manuscript. All authors read and approved the final manuscript.\n\nFunding\nEuropean Society of Degenerative Disease (ESDD) contributed to the study by supporting data analysis and collection.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nEthics approval does not apply to the present study.\n\nConsent for publication\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Sugarbaker PH Prevention and treatment of peritoneal metastases: a comprehensive review Indian J Surg Oncol 2019 10 3 23 10.1007/s13193-018-0856-1 \n2. Goéré D Passot G Gelli M Levine EA Bartlett DL Sugarbaker PH Complete cytoreductive surgery plus HIPEC for peritoneal metastases from unusual cancer sites of origin: results from a worldwide analysis issue of the Peritoneal Surface Oncology Group International (PSOGI) Int J Hyperth 2017 33 520 527 10.1080/02656736.2017.1301576 \n3. Riihimäki M Hemminki A Fallah M Thomsen H Sundquist K Sundquist J Metastatic sites and survival in lung cancer Lung Cancer 2014 86 1 78 84 10.1016/j.lungcan.2014.07.020 25130083 \n4. Abbate MI Cortinovis DL Tiseo M Vavalà T Cerea G Toschi L Peritoneal carcinomatosis in non-small-cell lung cancer: retrospective multicentric analysis and literature review Future Oncol 2019 15 9 989 994 10.2217/fon-2018-0469 30681378 \n5. Flanagan M Solon J Chang KH Deady S Moran B Cahill R Peritoneal metastases from extra-abdominal cancer - A population-based study Eur J Surg Oncol 2018 44 11 1811 1817 10.1016/j.ejso.2018.07.049 30139510 \n6. Patil T Aisner DL Noonan SA Bunn PA Purcell WT Carr LL Malignant pleural disease is highly associated with subsequent peritoneal metastasis in patients with stage IV non-small cell lung cancer independent of oncogene status Lung Cancer 2016 96 27 32 10.1016/j.lungcan.2016.03.007 27133746 \n7. Oken MM Creech RH Tormey DC Horton J Davis TE McFadden ET Toxicity and response criteria of the Eastern Cooperative Oncologic Group Am J Clin Oncol 1982 5 649 655 10.1097/00000421-198212000-00014 7165009 \n8. Socinski M Morris D Master GA Lilenbaum R American College of Chest Physicians: Chemotherapeutic management of stage IV non-small cell lung cancer Chest 2003 123 226s 243s 10.1378/chest.123.1_suppl.226S 12527582 \n9. Satoh H Ishikawa H Yamashita YT Kurishima K Ohtsuka M Sekizawa K Peritoneal carcinomatosis in lung cancer patients Oncol Rep 2001 8 1305 1307 11605054 \n10. Yoshimoto A Kasahara K Kawashima A Gastrointestinal metastases from primary lung cancer Eur J Cancer 2006 42 18 3157 3160 10.1016/j.ejca.2006.08.030 17079136 \n11. Sibio S Sammartino P Accarpio F Biacchi D Cornali T Cardi M Metastasis of pleural mesothelioma presenting as bleeding colonic polyp Ann Thorac Surg 2011 92 1898 1901 10.1016/j.athoracsur.2011.04.117 22051293 \n12. Iafrate F Sibio S Sammartino P Ciolina M Pichi A Accarpio F What caused gastrointestinal bleeding in a woman with a history of pleural mesothelioma? Metastatic diffuse epithelioid mesothelioma Gut. 2010 59 644 690 \n13. Reis-Filho JS Carrilho C Valenti C Leitão D Ribeiro CA Ribeiro SG Is TTF1 a good immunohistochemical marker to distinguish primary from metastatic lung adenocarcinomas? Pathol Res Pract 2000 196 12 835 840 10.1016/S0344-0338(00)80084-9 11156325 \n14. Di JZ Peng JY Wang ZG Prevalence, clinicopathological characteristics, treatment, and prognosis of intestinal metastasis of primary lung cancer: a comprehensive review Surg Oncol 2014 23 72 80 10.1016/j.suronc.2014.02.004 24656432 \n15. Balla A Subiela JD Bollo J Martínez C Rodriguez LC Gastrointestinal metastasis from primary lung cancer. Case series and systematic literature review Cir Esp 2018 96 184 197 10.1016/j.ciresp.2017.12.011 29567360 \n16. Jevremovic V Is gastrointestinal metastasis of primary lung malignancy as rare as reported in literature? A comparison between clinical cases and postmortem Stud Oncol Hematol Rev 2016 12 51 57 \n17. Kim MS Kook EH Ahh AH Jeon SY Yoon JH Han MS Gastrointestinal metastasis of lung cancer with special emphasis on a long-term survivor after operation J Cancer Res Clin Oncol 2009 135 297 301 10.1007/s00432-008-0424-0 18512073 \n18. Berger A Cellier C Daniel C Kron C Riquet M Barbier JP Small bowel metastases from primary carcinoma of the lung: clinical findings and outcome Am J Gastroenterol 1999 94 1884 1887 10.1111/j.1572-0241.1999.01224.x 10406253\n\n",
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"abstract": "The management of acute massive pulmonary embolism presents a clinical challenge as currently there is no consensus for definitive treatment. Early decision-making regarding surgical intervention is essential when the risk of mortality is high.",
"affiliations": "Division of Clinical Anesthesia Mie University Hospital Mie Japan.;Department of Anesthesiology Clinical Care Medicine Kanagawa Dental University Kanagawa Japan.",
"authors": "Tagawa|Tsuyoshi|T|https://orcid.org/0000-0001-5535-6803;Sakuraba|Shigeki|S|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2913\nCCR32913\nCase Report\nCase Reports\nAcute massive pulmonary embolism treated by urgent pulmonary embolectomy: A case report\nTAGAWA and SAKURABATagawa Tsuyoshi https://orcid.org/0000-0001-5535-6803\n1\[email protected] Sakuraba Shigeki \n2\n \n1 \nDivision of Clinical Anesthesia\nMie University Hospital\nMie\nJapan\n\n\n2 \nDepartment of Anesthesiology\nClinical Care Medicine\nKanagawa Dental University\nKanagawa\nJapan\n\n* Correspondence\n\nTsuyoshi Tagawa, Division of Clinical Anesthesia, Mie University Hospital, 2‐174 Edobashi, Tsu, Mie, 514‐8507, Japan.\n\nEmail: [email protected]\n\n03 5 2020 \n8 2020 \n8 8 10.1002/ccr3.v8.81502 1505\n10 8 2019 26 3 2020 10 4 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nThe management of acute massive pulmonary embolism presents a clinical challenge as currently there is no consensus for definitive treatment. Early decision‐making regarding surgical intervention is essential when the risk of mortality is high.\n\nThe management of acute massive pulmonary embolism presents a clinical challenge as currently there is no consensus for definitive treatment. Early decision‐making regarding surgical intervention is essential when the risk of mortality is high.\n\n\nacute pulmonary embolismintravenous immunoglobulinpatent foramen ovalepulmonary embolectomy source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:28.08.2020\n\n\nTagawa \nT \n, \nSakuraba \nS \n. Acute massive pulmonary embolism treated by urgent pulmonary embolectomy: A case report\n. Clin Case Rep . 2020 ;8 :1502 –1505\n. 10.1002/ccr3.2913\n==== Body\n1 INTRODUCTION\nAcute massive pulmonary embolism is a life‐threatening condition and must be immediately treated. The management of this condition typically presents a clinical challenge as currently there is no consensus for definitive treatment. Early decision‐making regarding surgical intervention is essential for successful management when the risk of mortality is high.\n\nAcute massive pulmonary embolism (PE) has been continually associated with a high rate of mortality despite advances in diagnosis and therapy.\n1\n The management of acute massive PE presents a clinical challenge as currently there is no established standard of care. Successful management strategies, primarily published in the form of case reports, include medical treatment along with cardiovascular support and anticoagulation, as well as more invasive interventions, such as pulmonary embolectomy. If acute massive PE is not diagnosed and treated early, it can cause hemodynamic deterioration, which warrants immediate surgery. Here, we describe the successful treatment of acute massive PE with pulmonary embolectomy.\n\n2 CASE REPORT\nA 37‐year‐old man with no medical history was admitted to a hospital with numbness in the arms and legs, as well as dysarthria and drowsiness. He was diagnosed with Bickerstaff brainstem encephalitis and treated with intravenous immunoglobulin (IVIG) for five days. He gradually recovered from coma and was nearly alert 2 weeks later. However, he suffered from sudden‐onset chest pain and abrupt reductions in blood pressure (BP) and oxygen saturation (SpO2). A chest computed tomography scan revealed massive emboli in both the lungs and thrombi in the bilateral atria (Figure 1). Consequently, heparin therapy was initiated and he was transferred to our institution for embolectomy. On arrival, he was alert and oriented with tetraparesis and dysarthria. His BP was 110/70 mm Hg, and heart rate was 120 beats/min. Arterial blood gas values with supplemental oxygen of 10 L/min administered via face mask were pH, 7.461; partial pressure of carbon dioxide, 43.6 mm Hg; and partial pressure of oxygen, 82.9 mm Hg. Transthoracic echocardiography revealed emboli in the pulmonary artery (PA) and bilateral atria; a right atrial embolus adherent to the tip of a central venous catheter (CVC) inserted from the femoral vein; and reduced blood flow in PA and consequent right ventricular dilatation, indicative of pulmonary hypertension, with an estimated ejection fraction of 59%.\n\nFigure 1 Preoperative chest computed tomography scan showing massive pulmonary emboli (A) and thrombi in the left (B) and right (C) atria (arrows)\n\nAnesthesia was induced by administering fentanyl (50 μg), propofol (100 mg), and rocuronium (50 mg). The trachea was intubated, and anesthesia was maintained with fentanyl and sevoflurane. After intubation, BP decreased without alteration in SpO2. Intravenous ephedrine and rapid volume infusion restored BP. A Swan‐Ganz catheter was placed at the level of the right internal jugular vein to avoid dislocation of the thrombi. After median sternotomy and pericardiotomy, the patient was heparinized and cannulated for cardiopulmonary bypass (CPB). An arterial cannula was placed in the femoral artery, and a superior vena cava cannula was passed through the right atrium (RA). Total CPB was initiated by placing tapes around the superior and inferior venae cavae. The ascending aorta was cross‐clamped. An incision was made in RA, which exposed a thrombus extending from RA through the patent foramen ovale (PFO) to the left atrium; the thrombus was removed en bloc under direct vision using forceps (Figure 2). After ensuring the absence of residual thrombi in the left atrium, PFO was closed. Next, main PA was opened and thrombi that extended to both PAs were extracted in a manner similar to that used for extracting the thrombus in RA (Figure 3). After completing embolectomy, the Swan‐Ganz catheter was introduced into right PA and CVC was removed. RA was again accessed to ensure that no additional embolic material entered from the inferior vena cava; RA was then closed. After assuring complete clot removal using transesophageal echocardiography, separation from CPB was achieved with an infusion of dopamine (5 μg/kg/min). Simultaneously, an infusion of prostaglandin E1 (0.03 μg/kg/min) was also initiated based on the possibility of pulmonary vasoconstriction.\n\nFigure 2 A, Thrombus extending from the right atrium through the patent foramen ovale to the left atrium. B, Rearranged thrombi extracted from bilateral atria\n\nFigure 3 A, Thrombi extending from the main pulmonary artery to both the pulmonary arteries. B, Rearranged thrombi removed from both pulmonary arteries\n\nSystemic anticoagulation treatment was immediately initiated after the surgery. On postoperative day 1, the patient was extubated. On postoperative day 10, IVIG was restarted. He regained the ability to walk and, following an uneventful recovery, was transferred to a regional hospital for neurological rehabilitation on postoperative day 40. He had maintained adequate health for 12 months with continued oral warfarin therapy.\n\n3 DISCUSSION\nThe prevalence of PE in hospitalized patients is approximately 1%.\n2\n, \n3\n Despite the current emphasis on deep venous thrombus prophylaxis, there is a failure rate of approximately 30%‐50%.\n4\n The risk factors for PE include multiple trauma, pregnancy, cancer, heart failure, chronic deep venous insufficiency or prior venous thrombosis, long‐bone fractures, prolonged bed rest, obesity, and oral contraceptive use.\n5\n In addition, IVIG therapy is associated with thromboembolic complications including PE.\n6\n, \n7\n, \n8\n In the present case, IVIG in combination with immobilization and the presence of an indwelling CVC were presumed to have induced the formation of thrombi.\n\nAlthough the treatment of massive PE remains controversial, there are two primary treatment modalities: thrombolytic treatment and pulmonary embolectomy. Thrombolysis is often effective but is associated with a high frequency of major bleeding complications, particularly intracranial hemorrhage.\n1\n, \n9\n, \n10\n Previously, pulmonary embolectomy was reserved for patients with massive PE and severe hemodynamic instability because of its association with high mortality rate. Recently, some clinicians have reported a high survival rate of approximately 90% among patients with PE treated with pulmonary embolectomy, which was attributed to improved surgical techniques, rapid diagnosis and triage, and careful patient selection.\n11\n, \n12\n Although selected hemodynamically stable patients with PE have been treated without CPB and have shown good results,\n13\n, \n14\n, \n15\n, \n16\n we performed embolectomy with CPB owing to thrombi in cardiac chambers. Goldhaber reported a more than 10‐fold increase in mortality risk in individuals with PFO and an approximately 50% mortality rate if free‐floating, right‐side heart thrombi were observed during echocardiography.\n17\n We believe that early decision‐making regarding surgical intervention was essential for successful management in the present case because the risk of death was sufficient to warrant immediate surgical correction.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nTT: drafted the manuscript, approved the manuscript, and collected the data. SS contributed to the critical revision and approval of the manuscript.\n\nACKNOWLEDGMENTS\nPublished with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nGoldhaber \nSZ \n, \nVisani \nL \n, \nDe Rosa \nM \n. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)\n. Lancet . 1999 ;353 :1386 ‐1389\n.10227218 \n2 \n\nStein \nPD \n, \nHenry \nJW \n. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy\n. Chest . 1995 ;108 :978 ‐981\n.7555172 \n3 \n\nSilverstein \nMD \n, \nHeit \nJA \n, \nMohr \nDN \n, et al, Trends in the incidents of deep vein thrombosis and pulmonary embolism: a 25‐year population‐based study\n. Arch Intern Med . 1998 ;158 :585 ‐593\n.9521222 \n4 \n\nAttia \nJ \n, \nRay \nJG \n, \nCook \nDJ \n, \nDouketis \nJ \n, \nGinsberg \nJS \n, \nGeerts \nWH \n. Deep vein thrombosis and its prevention in critically ill adults\n. Arch Intern Med . 2001 ;161 :1268 ‐1279\n.11371254 \n5 \n\nDohring \nDJ \n, \nArens \nJF \n. Pulmonary thromboembolism: disease recognition and patient management\n. Anesthesiology . 1990 ;73 :146 ‐160\n.2193557 \n6 \n\nGuo \nY \n, \nTian \nX \n, \nWang \nX \n, et al, Adverse effects of immunoglobulin therapy\n. Front Immunol . 2018 ;9 :1299 .29951056 \n7 \n\nSpäth \nPJ \n, \nGranata \nG \n, \nLa Marra \nF \n, et al, On the dark side of therapies with immunoglobulin concentrates: the adverse events\n. Front Immunol . 2015 ;6 :11 .25699039 \n8 \n\nLee \nYJ \n, \nShin \nJU \n, \nLee \nJ \n, et al, A case of deep vein thrombosis and pulmonary thromboembolism after intravenous immunoglobulin therapy\n. J Korean Med Sci . 2007 ;22 (4 ):758 ‐761\n.17728525 \n9 \n\nMeyer \nG \n, \nGisselbrecht \nM \n, \nDiehl \nJL \n, et al, Incidence and predictors of major hemorrhagic complications from thrombolytic therapy in patients with massive pulmonary embolism\n. Am J Med . 1998 ;105 :472 ‐477\n.9870831 \n10 \n\nHamel \nE \n, \nPacouret \nG \n, \nVincentelli \nD \n, et al, Thrombolysis or heparin therapy in massive pulmonary embolism with right ventricular dilation: results from a 128‐patient monocenter registry\n. Chest . 2001 ;120 :120 ‐125\n.11451826 \n11 \n\nAklog \nL \n, \nWilliams \nCS \n, \nByrne \nJG \n, et al, Acute pulmonary embolectomy: a contemporary approach\n. Circulation . 2002 ;105 :1416 ‐1419\n.11914247 \n12 \n\nYalamanchili \nK \n, \nFleisher \nAG \n, \nLehrman \nSG \n, et al, Open pulmonary embolectomy for treatment of major pulmonary embolism\n. Ann Thorac Surg . 2004 ;77 :819 ‐823\n.14992879 \n13 \n\nSenning \nA \n. Left anterior thoracotomy for pulmonary embolectomy with 29‐year follow‐up\n. Ann Thorac Surg . 1998 ;66 :1420 ‐1421\n.9800852 \n14 \n\nAshrafian \nH \n, \nKumar \nP \n, \nAthanasiou \nT \n, et al, Minimally invasive off‐pump pulmonary embolectomy\n. Cardiovasc Surg . 2003 ;11 :471 ‐473\n.14627969 \n15 \n\nHirnle \nT \n, \nHirnle \nG \n. A case of surgical treatment of acute pulmonary embolism without the use of extracorporeal circulation\n. Surgery . 2004 ;135 :461 ‐462\n.15041978 \n16 \n\nMoon \nSW \n, \nJo \nKH \n, \nWang \nYP \n, et al, Off‐pump open pulmonary embolectomy for major bilateral pulmonary emboli: report of a case\n. Surg Today . 2006 ;36 :274 ‐276\n.16493540 \n17 \n\nGoldhaber \nSZ \n. Echocardiography in the management of pulmonary embolism\n. Ann Intern Med . 2002 ;136 :691 ‐700\n.11992305\n\n",
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"abstract": "A forty-one-year-old man who, sought evaluation for a sudden hip flexion contracture and groin pain with a history of mechanical mitral valve replacement, had been misdiagnosed and treated as having lumbar discopathy for two days. This patient finally was diagnosed with compressive femoral neuropathy due to warfarin-induced retroperitoneal hematoma and successfully managed nonoperatively. This case is reported in order to draw attention to this rare presentation.",
"affiliations": "Department of Cardiovascular Surgery, School of Medicine, Balıkesir University, Bigadic, 10010 Balıkesir, Turkey.;Department of Cardiovascular Surgery, School of Medicine, Balıkesir University, Bigadic, 10010 Balıkesir, Turkey.;Department of Cardiovascular Surgery, School of Medicine, Balıkesir University, Bigadic, 10010 Balıkesir, Turkey.;Department of Cardiovascular Surgery, Samsun Hospital for Education and Research, İlkadım, 55090 Samsun, Turkey.;Department of Cardiovascular Surgery, Medical Park Usak Hospitals, 64000 Usak, Turkey.;Department of Cardiovascular Surgery, Acıbadem Bursa Hospital, 16110 Bursa, Turkey.",
"authors": "Gurbuz|Orcun|O|;Ercan|Abdulkadir|A|;Kumtepe|Gencehan|G|;Karal|Ilker Hasan|IH|;Velioglu|Yusuf|Y|;Ener|Serdar|S|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/450750Case ReportFemoral Nerve Palsy due to Anticoagulant Induced Retroperitoneal Hematoma Gurbuz Orcun \n1\n\n*\nErcan Abdulkadir \n1\nKumtepe Gencehan \n1\nKaral İlker Hasan \n2\nVelioglu Yusuf \n3\nEner Serdar \n4\n1Department of Cardiovascular Surgery, School of Medicine, Balıkesir University, Bigadic, 10010 Balıkesir, Turkey2Department of Cardiovascular Surgery, Samsun Hospital for Education and Research, İlkadım, 55090 Samsun, Turkey3Department of Cardiovascular Surgery, Medical Park Usak Hospitals, 64000 Usak, Turkey4Department of Cardiovascular Surgery, Acıbadem Bursa Hospital, 16110 Bursa, Turkey*Orcun Gurbuz: [email protected] Editor: Louis M. Aledort\n\n2014 16 10 2014 2014 4507501 8 2014 2 10 2014 Copyright © 2014 Orcun Gurbuz et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A forty-one-year-old man who, sought evaluation for a sudden hip flexion contracture and groin pain with a history of mechanical mitral valve replacement, had been misdiagnosed and treated as having lumbar discopathy for two days. This patient finally was diagnosed with compressive femoral neuropathy due to warfarin-induced retroperitoneal hematoma and successfully managed nonoperatively. This case is reported in order to draw attention to this rare presentation.\n==== Body\n1. Background\nThe requirement for anticoagulation after valve surgery and difficulty of stabilizing the warfarin dosage can cause severe complications. Bleeding is known to be the main complication of oral anticoagulant therapy. It is classified as major if it is intracranial or retroperitoneal or leads to death or results in hospitalization or needs blood transfusion. The major bleeding rate was reported between 0.41% and 5.5% per year in several trials in patients receiving long-term oral anticoagulant therapy for prosthetic heart valves [1]. Spontaneous iliopsoas and retroperitoneal hematomas as a complication of anticoagulant therapy have been reported in various cases, with a relatively low incidence as 0.5% [2–5]. In the majority of reported cases, the diagnosis is often delayed as symptoms and signs are nonspecific. Therefore, retroperitoneal hematoma should be suspected in patients with significant groin, flank, abdominal, and back pain, partial loss of quadriceps functions, or haemodynamic instability in patients who are anticoagulated. Rarely, it can cause flexion contracture of the hip due to compressive femoral palsy as in the present case [3, 5]. There is no large series of patients to base decisions regarding treatment because of the rare presentation. In this case, patient managed conservatively with blood transfusion, rapid reversal of INR (international normalized ratio) to prevent further bleeding, and leg elevation to reduce neural compression.\n\n2. Case Presentation\nA 41-year-old man was admitted to the emergency department for left hip flexion contracture and severe groin pain. He had been complaining of progressive lower abdomen and groin pain, paraesthesia, and weakness in his upper left thigh for three days. Therefore, this case was misdiagnosed and treated as lumbar discopathy previously in another hospital two days ago. He had a history of prosthetic mitral valve replacement (MVR) two years ago and was taking warfarin. Antiplatelet therapy (acetylsalicylic acid at 100 mg/day) was added to the medical therapy three months ago by a cardiologist from another hospital.\n\nOn physical examination, he presented with a fixed left hip in semiflexion (about 45°) and any further passive movement of the hip was giving him pain in the groin. He had a good general status, with blood pressure of 100/60 mm Hg, pulse 96 beats·min−1, respiratory rate 14 breaths·min−1, and an axillary temperature of 36.5°C. Both lower extremity pulses were symmetric and equal. Laboratory test revealed anaemia with a haemoglobin value of 8.9 g/L. The INR level was 4.1 and the prothrombin time (PT) was 45.1 seconds. Ultrasonography (US) detected 10 × 8 × 8 cm left iliopsoas hematoma. This finding was confirmed by computed tomography (CT) (Figures 1(a) and 1(b)).\n\nWe preferred conservative management due to stable parameters with careful hemodynamic and haemoglobin level monitoring. Right leg was kept elevated above the heart level to reduce nerve compression by hematoma. Warfarin and antiplatelet therapies were withdrawn. The INR was lowered to 1.9 within 24 hours after the administration of 10 mg vitamin K and 2 fresh frozen plasma units, so low molecular weight heparin (LMWH) therapy started. One hematite concentrate was administered in order to recover normal values. Flexion contracture recovered within 24 hours and left quadriceps strength improved to 3/5 and the patient began mobilization. Haemoglobin level did not reduce and hemodynamic parameters remained stable during hospitalization. A follow-up ultrasound scan was performed after 72 hours, and no growth was seen in the hematoma. On the third day, haemoglobin level was 9.9 g/L and INR was 1.32. The quadriceps strengthening exercise program was started on day three of hospitalization after being sure that bleeding ceased. The patient was discharged on the sixth day with normal laboratory findings and 3/5 strength in his left quadriceps. On his 21st day visit after hospitalization, strength of left quadriceps femoris was 4/5, haemoglobin level was 12.2 g/L, and US scan revealed a decrease in hematoma (3.5 × 2.5 cm). Abdominal CT confirmed partial resolution of the hematoma (Figures 2(a) and 2(b)). A single warfarin regimen without antiplatelet therapy was initiated after these findings. LMWH continued until the INR reached 2.5. All symptoms resolved during the next month, and the patient's sensation, strength, and reflexes returned to normal.\n\n3. Conclusions\nRetroperitoneal haematoma incidence in patients undergoing therapeutic anticoagulation varies between 0.6% and 6.6% among studies [1, 6]. The intensity of anticoagulant effect appears to be the most important risk factor for major hemorrhage, independent of the indication for therapy; all randomized controlled trials have reported a strong relationship between the targeted intensity of anticoagulant therapy and the risk of major bleeding [1, 7]. The optimal therapeutic range of anticoagulant therapy in the secondary prevention of vascular events lies between INRs from 2.0 to 3.9, with a target INR of 3.0. When the INR is above 5.0, the risk of serious bleeding complications becomes unacceptable [7]. Moreover, it has also been shown that adding antiplatelet medications to warfarin therapy significantly increases the incidence of major bleeding [1]. Accordingly, in this case, hematoma occurred after antiplatelet therapy had been started, but when INR had just reached over the therapeutic range.\n\nThe femoral nerve provides motor innervation to the quadriceps, sartorius, pectins, and iliopsoas muscle and supplies sensory innervation to the anteromedial thigh and medial leg. It lies between the iliacus and psoas muscles, which form a tendon inserting into the lesser trochanter of the femur. The entrapment of the femoral nerve in this area due to hematoma causes weakness in hip flexion and knee extension and has been reported more widely after hematologic disorders such as haemophilia [8, 9] and leukaemia [10]; other causes are uncommon [2–5, 11–14]. Some of the sudden symptoms such as lateral abdominal pain, hemiparesis, or hip flexion contractures are nonspecific and can refer to other diseases. Diagnosing such cases may be challenging for clinicians in the hemodynamically stable patient, especially when the INR level is not too high, as our patient has experienced. Therefore, the clinician should have a high index of suspicion and need to be aware of this rare presentation. An abdominal ultrasound can satisfactorily detect retroperitoneal hematoma; this will reduce morbidity and ameliorate recovery.\n\nThe treatment of spontaneous retroperitoneal hematomas causing femoral neuropathy remains controversial. Favourable results have been reported with conservative therapy, in hematological pathology [2–5, 8–10], but, in the case of progressive neurological dysfunction, urgent operative intervention has been suggested, especially in cases without disorders of haemostasis [11, 12]. In our case, we chose conservative therapy with close hemodynamic and neurological monitoring. Furthermore, the affected extremity was kept elevated for 2 days. Flexion contracture recovered rapidly within 24 hours, and the patient began mobilization. We think that rapid recovery of hip flexion contracture might have been caused by the elevation of the extremity by decreasing the compression of the nerve in the groin. Following an acute retroperitoneal hematoma, bleeding should be collected in the pelvic region due to gravity and it might compress the femoral nerve if it extends into the inguinal canal. In such cases, elevation of the affected extremity against gravity would direct the bleeding upwards and decompress the nerve.\n\nIn conclusion, in the presence of combined anticoagulant and antiplatelet therapy, iliopsoas hematoma may occur without a too high INR level. For every anticoagulated patient suffering from lower abdominal and pelvic pain, abdominal ultrasound or CT scanning might be performed to make an accurate diagnosis. Medical treatment can be combined with elevation of the affected extremity to decompress the femoral nerve entrapment.\n\nAbbreviations\nCT:Computed tomography\n\nINR: International normalized ratio\n\nLMWH:Low molecular weight heparin\n\nMVR:Mitral valve replacement\n\nPT:Prothrombin time\n\nUS:Ultrasonography.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this case report and all accompanying images.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Abdominal CT showed a large retroperitoneal hematoma, which extends through femoral triangle. White arrows in the pictures highlight left iliopsoas hematoma and its inguinal extension.\n\nFigure 2 Repeat CT sections after 3 weeks showed significant reduction of hematoma. White arrows in the pictures highlight left iliopsoas hematomas reduction and the reduction of its inguinal extension.\n==== Refs\n1 Levine M. N. Raskob G. Beyth R. J. Kearon C. Schulman S. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004 126 3 supplement 287S 310S 10.1378/chest.126.3_suppl.287S 2-s2.0-4644293243 15383476 \n2 Wada Y. Yanagihara C. Nishimura Y. Bilateral iliopsoas hematomas complicating anticoagulant therapy Internal Medicine 2005 44 6 641 643 10.2169/internalmedicine.44.641 2-s2.0-21644459715 16020897 \n3 Jamjoom Z. A. B. Al-Bakry A. Al-Momen A. Malabary T. Tahan A.-R. Yacub B. Bilateral femoral nerve compression by iliacus hematomas complicating anticoagulant therapy Surgery Today 1993 23 6 535 540 10.1007/BF00730631 2-s2.0-0027299691 8358198 \n4 Shah R. D. Nagar S. Shanley C. J. Janczyk R. J. Factors affecting the severity of spontaneous retroperitoneal hemorrhage in anticoagulated patients The American Journal of Surgery 2008 195 3 410 413 10.1016/j.amjsurg.2007.12.003 2-s2.0-40749103374 18241833 \n5 Chan Y. C. Morales J. P. Reidy J. F. Taylor P. R. Management of spontaneous and iatrogenic retroperitoneal haemorrhage: conservative management, endovascular intervention or open surgery? International Journal of Clinical Practice 2008 62 10 1604 1613 10.1111/j.1742-1241.2007.01494.x 2-s2.0-51349139436 17949429 \n6 Forfar J. C. A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment British Heart Journal 1979 42 2 128 132 10.1136/hrt.42.2.128 2-s2.0-0018625783 486273 \n7 Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. The European Atrial Fibrillation Trial Study Group The New England Journal of Medicine 1995 333 1 5 10 7776995 \n8 Dauty M. Sigaud M. Trossaërt M. Fressinaud E. Letenneur J. Dubois C. Iliopsoas hematoma in patients with hemophilia: a single-center study Joint Bone Spine 2007 74 2 179 183 10.1016/j.jbspin.2006.05.014 2-s2.0-34247352482 17336570 \n9 Balkan C. Kavakli K. Karapinar D. Iliopsoas haemorrhage in patients with haemophilia: results from one centre Haemophilia 2005 11 5 463 467 10.1111/j.1365-2516.2005.01123.x 2-s2.0-24644485701 16128889 \n10 Bauduceau O. de Revel T. Fogelman J. Amadou S. Souleau B. Nedellec G. Spontaneous hematoma of the iliac psoas muscle in chronic myeloid leukemia. A case report Annales de Medecine Interne 2003 154 3 183 186 2-s2.0-0037696804 12910048 \n11 Warfel B. S. Marini S. G. Lachmann E. A. Nagler W. Delayed femoral nerve palsy following femoral vessel catheterization Archives of Physical Medicine and Rehabilitation 1993 74 11 1211 1215 2-s2.0-0027496651 8239965 \n12 Hardy S. L. Femoral nerve palsy associated with an associated posterior wall transverse acetabular fracture Journal of Orthopaedic Trauma 1997 11 1 40 42 10.1097/00005131-199701000-00010 2-s2.0-0030638438 8990032 \n13 Papastefanou S. L. Stevens K. Mulholland R. C. Femoral nerve palsy: an unusual complication of anterior lumbar interbody fusion Spine 1994 19 24 2842 2844 10.1097/00007632-199412150-00020 2-s2.0-0028608141 7899989 \n14 Une D. Shimizu S. Nakanishi K. Bilateral iliopsoas hematomas under sedation: a complication of postoperative therapy after coronary artery bypass grafting Acta Medica Okayama 2010 64 1 71 73 2-s2.0-77952756630 20200588\n\n",
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{
"abstract": "Graft-versus-host disease (GVHD) is one of the major complications after hematopoietic stem cell transplantation and is responsible for post-therapeutic morbidity, mortality, and poor quality of life of recipients. Sclerodermatous graft-versus-host disease (sGVHD) is a rare variant of chronic GVHD characterized by deposition of collagen in the skin and other soft tissues and resulting in loss of range of motion and functional capabilities. Treatment of sGVHD is challenging and largely limited by systemic side effects. Ultraviolet A1 phototherapy has been reported to be effective in connective tissue disorders, including sGVHD. We report a case of sGVHD in a 15-year-old girl that was resistant to traditional therapy but showed improvement in cutaneous symptoms with ultraviolet A1 phototherapy three times a week for 6 weeks (10 J/cm(2) single dose, 180 J/cm(2) cumulative dose).",
"affiliations": "Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.;Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.;Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.;Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.;Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.",
"authors": "Lazzeri|Linda|L|;Tripo|Lara|L|;Pescitelli|Leonardo|L|;Ricceri|Federica|F|;Prignano|Francesca|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12794",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "33(2)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000293:Adolescent; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D011701:PUVA Therapy; D012594:Scleroderma, Localized",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e99-102",
"pmc": null,
"pmid": "26871550",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Pediatric Case of Sclerodermatous Graft-Versus-Host Disease Responsive to Ultraviolet A1 Phototherapy.",
"title_normalized": "a pediatric case of sclerodermatous graft versus host disease responsive to ultraviolet a1 phototherapy"
}
|
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{
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],
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"literaturereference": "LAZZERI L, TRIPO L, PESCITELLI L, RICCERI F, PRIGNANO F, UNKNOWN. A PEDIATRIC CASE OF SCLERODERMATOUS GRAFT-VERSUS-HOST DISEASE RESPONSIVE TO ULTRAVIOLET A1 PHOTOTHERAPY. PEDIATRIC DERMATOLOGY. 2016 JAN 01?4:1-4.",
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}
] |
{
"abstract": "Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare autoimmune disorder characterised by recurrent urticarial lesions and acquired hypocomplementemia with systemic manifestations. The authors present the case of a 70-year-old man who presented to the ophthalmology clinic with bilateral scleritis and ocular hypertension. He was diagnosed with HUVS after a 6-month period of bilateral scleritis, vestibulitis, significant weight loss, mononeuritis multiplex and recurrent urticarial vasculitis with pronounced persistent hypocomplementemia and the presence of anti-C1q antibodies. Disease control was eventually obtained with mycophenolate and prednisolone.",
"affiliations": "Canberra Health Services Library, ACT Government, Garren, Australian Capital Territory, Australia [email protected].;Ophthalmology Unit, Canberra Health Services, Garran, Australian Capital Territory, Australia.;ACT Pathology, Canberra Health Services, Garran, Australian Capital Territory, Australia.;Department of Immunology, Canberra Health Services, Garran, Australian Capital Territory, Australia.",
"authors": "Berry|Ella Claire|EC|http://orcid.org/0000-0001-6128-683X;Wells|Jane|J|;Morey|Adrienne|A|;Anantharajah|Anthea|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D003165:Complement System Proteins",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "dermatology; immunology; ophthalmology; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D003165:Complement System Proteins; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D015423:Scleritis; D014581:Urticaria; D014657:Vasculitis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33972296",
"pubdate": "2021-05-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypocomplementemic urticarial vasculitis syndrome presenting with bilateral scleritis.",
"title_normalized": "hypocomplementemic urticarial vasculitis syndrome presenting with bilateral scleritis"
}
|
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{
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},
{
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}
],
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},
"primarysource": {
"literaturereference": "Berry E, Wells J, Morey A, Anantharajah A.. Hypocomplementemic urticarial vasculitis syndrome presenting with bilateral scleritis. BMJ Case Rep. 2021;14:e240041:1-6",
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"qualification": "1",
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},
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"receiptdate": "20211221",
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},
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},
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}
] |
{
"abstract": "Cramp-fasciculation syndrome (CFS) is a rare muscle hyperexcitability syndrome that presents with muscle cramps, fasciculations, and stiffness, as well as pain, fatigue, anxiety, hyperreflexia, and paresthesias. Although familial cases have been reported, a genetic etiology has not yet been identified. We performed whole-exome sequencing followed by validation and cosegregation analyses on a father-son pair with CFS. Both subjects manifested other hypersensitivity-hyperexcitability symptoms, including asthma, gastroesophageal reflux, migraine, restless legs syndrome, tremor, cold hyperalgesia, and cardiac conduction defects. Most symptoms improved with carbamazepine, consistent with an underlying cation channelopathy. We identified a variant in the transient receptor potential ankyrin A1 channel (TRPA1) gene that selectively cosegregated with CFS and the other hypersensitivity-hyperexcitability symptoms. This variant (c.2755C>T) resulted in a premature stop codon at amino acid 919 (p.Arg919*) in the outer pore of the channel. TRPA1 is a widely distributed, promiscuous plasmalemmal cation channel that is strongly implicated in the pathophysiology of the specific hypersensitivity-hyperexcitability symptoms observed in these subjects. Thus, we have identified a novel TRPA1 variant that is associated with CFS as part of a generalized hypersensitivity-hyperexcitability disorder. These findings clarify the diverse functional roles of TRPA1, and underscore the importance of this channel as a potential therapeutic target.",
"affiliations": "Department of Neurology, NYU School of Medicine, New York, New York.;Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Neurology, NYU School of Medicine, New York, New York.;Department of Neurology, NYU School of Medicine, New York, New York.;Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.",
"authors": "Nirenberg|M J|MJ|http://orcid.org/0000-0003-3892-6733;Chaouni|R|R|;Biller|T M|TM|;Gilbert|R M|RM|;Paisán-Ruiz|C|C|",
"chemical_list": "D000927:Anticonvulsants; D018389:Codon, Nonsense; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D002220:Carbamazepine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/cge.13040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9163",
"issue": "93(1)",
"journal": "Clinical genetics",
"keywords": "\nTRPA1; asthma; cardiac; channelopathy; cramp; fasciculation; gastrointestinal; migraine; pain",
"medline_ta": "Clin Genet",
"mesh_terms": "D000927:Anticonvulsants; D001483:Base Sequence; D002220:Carbamazepine; D018389:Codon, Nonsense; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009468:Neuromuscular Diseases; D010375:Pedigree; D000074025:TRPA1 Cation Channel; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "0253664",
"other_id": null,
"pages": "164-168",
"pmc": null,
"pmid": "28436534",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19063707;20419599;27194300;24291101;24756722;20457836;20547126;20950342;25855297;25138211;21076024;1648679;23020579;26427606;23001121",
"title": "A novel TRPA1 variant is associated with carbamazepine-responsive cramp-fasciculation syndrome.",
"title_normalized": "a novel trpa1 variant is associated with carbamazepine responsive cramp fasciculation syndrome"
}
|
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"literaturereference": "NIRENBERG M,CHAOUNI R,BILLER T,GILBERT R,PAIS?N C. A NOVEL TRPA1 VARIANT IS ASSOCIATED WITH CARBAMAZEPINE- RESPONSIVE CRAMP-FASCICULATION SYNDROME. CLINICAL GENETICS (2018) 2018 JAN 01?93(1):164-168.",
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{
"abstract": "Pure red cell aplasia (PRCA) is a rare paraneoplastic syndrome observed in 2-5 % of thymomas. Literature reports great variability in its management. Based on an illustrative clinical case, we present a systematic literature review whose main objective is to evaluate the therapeutic management of PRCA. The literature search was performed based on the PICO method in the Medline and Scopus databases. The reference clinical case concerns a 51-year-old woman with stage IVa thymoma. After initial response to chemotherapy, a locoregional progression occurred with PRCA development that responded favorably under second line chemotherapy. The patient finally died in a context of bicytopenia with febrile neutropenia. The systematic review covers 135 articles published between 1950 and 2019. Thymectomy alone or in combination with other therapies showed a 31 % complete remission (CR) rate for PRCA of, whereas none was reported with anti-tumor treatments without thymectomy. Among immunomodulatory therapies, cyclosporin gave the highest percentage of CR (74 %). Finally, the combination of thymectomy and immunomodulatory treatments showed a CR rate of 45 %. Thymectomy appeared to be the most effective anti-tumor treatment for PRCA. Immunomodulatory therapies, particularly cyclosporine, are shown effective, but the risk of infectious complications must be considered. The optimal place of anti-tumor and immunomodulatory therapies against PRCA has yet to be determined.",
"affiliations": "Department of Internal Medecine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: [email protected].;Bibliothèque des Sciences de la Santé, Université libre de Bruxelles, Belgium. Electronic address: [email protected].;Department of Intensive Care and Oncological Emergencies & Thoracic Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: [email protected].;Institut du Thorax Curie Montsouris, Institut Curie, Paris, France. Electronic address: [email protected].;Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Laboratoire Facultaire de Médecine Factuelle de l'Université Libre de Bruxelles, Belgium. Electronic address: [email protected].",
"authors": "Lesire|Bastien|B|;Durieux|Valérie|V|;Grigoriu|Bogdan|B|;Girard|Nicolas|N|;Berghmans|Thierry|T|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2021.05.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "157()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Clinical case; Erythroblastopenia; Pure red cell aplasia; Systematic review; Thymic carcinoma; Thymoma",
"medline_ta": "Lung Cancer",
"mesh_terms": "D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D012010:Red-Cell Aplasia, Pure; D013934:Thymectomy; D013945:Thymoma; D013953:Thymus Neoplasms",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "131-146",
"pmc": null,
"pmid": "34049719",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Management of thymoma associated autoimmune pure red cell aplasia: Case report and systematic review of the literature.",
"title_normalized": "management of thymoma associated autoimmune pure red cell aplasia case report and systematic review of the literature"
}
|
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}
],
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] |
{
"abstract": "The Risk Evaluation and Mitigation Strategy program that the U.S. Food and Drug Administration has mandated has intensified the counseling associated with prescribing mycophenolate mofetil (MMF), because of its teratogenicity. In this brief report, two children are described who were prescribed MMF and within weeks developed psychiatric symptoms, with rapid resolution after discontinuation of the medication and no recurrence over 4 years of follow-up. Mood disorders are a rare but possible side effect that should be mentioned when discussing MMF with patients and families. Prompt discontinuation of the drug should lead to reversal of symptoms when the drug is implicated.",
"affiliations": "Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.",
"authors": "Arkin|Lisa|L|;Talasila|Sreya|S|;Paller|Amy S|AS|",
"chemical_list": "D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12845",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "33(3)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D003876:Dermatitis, Atopic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005148:Facial Dermatoses; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D019964:Mood Disorders; D009173:Mycophenolic Acid; D012008:Recurrence; D018570:Risk Assessment; D012494:Sampling Studies; D012594:Scleroderma, Localized; D012720:Severity of Illness Index; D014481:United States; D014486:United States Food and Drug Administration; D028761:Withholding Treatment",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e216-7",
"pmc": null,
"pmid": "27071734",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Mycophenolate Mofetil and Mood Changes in Children with Skin Disorders.",
"title_normalized": "mycophenolate mofetil and mood changes in children with skin disorders"
}
|
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{
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"activesubstancename": "FOLATE SODIUM"
},
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"drugdosagetext": "UNK",
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{
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},
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"drugdosagetext": "2.1429 MG (15 MG,1 IN 1 W)",
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"medicinalproduct": "METHOTREXATE SODIUM."
},
{
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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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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Off label use",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Eosinophilia",
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"reactionoutcome": "6"
}
],
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},
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{
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],
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{
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{
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{
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{
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{
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{
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{
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}
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},
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{
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"literaturereference": "ARKIN L, TALASILA S, PALLER AS. MYCOPHENOLATE MOFETIL AND MOOD CHANGES IN CHILDREN WITH SKIN DISORDERS. PEDIATR DERMATOL. 2016;33(3):E216-E217",
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] |
{
"abstract": "Low dose direct acting oral anticoagulants (LDDOACS) were approved for elderly atrial Fibrillation (AF) patients with limited information. A retrospective analysis collecting baseline characteristics and outcomes in AF patients ≥ 80 prescribed LDDOAC or warfarin (W), from a multidisciplinary practice between 1/1/11 (First LDDOAC available) and 5/31/17 was conducted. From 9660 AF patients, 514 ≥ 80 received a LDDOAC and 422 W. A multivariable comparison found LDDOAC patients were older (p <0.001), had lower creatinine clearance (CrCl) (p = 0.006), used more anti-platelet drugs (p <0.001), and more often had new onset AF verses those prescribed W (p <0.001). There were no clinically significant differences among those patients receiving Dabigatran 75 mgs BID (D), Rivaroxaban 15mgs (R) or Apixaban 2.5mgs BID (A). Forty-eight and 50% of the patients remained on their LDDOAC or W for the observation period (p = 0.55). Stroke/systemic embolism (SSE) and CNS bleeds were 1.16 vs 2.22%/yr., (p = 0.143) and 1.46 vs 0.93%/yr., (p = 0.24). Mortality and major bleeds were 6.26 vs 1.67%/yr., and 12.3vs 3.77%/yr. (p <0.001). SSE were 1.1%/yr for D, R, and A (p = 0.94). CNS bleeds were 2.2 for D, 1.7 for R and 0.8%/yr. for A: p = 0.53. Major bleeding was: 14.3 for D, 14.1 for R and 9.1%/yr. for A, p = 0.048 (with A < R, p = 0.01). Mortality was 5.5 for D, 4.2 for R and 9.5% for A, p = 0.031. In conclusion, half the patients remained on their assigned anti-coagulant. SSE and intracranial bleed rates were similar and low. Major bleeds and deaths were different between groups emphasizing the need for prospective randomized trials in this growing population with AF.",
"affiliations": "Bryn Mawr Hospital Main Line Health, Bryn Mawr, Pennsylvania; Sidney Kimmel Medical College at Jefferson University, Philadelphia, Pennsylvania.;Bryn Mawr Hospital Main Line Health, Bryn Mawr, Pennsylvania; Sidney Kimmel Medical College at Jefferson University, Philadelphia, Pennsylvania; Lankenau Medical Center Main Line Health, Wynnewood, Pennsylvania. Electronic address: [email protected].;Department of Epidemiology and Biostatistics, Drexel University, Philadelphia, Pennsylvania.;Bryn Mawr Hospital Main Line Health, Bryn Mawr, Pennsylvania.;Bryn Mawr Hospital Main Line Health, Bryn Mawr, Pennsylvania.;Bryn Mawr Hospital Main Line Health, Bryn Mawr, Pennsylvania.;Bryn Mawr Hospital Main Line Health, Bryn Mawr, Pennsylvania.",
"authors": "Chaudhry|Usman A|UA|;Ezekowitz|Michael D|MD|;Gracely|Edward J|EJ|;George|Winson T|WT|;Wolfe|Catrina M|CM|;Harper|Grace|G|;Harper|Glenn R|GR|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjcard.2021.04.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "152()",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D000367:Age Factors; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D000069604:Dabigatran; D004617:Embolism; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D015999:Multivariate Analysis; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D012189:Retrospective Studies; D000069552:Rivaroxaban; D020521:Stroke; D014859:Warfarin",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "69-77",
"pmc": null,
"pmid": "34162485",
"pubdate": "2021-08-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comparison of Low-Dose Direct Acting Anticoagulant and Warfarin in patients Aged ≥80 years With Atrial Fibrillation.",
"title_normalized": "comparison of low dose direct acting anticoagulant and warfarin in patients aged 80 years with atrial fibrillation"
}
|
[
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-112385",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": "022512",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ATRIAL FIBRILLATION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"medicinalproduct": "PRADAXA"
}
],
"patientagegroup": "6",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Embolism",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "EZEKOWITZ M, CHAUDHARY U, GRACELY E, GEORGE W, WOLFE C, HARPER G. ET AL. COMPARISON OF LOW?DOSE DIRECT ACTING ANTICOAGULANT AND WARFARIN IN PATIENTS AGED ?80 YEARS WITH ATRIAL FIBRILLATION. AMERICAN JOURNAL OF CARDIOLOGY. 2021?",
"literaturereference_normalized": "comparison of low dose direct acting anticoagulant and warfarin in patients aged 80 years with atrial fibrillation",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210701",
"receivedate": "20210701",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 19484428,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "BACKGROUND\nAnti-N-Methyl-D-Aspartate receptor (anti-NMDAR) encephalitis is responsive to immunotherapy and removal of tumor, but there is no consensus in the treatment of severe anti- NMDAR encephalitis with prolonged refractory status epilepticus (SE).\n\n\nMETHODS\nA 17-year-old girl presented as acute psychosis, refractory seizures, hyperkinesia, autonomic instability, and soon progressed to a dissociative state of coma. Anti-NMDAR antibodies were positive in serum and CSF. When most of the symptoms were alleviated after repeated one-byone immunotherapy during the first four months, the patient still remained in a coma with frequent seizures despite treatment with five different anti-epileptic drugs. We then proposed a three-combined immunotherapy of high-dose steroid, intravenous immunoglobulin and rituximab. After such treatment, her SE was soon resolved and this patient regained her consciousness before resection of ovarian teratoma. Although she had suffered from a prolonged period of refractory SE and coma for six months, she still had good recovery from encephalitis after a long-term immunotherapy.\n\n\nCONCLUSIONS\nA strong and long-term course of immunotherapy is necessary in treating severe refractory anti-NMDAR encephalitis. If traditional step-by-step way of immunotherapy is not strong enough to rapidly cure severe anti-NMDAR encephalitis, combined immunosuppressive agents can be considered to shorten the clinical course.",
"affiliations": "Department of Neurology, En Chu Kong Hospital, New Taipei City, Taiwan.;Department of Neurology, En Chu Kong Hospital, New Taipei City, Taiwan.",
"authors": "Lee|Lan-Hsin|LH|;Lu|Chien-Jung|CJ|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-768X",
"issue": "25(3)",
"journal": "Acta neurologica Taiwanica",
"keywords": null,
"medline_ta": "Acta Neurol Taiwan",
"mesh_terms": "D000293:Adolescent; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D007167:Immunotherapy; D013226:Status Epilepticus",
"nlm_unique_id": "9815355",
"other_id": null,
"pages": "99-103",
"pmc": null,
"pmid": "27854088",
"pubdate": "2016-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-term and Strong Immunotherapy to Treat Anti-N-Methyl- D-Aspartate Receptor Encephalitis with Refractory Status Epilepticus.",
"title_normalized": "long term and strong immunotherapy to treat anti n methyl d aspartate receptor encephalitis with refractory status epilepticus"
}
|
[
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"medicinalproduct": "LEVETIRACETAM."
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"medicinalproduct": "CLONAZEPAM."
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"medicinalproduct": "PHENYTOIN."
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],
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"patientonsetage": "17",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Coma",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201410"
}
},
"primarysource": {
"literaturereference": "LEE LH, LU CJ. LONG-TERM AND STRONG IMMUNOTHERAPY TO TREAT ANTI-N-METHYL-D-ASPARTATE RECEPTOR ENCEPHALITIS WITH REFRACTORY STATUS EPILEPTICUS. ACTA NEUROL TAIWAN. 2016;25(3):99-103",
"literaturereference_normalized": "long term and strong immunotherapy to treat anti n methyl d aspartate receptor encephalitis with refractory status epilepticus",
"qualification": "1",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20170102",
"receivedate": "20170102",
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"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13078442,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
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}
] |
{
"abstract": "BACKGROUND\nThis is the 28th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). All US poison centers upload case data automatically with a median time interval of 19.0 [11.9, 40.6] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.\n\n\nMETHODS\nWe analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 33 medical and clinical toxicologist reviewers using an ordinal scale of 1 (Undoubtedly responsible) - 6 (Unknown) to determine Relative Contribution to Fatality (RCF) of the exposure to the death.\n\n\nRESULTS\nIn 2010, 3,952,772 closed encounters were logged by NPDS: 2,384,825, human exposures, 94,823 animal exposures, 1,466,253 information calls, 6537 human confirmed nonexposures, and 334 animal confirmed nonexposures. Total encounters showed a 7.7% decline from 2009 while health care facility calls increased by 2.7%. Human exposures with more serious outcomes (minor, moderate, major or death) increased 4.5% while those with less serious outcomes (all other medical outcome categories) decreased 5.9%. All information calls decreased 12.6% and health care facility (HCF) information calls decreased 13.6%, Drug ID calls decreased 10.9%, and human exposures decreased 3.8%. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.5%), cosmetics/personal care products (7.7%), household cleaning substances (7.3%), sedatives/hypnotics/ antipsychotics (6.0%), and foreign bodies/toys/miscellaneous (4.2%). Analgesic exposures as a class increased the most rapidly by 32.8% over the last decade. The top f ve most common exposures in children age 5 years or less were cosmetics/personal care products (13.2%), analgesics (9.4%), household cleaning substances (9.2%), foreign bodies/toys/miscellaneous (7.2%), and topical preparations (6.8%). THC homolog and designer amphetamine (\"Bath Salts\") exposures were identified as emerging public health threats. Drug identification requests comprised 64.3% of all information calls. NPDS documented 1730 human exposures resulting in death with 1146 human fatalities judged related with an RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory.\n\n\nCONCLUSIONS\nThese data support the continued value of poison center expertise and need for specialized medical toxicology information to manage the more severe exposures, despite a decrease in calls involving less severe exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for public health surveillance for all types of exposures, public health event identification, resilience response and situational awareness tracking. NPDS is a model system for the nation and global public health.",
"affiliations": "FACEP, FACMT, American Association of Poison Control Centers, 515 King Street, Suite 510, Alexandria, VA 22314, USA.",
"authors": "Bronstein|Alvin C|AC|;Spyker|Daniel A|DA|;Cantilena|Louis R|LR|;Green|Jody L|JL|;Rumack|Barry H|BH|;Dart|Richard C|RC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2011.635149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "49(10)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D016208:Databases, Factual; D004781:Environmental Exposure; D006801:Humans; D011039:Poison Control Centers; D011041:Poisoning; D011159:Population Surveillance; D012952:Societies; D014481:United States",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "910-41",
"pmc": null,
"pmid": "22165864",
"pubdate": "2011-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "2010 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th Annual Report.",
"title_normalized": "2010 annual report of the american association of poison control centers national poison data system npds 28th annual 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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{
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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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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20100101"
}
},
"primarysource": {
"literaturereference": "BRONSTEIN AC, SPYKER DA, CANTILENA LR, GREEN JL, RUMACK BH, DART RC. 2010 Annual Report of the American Association of Poison Control Centers^ National Poison Data System (NPDS): 28th Annual Report. Clinical Toxicology. 2011;49:910-941",
"literaturereference_normalized": "2010 annual report of the american association of poison control centers national poison data system npds 28th annual report",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211214",
"receivedate": "20211214",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20181173,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 1,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "The recommended chemotherapy regimens for pancreatic cancer include the combination of 5-fluorouracil/leucovorin, oxaliplatin and irinotecan (FOLFIRINOX), nab-paclitaxel (nab-PTX) plus gemcitabine (GEM), GEM alone and tegafur/gimeracil/oteracil potassium (S-1) alone. Although the cost-effectiveness of metastatic pancreatic cancer chemotherapies has been extensively investigated, to the best of our knowledge, no study has specifically compared the cost-effectiveness among FOLFIRINOX, nab-PTX + GEM, GEM and S-1 regimens to date. The aim of the present study was to examine the cost-effectiveness of these four regimens. The expected costs were calculated based on data from patients with metastatic pancreatic cancer who were treated with the FOLFIRINOX, nab-PTX + GEM, GEM alone or S-1 alone. The median survival time (MST) from randomized controlled trials in the literature was used to evaluate the therapeutic effect of these regimens. The cost-effectiveness ratio was calculated using expected costs and MST for these four regimens. The expected costs per patient for the FOLFIRINOX, nab-PTX + GEM, GEM or S-1 regimens were ¥6,361,191.4, ¥4,802,063.6, ¥540,091.4 and ¥528,514.6, respectively, and the cost-effectiveness ratios per month were ¥642,544.6/MST, ¥470,790.5/MST, ¥81,832.0/MST and ¥55,633.1/MST, respectively. In conclusion, the nab-PTX + GEM and FOLFIRINOX regimens were associated with a high therapeutic efficacy and high cost. The GEM regimen exhibited a lower therapeutic efficacy compared with the nab-PTX + GEM and FOLFIRINOX regimens, but the findings of this study indicated that the GEM and S-1 regimens were the most cost-effective regimens.",
"affiliations": "Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan.;Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan.;Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan.;Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan.;Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan.;Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan.;Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan.",
"authors": "Kurimoto|Machiko|M|;Kimura|Michio|M|;Usami|Eiseki|E|;Iwai|Mina|M|;Hirose|Tatsuya|T|;Kawachi|Shiori|S|;Yoshimura|Tomoaki|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2017.1278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "7(1)",
"journal": "Molecular and clinical oncology",
"keywords": "FOLFIRINOX; S-1; adverse event; cost-effectiveness; gemcitabine; metastatic pancreatic cancer; nab-paclitaxel",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "125-130",
"pmc": null,
"pmid": "28685089",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "18421054;20414022;21561347;27637757;21228335;21502544;28426492;25117729;24131140;25991037;23547081;25788034;21969517;27056335;28381780;19581533",
"title": "Comparing the cost-effectiveness of FOLFIRINOX, nab-paclitaxel plus gemcitabine, gemcitabine and S-1 for the treatment of metastatic pancreatic cancer.",
"title_normalized": "comparing the cost effectiveness of folfirinox nab paclitaxel plus gemcitabine gemcitabine and s 1 for the treatment of metastatic pancreatic cancer"
}
|
[
{
"companynumb": "JP-CELGENEUS-JPN-20170607290",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "041",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "1000 MILLIGRAM/SQ. METER",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "GEMCITABINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "021660",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "125 MILLIGRAM/SQ. METER",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "125",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ABRAXANE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "1000 MILLIGRAM/SQ. METER",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "GEMCITABINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Aspartate aminotransferase increased",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood bilirubin increased",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Constipation",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Arthralgia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood creatinine increased",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Peripheral sensory neuropathy",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oedema",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dysgeusia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hyperkalaemia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KURIMOTO M. COMPARING THE COST EFFECTIVENESS OF FOLFIRINOX, NAB PACLITAXEL PLUS GEMCITABINE, GEMCITABINE AND S 1 FOR THE TREATMENT OF METASTATIC PANCREATIC CANCER. MOLECULAR AND CLINICAL ONCOLOGY. 2017;7:125-130.",
"literaturereference_normalized": "comparing the cost effectiveness of folfirinox nab paclitaxel plus gemcitabine gemcitabine and s 1 for the treatment of metastatic pancreatic cancer",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20170628",
"receivedate": "20170628",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13698343,
"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": "Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.",
"affiliations": "Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.;Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.;Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.;Department of Surgery, Herlev Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark.",
"authors": "Andersen|Kim Francis|KF|;Sjö|Lene Dissing|LD|;Kampmann|Peter|P|;Pedersen|Torben Bridstrup|TB|0000-0003-3274-5325",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/diagnostics11020310",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n10.3390/diagnostics11020310\ndiagnostics-11-00310\nInteresting Images\nHistiocytic Sarcoma: Challenging Course, Dismal Outcome\nAndersen Kim Francis 1*\nSjö Lene Dissing 2\nKampmann Peter 3\nhttps://orcid.org/0000-0003-3274-5325\nPedersen Torben Bridstrup 4\nCheng Zhen Academic Editor\n1 Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark\n2 Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; [email protected]\n3 Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; [email protected]\n4 Department of Surgery, Herlev Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark; [email protected]\n* Correspondence: [email protected]; Tel.: +45-3545-7068\n15 2 2021\n2 2021\n11 2 31018 1 2021\n13 2 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nHistiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution. Most commonly, it occurs as a primary malignancy. In approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated. The clinical presentation varies from a localized solitary mass to severe disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system. Systemic symptoms in terms of weight loss, fever and night sweats often occur. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma.\n\nhistiocytic sarcoma\nhematologic neoplasm\nhybrid imaging\n2-[18F]FDG PET/CT\n==== Body\nIntroduction\n\nHistiocytic sarcoma is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system [1,2]. With an incidence of 0.17/million individuals and a slight male preference, HS presents with a wide age distribution [1,3,4,5]. Most commonly, it occurs as a primary malignancy; however, in approximately 25% of the cases a presumed transdifferentiation of a preexisting hematolymphoid disorder can be demonstrated [6]. The clinical presentation varies from a localized solitary mass to a severely disseminated disease often with extranodal involvement including skin, soft tissue, the gastrointestinal tract and the hematopoietic system [7]. Systemic symptoms in terms of weight loss, fever and night sweats often occur [8]. The diagnostic work-up of HS is extremely challenging due to the rarity of the disease as well as a wide differential diagnosis in terms of a histologic overlap with diverse mimics [7]. No standardized treatment for HS exists and especially in a disseminated disease the clinical course is overly aggressive with a dismal outcome. The median overall survival from the time of diagnosis is approximately six months [4]. We report a 43-year-old previously healthy Caucasian male admitted to our hospitals with abdominal pain and a feeling of fatigue. We demonstrate both the challenges of a correct diagnosis and an effective treatment as well as the aggressive nature of histiocytic sarcoma (Figure 1, Figure 2, Figure 3 and Figure 4).\n\nTo summarize, this case clearly demonstrates the challenging course of patients with histiocytic sarcoma. The rareness and severe complexity of HS requires a multidisciplinary and specialized approach throughout the diagnostic workout, treatment and follow-up. A rapid establishment of a correct diagnosis, staging of the disease and a personalized, aggressive treatment strategy is essential to improve outcomes in these patients. Even so, the prognosis remains extremely dismal, especially in the case of a disseminated disease at the time of diagnosis.\n\nAuthor Contributions\n\nK.F.A., L.D.S., P.K. and T.B.P. acquired and interpreted the data. K.F.A., L.D.S., P.K. and T.B.P. drafted the manuscript. K.F.A. and L.D.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nThe patient gave his written consent for the acquisition and publication of the presented data.\n\nData Availability Statement\n\nNot applicable.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 A 43-year-old previously healthy male was admitted to the surgical unit by his general practitioner with suspicions of acute diverticulitis. The patient complained of constant pain in the epigastric region and under the right and left rib curvature for the previous week upon admission. The pain was intensified when bending forwards and accompanied by an unspecific feeling of fatigue. The patient reported similar symptoms three weeks prior to admission, which remitted spontaneously. Any systemic symptoms of fever, unintended weight loss or night sweats were denied. At admission, the patient had a slight tachycardia; all other vital parameters were normal. Initial laboratory data came out with an elevated C-reactive protein (CRP; 176 mg/L) and a slightly elevated total leukocyte count (9.8 × 109/L). Hepatic and renal biochemical markers were within normal ranges. On physical examination the abdomen was described as tender in the upper quadrants and around the umbilicus but without peritoneal reaction. On suspicion of an intraabdominal abscess, a computed tomography (CT) scan was performed showing free liquid surrounding the liver and the spleen as well as in the small pelvis. There was no free air. However, the upper abdomen was seen with a diffuse reaction in the fatty tissue around the pylorus and ventricle. Radiologically, a perforated ulcer was suspected. The patient underwent a diagnostic laparoscopy, revealing peritonitis in all quadrants and three liters of free fluid. There were no signs of feces, pus or bile. The greater omentum was adherent in a conglomerate consisting of the duodenum, ventricle, pancreas and transverse colon. It was not possible to get a sufficient overview of the structures laparoscopically and the procedure was converted to an explorative laparotomy revealing reactive, stearin-like changes spread in the peritoneal cavity ((A,B), white arrows). The conglomerate was dissected and the posterior part of the ventricle was inspected, revealing no ulcers. The duodenum was mobilized by the Kocher maneuver, also revealing no ulcers or perforation. Perioperatively, an esophago-gastro-duodenoscopy was performed, revealing no ulcerations or pathology. A piece of the omentum was removed for histopathological examination and an intraabdominal drain was placed before ending the procedure. The findings were suspected to be caused by pancreatitis. The postoperative course was uneventful, the drain was removed after seven days and the patient was discharged after eight days with a plan of outpatient follow-up. On postoperative day 17 he was readmitted for drainage of 3.5 L ascites, which had recollected. The pancreas was without signs of pancreatitis on a triple-phase CT. Diagnostic ultrasound described no gallstones.\n\nFigure 2 Histopathology of omental infiltrate and ascitic fluid: (A) Omental fatty tissue with diffuse infiltration of tumor cells (HE×4). (B) The tumor cells were large with vesicular nuclei. Frequent mitoses were seen (HE×40). (C) CD68PGM1 showing characteristic granular cytoplasmic staining (×40). (D) Cytomorphology of the tumor cells in ascitic fluid (×40). A histopathological examination of the resected tissue from the omentum demonstrated a dense and diffuse infiltration of the fatty tissue by large mononuclear cells with large vesicular nuclei with eosinophilic nucleoli. The cytoplasm was eosinophilic with some vacuolization. The cells were of a hematological origin and expressed CD45. They had a fully developed histiocytic differentiation profile with an immunohistochemical expression of CD68, CD163, CD4, CD56 and lysozyme and showed a high proliferative rate that in areas reached 50% (Ki-67). The precursor cell, dendritic cell, melanocytic, neuroendocrine cell, B-cell, T-cell and Langerhans cell markers were negative. No BRAF-mutation could be demonstrated. The PD-L1 was negative. Next generation sequencing (NGS) could not demonstrate any fusions. The NGS panel used was ‘Archers FusionPlex Lymphoma’, investigating the mutation, expression and fusion of 125 genes. Ascitic fluid cytology revealed malignant cells with the same phenotype as the tumor tissue in the omentum. The findings were most compatible with histiocytic sarcoma (HS). A differential diagnosis could be monoblastic leukemia, which was excluded on the examination of bone marrow biopsies. It took 24 days from initial hospitalization until diagnosis, which was confirmed by an expert second opinion. The following day the patient was transferred to a specialized hematological department at a tertiary hospital.\n\nFigure 3 Hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/CT (2-[18F]FDG PET/CT) was performed for the staging of the disease and as baseline for monitoring of the treatment response. Imaging performed 1 h post-injection of 4.0 MBq/kg 2-[18F]FDG showed a moderately metabolically active, irregular thickening of the peritoneal folds and extensive carcinomatosis-like infiltration in the omentum, mesentery and the pelvic cavity (A–D, yellow arrows). There was minor ascitic fluid in the abdominal and pelvic cavities. There were also metabolically active, enlarged lymph nodes in the mediastinum and upper retroperitoneum. The findings were considered highly suspicious for malignancy. At this point, plasma lactate dehydrogenase (LDH) levels, a future tumor marker in this patient, were elevated (366 U/L; reference range 105–205 U/L). An initial steroid treatment with prednisolone 100 mg/daily had a good effect on the tendency of the recollection of ascites. However, as no standardized treatment for this patient category without comorbidity exists, a hematological specialized tumor board, after consent from the patient, decided to administer a chemotherapy regimen of ifosfamide, carboplatin and etoposide (ICE), which was initiated one month after initial hospitalization. The patient tolerated the treatment well. At clinical follow-up after two cycles of ICE, the patient’s wellbeing was improved, the plasma LDH was normalized and imaging with 2-[18F]FDG PET/CT demonstrated a substantial partial response (PR), both metabolically and morphologically, of the previously described findings in the peritoneum. There were still metabolically active, carcinomatosis-like findings in the omentum, mesentery and on the liver surface (E–H, magenta arrows). There were no pathological lymph nodes. After completion of four cycles of ICE, the metabolic complete response (CR) and a further morphological PR were reported on follow-up 2-[18F]FDG PET/CT (not shown). The plasma LDH was still within a normal range. The patient tolerated the fifth and final cycle of ICE well.\n\nFigure 4 To reduce the risk of HS relapse, an experimental therapeutic approach with high-dose chemotherapy administering a BEAM (carmustine + etoposide + cytarabine + melphalan) regimen and a subsequent autologous stem cell transplant (SCT) was initiated. The patient tolerated the treatment well and at follow-up +60 days after BEAM/SCT the regeneration of bone marrow was considered complete and the tumor marker plasma LDH was still within the reference range (157 U/L). 2-[18F]FDG PET/CT (A) demonstrated a metabolic CR and a further morphological PR. There were now relatively symmetrically localized, metabolically active lymph nodes at the right root of the neck, in both sides of the mediastinum and the lung hilum (black arrow), compatible with possible granulomatous inflammation. Two months later the patient reported a gradual worsening of bone pain in the lumbar and pelvic region. The plasma LDH was now elevated (450 U/L) and thrombocyte and hemoglobin levels were low. A relapse of HS was suspected, which was confirmed by a bone marrow biopsy that showed a massive infiltration of almost 100% of malignant histiocytic cells with blastoid morphology and an immunohistochemical profile similar to previous specimens. Findings on 2-[18F]FDG PET/CT (B) were compatible with a relapse, demonstrating a heterogeneous, pathologically increased FDG-uptake in the bone marrow in the axial and peripheral skeleton (green arrows). There were metabolically active lymph nodes above and now also below the diaphragm. A malignant bone marrow infiltration with a myeloid expansion was considered the cause of the patient’s bone pain. The plasma LDH rose rapidly to 5100 U/L and salvage therapy with an acute myelogenous leukemia regime (CLAG-M; cladribine + cytarabine + mitoxantrone) was initiated. The treatment had a good effect on the patient’s bone pain and wellbeing. The plasma LDH was normalized within days and histopathological examinations showed no tumor cells in the blood and no malignant cells in the bone marrow biopsy. 2-[18F]FDG PET/CT (C) demonstrated a metabolic PR of previously malignant findings in the bone marrow. There were now splenic lesions compatible with abscesses. A second course of CLAG-M was administered and, as the patient had achieved a second CR confirmed by a bone marrow biopsy, a non-myeloablative allogeneic SCT was considered. However, within a short period of time the patient again reported bone pain and he developed cutaneous papules on the trunk end lower extremity from which a biopsy showed HS. The plasma LDH also increased rapidly and 2-[18F]FDG PET/CT (not shown) again demonstrated progression with a pathologically increased FDG-uptake in the bone marrow and new metabolically active cutaneous lesions on the abdomen. The findings were compatible with a systemic relapse and an allogeneic SCT was now not a feasible treatment option. Palliative treatment with a modified FLAG-Ida regime (fludarabine + cytarabine + idarubicin + filgrastim) initially had a good effect on the bone pain; the cutaneous lesions regressed and the plasma LDH decreased. However, the effect was short-lived and the patient experienced intermittent fever, bone pain, fatigue and blood cell counts that demonstrated cytopenia. The plasma LDH again increased. The patient’s clinical condition worsened significantly and after short periods of treatment with high-dose cytarabine and hydroxycarbamide, further treatment attempts with intensive regimen chemotherapy were considered futile. No appropriate protocolled treatment was found suitable for the patient and the treatment aim of long term survival was abated. The patient passed away shortly after, 15 months after his initial hospitalization.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Stein H. Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th ed. IARC Lyon, France 2017 154 196\n2. Yoshida C. Takeuchi M. Histiocytic sarcoma: Identification of its histiocytic origin using immunohistochemistry Intern. Med. 2008 47 165 169 10.2169/internalmedicine.47.0386 18239326\n3. Hornick J.L. Jaffe E.S. Fletcher C.D. Extranodal Histiocytic Sarcoma: Clinicopathologic Analysis of 14 Cases of a Rare Epithelioid Malignancy Am. J. Surg. Pathol. 2004 28 1133 1144 10.1097/01.pas.0000131541.95394.23 15316312\n4. Kommalapati A. Tella S.H. Durkin M. Go R.S. Goyal G. Histiocytic sarcoma: A population-based analysis of incidence, demographic disparities, and long-term outcomes Blood 2018 131 265 268 10.1182/blood-2017-10-812495 29183888\n5. Shimono J. Miyoshi H. Arakawa F. Sato K. Furuta T. Muto R. Yanagida E. Sasaki Y. Kurita D. Kawamoto K. Prognostic factors for histiocytic and dendritic cell neoplasms Oncotarget 2017 8 98723 98732 10.18632/oncotarget.21920 29228722\n6. Gounder M.M. Desai V. Kuk D. Agaram N.P. Arcila M. Durham B. Keohan M.L. Dickson M.A. D’Angelo S.P. Shukla N. Impact of surgery, radiation and systemic therapy on the outcomes of patients with dendritic cell and histiocytic sarcomas Eur. J. Cancer 2015 51 2413 2422 10.1016/j.ejca.2015.06.109 26298731\n7. Hung Y.P. Qian X. Histiocytic Sarcoma Arch. Pathol. Lab. Med. 2019 144 650 654 10.5858/arpa.2018-0349-RS 31070934\n8. Takahashi E. Nakamura S. Histiocytic Sarcoma: An Updated Literature Review Based on the 2008 WHO Classification J. Clin. Exp. Hematop. 2013 53 1 8 10.3960/jslrt.53.1 23801128\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "11(2)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "2-[18F]FDG PET/CT; hematologic neoplasm; histiocytic sarcoma; hybrid imaging",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33671860",
"pubdate": "2021-02-15",
"publication_types": "D016428:Journal Article",
"references": "23801128;26298731;18239326;15316312;29228722;31070934;29183888",
"title": "Histiocytic Sarcoma: Challenging Course, Dismal Outcome.",
"title_normalized": "histiocytic sarcoma challenging course dismal outcome"
}
|
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{
"abstract": "Chemotherapy extravasation can lead to serious patient harm in patients with cancer. For nurses who administer vesicant chemotherapy, extravasation is a primary concern. Regardless of nurse experience level and despite prevention strategies, extravasations occur. Literature related to nurse management of chemotherapy extravasation beyond initial treatment is lacking, and no descriptors are available for a formalized process. Communication gaps and a lack of standardized follow-up within a 1400-bed, quaternary care academic medical institution contributes to challenges in care continuity when patients transition between hospital and ambulatory settings. With chemotherapy extravasation, the site does not immediately exhibit signs of tissue injury, leading to a false sense of security. As a result, tissue damage can be significant by the time the patient returns for his or her regular appointment. Two oncology clinical nurse specialists (CNSs) recognized an opportunity to bridge the gap and overcome the challenges by addressing patient needs postextravasation. Between 2015 and 2016, a formal consult process was designed, approved, and implemented to observe, manage, and make recommendations for timely care and follow-up. Since implementation of the process, the oncology CNSs have received multiple requests for consultations. Nursing staff report increased comfort levels with this process in place. A formalized process for managing chemotherapy extravasations increases patient safety and patient and nurse satisfaction.",
"affiliations": "Cleveland Clinic, Cleveland, Ohio.;Cleveland Clinic, Cleveland, Ohio.",
"authors": "Karius|Diana L|DL|;Colvin|Christina M|CM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/NAN.0000000000000411",
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"issue": "44(1)",
"journal": "Journal of infusion nursing : the official publication of the Infusion Nurses Society",
"keywords": null,
"medline_ta": "J Infus Nurs",
"mesh_terms": "D000046:Academic Medical Centers; D003266:Continuity of Patient Care; D004358:Drug Therapy; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006761:Hospitals; D006801:Humans; D007275:Injections, Intravenous; D009369:Neoplasms; D009720:Nurse Clinicians; D009859:Oncology Nursing; D012017:Referral and Consultation",
"nlm_unique_id": "101124170",
"other_id": null,
"pages": "14-20",
"pmc": null,
"pmid": "33394869",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Managing Chemotherapy Extravasation Across Transitions of Care: A Clinical Nurse Specialist Initiative.",
"title_normalized": "managing chemotherapy extravasation across transitions of care a clinical nurse specialist initiative"
}
|
[
{
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}
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"literaturereference": "KARIUS D, COLVIN C. MANAGING CHEMOTHERAPY EXTRAVASATION ACROSS TRANSITIONS OF CARE: A CLINICAL NURSE SPECIALIST INITIATIVE. J INFUS NURS. 2021?44(1):14?20. DOI:UNKNOWN",
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{
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}
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},
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"literaturereference": "KARIUS D, COLVIN C. MANAGING CHEMOTHERAPY EXTRAVASATION ACROSS TRANSITIONS OF CARE A CLINICAL NURSE SPECIALIST INITIATIVE. JOURNAL OF INFUSION NURSING. 2021 JAN?44(1):14?20.",
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},
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},
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] |
{
"abstract": "OBJECTIVE\nEnterocutaneous (EC) fistula is an abnormal communication between the gastrointestinal tract and the skin. The majority of EC fistulas result from surgery. Only 15-25% of EC fistulas are spontaneous and they often result from underlying diseases such as Crohn's disease, radiation and chemotherapy.\n\n\nMETHODS\nA 62-year old woman who, in 2012, underwent Pylorus-preserving cephalic pancreaticoduodenectomy (PPPD sec. Traverso-Longmire), due to an advanced pancreatic ductal adenocarcinoma (pT3N1M1). After surgery, the patient underwent chemotherapy with folfirinox regimen. In December 2016, as a result of the appearance of metastatic liver lesions and perianastomotic recurrence, the patient underwent second line treatment with Gemcitabine and pab-paclitaxel. After five months from the beginning of this new second line therapy she presented an EC fistula. The fistula of the patient was successfully treated with total parenteral nutrition and with percutaneous injection of cyanoacrylic sealant.\n\n\nRESULTS\nThe result suggests the advisability of percutaneous injection of sealant devices, such as cyanoacrylate glue; in order to successfully control stable Enterocutaneous fistulas with acceptable morbidity and mortality especially in particular situations, such as, with low output EC fistulas without signs of complications or on patients considered not suitable for surgery, a conservative approach could ensure the control of the fistula.\n\n\nCONCLUSIONS\nThis approach is easy and safe, viable and useful for future trials on the efficacy in conservative treatment of EC fistula.",
"affiliations": null,
"authors": "Musa|N|N|;Aquilino|F|F|;Panzera|P|P|;Martines|G|G|",
"chemical_list": "D003487:Cyanoacrylates; D014014:Tissue Adhesives",
"country": "Italy",
"delete": false,
"doi": "10.11138/gchir/2017.38.5.256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-9005",
"issue": "38(5)",
"journal": "Il Giornale di chirurgia",
"keywords": null,
"medline_ta": "G Chir",
"mesh_terms": "D000072700:Conservative Treatment; D003487:Cyanoacrylates; D005260:Female; D006801:Humans; D007412:Intestinal Fistula; D008875:Middle Aged; D016577:Pancreaticoduodenectomy; D011183:Postoperative Complications; D012074:Remission Induction; D014014:Tissue Adhesives",
"nlm_unique_id": "9011768",
"other_id": null,
"pages": "256-259",
"pmc": null,
"pmid": "29280707",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16804873;27752970;11878791;19801322;19039271;23867370;18057983;16504896;22064337;27247538;15492564;22563283;17011904;28460205;11077786;11878790",
"title": "Successful conservative treatment of enterocutaneous fistula with cyanoacrylate surgical sealant: case report.",
"title_normalized": "successful conservative treatment of enterocutaneous fistula with cyanoacrylate surgical sealant case report"
}
|
[
{
"companynumb": "IT-PFIZER INC-2018003272",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
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},
{
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},
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"drugdosageform": "SOLUTION FOR INJECTION",
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"drugindication": "METASTASES TO LIVER",
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"medicinalproduct": "PACLITAXEL."
}
],
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"reaction": [
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2017"
}
},
"primarysource": {
"literaturereference": "MUSA, N.. SUCCESSFUL CONSERVATIVE TREATMENT OF ENTEROCUTANEOUS FISTULA WITH CYANOACRYLATE SURGICAL SEALANT: CASE REPORT. GIORNALE DI CHIRURGIA. 2017?38 (5):256-259",
"literaturereference_normalized": "successful conservative treatment of enterocutaneous fistula with cyanoacrylate surgical sealant case report",
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},
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},
{
"companynumb": "IT-MYLANLABS-2018M1005172",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
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"drugauthorizationnumb": "200145",
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{
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"drugdosageform": "SOLUTION FOR INJECTION",
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"drugindication": "METASTASES TO LIVER",
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"medicinalproduct": "PACLITAXEL."
}
],
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"reaction": [
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Enterocutaneous fistula",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2017"
}
},
"primarysource": {
"literaturereference": "MUSA N, AQUILINO F, PANZERA P, MARTINES G.. SUCCESSFUL CONSERVATIVE TREATMENT OF ENTEROCUTANEOUS FISTULA WITH CYANOACRYLATE SURGICAL SEALANT: CASE REPORT.. GIORNALE DI CHIRURGIA.. 2017?38(5):256-59",
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"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
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"receivedate": "20180130",
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},
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},
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"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
},
{
"companynumb": "IT-ACCORD-062723",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
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"medicinalproduct": "PACLITAXEL/PACLITAXEL LIPOSOME"
},
{
"actiondrug": "1",
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
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"medicinalproduct": "GEMCITABINE/GEMCITABINE HYDROCHLORIDE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Enterocutaneous fistula",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Enterococcus test positive",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Escherichia test positive",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201701"
}
},
"primarysource": {
"literaturereference": "MUSA N, AQUILINO F, PANZERA P, MARTINES G. SUCCESSFUL CONSERVATIVE TREATMENT OF ENTEROCUTANEOUS FISTULA WITH CYANOACRYLATE SURGICAL SEALANT: CASE REPORT. G CHIR. 2017 SEP-OCT?38(5):256-259.",
"literaturereference_normalized": "successful conservative treatment of enterocutaneous fistula with cyanoacrylate surgical sealant case report",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20180111",
"receivedate": "20180111",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Epidural corticosteroid injections (ESIs) are widely performed and have an unquantified risk of serious spinal adverse events (SSAEs). We sought to determine the rate of SSAEs following ESI and to compare the rates by spinal level, injection approach and corticosteroid formulation.\n\n\n\nWe included patients enrolled in Medicare parts A and B who had an ESI between 1 January 2009 and 30 September 2015. We identified potential cases as patients with spine-related diagnoses within 3 days after the first eligible ESI. Event categorization as probable, possible or non-case was based on review of medical records. The rates of probable and possible cases were expressed per 1 000 000 patients overall, and by spinal level, injection approach and corticosteroid formulation. A score test was used to compare these rates.\n\n\n\nWe identified 1 355 957 eligible ESIs during the study period. Of the 110 potential cases, 43 were selected for medical record review and 11 were categorized as probable, yielding a rate of 8.1 per 1 000 000 patients (95% CI 4.5 to 14.5). Risk of SSAEs was statistically higher with cervical/thoracic injections (29.4, 95% CI 12.5 to 68.8) compared with lumbar/sacral injections (5.1, 95% CI 2.3 to 11.0) (p value 0.001). Event rates for lumbar/sacral non-transforaminal injections was 8.8 (95% CI 4.0 to 19.1). Event rates for particulate (7.5, 95% CI 3.9 to 14.2) and non-particulate formulations (13.1, 95% CI 3.6 to 47.9) appeared similar (p value 0.47).\n\n\n\nBetween 2009 and 2015, rates of SSAEs following ESI in the Medicare population were low. Patients receiving cervical/thoracic ESIs were at higher risk of SSAE than those receiving lumbar/sacral ESIs. Event rates were similar for each corticosteroid formulation.",
"affiliations": "Division of Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, USA [email protected].;Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.;Acumen LLC, Burlingame, California, USA.;Acumen LLC, Burlingame, California, USA.;Division of Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, USA.;Division of Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, USA.;Acumen LLC, Burlingame, California, USA.;Acumen LLC, Burlingame, California, USA.;Centers for Medicare and Medicaid Services Washington DC Office, Washington, District of Columbia, USA.;Division of Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, USA.",
"authors": "Eworuke|Efe|E|0000-0001-8971-9748;Crisafi|Leah|L|;Liao|Jiemin|J|;Akhtar|Sandia|S|;Van Clief|Martha|M|;Racoosin|Judith A|JA|;Wernecke|Michael|M|;MaCurdy|Thomas E|TE|;Kelman|Jeffrey A|JA|;Graham|David J|DJ|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "England",
"delete": false,
"doi": "10.1136/rapm-2020-101778",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "46(3)",
"journal": "Regional anesthesia and pain medicine",
"keywords": "drug-related side effects and adverse reactions; epidemiology; injections; pain management; regional anesthesia; spinal",
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D006801:Humans; D007268:Injections, Epidural; D008161:Lumbosacral Region; D006278:Medicare; D013131:Spine; D014481:United States",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "203-209",
"pmc": null,
"pmid": "33277405",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk of serious spinal adverse events associated with epidural corticosteroid injections in the Medicare population.",
"title_normalized": "risk of serious spinal adverse events associated with epidural corticosteroid injections in the medicare population"
}
|
[
{
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{
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},
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"medicinalproduct": "ASPIRIN."
},
{
"actiondrug": null,
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"activesubstancename": "CORTICOSTEROID NOS"
},
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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": "Cauda equina syndrome",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Extradural haematoma",
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"reactionoutcome": "6"
}
],
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},
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"literaturereference_normalized": "risk of serious spinal adverse events associated with epidural corticosteroid injections in the medicare population",
"qualification": "3",
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},
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20211014"
},
{
"companynumb": "US-BAYER-2021-172674",
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{
"actiondrug": null,
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},
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{
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},
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"medicinalproduct": "ASPIRIN."
}
],
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"reaction": [
{
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}
],
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},
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"literaturereference_normalized": "risk of serious spinal adverse events associated with epidural corticosteroid injections in the medicare population",
"qualification": "1",
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},
"primarysourcecountry": "US",
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"receivedate": "20210713",
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},
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},
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},
{
"companynumb": "US-CIPLA LTD.-2021US04632",
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"patient": {
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{
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"activesubstance": {
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Extradural haematoma",
"reactionmeddraversionpt": "24.0",
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},
{
"reactionmeddrapt": "Cauda equina syndrome",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neurogenic bladder",
"reactionmeddraversionpt": "24.0",
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},
{
"reactionmeddrapt": "Spinal decompression",
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}
],
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20211014"
}
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{
"abstract": "Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7-2.0 cases/million habitants/year. ACCs are rare and usually endocrinologically functional. We present the case of a 59-year-old woman who experienced abdominal fullness for 6 months and increased abdominal circumference. A large pelvic tumor was observed. She underwent cytoreductive surgery and the pathological test results revealed local tumor necrosis and prominent lympho-vascular invasion. Neuroendocrine carcinoma was the first impression, but positivity for synaptophysin, alpha-inhibin, transcription factor enhancer 3 (TFE-3), calretinin (focal), and CD56 (focal) and high Ki-67-labeling proliferating index (>80%) confirmed the diagnosis of ectopic ACC. Ectopic primary aldosteronism could not be excluded. However, we did not perform saline infusion test or captopril test due to poor performance status. When pathological test reports reveal neuroendocrine features not typically found in the organ being examined, IHC staining should be performed to rule out ectopic ACC. Whether the ectopic ACC is functional or not requires complete survey.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan.;Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.",
"authors": "Tsai|Wen-Hsuan|WH|;Chen|Tze-Chien|TC|;Dai|Shuen-Han|SH|;Zeng|Yi-Hong|YH|",
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"doi": "10.3389/fendo.2021.662377",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.662377\nEndocrinology\nCase Report\nCase Report: Ectopic Adrenocortical Carcinoma in the Ovary\nTsai Wen-Hsuan 1\n\nChen Tze-Chien 2\nDai Shuen-Han 3\n\nZeng Yi-Hong 1 4 *\n\n1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan\n2 Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan\n3 Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan\n4 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan\nEdited by: Barbara Altieri, University Hospital of Wuerzburg, Germany\n\nReviewed by: Letizia Canu, University of Florence, Italy; Canan Ersoy, Uludağ University, Turkey\n\n*Correspondence: Yi-Hong Zeng, [email protected]\nThis article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n19 3 2021\n2021\n12 66237701 2 2021\n05 3 2021\nCopyright © 2021 Tsai, Chen, Dai and Zeng\n2021\nTsai, Chen, Dai and Zeng\nThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nAdrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7–2.0 cases/million habitants/year. ACCs are rare and usually endocrinologically functional. We present the case of a 59-year-old woman who experienced abdominal fullness for 6 months and increased abdominal circumference. A large pelvic tumor was observed. She underwent cytoreductive surgery and the pathological test results revealed local tumor necrosis and prominent lympho-vascular invasion. Neuroendocrine carcinoma was the first impression, but positivity for synaptophysin, alpha-inhibin, transcription factor enhancer 3 (TFE-3), calretinin (focal), and CD56 (focal) and high Ki-67-labeling proliferating index (>80%) confirmed the diagnosis of ectopic ACC. Ectopic primary aldosteronism could not be excluded. However, we did not perform saline infusion test or captopril test due to poor performance status. When pathological test reports reveal neuroendocrine features not typically found in the organ being examined, IHC staining should be performed to rule out ectopic ACC. Whether the ectopic ACC is functional or not requires complete survey.\n\nectopic\nadrenocortical carcinoma\novary\nimmunohistochemistry\nmetastasis\n==== Body\nIntroduction\n\nAdrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7–2.0 cases/million habitants/year. It occurs at any age, with two peaks in the first decade of life and between 40 and 50 years. Women are frequently affected (55–60%) (1). The adrenal glands are of dual embryological origin. The adrenal cortex is derived from the coelomic mesoderm of the urogenital ridge, and the adrenal medulla arises from the neural crest tissue (2). Ectopic adrenal rests exist along the migration path of adrenal cortex development, and these anatomic sites include the celiac plexus, kidney, ovary, broad ligament, testis, and spermatic cord (3, 4). The brain, lungs, and stomach have been reported to be rare sites of ectopic rests (3, 4). Ectopic adrenal tissue is found in 50% neonates, and most of the ectopic rests undergo atrophy (5). The occurrence of adrenal rest tissue in adults is 1% (6).\n\nTumors arising from adrenal rests are uncommon and most of them are functional, resulting in endocrinopathy diagnosed pre-operatively (7). Non-functional tumors are also uncommon and are usually discovered incidentally or during autopsy (7). Malignancies arising from adrenal rests are extremely rare with very few cases reported (8), showing a mean patient age of 36.4 years (0.4–65 years) and equal sex distribution (female:male ratio, 7:6). Studies have reported tumors located in the retroperitoneum (n = 5), testis/scrotum (n = 3), liver (n = 2), kidney (n = 1), spinal cord (n = 1), and pelvis (n = 1); 62% of the tumors were functional, with Cushing’s syndrome as the most common presentation (8). Herein, we present the case of a 59-year-old woman with ectopic ACC in the ovary. Consent has not been obtained because the patient is deceased.\n\nCase Report\n\nOur patient was a 59-year-old woman who had no past medical history. She delivered three children and entered menopause at the age of 49 years. She complained of lower abdominal fullness for 6 months and increased abdominal circumference. She also experienced stress urinary incontinence, without dysuria, urinary frequency, or urinary urgency. She lost up to 3 kg of body weight in 1 month and had oedema in both feet. There was no fever, bowel habit change, nausea, vomiting, abdominal pain, or tarry/bloody stool. She visited a hospital where a giant pelvic mass was found. She was transferred to our hospital in April 2019. The initial laboratory work report is shown in Table 1 . Profound elevated Lactate dehydrogenase (4123 IU/L, 98 – 192 IU/L), elevated Carbohydrate antigen 19-9 (39.34 U/mL, <37 U/mL) and Cancer antigen 125 (146.32 U/mL, <35 U/mL) was noted. Gynaecologic sonography showed a huge pelvic mass of approximately 22.5 × 13.3 × 16.1 cm in size. Computed tomography (CT) scans revealed a 23 × 17 × 21 cm heterogeneous mass occupying the lower abdomen and pelvic cavity with indistinct margin from the uterus and bilateral adnexa, suggestive of gynaecologic malignancy. There were multiple small peritoneal nodules, multiple enlarged para-aortic and bilateral iliac lymph nodes, and multiple small pulmonary metastases and lymph nodes over the left lower neck and left supra-clavicular regions ( Figure 1 ). The visible liver and adrenal glands were unremarkable. She underwent optimal cytoreductive surgery for symptom relief. Left neck mass excision was performed. The initial pathological test report suggested suspected neuroendocrine carcinoma over bilateral ovaries, bilateral fallopian tubes, and the uterus, with omentum and lymph node metastasis. Right ovarian neuroendocrine carcinoma, stage IVB pT3cN1bM1, was the initially postulated diagnosis.\n\nTable 1 Laboratory test for ovary tumor.\n\nWhite blood cell count\t8,500\t(4,000–10,000)/µL\t\nHemoglobin\t13.5\t(11–16) g/dL\t\nPlatelet count\t291,000\t(140,000–450,000)/µL\t\nCreatinine\t0.8\t(0.4–1.2) mg/dL\t\nAlanine aminotransferase\t31\t(14–40) IU/L\t\nSodium\t142\t(136–144) mEq/L\t\nPotassium\t3.8\t(3.5–5.1) mEq/L\t\nLactate dehydrogenase\t4,123\t(98–192) IU/L\t\nCarcinoembryonic antigen\t0.93\t(<5.00) ng/mL\t\nAlpha-Fetoprotein\t2.66\t(<10.00) ng/mL\t\nCarbohydrate antigen 19-9\t39.34\t(<37.00) U/mL\t\nCancer antigen 125\t146.32\t(<35.00) U/mL\t\n\nFigure 1 Image of pelvic tumor and metastasis. (A) Para-aortic lymph nodes and pelvic tumor. (B) Supraclavicular lymph nodes. (C) Sub-diaphragmatic seeding. (D) Lung metastasis.\n\nShe underwent postoperative chemotherapy with triweekly Etoposide (100mg/m2) and Cisplatin (100mg/m2). After consultation and discussion with another pathologist, the final pathological test report 2 months later showed ACC, probably arising from the adrenal cortical rest ( Figures 2 and 3 ). Weiss score was 8 after discussion with pathologist. Hypertension with normal potassium level was noted during admission. She took amlodipine 5mg per day. The endocrine profile is listed in Table 2 , which revealed normal aldosterone (12.8 ng/dL, 4.83–27 ng/dL) and decreased plasma renin activity (0.14 ng/mL/hr, 0.6–4.18 ng/mL/hr) level. ARR ratio was 91.4. Hence, ectopic primary aldosteronism could not be excluded. However, we did not perform saline infusion test or captopril test at that time because she was receiving chemotherapy and suffered from abdomen fullness, nausea and vomiting. She received dexamethasone as support therapy during chemotherapy. Leukopenia (900/µL) was noted. Cortisol and ACTH level was checked on the same day. Hence, the normal cortisol (10.54 μg/dL, 9.52–26.21 µg/dL) with elevated ACTH (70.26 pg/mL, 10–70 pg/mL) may be interpreted as acute illness. Follow up cortisol and ACTH level was 17.08 μg/dL and 20.15 pg/mL, respectively.\n\nFigure 2 Pathological findings of ovarian adrenocortical carcinoma. (A) A piece of tissue measuring 23 × 17 × 10 cm in size. (B) Sections of the huge ovary and uterine body tumor showing solid sheets and nests of tumor cells with monotonous morphology with large, centrally located nuclei and abundant cytoplasm. Focal tumor necrosis is present. Lymphovascular invasion is prominent. (C) Biopsy sample of the peritoneum cavity. (D) Lymph node metastasis: Lesion cells are arranged in thick trabeculae and in organoid pattern. They contain eosinophilic cytoplasm and small dark nuclei. High prevalence of mitotic figures is seen.\n\nFigure 3 Immunohistochemistry of ovarian adrenocortical carcinoma. (A) Chromogranin A 100×: negative; (B) Ki-67 200×: high Ki-67-labeling proliferating index (>80%); (C) Alpha-inhibin 100×: positive; (D) Calretinin 100×: focally positive; (E) CD56 100×: focally positive; (F) Synaptophysin 100×: focally positive; (G) TFE-3 100×: positive.\n\nTable 2 Hormone profile for ovarian adrenocortical carcinoma.\n\nCortisol\t10.54\t(9.52–26.21) µg/dL\t\nAdrenocorticotropic hormone\t70.26\t(10–70) pg/mL\t\nPlasma renin activity\t0.14\t(0.6–4.18) ng/mL/hr\t\nAldosterone\t12.8\t(4.83–27) ng/dL\t\nOestrogen\t<10\t(menopause <10–28) pg/mL\t\nTestosterone\t<0.1\t(<0.95) ng/mL\t\nDehydroepiandrosterone sulphate\t12.9\t(3.70–242.4) µg/dL\t\n\nShe received six courses of etoposide and cisplatin regimen and six courses of bevacizumab (900mg). However, LDH level elevated after completion of chemotherapy. Follow-up CT 6 months after the operation showed disease progression, with enlarged left supraclavicular and retrocaval lymph nodes, increased size of lung metastasis, and increased size and number of liver metastases and peritoneal seedings. She received mitotane 500mg per day 6 months after operation and mitotane was titrated to 1000mg per day. She used mitotane intermittently due to nausea, vomiting, poor appetite and dizziness. She was admitted to our hospital several times for poor appetite, vaginal bleeding, anaemia, and renal failure. She expired 9 months after cytoreductive surgery.\n\nDiscussion\n\nWe presented the case of a 59-year-old woman who was diagnosed with ectopic ACC in the ovary. Initial pathological studies revealed the presence of local tumor necrosis and prominent lympho-vascular invasion. The Ki-67 proliferation labelling index was very high (>80%). Immunohistochemically, tumor cells were focally positive for CD56 and synaptophysin but also focally positive for calretinin. Two months later, the pathologist confirmed the diagnosis of ectopic ACC based on positivity for synaptophysin, alpha-inhibin, TFE-3, calretinin (focal), and CD56 (focal) and a high Ki-67-labeling proliferating index (>80%), which was much higher than usual ACC. Melan-A and steroidogenic factor-1 (SF1) were not available in our hospital. Adrenal gland was unlikely to be the origin because there was no adrenal lesion identified in the serial image studies. Ectopic primary aldosteronism could not be excluded. However, we did not perform saline infusion test or captopril test at that time because she was receiving chemotherapy and suffered from abdomen fullness, nausea and vomiting. Hence, we would not define whether this ectopic ACC was functional or non-functional, which was our limitation. Mitotane was immediately considered when ectopic ACC was diagnosed. However, project application was required in Taiwan before we started mitotane. Despite that adjuvant radiotherapy (RT) is important for local tumor control (9), RT was not considered due to multiple distant metastasis in our patient.\n\nTo our knowledge, there were only two reported cases of ectopic adrenocortical carcinoma in the ovary. Chentli presented the case of a 34-year-old female referred for Cushing’s syndrome in the postpartum period. The adrenal origin of the ectopic tissue was confirmed by immunostaining positivity to inhibin-α, melan-A, steroidogenic factor-1 (SF1), and synaptophysin (10). In another study, a 4-year-old girl initially presented with signs of rapid (within 1 month) early puberty (breast development plus pubic and armpit hair) (11). A right ovary mass was noted when she was 15 years old. Pathological examination revealed a 20-cm ovarian steroid tumor. At 21 years of age, pulmonary metastasis was detected. Complete remission of lung metastasis was achieved 5 years after mitotane initiation. The medical history was suggestive of a slowly progressive tumor. The patient was alive for 10 years after the initial operation (11).\n\nAdrenal tumors in the ovary may originate from transformation of the adrenocortical embryonic remnants that break off during adrenal migration or descent of gonadal cells (12). Ectopic adrenal adenomas/carcinomas may result from the mutation of ovarian tissue and its steroid enzymes and/or acquisition of aberrant receptors (13). This pathological situation induces the ovary to synthesize adrenal hormones (14). Steroidogenic factor 1 (SF-1) is the most valid marker of ACC (15). Ki-67 can help define the diagnosis and prognosis of ACC. The general agreement is that ACCs have a Ki-67 labelling index of ≥5% (16). Ki-67 is a powerful prognostic marker in both localized and metastatic ACC (17–19). Positivity for steroid receptor coactivator-1 (SRC-1), inhibin, calretinin, synaptophysin, and melan A and negativity for Pax8, chromogranin, and high-molecular weight cytokeratin (HMWCK) on immunohistochemistry (IHC) studies may help distinguish ACC from other tumors (20).\n\nThe 5-year survival of patients with ACC is, respectively, 60–80%, 35–50%, and 0–28% in cases of tumors confined to the adrenal space, locally advanced disease, and metastatic disease (21). There is limited knowledge on the incidence and prognosis of ectopic ACC. In previous studies, the 5- and 10-year survival of patients who underwent resection of ectopic ACC was 26–38% and 7%, respectively (22–24). Surgical resection is the mainstay of treatment (22, 25). Patients with early mortality were found to have high rates of cortisol-secreting tumors and positive resection margins and high disease stages with nodal or synchronous distant metastasis (22–24). The importance of surgery was further confirmed by long-term survival attained with repeat resection of local or distant tumor recurrence (22). According to the presented cases, diagnosis of ectopic ACC is challenging; 50–60% of patients with ACC show clinical hormone excess (21). Hypercortisolism or mixed Cushing’s and virilizing symptoms are observed in the majority of these patients (21).\n\nConclusion\n\nWe presented a rare case of ectopic ACC in the ovary. ACC is a rare disease, and ectopic ACC is even rarer. There is limited knowledge of its incidence and prognosis. When encountering hypercortisolism or mixed Cushing’s and virilizing symptoms without detectable adrenal nor pituitary tumors, ectopic tumor should be suspected. On the other hand, when pathological tests reveal atypical neuroendocrine feature of the organ, further IHC staining should be performed to rule out ectopic ACC. Whether the ectopic ACC is functional or not requires complete survey.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Mackay Memorial Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nW-HT: writing and literature search. T-CC: medical and surgical practices. S-HD: analysis and interpretation. Y-HZ: concept, design, and medical practice. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nThe authors hereby thank Editage Taiwan for language assistance during the preparation of the manuscript.\n==== Refs\nReferences\n\n1 Kebebew E Reiff E Duh QY Clark OH McMillan A . Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg (2006) 30 (5 ):872–8. 10.1007/s00268-005-0329-x\n2 Barwick TD Malhotra A Webb JA Savage MO Reznek RH . Embryology of the adrenal glands and its relevance to diagnostic imaging. Clin Radiol (2005) 60 (9 ):953–9. 10.1016/j.crad.2005.04.006\n3 Ren PT Fu H He XW . Ectopic adrenal cortical adenoma in the gastric wall: case report. World J Gastroenterol (2013) 19 (5 ):778–80. 10.3748/wjg.v19.i5.778\n4 Makino K Kojima R Nakamura H Morioka M Iyama K Shigematsu K . Ectopic adrenal cortical adenoma in the spinal region: case report and review of the literature. Brain Tumor Pathol (2010) 27 (2 ):121–5. 10.1007/s10014-010-0270-z\n5 Anderson JR Ross AH . Ectopic adrenal tissue in adults. Postgrad Med J (1980) 56 (661 ):806–8. 10.1136/pgmj.56.661.806\n6 Souverijns G Peene P Keuleers H Vanbockrijck M . Ectopic localisation of adrenal cortex. Eur Radiol (2000) 10 (7 ):1165–8. 10.1007/s003309900263\n7 Goren E Engelberg IS Eidelman A . Adrenal rest carcinoma in hilum of kidney. Urology (1991) 38 (2 ):187–90. 10.1016/S0090-4295(05)80085-8\n8 Cornejo KM Afari HA Sadow PM . Adrenocortical Carcinoma Arising in an Adrenal Rest: a Case Report and Review of the Literature. Endocr Pathol (2017) 28 (2 ):165–70. 10.1007/s12022-017-9472-9\n9 Gharzai LA Green MD Griffith KA Else T Mayo CS Hesseltine E . Adjuvant Radiation Improves Recurrence-Free Survival and Overall Survival in Adrenocortical Carcinoma. J Clin Endocrinol Metab (2019) 104 (9 ):3743–50. 10.1210/jc.2019-00029\n10 Chentli F Terki N Azzoug S . Ectopic adrenocortical carcinoma located in the ovary. Eur J Endocrinol (2016) 175 (4 ):K17–23. 10.1530/EJE-16-0224\n11 Salle L Mas R Teissier-Clément MP . Ectopic adrenocortical carcinoma of the ovary: An unexpected outcome. Ann Endocrinol (Paris) (2020) 81 (5 ):516–8. 10.1016/j.ando.2020.07.1112\n12 Vassiliadi D Tsagarakis S . Unusual causes of Cushing’s syndrome. Arq Bras Endocrinol Metabol (2007) 51 (8 ):1245–52. 10.1590/S0004-27302007000800010\n13 Lacroix A Ndiaye N Tremblay J Hamet P . Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocr Rev (2001) 22 (1 ):75–110. 10.1210/edrv.22.1.0420 11159817\n14 Ayala AR Basaria S Udelsman R Westra WH Wand GS . Corticotropin-independent Cushing’s syndrome caused by an ectopic adrenal adenoma. J Clin Endocrinol Metab (2000) 85 (8 ):2903–6. 10.1210/jcem.85.8.6749\n15 Duregon E Volante M Giorcelli J Terzolo M Lalli E Papotti M . Diagnostic and prognostic role of steroidogenic factor 1 in adrenocortical carcinoma: a validation study focusing on clinical and pathologic correlates. Hum Pathol (2013) 44 (5 ):822–8. 10.1016/j.humpath.2012.07.025\n16 Creemers SG Hofland LJ Korpershoek E Franssen GJ van Kemenade FJ de Herder WW . Future directions in the diagnosis and medical treatment of adrenocortical carcinoma. Endocr Relat Cancer (2016) 23 (1 ):R43–69. 10.1530/ERC-15-0452\n17 Berruti A Fassnacht M Baudin E Hammer G Haak H Leboulleux S . Adjuvant therapy in patients with adrenocortical carcinoma: a position of an international panel. J Clin Oncol (2010) 28 (23 ):e401–2; author reply e3. 10.1200/JCO.2009.27.5958 20567001\n18 Beuschlein F Weigel J Saeger W Kroiss M Wild V Daffara F . Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab (2015) 100 (3 ):841–9. 10.1210/jc.2014-3182\n19 Libé R Borget I Ronchi CL Zaggia B Kroiss M Kerkhofs T . Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol (2015) 26 (10 ):2119–25. 10.1093/annonc/mdv329\n20 Weissferdt A Phan A Suster S Moran CA . Adrenocortical carcinoma: a comprehensive immunohistochemical study of 40 cases. Appl Immunohistochem Mol Morphol (2014) 22 (1 ):24–30. 10.1097/PAI.0b013e31828a96cf 23531850\n21 Fassnacht M Dekkers OM Else T Baudin E Berruti A de Krijger R . European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol (2018) 179 (4 ):G1–g46. 10.1530/EJE-18-0608 30299884\n22 Tran TB Postlewait LM Maithel SK Prescott JD Wang TS Glenn J . Actual 10-year survivors following resection of adrenocortical carcinoma. J Surg Oncol (2016) 114 (8 ):971–6. 10.1002/jso.24439\n23 Tritos NA Cushing GW Heatley G Libertino JA . Clinical features and prognostic factors associated with adrenocortical carcinoma: Lahey Clinic Medical Center experience. Am Surg (2000) 66 (1 ):73–9.\n24 Icard P Goudet P Charpenay C Andreassian B Carnaille B Chapuis Y . Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg (2001) 25 (7 ):891–7. 10.1007/s00268-001-0047-y\n25 Bani-Hani KE . Primary non-functional extra-adrenal adrenocortical carcinoma. Saudi Med J (2003) 24 (3 ):301–4.\n\n",
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"keywords": "adrenocortical carcinoma; ectopic; immunohistochemistry; metastasis; ovary",
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"title": "Case Report: Ectopic Adrenocortical Carcinoma in the Ovary.",
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{
"abstract": "A 59-year-old male with acute lymphoblastic leukemia developed sinus, tracheobroncheal, pulmonary, and intracerebral aspergillosis. All lesions except the intracerebral aspergillosis healed after combination antifungal treatment. Long-term voriconazole--but not posaconazole--therapy induced partial regression of the cerebral manifestations. At the time of writing, 3.5 years after the initial diagnosis, the patient is working half-time and suffers from a possible voriconazole-induced polyneuropathy.",
"affiliations": "Division of Hematology, Department of Medicine, Karolinska University Hospital and Institutet, Stockholm, Sweden. [email protected]",
"authors": "Björkholm|M|M|;Kalin|M|M|;Grane|P|P|;Celsing|F|F|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D011743:Pyrimidines; D014230:Triazoles; C101425:posaconazole; D000666:Amphotericin B; D000077336:Caspofungin; D065819:Voriconazole",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-011-0158-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "40(1)",
"journal": "Infection",
"keywords": null,
"medline_ta": "Infection",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D001232:Aspergillus fumigatus; D001921:Brain; D000077336:Caspofungin; D054022:Cerebrum; D054714:Echinocandins; D006801:Humans; D007830:Larynx; D055666:Lipopeptides; D008168:Lung; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020953:Neuroaspergillosis; D010256:Paranasal Sinuses; D010523:Peripheral Nervous System Diseases; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D055732:Pulmonary Aspergillosis; D011743:Pyrimidines; D013548:Sweden; D014057:Tomography, X-Ray Computed; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "81-5",
"pmc": null,
"pmid": "21779887",
"pubdate": "2012-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16207169;18560230;6696356;11170942;18171251;12689933;21512792;18808352;19011743;18177225;19255905;16885047;15642862;18642109;18726553",
"title": "Long-term treatment of invasive sinus, tracheobroncheal, pulmonary and intracerebral aspergillosis in acute lymphoblastic leukaemia.",
"title_normalized": "long term treatment of invasive sinus tracheobroncheal pulmonary and intracerebral aspergillosis in acute lymphoblastic leukaemia"
}
|
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},
{
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],
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}
},
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{
"abstract": "The co-occurrence of IgA nephropathy (IgAN) and positive anti-neutrophil cytoplasmic autoantibodies (ANCA) serology is uncommon. In the present case series and literature review, we aimed to clarify the impact of ANCA on pathogenesis, clinical and histopathology presentation, and outcome in IgAN patients. We report four patients with an overlap lesion of IgAN-ANCA positive. Also, we performed a narrative review of all biopsy-proven published case series. Only 1.2% patients had ANCA in our 330-biopsy-proven IgAN cohort. We compared our data with previous reports-6 case series and 3 small retrospective studies-a total of 103 patients. All patients but one had eGFR below 15 mL/min at diagnosis. Besides rapidly decreasing eGFR, all presented with proteinuria around 1.5 g/day and dysmorphic microhematuria, suggesting glomerular inflammation. Systemic symptoms suggestive for ANCA vasculitis were seen in half of our patients, but only one patient had hemorrhagic alveolitis. Patients from our cohort responded to the intensive immunosuppressive regimens used in ANCA-positive vasculitis with renal involvement. However, in the follow-up, one patient had a relapse followed by septic shock related to immunosuppression and one patient started hemodialysis. In the review, we found that IgAN-ANCA -positive patients are characterized by vasculitis-like lesions and clinically by a rapidly progressive decline in kidney function, which was reversed by an aggressive induction immunosuppressive protocol used in ANCA vasculitis. Checking ANCA serology seems useful in patients with rapidly progressive IgAN for therapeutic and prognostic reasons.",
"affiliations": "\"Dr. Carol Davila\" Teaching Hospital of Nephrology, Romanian Renal Registry, Street Calea Grivitei, No. 4, 010731, Bucharest, Romania. [email protected].;Ultrastructural Pathology, \"Victor Babes\" National Institute of Pathology, Bucharest, Romania.;\"Dr. Carol Davila\" Teaching Hospital of Nephrology, Romanian Renal Registry, Street Calea Grivitei, No. 4, 010731, Bucharest, Romania.;\"Dr. Carol Davila\" Teaching Hospital of Nephrology, Romanian Renal Registry, Street Calea Grivitei, No. 4, 010731, Bucharest, Romania.;Department of Cell Biology and Histology, \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;\"Dr. Carol Davila\" Teaching Hospital of Nephrology, Romanian Renal Registry, Street Calea Grivitei, No. 4, 010731, Bucharest, Romania.",
"authors": "Ștefan|Gabriel|G|http://orcid.org/0000-0002-7336-5874;Terinte-Balcan|George|G|;Stancu|Simona|S|;Zugravu|Adrian|A|;Gherghiceanu|Mihaela|M|;Mircescu|Gabriel|G|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-021-04888-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "41(7)",
"journal": "Rheumatology international",
"keywords": "ANCA vasculitis; Crescents; IgA nephropathy; Rapidly progressive",
"medline_ta": "Rheumatol Int",
"mesh_terms": null,
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1347-1355",
"pmc": null,
"pmid": "33999289",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "27189177;26413269;10720938;26567243;21800117;26413270;9403209;1320233;11007672;29204761;2516884;12090888;8287608;22147912;27339947;20042261;31702703",
"title": "IgA nephropathy with serum ANCA positivity: case series and literature review.",
"title_normalized": "iga nephropathy with serum anca positivity case series and literature review"
}
|
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{
"abstract": "OBJECTIVE\nThe objectives of this study were to evaluate the tolerability and efficacy of valproic acid (VPA) and lenalidomide.\n\n\nMETHODS\nIn this 3+3 design study, VPA was administered daily on a 7-day-on, 7-day-off schedule, and lenalidomide was administered daily for 28 days. Because of the response noted during the dose-escalation phase, 12 additional patients with adenoid cystic carcinoma (ACC) received the maximum tolerated dose (MTD) in a dose-expansion phase.\n\n\nRESULTS\nTwenty-six patients with advanced cancer (14 men/12 women), median age of 56 years (range 38-70 years), and a median number of two prior therapies (range 0-12) were enrolled. The most common toxicities were fatigue, rash, neutropenia, thrombocytopenia, and change in mental status. Dose-limiting toxic (DLT) effects were grade III confusion (n = 3), somnolence (n = 1), and gait disturbance (n = 1). The MTD was reached at VPA 30 mg/kg and lenalidomide 25 mg. Although only two of the 12 patients from the dose-expansion phase had DLT during the first cycle at the MTD, during subsequent cycles the majority of patients required dose reduction of VPA to 5-20 mg/kg because of fatigue and drowsiness. No significant tumor reductions were noticed in patients with ACC, but seven of these patients had stable disease over four cycles. Of non-ACC patients, one patient with melanoma and one patient with parathyroid carcinoma had stable disease for six cycles and eight cycles, respectively.\n\n\nCONCLUSIONS\nLenalidomide combined with VPA was well tolerated. We recommend starting VPA at 5 mg/kg and titrating upward to 20 mg/kg. No significant tumor reductions were noticed in patients with ACC.",
"affiliations": "Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Bilen|Mehmet Asim|MA|;Fu|Siqing|S|;Falchook|Gerald S|GS|;Ng|Chaan S|CS|;Wheler|Jennifer J|JJ|;Abdelrahim|Maen|M|;Erguvan-Dogan|Basak|B|;Hong|David S|DS|;Tsimberidou|Apostolia M|AM|;Kurzrock|Razelle|R|;Naing|Aung|A|",
"chemical_list": "D013792:Thalidomide; D014635:Valproic Acid; D000077269:Lenalidomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-015-2695-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "75(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": null,
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms; D013792:Thalidomide; D016896:Treatment Outcome; D014635:Valproic Acid",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "869-74",
"pmc": null,
"pmid": "25666183",
"pubdate": "2015-04",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Phase I trial of valproic acid and lenalidomide in patients with advanced cancer.",
"title_normalized": "phase i trial of valproic acid and lenalidomide in patients with advanced cancer"
}
|
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{
"abstract": "Between 2016 and 2017, the national mortality rate involving opioids continued its escalation; opioid deaths rose from 42,249 to 47,600, bringing the public health crisis to a new height. Considering that 69% of adults in the United States use online social media sites, a resource that builds a more complete understanding of prescription drug misuse and abuse could supplement traditional surveillance instruments. The Food and Drug Administration has identified 5 key risks and consequences of opioid drugs-misuse, abuse, addiction, overdose, and death. Identifying posts that discuss these key risks could lead to novel information that is not typically captured by traditional surveillance systems.\n\n\n\nThe goal of this study was to describe the trends of online posts (frequency over time) involving abuse, misuse, addiction, overdose, and death in the United States and to describe the types of websites that host these discussions. Internet posts that mentioned fentanyl, hydrocodone, oxycodone, or oxymorphone were examined.\n\n\n\nPosts that did not refer to personal experiences were removed, after which 3.1 million posts remained. A stratified sample of 61,000 was selected. Unstructured data were classified into 5 key risks by manually coding for key outcomes of misuse, abuse, addiction, overdose, and death. Sampling probabilities of the coded posts were used to estimate the total post volume for each key risk.\n\n\n\nAddiction and misuse were the two most commonly discussed key risks for hydrocodone, oxycodone, and oxymorphone. For fentanyl, overdose and death were the most discussed key risks. Fentanyl had the highest estimated number of misuse-, overdose-, and death-related mentions (41,808, 42,659, and 94,169, respectively). Oxycodone had the highest estimated number of abuse- and addiction-related mentions (3548 and 12,679, respectively). The estimated volume of online posts for fentanyl increased by more than 10-fold in late 2017 and 2018. The odds of discussing fentanyl overdose (odds ratios [OR] 4.32, 95% CI 2.43-7.66) and death (OR 5.05, 95% CI 3.10-8.21) were higher for social media, while the odds of discussing fentanyl abuse (OR 0.10, 95% CI 0.04-0.22) and addiction (OR 0.24, 95% CI 0.15-0.38) were higher for blogs and forums.\n\n\n\nOf the 5 FDA-defined key risks, fentanyl overdose and death has dominated discussion in recent years, while discussion of oxycodone, hydrocodone, and oxymorphone has decreased. As drug-related deaths continue to increase, an understanding of the motivations, circumstances, and consequences of drug abuse would assist in developing policy responses. Furthermore, content was notably different based on media origin, and studies that exclusively use either social media sites (such as Twitter) or blogs and forums could miss important content. This study sets out sustainable, ongoing methodology for surveilling internet postings regarding these drugs.",
"affiliations": "Rocky Mountain Poison and Drug Safety, Denver, CO, United States.;Rocky Mountain Poison and Drug Safety, Denver, CO, United States.;Rocky Mountain Poison and Drug Safety, Denver, CO, United States.;Rocky Mountain Poison and Drug Safety, Denver, CO, United States.",
"authors": "Black|Joshua C|JC|0000-0002-7329-2740;Margolin|Zachary R|ZR|0000-0003-2600-0511;Olson|Richard A|RA|0000-0002-4587-7637;Dart|Richard C|RC|0000-0001-5989-9354",
"chemical_list": "D000701:Analgesics, Opioid; D006853:Hydrocodone; D010111:Oxymorphone; D010098:Oxycodone; D005283:Fentanyl",
"country": "Canada",
"delete": false,
"doi": "10.2196/17073",
"fulltext": "\n==== Front\nJMIR Public Health Surveill\nJMIR Public Health Surveill\nJPH\nJMIR Public Health and Surveillance\n2369-2960 JMIR Publications Toronto, Canada \n\nv6i2e17073\n32597786\n10.2196/17073\nOriginal Paper\nOriginal Paper\nOnline Conversation Monitoring to Understand the Opioid Epidemic: Epidemiological Surveillance Study\nSanchez Travis Weiner Scott Lansky Amy Bae Sang Won Black Joshua C PhDhttps://orcid.org/0000-0002-7329-27401Rocky Mountain Poison and Drug Safety1391 N Speer Blvd #600M/C 0180Denver, CO, 80204United States1 303 389 [email protected] Margolin Zachary R MSc1https://orcid.org/0000-0003-2600-0511 Olson Richard A MA1https://orcid.org/0000-0002-4587-7637 Dart Richard C MD, PhD1https://orcid.org/0000-0001-5989-9354 \n1 \nRocky Mountain Poison and Drug Safety\nDenver, CO\nUnited States\n\nCorresponding Author: Joshua C Black [email protected]\nApr-Jun 2020 \n29 6 2020 \n6 2 e1707315 11 2019 10 2 2020 6 4 2020 12 5 2020 ©Joshua C Black, Zachary R Margolin, Richard A Olson, Richard C Dart. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 29.06.2020.2020This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Public Health and Surveillance, is properly cited. The complete bibliographic information, a link to the original publication on http://publichealth.jmir.org, as well as this copyright and license information must be included.Background\nBetween 2016 and 2017, the national mortality rate involving opioids continued its escalation; opioid deaths rose from 42,249 to 47,600, bringing the public health crisis to a new height. Considering that 69% of adults in the United States use online social media sites, a resource that builds a more complete understanding of prescription drug misuse and abuse could supplement traditional surveillance instruments. The Food and Drug Administration has identified 5 key risks and consequences of opioid drugs—misuse, abuse, addiction, overdose, and death. Identifying posts that discuss these key risks could lead to novel information that is not typically captured by traditional surveillance systems.\n\nObjective\nThe goal of this study was to describe the trends of online posts (frequency over time) involving abuse, misuse, addiction, overdose, and death in the United States and to describe the types of websites that host these discussions. Internet posts that mentioned fentanyl, hydrocodone, oxycodone, or oxymorphone were examined.\n\nMethods\nPosts that did not refer to personal experiences were removed, after which 3.1 million posts remained. A stratified sample of 61,000 was selected. Unstructured data were classified into 5 key risks by manually coding for key outcomes of misuse, abuse, addiction, overdose, and death. Sampling probabilities of the coded posts were used to estimate the total post volume for each key risk.\n\nResults\nAddiction and misuse were the two most commonly discussed key risks for hydrocodone, oxycodone, and oxymorphone. For fentanyl, overdose and death were the most discussed key risks. Fentanyl had the highest estimated number of misuse-, overdose-, and death-related mentions (41,808, 42,659, and 94,169, respectively). Oxycodone had the highest estimated number of abuse- and addiction-related mentions (3548 and 12,679, respectively). The estimated volume of online posts for fentanyl increased by more than 10-fold in late 2017 and 2018. The odds of discussing fentanyl overdose (odds ratios [OR] 4.32, 95% CI 2.43-7.66) and death (OR 5.05, 95% CI 3.10-8.21) were higher for social media, while the odds of discussing fentanyl abuse (OR 0.10, 95% CI 0.04-0.22) and addiction (OR 0.24, 95% CI 0.15-0.38) were higher for blogs and forums.\n\nConclusions\nOf the 5 FDA-defined key risks, fentanyl overdose and death has dominated discussion in recent years, while discussion of oxycodone, hydrocodone, and oxymorphone has decreased. As drug-related deaths continue to increase, an understanding of the motivations, circumstances, and consequences of drug abuse would assist in developing policy responses. Furthermore, content was notably different based on media origin, and studies that exclusively use either social media sites (such as Twitter) or blogs and forums could miss important content. This study sets out sustainable, ongoing methodology for surveilling internet postings regarding these drugs.\n\nepidemiological surveillanceinfoveillanceinfodemiologyopioidssocial mediamisuseabuseaddictionoverdosedeath\n==== Body\nIntroduction\nCurbing the opioid misuse and abuse epidemic has proven to be a challenging public health problem [1-4]. Although opioids are effective for the management of pain related to acute injury or cancer [5], they have a high potential for causing dependence; opioids are more likely to be abused or misused than other pain management treatments, which has resulted in an alarming increase in the number of overdose deaths compared to the number of other nonprescription opioid-related deaths [5]. The mortality data indicate a continued rise—the national mortality rate involving opioids rose 12.0% from 2016 to 2017 [6]. Oxycodone and hydrocodone are among the most highly dispensed prescription opioids and are also among the most common prescription opioids involved in overdose [7].\n\nThe United States Food and Drug Administration (FDA) has responded by identifying 5 key risks and consequences that are part of boxed warnings for opioids: misuse, abuse, addiction, overdose, and death [8]. Understanding the qualitative nature of these risks and consequences (herein termed key risks) has also been highlighted as important supportive information to establish context for societal, behavioral, and clinical aspects of risk; this qualitative information could be used to support submissions for abuse-deterrent labeling of opioid products [9]. Reviewing internet postings provides an opportunity to delve into the societal and behavioral causes of the 5 key risks.\n\nOne of the more recent additions to public health surveillance of opioids is the monitoring of internet discussions on public blogs, forums, and social media [10]. In contrast to surveys, interviews, or other traditional public health data collection methods, the use of social media, blogs, and forums as a tool for data collection allows for the observation of real-time, unsolicited opinions, feelings, or thoughts [11]. It is possible that online users feel more comfortable sharing covert behaviors in this setting which allows for more truthful perspectives to be shared. Given the danger surrounding some drugs, these unsolicited expressions could shed light in areas that traditional survey instruments cannot. Examples of recent uses of social media data in research include discovering adverse drug events [12], studying addiction [13], tracking the popularity of marijuana concentrates [14], quantifying drug abuse [15], and characterizing discussion surrounding the introduction of an abuse-deterrent product [16].\n\nThe Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System is a compilation of individual data collection programs that collect product-specific and geography-specific data to form a mosaic understanding of the abuse, misuse, and diversion of prescription drugs [1]. The Web Monitoring Program, established in 2014, focuses on the collection and organization of real-time web content about prescription drugs from over 150 million sites on the internet, including social media, blogs, and forums. The RADARS System Web Monitoring Program combines qualitative and quantitative data collection methods; a team of trained researchers collect daily opioid-related posts and manually code them for variables of interest [16].\n\nThe purpose of this study was to characterize the trends of abuse, misuse, addiction, overdose, and death in the United States using internet posts that mention fentanyl, hydrocodone, oxycodone, or oxymorphone and to establish a sustainable ongoing methodology for surveilling internet postings regarding these drugs.\n\nMethods\nData Collection\nData were collected by scraping internet posts that mentioned 1 of 4 drugs of interest: fentanyl, hydrocodone, oxycodone, or oxymorphone. These drugs were selected because they have been involved in a variety of behaviors, have been subject to differential regulation, or were frequently prescribed in the United States. Branded oxymorphone and oxycodone products have undergone increasingly restrictive regulation due to findings related to their abuse (such as Opana ER [17] and OxyContin [18]), the potency of fentanyl likely makes it a desirable substance for diversion [19], and hydrocodone is often prescribed within the United States [20]. Posts underwent an algorithmic screening process where posts without substantive content were removed. The remaining posts were sampled and the contents of these posts were reviewed manually and categorized as misuse, abuse, addiction, overdose, or death. Posts that indicate discussion of counterfeit formulations (such as heroin mixed with homemade fentanyl) were excluded prior to analysis.\n\nData for this project were collected as part of RADARS System ongoing surveillance of the abuse, misuse, and diversion of prescription opioids. All data were collected using a web-crawling platform (Salesforce.com Inc) that scrapes data from public websites that permit content viewing by a third party. Examples of sites that permit this type of crawling include Twitter, Reddit, public blogs and forums, and comment sections on many news sites, while private sites such as personal Facebook pages, Bluelight, and other password-protected sites do not permit this type of crawling. Posts mentioning fentanyl, hydrocodone, oxycodone, or oxymorphone were identified based on specified search-string criteria (such as opioid name, associated misspellings, product names, and unique slang terms) for the 4 opioids (Multimedia Appendix 1). The keywords for each drug substance and product were generated using a phonetic algorithm and then validated using number of hits when entered into a common search engine. Other keywords were identified during the manual coding process.\n\nThe study protocol was reviewed and approved by the Colorado Multiple Institutional Review Board prior to the initiation of the RADARS System Web Monitoring Program. Since the publicly available posts were obtained through the Web Monitoring Program and are reported in an aggregated, anonymous manner, it was determined that it was not necessary to consider the Web Monitoring Program as research involving human subjects.\n\nData Cleaning\nAs part of routine web monitoring, posts were screened for predetermined exclusion criteria using a 2-step process. The scraped posts were programmatically screened for predetermined keywords; phrases associated with uninformative posts were excluded. Programmatic exclusions did not remove all uninformative posts; therefore, manual screening for exclusion was also used. The exclusion criteria (for both steps) were defined as posts occurring outside of the surveillance period; in a language other than English; originating outside of the United States; from originating sources other than social media, blogs, or forums; containing the name of a drug of interest that was used in a context unrelated to that drug; that were considered spam (unsolicited online messages); that referenced online pharmacies, news, or pop-culture with no further commentary concerning the drug of interest; or for which the coder was unable to determine a theme. For posts that met one or more exclusion criteria, only the originating posts were removed. If related posts contained informative content (such as a comment mentioning overdose appearing below a news article), then they were not excluded.\n\nEach post was classified by origin as either social media or blogs and forums based on the originating website. Social media posts originated from sites with a focus on social networking; users on these sites are typically not anonymous, discussions are unguided in nature (ie, not limited to predetermined topics), and commentary is often brief by design (character limits). Examples of social media sites include Twitter, Facebook business pages (which have different privacy rules than those of personal Facebook pages), and Myspace. Blog or forum posts originated from sites that, often, are created to facilitate conversation among users with similar interests; users are often anonymous or not connected to a real-world identity, discussions are topic-specific, and commentary is not limited and can be extensive in nature. Examples of blogs and forums include Reddit, Blogger, and specialized medical forums.\n\nSample Design\nDue to the very large volume of posts collected, sampling was necessary to identify a subset of posts for manual coding. Posts were required to have occurred between January 1, 2015 and December 31, 2018. A total of 5,048,517 posts were collected for sampling. A stratified random sample without replacement and with proportional allocation was taken from the population of identified posts. Strata included both time (by week) and origin (social media or blogs and forums) of the online posts. If there were less than 2 posts that fell into a given week, that week was folded into a biweekly stratum and weights were adjusted accordingly [21]. The sample size for each opioid was determined based on an expected proportion of 0.05 with a measured precision of 0.015. Sample sizes were selected such that 95% of all confidence intervals of the proportion (calculated from the hypergeometric distribution) obtained the desired precision [22].\n\nDefinitions\nA team of 3 trained coders manually reviewed the sample of posts in order to identify reasons for opioid-use outcomes (abuse and misuse), and key medical outcome measures (addiction, overdose, and death). Table 1 contains definitions of the terms as they were used in this study. Extensive training was conducted to ensure that consistent coding was achieved across the team of three coders. A codebook with outlined definitions, examples, and scenarios specific to these data was utilized in the training of each of the 3 coders. Training was complete when the trainee was able to meet the predefined criteria for interrater reliability. These definitions are specific to the RADARS System Web Monitoring Program and may differ from those of other surveillance programs. Each post may contain one or more key risks; are defined as the discussion of any instance of actual misuse, abuse, addiction, overdose, or death involving a drug or drug class of interest; and may include multiple mentions of the opioid or opioids of interest in a single post. Because misuse and abuse were defined similarly, they were coded into a single variable. In any cases of disagreement in coding, the case data were reconciled by an additional coder, and, when necessary, a senior researcher verified the coding.\n\nTable 1 Definitions of terms used in the RADARS System Web Monitoring Program.\n\nTerm\tDefinition\t\nAbuse\t“A mention that indicates the use of a drug to gain a high, euphoric effect or some other psychotropic effect.”\t\nAddiction\t“A mention that indicates one or more of the following: 1) psychological or physical dependence on a drug; 2) tolerance to the psychotropic effects of a drug; 3) withdrawal effects when discontinuing use of a drug.”\t\nDeath\t“A mention that indicates a death has occurred due to a drug of interest.”\t\nMention\t“Any occasion of a reference to a drug or drug class that appears in a post. One post may contain multiple mentions.”\t\nMisuse\t“A mention that indicates the improper or incorrect use of a drug for reason other than the pursuit of a psychotropic effect.”\t\nOverdose\t“A mention that indicates the accidental or intentional overdose of a drug, using a dangerous amount of a drug (i.e. a quantity greater than recommended or generally prescribed), or use which may result in a medical intervention.”\t\nPost\t“A single point of communication entered by one individual at one specific time point.”\t\nStatistical Analysis\nAfter manual coding, sampling weights were applied to calculate the estimated number and percentage of posts for each substance in the original population. Odds ratios (OR) and corresponding 95% confidence intervals were calculated from weighted logistic regression for the origin of the posts (social media versus blogs and forums) using all posts in the study period; odds ratios greater than 1.0 indicated higher odds that the post originated from social media. Interrater reliability was calculated between the 3 coders. Predefined acceptability criteria were set, and results were deemed acceptable if 3-way agreement was greater than 90% and if the average coefficient (Gwet AC1) was greater than 0.60 [23]. Statistical analyses were performed in R (3.4.2) and in SAS (version 9.4; SAS Institute Inc).\n\nResults\nFrequency of Posts Discussing Key Risks\nFigure 1 depicts the data cleaning process and provides the number of opioid-specific mentions that were sampled and the number of mentions that were analyzed after exclusion criteria were applied. In the final sample (n=24,837), the outcomes were infrequently observed. Out of all posts for all drugs, 1.95% (485/24,837) mentioned misuse, 0.67% (166/24,837) mentioned abuse, 2.35% (584/24,837) mentioned addiction, 1.53% (379/24,837) mentioned overdose, and 2.15% (534/24,837) mentioned death.\n\nFigure 1 Flowchart of data cleaning process for data collected from the 1st quarter of 2015 through to the 4th quarter of 2018 where percentages represent the proportion of exclusions at each step.\n\nInterrater reliability was acceptable according to both criteria for all the coding variables. Three-way percent agreement was high for misuse and abuse (97.8%), addiction (99.4%), overdose (99.9%), and death (99.6%). Gwet AC1 coefficient was also high for misuse and abuse (0.98), addiction (0.99), overdose (1.0), and death (1.0)\n\nTable 2 describes the estimated number of mentions by drug on the public internet that discuss the 5 key risks. The top 3 highest estimated frequencies involved fentanyl (death, overdose, and misuse). Misuse had the highest estimated frequency for hydrocodone. Addiction had the highest estimated frequency for oxycodone. All key risks involving oxymorphone were infrequently discussed, with fewer than 600 posts discussing each of the 5 key risks. Fentanyl-related death had the highest estimated frequency of any key risk–drug combinations which was from 10- to 100-fold higher than the frequency of death mentions for other drugs. Figure 2, Figure 3, Figure 4, and Figure 5 describe the estimated number of posts (per 10,000 posts) for fentanyl, hydrocodone, oxycodone, and oxymorphone, respectively, throughout the surveillance period. The estimated number of posts discussing misuse, abuse, and addiction generally decreased across the study period for hydrocodone, oxycodone, and oxymorphone. Discussions of fentanyl misuse, overdose, and death surged at the end of 2017 and continued to surge through 2018.\n\nTable 2 Number of posts analyzed in samples and corresponding population estimates.\n\nKey risks\tDrug Mentions\t\n \tFentanyl\tHydrocodone\tOxycodone\tOxymorphone\t\n \tSample analyzeda (n=4649), n\tPopulation \nestimateb, \nn (95% CI)\tSample analyzed, n (n=8974)\tPopulation \nestimate, \nn (95% CI)\tSample analyzed, n (n=8100)\tPopulation \nestimate, \n(95% CI)\tSample analyzed, n (n=3114)\tPopulation \nestimate, \nn (95% CI)\t\nAbuse\t24\t627 \n(351-902)\t42\t2181 \n(1503-2858)\t43\t3548 \n(2424-4672)\t57\t189 \n(140-239)\t\nMisuse\t130\t41808 \n(34,058-49,559)\t199\t10379 \n(8857-11,900)\t107\t7997 \n(6393-9601)\t49\t165 \n(118-211)\t\nAddiction\t73\t4435 \n(3209-5662)\t183\t8766 \n(7419-10,113)\t176\t12679 \n(10,721-14,637)\t152\t526 \n(442-610)\t\nOverdose\t271\t42659 \n(34,750-50,568)\t36\t1911 \n(1257-2564)\t48\t3633 \n(2583-4682)\t24\t84 \n(50-119)\t\nDeath\t427\t94169 \n(83,575-104,763)\t23\t913 \n(514-1312)\t47\t3291 \n(2326-4256)\t37\t125 \n(84-166)\t\naSample analyzed refers to the number of posts manually reviewed by the team of coders.\n\nbPopulation estimate refers to the extrapolated number of posts.\n\nFigure 2 Estimated number of quarterly fentanyl posts.\n\nFigure 3 Estimated number of quarterly hydrocodone posts.\n\nFigure 4 Estimated number of quarterly oxycodone posts.\n\nFigure 5 Estimated number of quarterly oxymorphone posts.\n\nOrigin of Posts Discussing Key Risks\nSubstantial proportions of posts discussing key risks originated outside of social media. An estimated 48.0% (95% CI 46.2%-49.8%) of oxymorphone posts, 16.8% (95% CI 15.9%-17.6%) of oxycodone posts, 18.3% (95% CI 17.5%-19.1%) of hydrocodone posts, and 14.6% (95% CI 13.6%-15.6%) of fentanyl posts originated from blogs and forums. Out of all social media posts discussing key risks, Twitter was a substantial origin. An estimated 19.9% (95% CI 18.9%-20.8%) of oxymorphone social media posts, 49.8% (95% CI 48.9%-50.7%) of oxycodone social media posts, 62.8% (95% CI 61.9%-63.7%) of hydrocodone social media posts, and 30.6% (95% CI 29.8%-31.4%) of fentanyl social media posts originated from Twitter. Odds ratios for the origin of discussion of key risks are shown in Figure 6. For ease of presentation, all odds ratios refer to social media as the reference. For all drugs, the estimated odds of discussing addiction were higher in blogs and forums than in social media. Odds of posting about addiction on social media were smaller than on blogs and forums; odds ratios ranged from (fentanyl) 0.24 (95% CI 0.15-0.38) to (oxymorphone) 0.46 (95% CI 0.32-0.67). Conversely, the estimated odds of discussing death were higher in social media than in blogs and forums for all drugs. The odds ratios for discussions of misuse, abuse, and overdose also differed by drug. Notably there was a distinct separation of fentanyl abuse and addiction discussions from fentanyl overdose and death discussions. Odds of discussing fentanyl overdose and death were higher for social media (overdose: OR 4.32, 95% CI 2.43-7.66; death OR 5.05, 95% CI 3.10-8.21), while odds of discussing fentanyl abuse and addiction were higher for blogs and forums (abuse: OR 0.10, 95% CI 0.04-0.22; addiction: OR 0.24, 95% CI 0.15-0.38). For other drugs, odds of discussing misuse were higher in blogs and forums.\n\nFigure 6 Post origin by key risk across drugs. Odds ratios greater than 1.0 indicate higher likelihood of discussion on social media.\n\nDiscussion\nPrincipal Findings\nThe purpose of this study was to demonstrate a sustainable, ongoing methodology of evaluating internet posts that mention drugs by presenting the trends of online discussion regarding abuse, misuse, addiction, overdose, and death and documenting the post origin of these key risks. The estimated numbers of posts that discussed misuse, abuse, and addiction decreased for hydrocodone, oxycodone, and oxymorphone over the surveillance period, which is not surprising since prescription guidelines have tightened the availability of these drugs [24]. Discussion of fentanyl rose sharply in 2017 and 2018, coincident with increased fentanyl mortality, increased illicit fentanyl production, and public awareness campaigns about the dangers of fentanyl. Further content evaluation of fentanyl posts could elucidate specific societal events that caused the sudden increase. Three strengths of the study results presented herein that distinguished this surveillance system from other opioid abuse internet surveillance programs [10] were that content coverage included originating sources beyond social media; the focus was on the FDA key risks—misuse, abuse, addiction, overdose, and death; and the originating sources of these key risk discussions were identified. It was noted that discussions of several key risks were more likely to be found on blogs and forums than on social media. This could result in selection bias in studies that focus only on social media. For example, if a study on substance-use behavior involving these four opioids used only social media, the post content would select against discussions of addiction and addiction-related behaviors.\n\nAnonymity has a profound influence on the likelihood of revealing sensitive behaviors [25]. Traditional public health surveillance programs typically rely on confidentiality, and use of anonymous posts and social media may allow for reporting of behaviors or opinions not normally captured by traditional systems. Moreover, the diversity of online data sources used in this study allowed more comprehensive assessment of online discussion content than that which would have been allowed with an approach that targeted a single social media site (such as Twitter) or forum (such as drugs-forum). One review of studies that collected data on illicit drug use from a variety of platforms [10] found 14 studies that met inclusion criteria. Using our definition of media originating source, only 2 of those studies collected data from blogs and forums. Our results show that the discussions on social media often involve different information or outcomes compared to those on blogs and forums. There could be several reasons for this; social media posts were more likely to discuss overdose and death, outcomes that could elicit strong emotion and vocal responses. Blogs and forums were more related to misuse, abuse, and addiction, outcomes that could generate less strong response. We speculate the blogs and forums tend to have larger character limits, and could be better suited for complex topics, such as addiction. As social media are commonly associated with an actual identity of the user, it is frequently less anonymous and can easily be searched by employers, family, and friends; this might drive discussion of stigmatizing behaviors, such as misuse, abuse, and addition, to blogs and forums where individuals can use pseudonyms. Research focused on overdose and death outcomes will likely find more valuable data on social media, while research around misuse, abuse, and addiction should look toward blogs and forums; however, a mosaic approach should ideally include both originating sources. Our results indicated that content originated from different sectors of the internet for addiction and death discussions, and qualitative analyses that focus only on subregions of the internet could miss important information on these key risks.\n\nDue to the unsolicited nature of internet postings, qualitative analysis of web content can be used to identify unknown knowledge gaps in substance-abuse research. For future research efforts using the method reported here, data can be examined for polysubstance use, methods of tampering with abuse-deterrent formulations, or low-frequency side effects. Furthermore, negative outcomes are not the only topic to study. Events can stimulate online discussion that supports the proper therapeutic use of a drug or discussions can compare the efficacy of similar drug products.\n\nLimitations\nOne limitation of this study is that only publicly available websites were studied. Unique information likely exists on websites with policies that prevent public scraping (such as most of Facebook or Bluelight). The second limitation was the unstructured nature of the raw data and the potential ambiguity associated with manually coding these key risks, which was addressed by team meetings to ascertain group consensus. Furthermore, interrater reliability was assessed and found to be satisfactory. Finally, separating illicit from licit fentanyl was challenging, and likely much of the discussion referred to illicit instead of licit fentanyl.\n\nConclusions\nUse of internet posts reveals a unique perspective to the opioid epidemic that is not found using traditional surveillance systems and can be a gateway to understanding qualitative aspects of drug use. Anonymity and the unsolicited nature of these data offer advantages to understanding emerging trends. Surveillance of diverse content providers should be used to understand how policy or other interventions are received by the broader community.\n\nThis work was supported by the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System. The RADARS System is supported by subscriptions from pharmaceutical manufacturers, government, and nongovernment agencies for surveillance, research, and reporting services. RADARS System is the property of Denver Health and Hospital Authority, a political subdivision of the State of Colorado. Denver Health retains exclusive ownership of all data, databases, and systems. No subscriber participated in the conception, analysis, drafting, or review of this manuscript.\n\nAuthors' Contributions: All authors contributed equally to the work.\n\nConflicts of Interest: Authors were employed by Denver Health and Hospital Authority during this work.\n\nAppendix\nMultimedia Appendix 1 Search keyword examples.\n\n Abbreviations\nFDAFood and Drug Administration\n\nRADARSResearched Abuse, Diversion and Addiction‐Related Surveillance\n==== Refs\n1 Dart RC Surratt HL Cicero TJ Parrino MW Severtson SG Bucher-Bartelson B Green JL Trends in opioid analgesic abuse and mortality in the United States N Engl J Med 2015 1 15 372 3 241 8 10.1056/NEJMsa1406143 25587948 25587948 \n2 Manchikanti L Helm S Fellows B Janata JW Pampati V Grider JS Boswell MV Opioid epidemic in the United States Pain Physician 2012 7 15 3 Suppl ES9 38 22786464 22786464 \n3 Rudd RA Aleshire N Zibbell JE Gladden RM Increases in drug and opioid overdose deaths--United States, 2000-2014 MMWR Morb Mortal Wkly Rep 2016 1 01 64 50-51 1378 82 10.15585/mmwr.mm6450a3 10.15585/mmwr.mm6450a3 26720857 26720857 \n4 Vowles KE McEntee ML Julnes PS Frohe T Ney JP van der Goes David N Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis Pain 2015 4 156 4 569 76 10.1097/01.j.pain.0000460357.01998.f1 25785523 25785523 \n5 Cheatle MD Prescription opioid misuse, abuse, morbidity, and mortality: balancing effective pain management and safety Pain Med 2015 10 16 Suppl 1 S3 8 10.1111/pme.12904 26360931 26360931 \n6 Scholl L Seth P Kariisa M Wilson N Baldwin G Drug and opioid-involved overdose deaths - United States, 2013-2017 MMWR Morb Mortal Wkly Rep 2018 1 04 67 5152 1419 1427 10.15585/mmwr.mm675152e1 10.15585/mmwr.mm675152e1 30605448 30605448 \n7 Ossiander EM Using textual cause-of-death data to study drug poisoning deaths Am J Epidemiol 2014 4 01 179 7 884 94 10.1093/aje/kwt333 24521559 24521559 \n8 FDA announces enhanced warnings for immediate-release opioid pain medications related to risks of misuse, abuse, addiction, overdose and death US Food & Drug Administration 2016 3 22 2020-05-12 https://www.fda.gov/news-events/press-announcements/fda-announces-enhanced-warnings-immediate-release-opioid-pain-medications-related- risks-misuse-abuse \n9 Center for Drug Evaluation and Research Abuse-Deterrent Opioids—Evaluation and Labeling: Guidance for Industry US Food and Drug Administration 2015 4 2020-05-12 https://www.fda.gov/files/drugs/published/Abuse-Deterrent-Opioids-Evaluation-and-Labeling.pdf \n10 Kazemi DM Borsari B Levine MJ Dooley B Systematic review of surveillance by social media platforms for illicit drug use J Public Health (Oxf) 2017 12 01 39 4 763 776 10.1093/pubmed/fdx020 28334848 28334848 \n11 Dredze M How social media will change public health IEEE Intell Syst 2012 7 27 4 81 84 10.1109/MIS.2012.76 \n12 Harpaz R DuMouchel W Shah NH Madigan D Ryan P Friedman C Novel data-mining methodologies for adverse drug event discovery and analysis Clin Pharmacol Ther 2012 6 91 6 1010 21 10.1038/clpt.2012.50 22549283 22549283 \n13 Dwyer R Fraser S Addicting via hashtags: how is Twitter making addiction? Contemp Drug Probl 2016 3 23 43 1 79 97 10.1177/0091450916637468 \n14 Daniulaityte R Nahhas RW Wijeratne S Carlson RG Lamy FR Martins SS Boyer EW Smith GA Sheth A \"Time for dabs\": analyzing Twitter data on marijuana concentrates across the U.S Drug Alcohol Depend 2015 10 01 155 307 11 10.1016/j.drugalcdep.2015.07.1199 26338481 26338481 \n15 Cameron D Smith GA Daniulaityte R Sheth AP Dave D Chen L Anand G Carlson R Watkins KZ Falck R PREDOSE: a semantic web platform for drug abuse epidemiology using social media J Biomed Inform 2013 12 46 6 985 97 10.1016/j.jbi.2013.07.007 23892295 23892295 \n16 Vosburg SK Haynes C Besharat A Green JL Changes in drug use patterns reported on the web after the introduction of ADF OxyContin: findings from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Web Monitoring Program Pharmacoepidemiol Drug Saf 2017 9 26 9 1044 1052 10.1002/pds.4248 28653782 28653782 \n17 FDA requests removal of Opana ER for risks related to abuse US Food and Drug Administration 2017 6 08 2020-06-09 https://www.fda.gov/news-events/press-announcements/fda-requests-removal-opana-er-risks-related-abuse \n18 FDA Actions on OxyContin Products US Food and Drug Administration 2013 4 16 2020-06-09 https://www.fda.gov/drugs/information-drug-class/fda-actions-oxycontin-products-4162013 \n19 Gutstein HB Akil H Brunton L Parker K Buxton I Blumenthal D Opioid analgesics Goodman and Gilman's the pharmacological basis of therapeutics, 11th ed 2006 New York McGraw‐Hill 547 590 \n20 Prescription opioids Centers for Disease Control and Prevention 2017 8 29 2020-06-09 https://www.cdc.gov/drugoverdose/opioids/prescribed.html \n21 Rust K Kalton G Strategies for collapsing strata for variance estimation J Off Stat 1987 3 1 69 81 \n22 Korn EL Graubard BI Confidence intervals for proportions with small expected number of positive counts estimated from survey data Survey Methodology 1998 12 24 2 193 201 \n23 Altman DG Practical Statistics for Medical Research 1999 Boca Raton Chapman and Hall/CRC Press \n24 Dowell D Haegerich TM Chou R CDC guideline for prescribing opioids for chronic pain--United States, 2016 JAMA 2016 4 19 315 15 1624 45 10.1001/jama.2016.1464 26977696 26977696 \n25 Ong AD Weiss DJ The Impact of Anonymity on Responses to Sensitive Questions J Appl Social Pyschol 2000 8 30 8 1691 1708 10.1111/j.1559-1816.2000.tb02462.x\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2369-2960",
"issue": "6(2)",
"journal": "JMIR public health and surveillance",
"keywords": "abuse; addiction; death; epidemiological surveillance; infodemiology; infoveillance; misuse; opioids; overdose; social media",
"medline_ta": "JMIR Public Health Surveill",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D004813:Epidemiology; D005260:Female; D005283:Fentanyl; D006801:Humans; D006853:Hydrocodone; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D000080052:Opioid Epidemic; D010098:Oxycodone; D010111:Oxymorphone; D011159:Population Surveillance; D061108:Social Media; D019966:Substance-Related Disorders; D014481:United States",
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"pages": "e17073",
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"pmid": "32597786",
"pubdate": "2020-06-29",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Online Conversation Monitoring to Understand the Opioid Epidemic: Epidemiological Surveillance Study.",
"title_normalized": "online conversation monitoring to understand the opioid epidemic epidemiological surveillance study"
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"literaturereference": "BLACK J, OLSON R, DART R, MARGOLIN Z. ONLINE CONVERSATION MONITORING TO UNDERSTAND THE OPIOID EPIDEMIC: EPIDEMIOLOGICAL SURVEILLANCE STUDY. JMIR PUBLIC HEALTH AND SURVEILLANCE. 2020?6(2) E17073:1?11.",
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{
"abstract": "BACKGROUND\nFungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required.\n\n\nOBJECTIVE\nWe conducted a multicentre, open-label, randomised, non-inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever.\n\n\nMETHODS\nPatients with haematological malignancies who developed fever refractory to broad-spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d).\n\n\nRESULTS\nObserved overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model-based estimate of a 4% difference (90% CI, -12% to 20%), did not fulfil the statistical non-inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3-4 hypokalaemia-related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07).\n\n\nCONCLUSIONS\nivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non-inferiority.",
"affiliations": "Department of Hematologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.;Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.;Department of Hematology and Internal Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.;Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Internal Medicine, National Hospital Organization Hiroshima-Nishi Medical Center, Otake, Japan.;Department of Hematology, National Hospital Organization Mito Medical Center, Higashiibarakigun, Japan.;Department of Hematology, National Hospital Organization Minami-Okayama Medical Center, Okayama, Japan.;Stem Cell Transplantation Center, National Hospital Organization Yonago Medical Center, Yonago, Japan.;Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.;Department of Hematology and Internal Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.;Department of Internal Medicine, National Hospital Organization Hiroshima-Nishi Medical Center, Otake, Japan.;Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.;Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Hematology, National Hospital Organization Mito Medical Center, Higashiibarakigun, Japan.;Department of Hematology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Hematology, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Hematology, National Hospital Organization Nagasaki Medical Center, Omura, Japan.;Department of Hematologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Bacteriology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.;Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.",
"authors": "Yoshida|Isao|I|https://orcid.org/0000-0001-5234-0507;Saito|Akiko M|AM|;Tanaka|Shiro|S|;Choi|Ilseung|I|;Hidaka|Michihiro|M|;Miyata|Yasuhiko|Y|;Inoue|Yoshiko|Y|;Yamasaki|Satoshi|S|;Kagoo|Toshiya|T|;Iida|Hiroatsu|H|;Niimi|Hiromasa|H|;Komeno|Takuya|T|;Yoshida|Chikamasa|C|;Tajima|Fumihito|F|;Yamamoto|Hideyuki|H|;Takase|Ken|K|;Ueno|Hironori|H|;Shimomura|Takeshi|T|;Sakai|Tatsunori|T|;Nakashima|Yasuhiro|Y|;Yoshida|Chikashi|C|;Kubonishi|Shiro|S|;Sunami|Kazutaka|K|;Yoshida|Shinichiro|S|;Sakurai|Aki|A|;Kaneko|Yukihiro|Y|;Miyazaki|Yoshitsugu|Y|;Nagai|Hirokazu|H|",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D017964:Itraconazole; D000666:Amphotericin B",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.13100",
"fulltext": "\n==== Front\nMycoses\nMycoses\n10.1111/(ISSN)1439-0507\nMYC\nMycoses\n0933-7407 1439-0507 John Wiley and Sons Inc. Hoboken \n\n10.1111/myc.13100\nMYC13100\nOriginal Article\nOriginal Articles\nIntravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever\nYOSHIDA et al.Yoshida Isao https://orcid.org/0000-0001-5234-0507\n1\[email protected] Saito Akiko M. \n2\n Tanaka Shiro \n3\n Choi Ilseung \n4\n Hidaka Michihiro \n5\n Miyata Yasuhiko \n6\n Inoue Yoshiko \n5\n Yamasaki Satoshi \n7\n Kagoo Toshiya \n8\n Iida Hiroatsu \n6\n Niimi Hiromasa \n9\n Komeno Takuya \n10\n Yoshida Chikamasa \n11\n Tajima Fumihito \n12\n Yamamoto Hideyuki \n6\n Takase Ken \n7\n Ueno Hironori \n8\n Shimomura Takeshi \n9\n Sakai Tatsunori \n5\n Nakashima Yasuhiro \n4\n Yoshida Chikashi \n10\n Kubonishi Shiro \n13\n Sunami Kazutaka \n13\n Yoshida Shinichiro \n14\n Sakurai Aki \n1\n Kaneko Yukihiro \n15\n\n16\n Miyazaki Yoshitsugu \n16\n Nagai Hirokazu \n6\n \n1 \nDepartment of Hematologic Oncology\nNational Hospital Organization Shikoku Cancer Center\nMatsuyama\nJapan\n\n\n2 \nClinical Research Center\nNational Hospital Organization Nagoya Medical Center\nNagoya\nJapan\n\n\n3 \nDepartment of Clinical Biostatistics\nGraduate School of Medicine\nKyoto University\nKyoto\nJapan\n\n\n4 \nDepartment of Hematology\nNational Hospital Organization Kyushu Cancer Center\nFukuoka\nJapan\n\n\n5 \nDepartment of Hematology\nNational Hospital Organization Kumamoto Medical Center\nKumamoto\nJapan\n\n\n6 \nDepartment of Hematology\nNational Hospital Organization Nagoya Medical Center\nNagoya\nJapan\n\n\n7 \nDepartment of Hematology and Clinical Research Institute\nNational Hospital Organization Kyushu Medical Center\nFukuoka\nJapan\n\n\n8 \nDepartment of Hematology and Internal Medicine\nNational Hospital Organization Tokyo Medical Center\nTokyo\nJapan\n\n\n9 \nDepartment of Internal Medicine\nNational Hospital Organization Hiroshima‐Nishi Medical Center\nOtake\nJapan\n\n\n10 \nDepartment of Hematology\nNational Hospital Organization Mito Medical Center\nHigashiibarakigun\nJapan\n\n\n11 \nDepartment of Hematology\nNational Hospital Organization Minami‐Okayama Medical Center\nOkayama\nJapan\n\n\n12 \nStem Cell Transplantation Center\nNational Hospital Organization Yonago Medical Center\nYonago\nJapan\n\n\n13 \nDepartment of Hematology\nNational Hospital Organization Okayama Medical Center\nOkayama\nJapan\n\n\n14 \nDepartment of Hematology\nNational Hospital Organization Nagasaki Medical Center\nOmura\nJapan\n\n\n15 \nDepartment of Bacteriology\nOsaka City University Graduate School of Medicine\nOsaka\nJapan\n\n\n16 \nDepartment of Chemotherapy and Mycoses\nNational Institute of Infectious Diseases\nTokyo\nJapan\n\n* Correspondence\n\nIsao Yoshida, Department of Hematologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.\n\nEmail: [email protected]\n\n28 5 2020 \n8 2020 \n63 8 10.1111/myc.v63.8794 801\n19 11 2019 30 4 2020 04 5 2020 © 2020 The Authors. Mycoses published by Blackwell Verlag GmbHThis 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\nFungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required.\n\nObjective\nWe conducted a multicentre, open‐label, randomised, non‐inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever.\n\nMethods\nPatients with haematological malignancies who developed fever refractory to broad‐spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d).\n\nResults\nObserved overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model‐based estimate of a 4% difference (90% CI, −12% to 20%), did not fulfil the statistical non‐inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3‐4 hypokalaemia‐related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07).\n\nConclusion\nivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non‐inferiority.\n\nantifungal agentschemotherapy‐induced febrile neutropaeniahaematological malignancieshypokalaemiaintravenous itraconazoleliposomal amphotericin Bprobable invasive fungal diseaseprospective randomised controlled trialGrant‐in‐Aid for Clinical Research from the National Hospital Organization 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\n\n\nYoshida \nI \n, \nSaito \nAM \n, \nTanaka \nS \n, et al. Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever\n. Mycoses . 2020 ;63 :794 –801\n. 10.1111/myc.13100 \n32391919 \n\n\n\nClinical Trial Registration: UMIN‐CTR identifier: UMIN000005529\n\n\nhttps://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006558\n==== Body\n1 INTRODUCTION\nFebrile neutropaenia, one of the most serious complications that occur following chemotherapy for haematological malignancies, is caused by bacterial or fungal infections.\n1\n, \n2\n, \n3\n\n\n\nGiven the resistance or breakthrough infections seen with fungi that are resistant to already existing antifungal agents,\n4\n, \n5\n, \n6\n, \n7\n, \n8\n it is increasingly important to select the right antifungal agent for applications such as prophylaxis, empirical treatment and pre‐emptive treatment.\n\nA previous prospective study compared empirical treatment of liposomal amphotericin B (LAmB) with amphotericin B deoxycholate as the control group.\n9\n The results showed that LAmB was equally effective as amphotericin B deoxycholate and more safety. Subsequently, prospective comparative studies between LAmB and voriconazole,\n10\n and LAmB and caspofungin\n11\n were performed, which showed that voriconazole was inferior and caspofungin was non‐inferior to LAmB. Therefore, caspofungin is currently considered the standard of care as empirical therapy. However, there are many reports of breakthrough fungal infections after treatment with echinocandin‐type antifungal agents, such as caspofungin.\n4\n, \n8\n, \n12\n\n\n\nItraconazole (ITCZ) is a triazole antifungal agent with broad‐spectrum activity against Candida, Aspergillus, Trichosporon and mucormycosis. However, the originally developed ITCZ capsule has poor intestinal absorption and the concentrations are not stable but have a high intra‐ and interindividual variability. To overcome this weakness, intravenous itraconazole (ivITCZ) was developed. The results of a prospective, randomised study comparing ivITCZ and the conventionally used intravenous amphotericin B deoxycholate\n13\n concluded that ivITCZ showed similar efficacy and increased safety as empirical fungal therapy.\n\nivITCZ has a broad antifungal spectrum in vitro, including against Aspergillus species, \n14\n and good bioavailability. We hypothesised that ivITCZ, which is non‐inferior to amphotericin B deoxycholate, would have similar efficacy and lower toxicity as compared to LAmB as a control drug. Therefore, we planned a prospective randomised, non‐inferiority study of ivITCZ and LAmB.\n\n2 PATIENTS AND METHODS\nThis multicentre study was approved by the institutional review board of each participating institution. All patients provided written informed consent prior to enrolment. The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to and the appropriate ethical review committee approval has been received.\n\nPatients aged 20‐79 years who received chemotherapy for haematological malignancies were eligible for this study within 30 days. Neutrophil count was less than 500/μL for at least 96 hours in all the patients. Patients who had a fever with an axillary body temperature of more than 37.4°C persisting more than 96 hours after the start of treatment with broad‐spectrum antibacterial drugs were enrolled. Patients with proven invasive fungal disease or confirmed bacterial or viral infection at enrolment, along with a history of fungal infection, were excluded. A prospective randomised controlled trial was conducted with five stratification factors (risk, antifungal prophylaxis, age ≥ 60 years, gender and institution). High‐risk patients were defined as those after allogeneic transplantation or chemotherapy for recurrent acute leukaemia; low risk was defined as otherwise. Only prophylactic administration of amphotericin B syrup, micafungin and miconazole gel was allowed. Registration of such patients was possible if the previous prophylactic antifungal agent was terminated 2 weeks before study enrolment. Details of this are described elsewhere.\n15\n\n\n\nIn the LAmB group, 3.0 mg/kg body weight of LAmB was administered intravenously. If significant weight gain (±10%) occurred for reasons other than fluid retention, the dose was adjusted. In the ivITCZ group, 200 mg of itraconazole was administered as an intravenous infusion. The first five doses were administered at 12‐hour intervals, while they were administered at 24‐hour intervals from the sixth dose onwards.\n\nIn all patients, chest computed tomography (CT), blood culture tests and β‐D‐glucan and galactomannan antigen assays were performed before and after the start of study treatment, and plasma levels of β‐D‐glucan and galactomannan antigen assays were performed weekly and chest CT were performed biweekly thereafter. Blood culture tests were also performed at the end of the study treatment. Based on these results, fungal infection was evaluated using the 2008 updated European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group efficacy criteria.\n16\n\n\n\nThe primary endpoint of this study was the presence or absence of an overall favourable response (OFR). Patients meeting all five of the following criteria were considered to have an overall favourable response. Additionally, cases meeting criteria (2) through (4) in the absence of any baseline infection were also considered to have an overall favourable response.\nSuccessful treatment of baseline infection by the end of the study treatment;\n\nAbsence of breakthrough infection;\n\nSurvival until 7 days after completion of treatment;\n\nNo discontinuation of treatment due to drug‐related toxicity; and\n\nResolution of fever during neutropaenia (axillary temperature ≤ 37.4°C for at least 48 hours).\n\n\n\n\nThe secondary endpoints were as follows:\nSuccessful treatment of baseline infection\n\nDevelopment of breakthrough infection\n\nSurvival until 7 days after completion of treatment\n\nDiscontinuation of treatment due to drug‐related toxicity\n\nResolution of fever during neutropaenia\n\nAdverse events (AEs)\n\n\n\n\nAEs occurring from the start of treatment until 14 days after the end of treatment were assessed for category and worst grade according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0.\nProbable invasive fungal disease.\n16\n\n\n\n\n\n\n2.1 Statistical analysis\nThis study intended to demonstrate the principal hypothesis that ivITCZ is not more than 10% inferior (acceptable range) in terms of OFR compared to treatment with standard LAmB therapy. The sample size needed to demonstrate non‐inferiority with a 5% one‐sided significance level and 90% power was calculated as 395 subjects per group, and a target sample size of 850 subjects was deemed essential in consideration of ineligible cases. Associations between the primary and secondary endpoints and treatment interventions were assessed using Fisher's exact test for superiority. All other statistical tests were two‐sided and interpreted at the 5% significance level.\n\nUpon enrolment, patients were randomly assigned to either group using an electronic data capture and allocation system. The random allocation factors included risk (high or low), prophylactic antifungal treatment (yes or no), study institution, sex and age (age at enrolment <60 years or ≥60 years). High‐risk subjects were defined as allograft patients or patients with recurrent acute leukaemia. All other patients were considered low risk. An academic statistician conducted all analyses using SAS software version 9.4 (SAS Institute).\n\n3 RESULTS\nOne hundred and three patients with a median age of 60 years (range 51‐68 years) were enrolled from 12 centres of the National Hospital Organisation in Japan between March 2011 and February 2015 and randomly assigned to two groups, the LAmB group (53 patients) and the ivITCZ group (50 patients), for the intention‐to‐treat (ITT) analysis (Figure 1). Two of the 53 patients assigned to the LAmB group and one of the 50 assigned to the ivITCZ group discontinued the study due to deviations from the enrolment criteria. Of the two LAmB group patients who were found ineligible, the fever in one of them was of less than 96 hours duration under neutropaenic conditions, while the other patient was found to have blood cultures proven of Candida glabrata at enrolment. The excluded patient in the ivITCZ group showed coagulase‐negative staphylococci on blood culture testing that was performed at the time of study enrolment. Therefore, these patients were disqualified before treatment began and were excluded from the study.\n\nFIGURE 1 Diagram of participant enrolment\n\nApproximately half of all patients were male, over the age of 60 years. About one‐third of all patients were at high risk and were receiving antifungal prophylaxis. The two groups were similar in terms of age at enrolment, gender, risk, prophylactic antifungal treatment and disease extent (Table 1).\n\nTABLE 1 Patient characteristics\n\nCharacteristic\t\tLiposomal Amphotericin B (N = 52)\tIntravenous Itraconazole (N = 50)\tTotal\t\nAge at enrolment (y)\t<60\t25\t22\t47\t\n≥60\t27\t28\t55\t\nSex\tMale\t27\t27\t54\t\nFemale\t25\t23\t48\t\nRisk\tHigh\na\n\n\t13\t15\t28\t\nLow\t39\t35\t74\t\nProphylactic antifungal treatment\tYes\nb\n\n\t18\t14\t32\t\nNo\t34\t36\t70\t\nDisease\tAcute myelogenous leukaemia\t35\t33\t68\t\nAcute lymphoblastic leukaemia\t2\t3\t5\t\nMixed phenotype acute leukaemia\t0\t1\t1\t\nB‐cell non‐Hodgkin lymphoma, multiple myeloma\t9\t9\t18\t\nNatural killer cell/T‐cell lymphoma\t1\t2\t3\t\nHodgkin lymphoma\t2\t0\t2\t\nMyelodysplastic syndrome/Myeloproliferative neoplasm\t0\t1\t1\t\nMyeloproliferative neoplasm\t3\t0\t3\t\nMyelodysplastic syndrome\t0\t1\t1\t\na High‐risk patients were defined as patients after allogeneic transplantation or chemotherapy for recurrent acute leukaemia; low risk was defined as otherwise.\n\nb Only amphotericin B syrup, micafungin and miconazole gel were allowed as prophylactic drugs. For patients who received any of these drugs, registration for participation in this study was allowed if the previous antifungal agent was terminated 2 weeks before the start of study enrolment.\n\nJohn Wiley & Sons, LtdTen patients discontinued treatment due to toxicity of LAmB and five patients discontinued treatment due to toxicity of ivITCZ. The difference between the groups was not statistically significant (19.2% vs 10.0%; P = .26). The study treatment completion rate in the LAmB group was 69.2% (95% CI 54.9%‐81.3%), and that in the ivITCZ group was 80.0% (95% CI 66.3%‐90.0%) (P = .26).\n\nThe main reason for discontinuing study treatment was the toxicity associated with each group's study intervention. Four patients in the ivITCZ group who discontinued study treatment switched to LAmB as alternative systemic antifungal therapy within 7 days of discontinuation. None of the patients in the LAmB group switched to ivITCZ.\n\nThe average number of days of study treatment in the LAmB group was 14.4 days (range 1‐47 days), and the first actual dose administered in this group was 162.6 ± 24.2 mg per dose. The average number of days of study treatment in the ivITCZ group was 14.0 days (range 5‐32 days), with a single dose of 200 mg per dose, with 30% of patients receiving two doses on the first day of treatment.\n\nThe OFR rate was 32.7% in the LAmB group and 36.0% in the ivITCZ group, with a difference of 4% (90% CI, −12% to 20%), which did not meet the statistical criteria for itraconazole non‐inferiority (Table 2). These rates were not related to antifungal prophylaxis or risk. All patients in both groups survived until 7 days after termination of the antifungal treatment. Results were no statistical significance between the two groups for documented breakthrough fungal infections (LAmB vs itraconazole, 3.8% vs 0.0%, P = .50), treatment discontinuation due to drug‐related toxicity (LAmB vs itraconazole, 19.2% vs 10.0%, P = .26) and fever resolution during neutropaenia (LAmB vs itraconazole; 38.5% vs 42.0%, P = .84). There were no baseline fungal infections in either group. Breakthrough infections were observed only in the LAMB group. Of two patients diagnosed with a breakthrough infection, Candida albicans was detected in a blood culture test in one patient and a Candida species was detected in a liver biopsy specimen in the other patient. The former case was probably a result of progression from invasive fungal disease. Five patients who received LAmB were subsequently diagnosed with a probable invasive fungal disease, but none of the patients who received ivITCZ had probable invasive fungal disease (P = .06). Of the five patients diagnosed with probable invasive fungal disease in the LAmB group, CT imaging findings were compatible with fungal infection in all five patients. In both β‐D‐glucan and galactomannan antigen tests, two subjects had higher cut‐off values. CT before the start of the study was performed in 45 cases. There were 39 cases of chest CT, 2 cases of abdominal CT and 2 cases of whole‐body CT. Follow‐up CT was performed in 32 cases. There were 29 cases of chest CT, 1 case of abdominal CT and 2 cases of whole‐body CT. The follow‐up CT in this study remained at about 30%.\n\nTABLE 2 Clinical outcomes\n\nVariables\tLiposomal Amphotericin B(N = 52)\tIntravenous Itraconazole (N = 50)\tDifference in proportions\na\n\n\t90% CI\t95% CI\t\nP‐value\t\nN\t%\tN\t%\t\nOverall favourable response\t17\t32.7\t18\t36.0\t0.04\t−0.12\t0.20\t−0.15\t0.23\t‐\t\nSuccessful treatment of baseline infection by the end of treatment\nb\n\n\t‐\t\t‐\t\t‐\t‐\t‐\t‐\t‐\t‐\t\nAbsence of breakthrough infection\t50\t96.2\t50\t100.0\t0.04\t‐\t‐\t−0.27\t0.34\t.50\t\nSurvival 7 d after termination of antifungal treatment\nc\n\n\t52\t100.0\t50\t100.0\t0\t‐\t‐\t‐\t‐\t1.00\t\nNo discontinuation of antifungal treatment due to drug‐related toxicity\t42\t81.8\t45\t90.0\t0.11\t‐\t‐\t−0.08\t0.30\t.26\t\nFever resolution during neutropenia (axillary temperature ≤ 37.4°C for at least 48 h)\t20\t38.5\t21\t42.0\t0.04\t‐\t‐\t−0.15\t0.23\t.84\t\nDiscontinuation of antifungal treatment due to drug‐related toxicity\t10\t19.2\t5\t10.0\t−0.11\t‐\t‐\t−0.30\t0.08\t.26\t\nProbable invasive fungal disease\t5\t9.6\t0\t0.0\t−0.08\t‐\t‐\t−0.38\t0.23\t.06\t\nNote\nA positive value indicated favourable results for the intravenous itraconazole group. Non‐inferiority of intravenous itraconazole compared with liposomal amphotericin B was concluded if the lower limit of the 90% confidence interval was larger than −0.1.\n\na Adjusted for risk (high or low), prophylactic antifungal treatment (yes or no), sex and age (age at enrolment < 60 y or ≥60 y).\n\nb There were no cases with baseline infections.\n\nc Could not be calculated because all the patients survived.\n\nJohn Wiley & Sons, LtdAEs that occurred between the start of study treatment and 14 days after the end of treatment included hypokalaemia, γ‐glutamyl transferase elevation, alanine transaminase elevation and nausea in the LAmB group, and hypokalaemia, dyspnoea and hypoxaemia in the ivITCZ group (Table 3). The cumulative number of grade 3‐4 AEs in the LAmB and ivITCZ groups was 297 and 248, respectively. The frequency of these events tended to be higher in the LAmB group than in the ivITCZ group (P = .07). The ivITCZ group had five cases of grade 3 dyspnoea and six cases of grade 3 hypoxia. The corresponding number of cases in the LAmB group was two each. The incidence of grade 3 and 4 hypokalaemia was 18 (34.6%) and 11 (21.2%) in the LAmB group and 9 (18.0%) and 5 (10.0%) in the ivITCZ group, respectively. The ivITCZ group had a significantly lower incidence of grades 3‐4 hypokalaemia compared to the LAmB group (P < .01).\n\nTABLE 3 Adverse events\n\n\tLiposomal Amphotericin B Group (n = 52)\tIntravenous Itraconazole Group (n = 50)\t\nGrade 3\tGrade 4\tGrade 3\tGrade 4\t\nN\t%\tN\t%\tN\t%\tN\t%\t\nElevated alkaline phosphatase\t1\t1.92\t0\t0.00\t1\t2.00\t0\t0.00\t\nElevated alanine transaminase\t4\t7.69\t0\t0.00\t0\t0.00\t1\t2.00\t\nElevated aspartate transaminase\t1\t1.92\t0\t0.00\t2\t4.00\t0\t0.00\t\nIncrease in total bilirubin\t2\t3.85\t0\t0.00\t1\t2.00\t1\t2.00\t\nElevated creatinine levels\t2\t3.85\t0\t0.00\t1\t2.00\t0\t0.00\t\nElevated γ‐glutamyltransferase levels\t5\t9.62\t0\t0.00\t2\t4.00\t0\t0.00\t\nHypomagnesemia\t1\t1.92\t0\t0.00\t0\t0.00\t0\t0.00\t\nHypokalaemia\t18\t34.62\t11\t21.15\t9\t18.00\t5\t10.00\t\nHyponatremia\t0\t0.00\t0\t0.00\t0\t0.00\t1\t2.00\t\nChills\t1\t1.92\t0\t0.00\t0\t0.00\t0\t0.00\t\nNausea\t4\t7.69\t0\t0.00\t2\t4.00\t0\t0.00\t\nHeadache\t2\t3.85\t0\t0.00\t0\t0.00\t0\t0.00\t\nDyspnoea\t2\t3.85\t0\t0.00\t5\t10.00\t0\t0.00\t\nHypoxia\t2\t3.85\t0\t0.00\t6\t12.00\t0\t0.00\t\nAllergic reactions/hypersensitivity\t0\t0.00\t1\t1.92\t0\t0.00\t0\t0.00\t\nHypotension\t0\t0.00\t0\t0.00\t0\t0.00\t2\t4.00\t\nNote\nGrade 3‐4 adverse effects, including ventricular arrhythmia, hot flashes, vomiting, cardiac ischaemia/infarction, cardiopulmonary arrest and hypertension did not occur in either group.\n\nJohn Wiley & Sons, Ltd4 DISCUSSION\nThis is the first randomised controlled trial to directly compare LAmB with ivITCZ as empirical antifungal therapy in patients with persistent febrile neutropaenia, although the number of cases assessed was much smaller than what was originally planned. After study commencement, the number of participants did not increase due to factors such as the approval of caspofungin for use in Japan after the start of the study and the limited number of prophylactic antifungal drugs allowed in the protocol. The reason for limiting prophylaxis was due to the fact that itraconazole is an azole antifungal and that fluconazole, which is often used as a prophylactic, is also an azole antifungal. In the protocol at the start of the study, if another antifungal drug was used, registration in the study was only allowed after more than 4 weeks had elapsed since discontinuation of the previous drug, although the protocol was revised to allow patient registration if more than 2 weeks had elapsed from discontinuation of previous antifungal therapy. Nevertheless, the number of cases registered still did not increase adequately. Prior to the start of this study, an interim analysis was planned, with a final analysis with a 4.9% significance level and an interim analysis with a 0.1% significance level. Since the interim analysis was not actually performed, the analysis was performed at a significance level of 5% (corresponding to the 90% CI). At this level of significance, the OFR ratio was 32.7% in the LAmB group and 36.0% in the ivITCZ group, indicating slightly better results in the ivITCZ group (difference in the ratio of 0.04). However, for the determination of non‐inferiority, the lower limit of the 90% CI was −0.12, which was smaller than the preset tolerance (non‐inferiority margin) of −0.10. Hence, the non‐inferiority of ivITCZ was not proved. Successful treatment of baseline infection and resolution of fever during neutropaenia as a component of OFR may have been limiting. The definition of axillary temperature ≤37.4°C for at least 48 hours is too strict that makes it difficult to compare with other studies.\n\nThe overall safety profile tended to be better in the ivITCZ group than in the LAmB group (P = .07). The difference was especially noticeable for hypokalaemia (P < .01). Four patients in the ivITCZ group who discontinued study treatment switched to LAmB within 7 days of discontinuation. The reasons for discontinuation were ineffectiveness of therapy in two cases and AEs excluding hypokalaemia in two cases. Grade 4 hypokalaemia subsequently occurred in three patients switched to LAmB. Therefore, these three patients were counted as grade 4 hypokalaemia in the ivITCZ group. Many of the patients with grade 3‐4 hypokalaemia required potassium supplementation. Further, since oral potassium supplementation was inadequate because of the extremely low levels of potassium, intravenous potassium drips were necessary. Hypokalaemia is a common complication of LAmB therapy, which sometimes triggers severe arrhythmia in patients with diarrhoea. It is one of the most fatal transplant complications in acute graft vs host disease (GVHD) patients, many of whom experience severe diarrhoea. Therefore, avoidance of hypokalaemia is very important in the management of haematological malignancies, including during hematopoietic transplantation.\n\nA meta‐analysis of randomised controlled trials by Chen et al\n17\n reported that ITCZ has a significantly better initial treatment response rate (RR) compared to amphotericin B deoxycholate (RR = 1.33, 95% CI: 1.10‐1.61). In terms of its in vitro antifungal spectrum, amphotericin B shows a broader spectrum of activity than itraconazole; Boogaerts and colleagues reported that both intravenous and oral solutions of ITCZ are as effective and safer than amphotericin B deoxycholate as empirical antifungal therapy in cancer patients with febrile neutropaenia.\n13\n In addition, since the oral solution formulation resulted in a higher blood concentration than the capsule formulation, 65 persons were changed from an injection to an oral solution. In our study, since the ITCZ blood concentration of cases was not measured, only the intravenous formulation was used without switching to the oral solution.\n\nIn the LAmB group in our study, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Further, there was no significant difference between groups in terms of probable invasive fungal disease or breakthrough infection. Although the small sample size is a study limitation, it is noteworthy that there was no case proven to be highly likely to be invasive mycosis in the ivITCZ group.\n\nSome reports have described resistance to LAmB,\n18\n caspofungin\n4\n and micafungin,\n8\n, \n12\n, \n19\n which are classified as echinocandins, and itraconazole\n14\n and voriconazole,\n5\n, \n6\n, \n7\n which are classified as azoles. Increasing the frequency of use of one type of antifungal agent might increase the resistance to various fungi. Increased breakthrough infections due to resistance might lead to fatal outcomes. The use of different types of antifungals that are nearly as effective as empirical treatments might, on the other hand, reduce fungal resistance.\n\nAlthough the differences between the groups were not significant in this study, the treatment discontinuation rate and AE frequency due to drug‐related toxicity were lower in the ivITCZ group than in the LAmB group, indicating its safety impact. Further, the toxicity of ivITCZ was at least not greater than that of LAmB. Hence, although we were unable to prove the non‐inferiority of ivITCZ as compared to LAmB, given that LAmB is more expensive than ivITCZ, our results suggest that it might be worth considering using ivITCZ as an alternative antifungal agent in the empirical treatment of patients with haematological malignancies with persistent fever and neutropaenia.\n\nCONFLICT OF INTEREST\nIY reports personal fees from Celgene, Mundipharma, Bristol‐Myers Squib, Shire Japan, Janssen Pharmaceuticals, Mochida Pharmaceutical Co., Ltd., MSD KK, Takeda Pharmaceutical Co. Ltd. and Taiho Pharmaceutical, and grants and personal fees from Kyowa Hakko Kirin Co. and Chugai Pharmaceutical Co. that were not related to the submitted work. MH reports grants from Chugai Pharmaceutical Co. that were not related to the submitted work. YM reports personal fees from Janssen Pharmaceuticals that were not related to the submitted work. CY reports personal fees from Sumitomo Dainippon Pharma Co., Ltd., and Janssen Pharmaceutical KK that were not related to the submitted work. KS reports grants from the National Hospital Organization during the conduct of the study, grants from Novartis, GlaxoSmithKline, Janssen Pharmaceutical, AbbVie Inc, Sanofi, MSD KK, Alexion Pharmaceuticals and Daiichi Sankyo, and grants and personal fees from Takeda Pharmaceutical, Bristol‐Myers Squibb, Ono pharmaceutical and Celgene that were not related to the submitted work. SY reports grants from Kyowa Kirin Co., and Chugai Pharmaceutical, and personal fees from MSD KK that were not related to the submitted work. YK reports grants from the Research Program on Emerging and Re‐emerging Infectious Diseases from the Japan Agency for Medical Research and Development (AMED), Grant‐in‐Aid for Scientific Research (C) from the Japan Society for the Promotion of Science and Pfizer Academic Contributions, as well as personal fees from MSD KK, Meiji Seika Pharma Co. Ltd., Pfizer Japan Inc, Astellas Pharma Inc and Biofermin Pharmaceutical Co. Ltd. that were not related to the submitted work. HN reports grants and personal fees from Janssen Pharmaceutical KK, Celgene Corporation, Mundipharma KK, Bayer Yakuhin Ltd., Takeda Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., Bristol‐Myers Squibb, Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc, Zenyaku Kogyo Co., Ltd., AstraZeneca PLC and SymBio Pharmaceuticals Ltd., grants from AbbVie GK, Solasia Pharma KK, HUYA Bioscience International, Otsuka Pharmaceutical Co., Ltd. and IQVIA Services Japan KK, and personal fees from Roche Ltd. and Sanofi KK that were not associated with the submitted work. The other authors have nothing to disclose.\n\nAUTHOR CONTRIBUTIONS\nIY involved in the conception, design and funding acquisition. IY and AMS involved in the protocol writing. ST performed the statistical analysis design. IY, IC, MH, YM, YI, SY, TK, HI, HN, TK, CY, FT, HY, KT, HU, TS, TS, YN, CY, SK, KS, SY, AS and HN involved in the provision of study materials or patients. IY, AMS, IC, MH, YM, YI, SY, TK, HI, HN, TK, CY, FT, HY, KT, HU, TS, TS, YN, CY, SK, KS, SY, AS and HN involved in the provision or collection of data. IY, AMS and ST performed the data analysis and interpretation. YK and YM involved in the evaluation of fungi. IY, AMS and ST involved in the manuscript writing. All authors performed the final approval of the manuscript.\n\nSupporting information\nSupplementary Material\n\nClick here for additional data file.\n\n ACKNOWLEDGEMENTS\nThe authors would like to thank Dr Yasunobu Abe (National Hospital Organization Kyushu Cancer Center) for recruiting patients for this trial. The authors are grateful to all the patients, families, nurses and physicians who participated in this study. The authors would also like to show their appreciation to the independent monitoring committee members, Drs. Kazuo Tamura (Fukuoka University hospital), Yoshinobu Maeda (Okayama University hospital) and Koji Izutsu (National Cancer Center hospital). This study was supported by a Grant‐in‐Aid for Clinical Research from the National Hospital Organization.\n==== Refs\nREFERENCES\n1 \n\nPannuti \nC \n, \nGingrich \nR \n, \nPfaller \nMA \n, \nKao \nC \n, \nWenzel \nRP \n. Nosocomial pneumonia in patients having bone marrow transplant. Attributable mortality and risk factors\n. Cancer . 1992 ;69 :2653 ‐2662\n.1315207 \n2 \n\nAndriole \nVT \n. Infections with Aspergillus species\n. Clin Infect Dis . 1993 ;17 (Suppl 2 ):S481 ‐S486\n.8274614 \n3 \n\nVartivarian \nSE \n, \nAnaissie \nEJ \n, \nBodey \nGP \n. Emerging fungal pathogens in immunocompromised patients: classification, diagnosis, and management\n. Clin Infect Dis . 1993 ;17 (Suppl 2 ):S487 ‐S491\n.8274615 \n4 \n\nGoodman \nD \n, \nPamer \nE \n, \nJakubowski \nA \n, \nMorris \nC \n, \nSepkowitz \nK \n. Breakthrough trichosporonosis in a bone marrow transplant recipient receiving caspofungin acetate\n. Clin Infect Dis . 2002 ;35 :E35 ‐E36\n.12115115 \n5 \n\nMarty \nFM \n, \nCosimi \nLA \n, \nBaden \nLR \n. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem‐cell transplants\n. N Engl J Med . 2004 ;350 :950 ‐952\n.14985500 \n6 \n\nSiwek \nGT \n, \nDodgson \nKJ \n, \nde Magalhaes‐Silverman \nM \n, et al. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis\n. Clin Infect Dis . 2004 ;39 :584 ‐587\n.15356827 \n7 \n\nVigouroux \nS \n, \nMorin \nO \n, \nMoreau \nP \n, et al. Zygomycosis after prolonged use of voriconazole in immunocompromised patients with hematologic disease: attention required\n. Clin Infect Dis . 2005 ;40 :e35 ‐e37\n.15712069 \n8 \n\nMatsue \nK \n, \nUryu \nH \n, \nKoseki \nM \n, \nAsada \nN \n, \nTakeuchi \nM \n. Breakthrough trichosporonosis in patients with hematologic malignancies receiving micafungin\n. Clin Infect Dis . 2006 ;42 :753 ‐757\n.16477548 \n9 \n\nWalsh \nTJ \n, \nFinberg \nRW \n, \nArndt \nC \n, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group\n. N Engl J Med . 1999 ;340 :764 ‐771\n.10072411 \n10 \n\nWalsh \nTJ \n, \nPappas \nP \n, \nWinston \nDJ \n, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever\n. N Engl J Med . 2002 ;346 :225 ‐234\n.11807146 \n11 \n\nWalsh \nTJ \n, \nTeppler \nH \n, \nDonowitz \nGR \n, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia\n. N Engl J Med . 2004 ;351 :1391 ‐1402\n.15459300 \n12 \n\nKimura \nM \n, \nAraoka \nH \n, \nYamamoto \nH \n, et al. Micafungin breakthrough fungemia in patients with hematological disorders\n. Antimicrob Agents Chemother . 2018 ;62 :e02183 ‐e12117\n.29530846 \n13 \n\nBoogaerts \nM \n, \nWinston \nDJ \n, \nBow \nEJ \n, et al. Beule K. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad‐spectrum antibacterial therapy. A randomized, controlled trial\n. Ann Intern Med . 2001 ;135 :412 ‐422\n.11560454 \n14 \n\nPfaller \nMA \n, \nBoyken \nL \n, \nHollis \nRJ \n, \nMesser \nSA \n, \nTendolkar \nS \n, \nDiekema \nDJ \n. In vitro susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species to itraconazole: global survey of 9,359 isolates tested by clinical and laboratory standards institute broth microdilution methods\n. J Clin Microbiol . 2005 ;43 :3807 ‐3810\n.16081915 \n15 \n\nYoshida \nI \n.Multi‐centre prospective randomized trial intravenous itraconazole versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia (ILEAN study); university hospital medical information network clinical trial registry (UMIN000005529)\n. 2011 \nhttps://upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000006558. Accessed November 5, 2019\n16 \n\nDe Pauw \nB \n, \nWalsh \nTJ \n, \nDonnelly \nJP \n, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group\n. Clin Infect Dis . 2008 ;46 :1813 ‐1821\n.18462102 \n17 \n\nChen \nK \n, \nWang \nQ \n, \nPleasants \nRA \n, et al. Empirical treatment against invasive fungal diseases in febrile neutropenic patients: a systematic review and network meta‐analysis\n. BMC Infect Dis . 2017 ;17 :159 .28219330 \n18 \n\nItakusu \nK \n, \nInoue \nT \n, \nAbe \nM \n, et al. Acute myeloid leukemia with sudden onset bilateral lower extremity paralysis caused by disseminated mucormycosis following unrelated bone marrow transplantation\n. Rinsho Ketsueki . 2019 ;60 :17 ‐21\n.30726818 \n19 \n\nMorita \nK \n, \nHonda \nA \n, \nKoya \nJ \n, et al. Three cases of candida fermentati fungemia following hematopoietic stem cell transplantation\n. J Infect Chemother . 2018 ;24 :576 ‐578\n.29371065\n\n",
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"issn_linking": "0933-7407",
"issue": "63(8)",
"journal": "Mycoses",
"keywords": "antifungal agents; chemotherapy-induced febrile neutropaenia; haematological malignancies; hypokalaemia; intravenous itraconazole; liposomal amphotericin B; probable invasive fungal disease; prospective randomised controlled trial",
"medline_ta": "Mycoses",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D064146:Chemotherapy-Induced Febrile Neutropenia; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D055815:Young Adult",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "794-801",
"pmc": null,
"pmid": "32391919",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "29530846;15356827;11807146;11560454;15459300;8274615;14985500;10072411;30726818;15712069;16477548;18462102;12115115;29371065;16081915;8274614;1315207;32391919;28219330",
"title": "Intravenous itraconazole compared with liposomal amphotericin B as empirical antifungal therapy in patients with neutropaenia and persistent fever.",
"title_normalized": "intravenous itraconazole compared with liposomal amphotericin b as empirical antifungal therapy in patients with neutropaenia and persistent fever"
}
|
[
{
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{
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Blood alkaline phosphatase increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic product effect incomplete",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gamma-glutamyltransferase increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hyponatraemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood creatinine increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aspartate aminotransferase increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypoxia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypokalaemia",
"reactionmeddraversionpt": "23.1",
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},
{
"reactionmeddrapt": "Blood bilirubin increased",
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},
{
"reactionmeddrapt": "Dyspnoea",
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}
],
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},
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"literaturereference": "INTRAVENOUS ITRACONAZOLE COMPARED WITH LIPOSOMAL AMPHOTERICIN B AS EMPIRICAL ANTIFUNGAL THERAPY IN PATIENTS WITH NEUTROPAENIA AND PERSISTENT FEVER. MYCOSES. 2020?63:794-801.",
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"qualification": null,
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},
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},
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},
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}
] |
{
"abstract": "The study aimed to test whether directives on opioid prescribing released by the Veterans Health Administration (VHA) or the Food and Drug Administration (FDA) had an impact on prescribing among VHA providers.\n\n\n\nWe used the VHA's linked pharmacy and patient medical records database to identify new prescriptions written for propoxyphene, fentanyl, and controlled release (CR) oxycodone between 1/1/2000 and 12/31/2009. We plotted the monthly proportion of these prescriptions that complied with components of four specific safety alerts or directives for these substances issued by the VHA or FDA between 1/1/2001 and 12/31/2008. We modeled compliance using interrupted time series analysis and a generalized additive model with the addition of an indicator variable to flag prescriptions that followed the directive's release date.\n\n\n\nA total of 32.2 million new prescriptions for fentanyl, oxycodone CR, and propoxyphene were written for VHA patients meeting inclusion criteria. Compliance with guidelines in the directives increased steadily throughout the entire study period, with no clinically meaningful inflection point near the date of each directive's release. Generalized additive modeling and interrupted time series analysis found that the indicator flag slightly improved the fit of the data, but visual inspection of the plots revealed no change at a level of practical significance.\n\n\n\nWhile prescribing compliance increased throughout the period, release of FDA and VHA alerts and guidelines did not appear to contribute to this change. Given the fivefold increase in the rate of drug-related overdose deaths since 1990, identifying effective methods to communicate safety messages and change prescriber behavior remains a priority for future work. Copyright © 2016 John Wiley & Sons, Ltd.",
"affiliations": "Harvard Injury Control Research Center, Harvard School of Public Health, Boston, MA, USA.;VA Boston Healthcare System, Massachusetts Area Veterans Research and Information Center (MAVERIC), Boston, MA, USA.;VA Boston Healthcare System, Massachusetts Area Veterans Research and Information Center (MAVERIC), Boston, MA, USA.;VA Boston Healthcare System, Massachusetts Area Veterans Research and Information Center (MAVERIC), Boston, MA, USA.;VA Boston Healthcare System, Massachusetts Area Veterans Research and Information Center (MAVERIC), Boston, MA, USA.;Harvard Injury Control Research Center, Harvard School of Public Health, Boston, MA, USA.",
"authors": "Barber|Catherine|C|;Gagnon|David|D|;Fonda|Jennifer|J|;Cho|Kelly|K|;Hermos|John|J|;Miller|Matthew|M|",
"chemical_list": "D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D010098:Oxycodone; D011431:Dextropropoxyphene; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1002/pds.4066",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "26(1)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "opioid analgesics; pharmacoepidemiology; physicians; poisoning; prescribing patterns",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000701:Analgesics, Opioid; D016208:Databases, Factual; D003692:Delayed-Action Preparations; D011431:Dextropropoxyphene; D005283:Fentanyl; D019983:Guideline Adherence; D006801:Humans; D065186:Interrupted Time Series Analysis; D008962:Models, Theoretical; D010098:Oxycodone; D017410:Practice Guidelines as Topic; D010818:Practice Patterns, Physicians'; D014481:United States; D014493:United States Department of Veterans Affairs",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "40-46",
"pmc": null,
"pmid": "27530106",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Assessing the impact of prescribing directives on opioid prescribing practices among Veterans Health Administration providers.",
"title_normalized": "assessing the impact of prescribing directives on opioid prescribing practices among veterans health administration providers"
}
|
[
{
"companynumb": "US-JNJFOC-20170120422",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "019813",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugindication": "PAIN",
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"drugrecurreadministration": "3",
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"drugtreatmentduration": null,
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"medicinalproduct": "FENTANYL."
}
],
"patientagegroup": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Accidental overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BARBER C, GAGNON D, FONDA J, CHO K, HERMOS J, MILLER M. ASSESSING THE IMPACT OF PRESCRIBING DIRECTIVES ON OPIOID PRESCRIBING PRACTICES AMONG VETERANS HEALTH ADMINISTRATION PROVIDERS.. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY 2017;26/1:40-46.",
"literaturereference_normalized": "assessing the impact of prescribing directives on opioid prescribing practices among veterans health administration providers",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170125",
"receivedate": "20170125",
"receiver": {
"receiverorganization": "FDA",
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170428"
}
] |
{
"abstract": "An 85-year-old male presented with 1-year history of a right breast mass. Needle biopsy of the mass revealed diffuse proliferation of large lymphoid cells that were positive for CD20, BCL2, BCL6, and MUM1 and negative for CD5, CD10, MYC, and EBER. The patient was diagnosed as having diffuse large B-cell lymphoma, a type of primary breast lymphoma (PBL). Sex hormone imbalance, which causes conditions such as gynecomastia, is associated with PBL development in males. Estramustine is a nitrogen mustard moiety linked to estradiol. For 5 years, the patient underwent estramustine therapy for treating prostate cancer. Our case suggests an important role of estrogen in PBL development.",
"affiliations": "Hematology, University of Occupational and Environmental Health.;Hematology, University of Occupational and Environmental Health.;Hematology, University of Occupational and Environmental Health.;Hematology, University of Occupational and Environmental Health.;Hematology, University of Occupational and Environmental Health.;Hematology, University of Occupational and Environmental Health.;Pathology and Cell Biology, University of Occupational and Environmental Health.;Hematology, University of Occupational and Environmental Health.",
"authors": "Goto|Midori|M|;Kitamura|Noriaki|N|;Tanaka|Aya|A|;Katsuragi|Takefumi|T|;Higashi|Takehiro|T|;Morimoto|Hiroaki|H|;Shimajiri|Shohei|S|;Tsukada|Junichi|J|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D004961:Estramustine",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.2411",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Diffuse large B-cell lymphoma; Estramustine; Male; Primary breast lymphoma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal; D001943:Breast Neoplasms; D004961:Estramustine; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011471:Prostatic Neoplasms",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "2411-2413",
"pmc": null,
"pmid": "29332876",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary breast diffuse large B-cell lymphoma developing subsequent to estramustine therapy for prostate cancer.",
"title_normalized": "primary breast diffuse large b cell lymphoma developing subsequent to estramustine therapy for prostate cancer"
}
|
[
{
"companynumb": "JP-PFIZER INC-2018036324",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESTRAMUSTINE PHOSPHATE"
},
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROSTATE CANCER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"medicinalproduct": "ESTRAMUSTINE PHOSPHATE"
}
],
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"patientonsetage": "85",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": "54",
"reaction": [
{
"reactionmeddrapt": "Diffuse large B-cell lymphoma",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Second primary malignancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GOTO, M.. PRIMARY BREAST DIFFUSE LARGE B-CELL LYMPHOMA DEVELOPING SUBSEQUENT TO ESTRAMUSTINE THERAPY FOR PROSTATE CANCER. THE JAPANESE JOURNAL OF CLINICAL HEMATOLOGY. 2017?58(12):2411-2413",
"literaturereference_normalized": "primary breast diffuse large b cell lymphoma developing subsequent to estramustine therapy for prostate cancer",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180316",
"receivedate": "20180129",
"receiver": {
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},
"reporttype": "1",
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"safetyreportversion": 5,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Rheumatoid arthritis (RA) is a chronic, erosive, symmetrical inflammatory disease that can progress to synovial destruction, severe disability and premature mortality. Immunotherapies, while beneficial, can cause significant adverse events. Three patients with RA treated in our facility with hyperbaric oxygen (HBO₂) for unrelated diagnoses all reported significant but unanticipated improvement in RA-related pain, increased activity and improved sleeping patterns. Two improved while continuing traditional RA medications; the other patient had all RA meds held due to cancer and postoperative wound healing problems. The significant symptomatic improvement in these three patients led us to hypothesize that HBO₂ for patients with RA may result in decreased joint pain, increased activity level, improvement in sleeping patterns and possibly a decreased need for standard rheumatologic medications, effectively reducing or avoiding the effects of immunosuppression. A clinical trial is planned to objectively assess these findings.",
"affiliations": "David Grant Medical Center (DGMC), 101 Bodin Circle, Travis Air Force Base, CA U.S.;David Grant Medical Center (DGMC), 101 Bodin Circle, Travis Air Force Base, CA U.S.;David Grant Medical Center (DGMC), 101 Bodin Circle, Travis Air Force Base, CA U.S.;David Grant Medical Center (DGMC), 101 Bodin Circle, Travis Air Force Base, CA U.S.",
"authors": "Slade|John B|JB|;Potts|Mary V|MV|;Flower|Alan M|AM|;Sky|Karen M||;Sit|Michelle T|MT|;Schmidt|Thomas W|TW|",
"chemical_list": "D018501:Antirheumatic Agents",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1066-2936",
"issue": "43(4)",
"journal": "Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc",
"keywords": "hyperbaric oxygen; rheumatoid arthritis",
"medline_ta": "Undersea Hyperb Med",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D018771:Arthralgia; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D008297:Male; D008875:Middle Aged; D059408:Pain Management",
"nlm_unique_id": "9312954",
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"pages": "467-472",
"pmc": null,
"pmid": "28763177",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pain improvement in rheumatoid arthritis with hyperbaric oxygen: report of three cases.",
"title_normalized": "pain improvement in rheumatoid arthritis with hyperbaric oxygen report of three cases"
}
|
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] |
{
"abstract": "Fascioliasis is caused by the trematode liver fluke Fasciola hepatica. Humans are accidental hosts getting infected after ingesting contaminated plants or water. 90 million people in 75 nations are at risk of infection with F hepatica. Immunosuppressed patients are higher risk of acquiring infection and may present with atypical manifestations. Patients can present with hepatic involvement, biliary features or a combination of both. Confirmation of the diagnosis is by demonstration of live parasites or eggs in bile or feces, serology (immunoelectrophoresis, indirect immunofluorescence, indirect hemagglutination), ELISA, typical imaging findings or a combination of any of the above. The drug of choice for treatment is triclabendazole. Fascioliasis should always be considered as a possibility in post-LT patients with findings of hepatobiliary disorder from endemic areas. Unfamiliarity with this infection in non-endemic areas often eludes prompt diagnosis thereby increasing the morbidity. We report the first case of fascioliasis in a pediatric liver transplant recipient leading to graft loss and mortality.",
"affiliations": "Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, India.;Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, India.;Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, India.;Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, India.;Department of Infectious Diseases, Gleneagles Global Health City, Chennai, India.;Institute of Liver Disease and Transplantation, Dr. Rela Institute and Medical Centre, Bharat Institute of Higher Education and Research, Chennai, India.",
"authors": "Kelgeri|Chaya|C|;Valamparampil|Joseph|J|;Shanmugam|Naresh|N|;Srinivas Reddy|Mettu|M|;Swaminathan|Subramanian|S|;Rela|Mohamed|M|",
"chemical_list": "D003287:Contrast Media; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13521",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(6)",
"journal": "Pediatric transplantation",
"keywords": "\nFasciola hepatica\n; graft loss; liver transplantation; parasitic infection",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000818:Animals; D002648:Child; D002761:Cholangitis; D003287:Contrast Media; D058625:End Stage Liver Disease; D005210:Fasciola hepatica; D005211:Fascioliasis; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007194:India; D016031:Liver Transplantation; D009018:Morocco; D009173:Mycophenolic Acid; D033581:Stem Cell Transplantation; D016559:Tacrolimus; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13521",
"pmc": null,
"pmid": "31240781",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "An unusual cause of graft loss in pediatric liver transplant recipient-Fasciola hepatica.",
"title_normalized": "an unusual cause of graft loss in pediatric liver transplant recipient fasciola hepatica"
}
|
[
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},
{
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},
{
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},
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"reactionmeddrapt": "Klebsiella infection",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Graft loss",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KELGERI C, VALAMPARAMPIL J, SHANMUGAM N, REDDY MS, SWAMINATHAN S, RELA M. AN UNUSUAL CAUSE OF GRAFT LOSS IN PEDIATRIC LIVER TRANSPLANT RECIPIENT-FASCIOLA HEPATICA. PEDIATRIC TRANSPLANTATION. 2019?23 (6):E13521",
"literaturereference_normalized": "an unusual cause of graft loss in pediatric liver transplant recipient fasciola hepatica",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20190916",
"receivedate": "20190916",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16808916,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191005"
}
] |
{
"abstract": "OBJECTIVE\nTo assess the effectiveness of nebulized fentanyl used for analgesia in renal colic.\n\n\nMETHODS\nThis research was planned as a randomized, blinded study in which prospectively collected data were analyzed retrospectively to compare nebulized and intravenous (iv) fentanyl therapies. Patients with renal colic with 'moderate' or worse pain on a four-point verbal pain score (VPS) or with pain of 20mm or above on a 100-mm visual analogue score (VAS) at time of presentation were randomized into iv fentanyl (n=62) or nebulized fentanyl (n=53) study groups. Decreases in VAS and VPS scores at 15 and 30min compared to baseline, rescue analgesia requirements and side-effects between the groups were compared.\n\n\nRESULTS\nBoth iv fentanyl and nebulized fentanyl provided effective analgesia in renal colic patients at the end of 30min. However, iv fentanyl provided more rapid and more effective analgesia than nebulized fentanyl. Patients receiving iv fentanyl had lower rescue analgesia requirements than those receiving nebulized fentanyl (37.1% vs 54.7%), although the difference was not statistically significant (p=0.058). In addition, side-effects were more common in the iv fentanyl group compared to the nebulized fentanyl group (22.1% vs 9.4%), although the difference was also not significant (p=0.058).\n\n\nCONCLUSIONS\nNebulized fentanyl provides effective analgesia in patients with renal colic. However, iv fentanyl exhibits more rapid and more powerful analgesic effects than nebulized fentanyl. Nonetheless, due to its ease of use and few potential risks and side-effects the nebulized form can be used as an alternative in renal colic.",
"affiliations": "Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey. Electronic address: [email protected].",
"authors": "Imamoglu|Melih|M|;Aygun|Ali|A|;Bekar|Omer|O|;Erdem|Erkan|E|;Cicek|Mustafa|M|;Tatli|Ozgur|O|;Karaca|Yunus|Y|;Sahin|Aynur|A|;Turkmen|Suha|S|;Turedi|Suleyman|S|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2017.01.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "35(5)",
"journal": "The American journal of emergency medicine",
"keywords": "Acute renal colic; Analgesics; Fentanyl; Renal colic; Ureteral colic",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000328:Adult; D000701:Analgesics, Opioid; D004311:Double-Blind Method; D005260:Female; D005283:Fentanyl; D006801:Humans; D008297:Male; D009330:Nebulizers and Vaporizers; D010146:Pain; D059408:Pain Management; D016032:Randomized Controlled Trials as Topic; D056844:Renal Colic; D012189:Retrospective Studies; D016896:Treatment Outcome; D064232:Visual Analog Scale",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "757-763",
"pmc": null,
"pmid": "28119014",
"pubdate": "2017-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "A retrospective analysis of nebulized versus intravenous fentanyl for renal colic.",
"title_normalized": "a retrospective analysis of nebulized versus intravenous fentanyl for renal colic"
}
|
[
{
"companynumb": "TR-DEPOMED, INC.-TR-2017DEP001639",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "055",
"drugauthorizationnumb": "022569",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
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"medicinalproduct": "FENTANYL."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "022569",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANALGESIC THERAPY",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FENTANYL."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Respiratory distress",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "IMAMOGLU M, AYGUN A, BEKAR O, ERDEM E, CICEK M, TATLI O, ET AL.. A RETROSPECTIVE ANALYSIS OF NEBULIZED VERSUS INTRAVENOUS FENTANYL FOR RENAL COLIC. AMERICAN JOURNAL OF EMERGENCY MEDICINE. 2017;35(5):757-763",
"literaturereference_normalized": "a retrospective analysis of nebulized versus intravenous fentanyl for renal colic",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20170818",
"receivedate": "20170818",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
}
] |
{
"abstract": "Microsporidiosis is an emerging opportunistic infection in immunocompromised patients. We report a case of fatal disseminated Anncaliia algerae infection in a profoundly immunosuppressed pancreas and kidney transplant recipient.",
"affiliations": "Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.;Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.;Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.;William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.;William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.;Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.;Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia.;Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.",
"authors": "Anderson|Neil W|NW|;Muehlenbachs|Atis|A|;Arif|Sana|S|;Bruminhent|Jackrapong|J|;Deziel|Paul J|PJ|;Razonable|Raymund R|RR|;Wilhelm|Mark P|MP|;Metcalfe|Maureen G|MG|;Qvarnstrom|Yvonne|Y|;Pritt|Bobbi S|BS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofz285",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2328-8957",
"issue": "6(7)",
"journal": "Open forum infectious diseases",
"keywords": "Brachiola; Nosema; immunocompromised; microspo-ridiosis; microsporidia; opportunistic",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofz285",
"pmc": null,
"pmid": "31304191",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "12037040;15229306;16004367;16020683;16081959;16792818;20958855;22709509;27704013;30014835;9634430",
"title": "A Fatal Case of Disseminated Microsporidiosis Due to Anncaliia algerae in a Renal and Pancreas Allograft Recipient.",
"title_normalized": "a fatal case of disseminated microsporidiosis due to anncaliia algerae in a renal and pancreas allograft recipient"
}
|
[
{
"companynumb": "US-DRREDDYS-USA/USA/20/0123512",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "090509",
"drugbatchnumb": "UNKNOWN",
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"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
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"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": null,
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"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
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"drugindication": "APLASTIC ANAEMIA",
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"medicinalproduct": "PREDNISONE."
},
{
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"activesubstancename": "CYCLOSPORINE"
},
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"medicinalproduct": "CICLOSPORIN"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
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"drugbatchnumb": "UNKNOWN",
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
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"activesubstancename": "METHYLPREDNISOLONE"
},
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"medicinalproduct": "METHYLPREDNISOLONE."
},
{
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"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": null,
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"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": "5",
"patientonsetage": "60",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cytomegalovirus chorioretinitis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aspergillus infection",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Eschar",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Herpes zoster cutaneous disseminated",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia influenzal",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia cytomegaloviral",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pneumonia fungal",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin necrosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Atypical mycobacterial pneumonia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tongue ulceration",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Microsporidia infection",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Sinusitis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Atypical mycobacterial infection",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pancytopenia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ANDERSON NW, MUEHLENBACHS A, ARIF S, BRUMINHENT J, DEZIEL PJ, RAZONABLE RR ET AL. A FATAL CASE OF DISSEMINATED MICROSPORIDIOSIS DUE TO ANNCALIIA ALGERAE IN A RENAL AND PANCREAS ALLOGRAFT RECIPIENT. OPEN FORUM INFECTIOUS DISEASES. 2019? 6(7):ARTICLE NUMBER OFZ285. DOI: 10.1093/OFID/OFZ285.",
"literaturereference_normalized": "a fatal case of disseminated microsporidiosis due to anncaliia algerae in a renal and pancreas allograft recipient",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201013",
"receivedate": "20200603",
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20210113"
},
{
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"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
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},
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"medicinalproduct": "METHYLPREDNISOLONE."
},
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},
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},
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},
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] |
{
"abstract": "Diffuse large B-cell lymphomas (DLBCL) with MYC translocations combined with translocations involving BCL-2 or BCL-6 are referred to as double-hit lymphomas. These lymphomas are generally refractory to currently available therapies and have a poor prognosis. Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of DLBCL, which shares clinical, pathologic, and genetic similarities with classical Hodgkin's lymphoma. Unlike DLBCL, rearrangements involving MYC, BCL-2, and BCL-6 are typically absent in PMBL. We present a patient with PMBL who had increased gene copy numbers of MYC and BCL-2 along with increased protein expression of BCL-2 (c-Myc expression was about 15%-20% by immunostain). The disease was refractory to standard and salvage chemotherapies. The lymphoma, however, responded to brentuximab vedotin, a CD30-directed chemoimmunoconjugate.",
"affiliations": "Department of Internal Medicine, Texas Tech University of Health Sciences Center, Texas, USA.;Department of Pathology, Texas Tech University of Health Sciences Center, Texas, USA.;Division of Hematology/Oncology, Department of Internal Medicine, Texas Tech University of Health Sciences Center, El Paso, Texas, USA.;Division of Hematology/Oncology, Department of Internal Medicine, Texas Tech University of Health Sciences Center, El Paso, Texas, USA.",
"authors": "Badri|Nabeel|N|;Ngamdu|Kyari Sumayin|KS|;Torabi|Alireza|A|;Guar|Sumit|S|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D017730:Ki-1 Antigen; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D000079963:Brentuximab Vedotin",
"country": "India",
"delete": false,
"doi": "10.4103/jcrt.JCRT_696_16",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "16(1)",
"journal": "Journal of cancer research and therapeutics",
"keywords": "B-cell lymphomas 2; B-cell lymphomas 6; MYC; brentuximab; diffuse large B-cell lymphomas; primary mediastinal B-cell lymphoma",
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D000079963:Brentuximab Vedotin; D005260:Female; D006801:Humans; D017730:Ki-1 Antigen; D016403:Lymphoma, Large B-Cell, Diffuse; D008479:Mediastinal Neoplasms; D009154:Mutation; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "183-185",
"pmc": null,
"pmid": "32362635",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Brentuximab vedotin demonstrates an objective response in a patient with refractory CD30+ primary mediastinal B-cell lymphoma.",
"title_normalized": "brentuximab vedotin demonstrates an objective response in a patient with refractory cd30 primary mediastinal b cell lymphoma"
}
|
[
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"patient": {
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{
"abstract": "Papillary carcinoma of the breast is a rare type of breast malignancy, making up less than 2% of breast cancers, and only some are encapsulated papillary carcinoma. Usually, EPC are low-grade luminal like tumors. The authors report a case of a 50-year-old female with the diagnosis of an unusual high-grade triple negative encapsulated papillary carcinoma with an area of invasive papillary carcinoma and negative axillary lymph nodes. Considering its rarity, the description of this case and its clinical management are important in order to better understand this entity and choose the best clinical approach.",
"affiliations": "Co-primeiro autor. Breast Unit. General Surgery Department. Hospital São Bernardo. Centro Hospitalar de Setúbal. Setúbal. Portugal.;Co-primeiro autor. Breast Unit. General Surgery Department. Hospital São Bernardo. Centro Hospitalar de Setúbal. Setúbal. Portugal.;Breast Unit. General Surgery Department. Hospital São Bernardo. Centro Hospitalar de Setúbal. Setúbal. Portugal.;Breast Unit. General Surgery Department. Hospital São Bernardo. Centro Hospitalar de Setúbal. Setúbal. Portugal.",
"authors": "De Sousa|Xavier|X|;Ferreira|Pedro Santos|PS|;Martins|Isabel Lopes|IL|;Rigueira|Manuel Vitor|MV|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.11737",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": null,
"journal": "Acta medica portuguesa",
"keywords": "Breast Neoplasms; Carcinoma, Papillary; Lymph Nodes",
"medline_ta": "Acta Med Port",
"mesh_terms": null,
"nlm_unique_id": "7906803",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33159719",
"pubdate": "2019-06-17",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An Unusual Case of Invasive Encapsulated Papillary Carcinoma of the Breast: A Case Report.",
"title_normalized": "an unusual case of invasive encapsulated papillary carcinoma of the breast a case report"
}
|
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"medicinalproduct": "DOCETAXEL."
}
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}
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},
"primarysourcecountry": "PT",
"receiptdate": "20201103",
"receivedate": "20201103",
"receiver": {
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},
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},
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"seriousnesscongenitalanomali": null,
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}
] |
{
"abstract": "Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions.",
"affiliations": "Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Department of Pediatrics, Yokohama City University Hospital, Yokohama, Japan.;BC Children's Hospital Research Institute, Vancouver, BC, Canada.;BC Children's Hospital Research Institute, Vancouver, BC, Canada.;Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.",
"authors": "Loucks|Catrina M|CM|;Yan|Kevin|K|;Tanoshima|Reo|R|;Ross|Colin J D|CJD|;Rassekh|Shahrad R|SR|;Carleton|Bruce C|BC|https://orcid.org/0000-0002-4485-4054",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bcpt.13593",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-7835",
"issue": null,
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": "\nRARG\n; \nSLC28A3\n; \nUGT1A6\n; adverse drug reactions; anthracyclines; cardiotoxicity; children; paediatric cancer; pharmacogenetics; pharmacogenomics; precision medicine",
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": null,
"nlm_unique_id": "101208422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33900042",
"pubdate": "2021-04-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pharmacogenetic testing to guide therapeutic decision-making and improve outcomes for children undergoing anthracycline-based chemotherapy.",
"title_normalized": "pharmacogenetic testing to guide therapeutic decision making and improve outcomes for children undergoing anthracycline based chemotherapy"
}
|
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},
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{
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"medicinalproduct": "CRIZOTINIB"
},
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},
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"medicinalproduct": "RUXOLITINIB"
}
],
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{
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}
],
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},
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"literaturereference": "Loucks CM, Yan K, Tanoshima R, Ross CJD, Rassekh SR, Carleton BC. Pharmacogenetic testing to guide therapeutic decision-making and improve outcomes for children undergoing anthracycline-based chemotherapy. Basic-Clin-Pharmacol-Toxicol 2022;130 (Spec. issue S1):95-99.",
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"qualification": "3",
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},
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"receiptdate": "20220503",
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},
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},
"serious": 1,
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}
] |
{
"abstract": "The risk of melanoma in organ transplant recipients (OTR) is increased compared with the general population. This retrospective study registered all cases of post-transplant melanoma in kidney, heart, lung, and liver transplant recipients followed in our specialized post-transplant Dermatology Clinic since 1991. The yearly prevalence of melanoma and skin carcinoma between 2000 and 2015 was computed and compared in this population. Based on another cohort of kidney transplant recipients grafted since 2005, adjusted age- and sex-standardized incidence ratio (SIR) was calculated using a renal transplantation registry. In our overall OTR cohort, between 1991 and 2000, five melanomas occurred in 1800 OTRs (0.28%), whereas between 1991 and 2015, 53 melanomas were diagnosed in 49 of 4510 OTR (1.09%), representing a 3.9-fold increase in prevalence after 2000. Remarkably, the prevalence of nonmelanoma skin cancers remained unchanged over this period. Two deaths related to melanoma were recorded with an overall follow-up of 62 months. In our cohort of 1102 renal transplant recipients, the SIR of melanoma was 4.52. Our data suggest that contrasting with nonmelanoma skin cancer, the risk of post-transplant melanoma has considerably increased over the last decade.",
"affiliations": "Department of Dermatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.;Department of Dermatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.;Unité de Recherche Clinique, Pôle Information Médicale Evaluation Recherche, Hospices Civils de Lyon, Lyon, France.;Department of Dermatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.;Department of Transplantation and Nephrology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.;Department of Transplant Cardiology, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France.;Department of Transplant Cardiology, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France.;Department of Dermatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.;Department of Dermatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.",
"authors": "Fattouh|Kinda|K|http://orcid.org/0000-0002-6566-8955;Ducroux|Emilie|E|;Decullier|Evelyne|E|;Kanitakis|Jean|J|;Morelon|Emmanuel|E|;Boissonnat|Pascale|P|;Sebbag|Laurent|L|;Jullien|Denis|D|;Euvrard|Sylvie|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/tri.13011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "30(11)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "immunosuppression; incidence; melanoma; organ transplantation; skin cancer",
"medline_ta": "Transpl Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005260:Female; D005602:France; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D016377:Organ Transplantation; D011183:Postoperative Complications; D015995:Prevalence; D012189:Retrospective Studies; D012878:Skin Neoplasms; D055815:Young Adult",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "1172-1180",
"pmc": null,
"pmid": "28700114",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Increasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study.",
"title_normalized": "increasing incidence of melanoma after solid organ transplantation a retrospective epidemiological study"
}
|
[
{
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{
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"activesubstancename": "CYCLOSPORINE"
},
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"abstract": "BACKGROUND\nThyroid associated orbitopathy (TAO) is defined as an immune mediated inflammatory process affecting the extraocular muscles, connective and adipose tissue of uncertain etiopathogenesis. TAO are classically described in Grave's disease (GD) however it may occur in euthyroid and hypothyroid patients. Those patients usually test positive for Thyroid Stimulating Hormone receptor antibodies (TRAb). For instance, only few cases of severe Hashimoto's thyroiditis (HT) associated orbitopathy with negative TRAb are reported to date.\n\n\nMETHODS\nHerewith we report a rare case of a middle-aged female who presented with bilateral progressive upper and lower palpebral edema and a unilateral marked proptosis associated with asthenia, headache and decrease in visual acuity. Biological investigation was notable for high levels of anti-thyroid peroxidase antibodies (Anti-TPO) in an otherwise euthyroid patient with negative TRAb. Orbital Magnetic resonance imaging revealed edema of the extraocular muscles and inflammation of periorbital soft tissue. The patient received a treatment with intravenous methylprednisolone followed by oral treatment with prednisone. This regimen was both effective and safe with minimal metabolic side effects in our patient.\n\n\nCONCLUSIONS\nMinor ocular manifestations of HT are common; however, severe sight threatening ophtalmopathy in the absence of TRAb is rare. Multiple differential diagnosis should be considered and investigated before diagnosing this rare entity. Management of similar cases is currently based on reports and no clear guidelines have been elaborated, corticosteroids is the mainstream of treatment with a potential benefit of selenium supplementation in mild to moderate cases.",
"affiliations": "Faculty of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Jounieh, Lebanon. [email protected].;Faculty of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Jounieh, Lebanon.;Faculty of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Jounieh, Lebanon.;Faculty of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Jounieh, Lebanon. [email protected].;Bahman Hospital, Beirut, Lebanon.",
"authors": "El Othman|Radwan|R|;Ephrem|Christelle|C|;Touma|Elsie|E|;Hallit|Souheil|S|http://orcid.org/0000-0001-6918-5689;El Othman|Rola|R|",
"chemical_list": "D001323:Autoantibodies; D007453:Iodide Peroxidase",
"country": "England",
"delete": false,
"doi": "10.1186/s12902-020-00658-6",
"fulltext": "\n==== Front\nBMC Endocr Disord\nBMC Endocr Disord\nBMC Endocrine Disorders\n1472-6823 BioMed Central London \n\n658\n10.1186/s12902-020-00658-6\nCase Report\nA case report of thyroid-associated Orbitopathy with elevated TPO antibodies\nEl Othman Radwan [email protected] 1 Ephrem Christelle 12 Touma Elsie 1 http://orcid.org/0000-0001-6918-5689Hallit Souheil [email protected] 13 El Othman Rola 4 1 grid.444434.70000 0001 2106 3658Faculty of Medicine and Medical Sciences, Holy Spirit University of Kaslik (USEK), Jounieh, Lebanon \n2 Department of Internal Medicine, University Hospital Center- Notre Dame des Secours, Byblos, Lebanon \n3 INSPECT-LB: Institut National de Sante Publique, Epidemiologie Clinique et Toxicologie-Liban, Beirut, Lebanon \n4 Bahman Hospital, Beirut, Lebanon \n27 11 2020 \n27 11 2020 \n2020 \n20 17610 2 2020 22 11 2020 © The Author(s) 2020Open 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.Background\nThyroid associated orbitopathy (TAO) is defined as an immune mediated inflammatory process affecting the extraocular muscles, connective and adipose tissue of uncertain etiopathogenesis. TAO are classically described in Grave’s disease (GD) however it may occur in euthyroid and hypothyroid patients. Those patients usually test positive for Thyroid Stimulating Hormone receptor antibodies (TRAb). For instance, only few cases of severe Hashimoto’s thyroiditis (HT) associated orbitopathy with negative TRAb are reported to date.\n\nCase presentation\nHerewith we report a rare case of a middle-aged female who presented with bilateral progressive upper and lower palpebral edema and a unilateral marked proptosis associated with asthenia, headache and decrease in visual acuity. Biological investigation was notable for high levels of anti-thyroid peroxidase antibodies (Anti-TPO) in an otherwise euthyroid patient with negative TRAb. Orbital Magnetic resonance imaging revealed edema of the extraocular muscles and inflammation of periorbital soft tissue. The patient received a treatment with intravenous methylprednisolone followed by oral treatment with prednisone. This regimen was both effective and safe with minimal metabolic side effects in our patient.\n\nConclusion\nMinor ocular manifestations of HT are common; however, severe sight threatening ophtalmopathy in the absence of TRAb is rare. Multiple differential diagnosis should be considered and investigated before diagnosing this rare entity. Management of similar cases is currently based on reports and no clear guidelines have been elaborated, corticosteroids is the mainstream of treatment with a potential benefit of selenium supplementation in mild to moderate cases.\n\nKeywords\nHashimoto’s thyroiditisHashimoto’s diseaseOrbitopathyOphtalmopathyCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nThyroid associated orbitopathy (TAO) is commonly defined as an immune mediated inflammatory process affecting the extraocular muscles, connective and adipose tissue of uncertain etiopathogenesis [1]. Common findings are periocular tissue edema, decreased visual acuity, ocular pain and exophthalmos; negatively impacting patient’s quality of life. In severe cases, inflammatory mediated optic nerve compression may cause loss of vision. Both eyes are usually affected with only 10–14% of patients having unilateral ocular involvement. TAO are classically described in Grave’s disease however it may occur in euthyroid and hypothyroid patients; accounting for 4.3% of all TAO [2]. Those patients usually test positive for Thyroid Stimulating Hormone receptor antibodies (TRAb) and are thus diagnosed to have euthyroid or hypothyroid GD. Several studies have revealed the correlation between TAO and serum TRAb levels; however, a different mechanism is likely to be behind this rare manifestation of Hashimoto’s Thyroiditis or euthyroid patients with negative TRAb [1]. Although upper eyelid retraction has been described as a common feature of Hashimoto’s thyroiditis; severe orbitopathy associated with Hashimoto’s thyroiditis has been rarely reported in the literature with limited clinical experience regarding its management and outcome. Herewith we report a case of middle-aged woman who initially presented with euthyroid associated orbitopathy and elevated TPO antibodies and subsequently developed subclinical hypothyroidism.\n\nCase presentation\nA 52-year old unemployed Caucasian female was referred by her general physician to internal medicine and clinical immunology clinic for a ten-month history of progressive tender to touch bilateral upper and lower palpebral edema, affecting mainly the right eye (Fig. 1). Edema was associated with an upper eye lid retraction and a marked proptosis mainly to the left. In her medical history, the patient is known to have dyslipidemia for which she is receiving 5 mg of Rosuvastatin daily and 1.5 mg of Bromazepam daily for an old unspecific anxiety disorder for which she is not receiving constant psychiatric follow-up. The patient is known to have a single kidney to the right following a non-functional left kidney nephrectomy in childhood. No past personal history of exposure to radioactive iodine is noted nor familial history of thyroid diseases. The patient reported an associated asthenia, anorexia, a recent bilateral decrease in visual acuity mainly affecting the right eye, blurring and double vision along with vertigo and a chronic tension headache. The patient is a heavy smoker (40 cigarettes daily for more than 30 years). Patient was overweight with a Body mass index (BMI) of 26.9 kg/m2. Physical examination was particular for an ocular proptosis mainly in the left eye, low grade pain on orbital palpation and a multinodular hypertrophic thyroid gland. Ophthalmological examination revealed bilateral keratoconus especially in the right eye with an ipsilateral decrease in visual acuity and a clinical activity score (CAS) of 3 at presentation. Physical examination including neurological examination was otherwise normal.\nFig. 1 Patient at presentation with palpebral edema and proptosis\n\n\n\nInvestigations\nPatient was admitted to the hospital for further investigation and management. Initial blood investigations showed normal complete blood count, C reactive protein level, erythrocyte sedimentation rate, procalcitonin, electrolytes, BUN, serum creatinine, liver biochemistry and serum protein electrophoresis. Fasting lipid profile was as follows: Triglyceride 144 mg/dL, total cholesterol 163 mg/dL, Low-density lipoprotein (LDL) 103 mg/dL and High-density lipoprotein (HDL) 44 mg/dL.\n\nThe initial biological investigation was followed by a cerebral and orbital 1.5 Tesla Magnetic Resonance Imaging (MRI) under sedation for claustrophobia, which revealed a tumefaction and edema of the extraocular muscles including the right inferior and right lateral muscle and to a lesser extent the left inferior orbital muscle with slight infiltration of the orbital fat and inflammation of the periorbital soft tissue especially to the right (Fig. 2). Optical nerves were of normal thickness and signal. Imagery findings were suggestive of an orbital inflammatory pseudo-tumor.\nFig. 2 Orbital MRI at presentation showing tumefaction and edema of the extraocular muscles of the orbit (right inferior and right lateral muscle) with inflammation of the periorbital soft tissue\n\n\n\nBased on the initial work-up four major differential diagnosis were investigated: sarcoidosis, tuberculosis, thyroid associated orbitopathy and a lymphoproliferative process.\n\nIn order to make a definitive diagnosis a panel of additional laboratory examinations was performed and is summarized in Table 1. Furthermore, a high resolution chest computerized tomography (CT) with contrast was performed and revealed no argument in favor of sarcoidosis.\nTable 1 Results summary of biological markers studied upon presentation\n\n\tValue\tReference Range\t\nAngiotensin converting enzyme (ACE)\t35.8 U/L\t8–65 U/L\t\nTuberculin skin test (TST)\t< 5 mm\t0–5 mm: Negative\t\nSerum proteins electrophoresis\tNormal pattern\t\t\nThyroid stimulating hormone (TSH)\t0.615 μIU/mL\t0.27–4.2 μIU/mL\t\nFree thyroxine (F T4)\t14.05 pmol/L\t12–22 pmol/L\t\nFree triiodothyronine (F T3)\t2.94 pmol/L\t3.1–6.8 pmol/L\t\nAnti-thyroid peroxidase (Anti-TPO)\t855.28 IU/mL\t0–5.6 IU/mL\t\nTSH receptor antibodies (TRAb) by enzyme immunoassay\t< 0.6 IU/L\tNegative: < 1 IU/L\t\nAnti-nuclear antibodies by immunofluorescence (ANA by IF)\t< 1/100\t< 1/100: Negative\t\nPerinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA)\t< 20 RU/ML\t< 20 RU/ML: Negative\t\nCytoplasmic anti-neutrophil cytoplasmic antibodies (C-ANCA)\t< 20 RU/ML\t< 20 RU/ML: Negative\t\nIgG4 - Nephelometry\t151 mg/dL\t3–201 mg/dL\t\n\n\nThe diagnosis of thyroid associated orbitopathy was made; thyroid gland echography showed a polylobulated thyroid gland with heterogeneous echostructure and multiple solid nodules along with inflammatory regional lymph nodes.\n\nTreatment, outcome and follow-up\nAn urgent high dose intra-venous (IV) steroid therapy was administered at day 2 of hospitalization for 4 days at a dose of 0.5 mg/Kg of methylprednisolone twice daily which resulted in significant reduction in palpebral edema and limited the progression of the decrease in visual acuity. IV steroid therapy was followed by 2 months treatment with oral prednisone starting with 60 mg daily with progressive tapering of half dose every 2 weeks. Patient was instructed to quit smoking due to its deleterious effect on her orbitopathy; however, the patient only managed to reduce her tobacco consumption to 20 cigarettes daily over a period of 2 months.\n\nPatient was regularly followed every 2 weeks to ensure compliance, assess evolution and determine potential side effects. Upon the completion of 2 months treatment with oral prednisone a marked regression of the palpebral edema was noted with no further deterioration in her visual acuity. An orbital MRI was performed upon completion of oral therapy and showed a resolution of the edematous anomaly of the right lower muscle, absence of extraocular muscles signal abnormality with symmetrical globes and regression of the grade II proptosis to the right (Fig. 3). In addition, biological markers evaluation was performed upon the completion of oral therapy and showed minor metabolic side effects of the treatment namely a mild elevation in total cholesterol and LDL levels (Table 2). Furthermore, thyroid function evaluation upon completion of treatment was notable for a slight increase in TSH with normal FT3 and FT4 (Table 2). Even though, steroids are usually associated with a decrease in TSH level through its effect on TRH [3]. However, in our case TSH level slightly increased after completion of steroids treatment with normal FT4 falling in subclinical hypothyroid range; hence, suggesting the diagnosis Hashimoto’s Thyroiditis. Patient was scheduled to have a follow-up visit every 3 months for the next 1 year in order to monitor for development of overt hypothyroidism requiring further treatment. No weight changes were recorded. At 6 months follow-up patient was symptom free with no ocular proptosis, no further deterioration in her visual acuity beyond the baseline and a minor residual right palpebral edema (Fig. 4) with a clinical activity score of 1. The patient equally reported an improvement in her asthenia and a reduction in frequency of her tension headaches.\nFig. 3 Follow-up orbital MRI performed upon completion of oral therapy; showing resolution of the edematous anomaly of the extraocular muscles and regression of proptosis to the right\n\nTable 2 Results summary of biological markers studied upon completion of treatment\n\n\tValue\tReference Range\t\nHemoglobin A1C\t5.7%\t< 6%\t\nTotal Cholesterol\t212 mg/100 mL\t120–220 mg/100 mL\t\nHigh Density Lipoprotein (HDL)\t45 mg/100 mL\t45–64 mg/100 mL\t\nLow Density Lipoprotein (LDL)\t139 mg/100 mL\t80–150 mg/100 mL\t\nTriglycerides\t152 mg/100 mL\t50–200 mg/100 mL\t\nThyroid stimulating hormone (TSH)\t4.83 μIU/mL\t0.45–4.5 μIU/mL\t\nFree thyroxine (F T4)\t1.25 ng/100 mL\t0.7–1.85 ng/100 mL\t\nTotal triiodothyronine (T T3)\t1.2 ng/mL\t0.8–2.02 ng/mL\t\nFig. 4 Patient at 6 months follow-up visit with a marked resolution of proptosis and palpebral edema\n\n\n\nDiscussion and conclusions\nThyroid associated orbitopathy is far more common in Grave’s disease accounting for 90% of cases [4]. Its pathophysiology has been extensively studied and it’s related to TRAb that is expressed on both thyroid follicular cells and orbital fibroblasts [5, 6]. In fact, the autoimmunity affecting the receptors on orbital tissues causes local inflammation, hyaluronic acid deposition and expansion of local adipose tissue eventually leading to connective tissues remodeling and fibrosis in advanced stages [7–9]. However, only few reports address the cases of severe orbitopathy associated with euthyroid or hypothyroid state. The largest study regarding the prevalence of orbitopathy among HT patients was conducted by Kahaly and al. on 700 patients and revealed that clinically significant TAO was present in only 6% of cases [10] additionally the study revealed that patient with Hashimoto’s disease associated orbitopathy were heavy smokers and less likely to suffer from other autoimmune disease in comparison with patient with HT without TAO. Similarly our patient is a heavy smoker and was not diagnosed to have another autoimmune disease. The TRAb theory may explain the presence of TAO in HT patients with positive TSAb (Thyroid Stimulating Antibody) a subtype of TRAb. In fact, Kahaly and al. found a positive correlation between the levels of TSAb and the severity of TAO. Additionally, their work has showed that only 5.5% of patient with HT and negative TSAb had clinically overt orbitopathy versus 68% with positive TSAb [10]. Hence, further emphasizing the implication of TSAb/TRAb is the pathogenesis of TAO. However, the pathogenesis of TAO in patients with negative TRAb remains unknown. One hypothesis is that autoimmunity is directed toward calsequestrin in extraocular skeletal muscles and against collagen XIII in orbital fibroblasts [9]. Furthermore, several studies have shown that low vitamin D was correlated with abnormal thyroid function tests and the presence of antithyroid antibodies [11–13]. In one retrospective study, Lahooti et al. concluded that vitamin D deficiency was a risk factor for TAO in GD, but not in HT. Thus suggesting a potential different pathogenesis [14].\n\nUnilateral exophthalmos has a wide set of differential diagnosis including orbital primary and secondary neoplasms (e.g. lymphoma, rhabdomyomas, metastasis), specific orbital inflammation (e.g. sarcoidosis), infections, vascular etiologies, myositis, orbital pseudotumor, IgG4-related diseases, TAO … [15–17] A gold standard for diagnosis is Magnetic resonance imaging a noninvasive imaging allowing evaluation of soft tissue with great accuracy [18].\n\nOcular manifestations of thyroid diseases are frequent with upper eyelid retraction being the most common ocular sign in HT and retrobulbar pain the most prevalent ocular symptom [19, 20]. For instance, severe TAO among HT patients is a rare finding. Most reported cases describes patients with bilateral TAO rather than unilateral ocular involvement and mostly with positive TRAb and an excellent response to glucocorticoids [21–23]. Therapy with intravenous corticosteroids represent the cornerstone in the management of severe TAO with a good response rate of 70–80% versus 50–60% for oral therapy with fewer side effects for short-term IV regimen [24–26]. According to the European Group on Graves’ Orbitopathy the most common schedule for IV steroid treatment is a cumulative dose of 4.5 g of methylprednisolone divided over 12 weeks (0.5 g/week for the first 6 weeks followed by 0.25 g/week for the second 6 weeks) without exceeding a cumulative dose of 8 g per 12 weeks [27]. In addition, studies have shown that adding selenium to the treatment regimen of mild to moderate orbitopathy was effective in reducing local inflammation, decrease Anti-TPO production and improve thyroid morphology [28]. Due to the limited number of cases of HT associated orbitopathy, no conventional guidelines exist regarding its management; most reported cases were treated with 1 to 5 g of methylprednisolone during the 1st week followed by a tapered glucocorticoid dose over several weeks [21–23]. Our patient has received a reduced dose of IV methylprednisolone equivalent to a cumulative of 0.3 g infused over a period of 4 days followed by 2 months of oral prednisone treatment starting with 60 mg daily and tapered by half every 2 weeks. This regimen was both effective and safe with minimal metabolic side effects in our patient.\n\nIn conclusion, minor ocular manifestations of HT are common; however, severe orbitopathy in the absence of TRAb is rare and should be diagnosed early in the evolution of the disease in order to prevent sight threatening complications. In the present we are reporting a case of moderate to severe orbitopathy associated with HT a rare entity to date especially with negative TRAb. Multiple differential diagnosis should be considered and investigated before concluding the presence of this rare entity. MRI of the orbit remains the cornerstone in the diagnosis. Management of similar cases is currently based on reports and no clear guidelines have been elaborated, corticosteroids following various regimen is the mainstream of treatment with a potential benefit of selenium supplementation in mild to moderate orbitopathy. Further studies are warranted to determine the exact pathogenesis of this rare manifestation of TRAb negative HT especially that TPO antibodies are equally present in 80% of GD patients [29] thus suggesting an involvement of these antibodies in the pathophysiology of orbitopathy in both GD and HT.\n\nAbbreviations\nTAOThyroid associated orbitopathy\n\nGDGrave’s disease\n\nTRAbThyroid Stimulating Hormone receptor antibodies\n\nHTHashimoto’s thyroiditis\n\nAnti-TPOAnti-thyroid peroxidase antibodies\n\nBUNBlood urea nitrogen\n\nLDLLow-density lipoprotein\n\nHDLHigh-density lipoprotein\n\nMRIMagnetic Resonance Imaging\n\nCTComputerized tomography\n\nIVIntra-venous\n\nACEAngiotensin converting enzyme\n\nTSTTuberculin skin test\n\nTSHThyroid stimulating hormone\n\nF T4Free thyroxine\n\nF T3Free triiodothyronine\n\nANAAnti-nuclear antibodies\n\nIFImmunofluorescence\n\nP-ANCAPerinuclear anti-neutrophil cytoplasmic antibodies\n\nC-ANCACytoplasmic anti-neutrophil cytoplasmic antibodies\n\nTSAbThyroid Stimulating Antibody\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSouheil Hallit and Rola El Othman are last co-authors\n\nAcknowledgements\nWe would like to thank the patient for agreeing to write her case as a report.\n\nAuthors’ contributions\nREO wrote the case report. CE and ET performed the data collection. SH and REO reviewed the paper for intellectual content. All authors critically revised the manuscript, read and approved its final version.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll data pertaining to this patient are included in this report.\n\nEthics approval and consent to participate\nAn approval from an ethics committee was not needed for this case report since it involved one patient.\n\nConsent for publication\nA written informed consent for publication was obtained from the patient and is available for review by the editor of this journal.\n\nCompeting interests\nThere authors have no conflict of interest to disclose.\n==== Refs\nReferences\n1. Yoshihara A Yoshimura Noh J Nakachi A Severe thyroidassociated orbitopathy in Hashimoto’s thyroiditis. Report of 2 cases Endocr J 2011 58 343 348 10.1507/endocrj.K11E-019 21427503 \n2. Cyranska-Chyrek E Olejarz M Szczepanek-Parulska E Stajgis P Pioch A Ruchala M Severe unilateral orbitopathy in a patient with Hashimoto's thyroiditis - a case report BMC Ophthalmol 2019 19 1 9 10.1186/s12886-018-1018-5 30621642 \n3. Haugen BR Drugs that suppress TSH or cause central hypothyroidism. Best practice & research Clin Endocrinol Metab 2009 23 6 793 800 10.1016/j.beem.2009.08.003 \n4. Moncef B Anne LV Orbitopathie dysthyroïdienne. (P. Chanson, & P. Bougnères, Eds.) Méd Clin Endocrinol Diab 2018 92 73 78 \n5. Mengistu M Lukes YG Nagy EV Burch HB Carr FE Lahiri S TSH receptor gene expression in retroocular fibroblasts J Endocrinol Investig 1994 17 6 437 441 10.1007/BF03347732 7523481 \n6. Paschke R Metcalfe A Alcalde L Vassart G Weetman A Ludgate M Presence of nonfunctional thyrotropin receptor variant transcripts in retroocular and other tissues J Clin Endocrinol Metab 1994 79 5 1234 1238 7962314 \n7. Iyer S Bahn R Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor Best Pract Res Clin Endocrinol Metab 2012 26 3 281 289 10.1016/j.beem.2011.10.003 22632365 \n8. Shan SJ Douglas RS The pathophysiology of thyroid eye disease J Neuroophthalmol 2014 34 2 177 185 10.1097/WNO.0000000000000132 24821101 \n9. Lahooti H Parmar KR Wall JR Pathogenesis of thyroid-associated ophthalmopathy: does autoimmunity against calsequestrin and collagen XIII play a role? Clin Ophthalmol 2010 4 417 425 20505833 \n10. Kahaly GJ Diana T Glang J Kanitz M Pitz S Konig J Thyroid stimulating antibodies are highly prevalent in Hashimoto's thyroiditis and associated Orbitopathy J Clin Endocrinol Metab 2016 101 5 1998 2004 10.1210/jc.2016-1220 26964732 \n11. Bozkurt NC Karbek B Ucan B Sahin M Cakal E Ozbek M The association between severity of vitamin D deficiency and Hashimoto's thyroiditis Endocr Pract 2013 19 3 479 484 10.4158/EP12376.OR 23337162 \n12. Kim D Low vitamin D status is associated with hypothyroid Hashimoto's thyroiditis Hormones (Athens) 2016 15 3 385 393 27394703 \n13. Mansournia N Mansournia MA Saeedi S Dehghan J The association between serum 25OHD levels and hypothyroid Hashimoto's thyroiditis J Endocrinol Investig 2014 37 5 473 476 10.1007/s40618-014-0064-y 24639121 \n14. Lahooti H Edirimanne S Walsh JP Delbridge L Hibbert EJ Wall JR Single nucleotide polymorphism 1623 a/G (rs180195) in the promoter of the thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy Clin Ophthalmol 2017 11 1337 1345 10.2147/OPTH.S136070 28794611 \n15. Boddu N Jumani M Wadhwa V Bajaj G Faas F Not all Orbitopathy is Graves': discussion of cases and review of literature Front Endocrinol (Lausanne) 2017 8 184 10.3389/fendo.2017.00184 28824545 \n16. McNab AA McKelvie P IgG4-related ophthalmic disease. Part II: clinical aspects Ophthalmic Plast Reconstr Surg 2015 31 3 167 178 10.1097/IOP.0000000000000364 25564258 \n17. Ruchala M Szczepanek E Puszczewicz M Sosnowski P Sowinski J Not a graves' situation Am J Med 2011 124 3 210 214 10.1016/j.amjmed.2010.11.006 21396501 \n18. Kahaly GJ Imaging in thyroid-associated orbitopathy Eur J Endocrinol 2001 145 2 107 118 10.1530/eje.0.1450107 11454505 \n19. Tjiang H Lahooti H McCorquodale T Parmar KR Wall JR Eye and eyelid abnormalities are common in patients with Hashimoto's thyroiditis Thyroid. 2010 20 3 287 290 10.1089/thy.2009.0199 20146657 \n20. Kan E Kan EK Ecemis G Colak R Presence of thyroid-associated ophthalmopathy in Hashimoto's thyroiditis Int J Ophthalmol 2014 7 4 644 647 25161935 \n21. Grzesiuk W Szydlarska D Pragacz A Bar-Andziak E Thyroid-associated orbitopathy in patients with Hashimoto's thyroiditis: a case report Pol Arch Med Wewn 2008 118 5 318 321 18619184 \n22. Kirmizibekmez H Yesiltepe Mutlu RG Atypical presentation of Hashimoto's disease in an adolescent: thyroid-associated Ophthalmopathy J Clin Res Pediatr Endocrinol 2014 6 4 262 265 10.4274/jcrpe.1450 25541900 \n23. Verma R Gupta M Mehta VK Thyroid associated orbitopathy BMJ Case Rep 2013 2013 bcr2013009920 23737589 \n24. Ruchala M Sawicka-Gutaj N Advances in the pharmacological treatment of Graves' orbitopathy Expert Rev Clin Pharmacol 2016 9 7 981 989 10.1586/17512433.2016.1165606 26966785 \n25. Bartalena L Baldeschi L Boboridis K Eckstein A Kahaly GJ Marcocci C The 2016 European thyroid association/European group on Graves' Orbitopathy guidelines for the Management of Graves' Orbitopathy Eur Thyroid J 2016 5 1 9 26 10.1159/000443828 27099835 \n26. Zang S Ponto KA Kahaly GJ Clinical review: intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity J Clin Endocrinol Metab 2011 96 2 320 332 10.1210/jc.2010-1962 21239515 \n27. Bartalena L Baldeschi L Boboridis K Eckstein A Kahaly G J, Marcocci C, Perros P, Salvi M, Wiersinga W, M: the 2016 European thyroid association/European group on Graves' Orbitopathy guidelines for the Management of Graves' Orbitopathy Eur Thyroid J 2016 5 9 26 10.1159/000443828 27099835 \n28. Drutel A Archambeaud F Caron P Selenium and the thyroid gland: more good news for clinicians Clin Endocrinol 2013 78 2 155 164 10.1111/cen.12066 \n29. Fröhlich E Wahl R Thyroid autoimmunity: role of anti-thyroid antibodies in thyroid and extra-thyroidal diseases Front Immunol 2017 8 521 10.3389/fimmu.2017.00521 28536577\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1472-6823",
"issue": "20(1)",
"journal": "BMC endocrine disorders",
"keywords": "Case report; Hashimoto’s disease; Hashimoto’s thyroiditis; Ophtalmopathy; Orbitopathy",
"medline_ta": "BMC Endocr Disord",
"mesh_terms": "D001323:Autoantibodies; D005260:Female; D049970:Graves Ophthalmopathy; D006801:Humans; D007453:Iodide Peroxidase; D008875:Middle Aged; D011379:Prognosis",
"nlm_unique_id": "101088676",
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"pmid": "33246456",
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"title": "A case report of thyroid-associated Orbitopathy with elevated TPO antibodies.",
"title_normalized": "a case report of thyroid associated orbitopathy with elevated tpo antibodies"
}
|
[
{
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{
"abstract": "A case report is presented of an adolescent male who developed hypothyroidism and cardiomyopathy 6 months after he began taking lithium and imipramine for a severe conduct disorder. After discontinuation of psychiatric medications and institution of thyroid hormone replacement therapy, he developed asymptomatic but potentially serious dysrhythmias. Evidence for potential cardiac toxicity of combined lithium and tricyclic antidepressant therapy is reviewed. Repeated assessment of cardiac function during such therapy is advised.",
"affiliations": "Division of Emergency Medicine, Ohio State University, Columbus.",
"authors": "Dietrich|A|A|;Mortensen|M E|ME|;Wheller|J|J|",
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"journal": "The Journal of adolescent health : official publication of the Society for Adolescent Medicine",
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"medline_ta": "J Adolesc Health",
"mesh_terms": "D000293:Adolescent; D005117:Cardiac Complexes, Premature; D009202:Cardiomyopathies; D002648:Child; D002653:Child Behavior Disorders; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D006333:Heart Failure; D006439:Hemodynamics; D006801:Humans; D007037:Hypothyroidism; D007099:Imipramine; D008094:Lithium; D008297:Male; D009200:Myocardial Contraction; D013974:Thyroxine; D016277:Ventricular Function, Left",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiac toxicity in an adolescent following chronic lithium and imipramine therapy.",
"title_normalized": "cardiac toxicity in an adolescent following chronic lithium and imipramine therapy"
}
|
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{
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{
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{
"reactionmeddrapt": "Rales",
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},
{
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},
{
"reactionmeddrapt": "Cardiac failure congestive",
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},
{
"reactionmeddrapt": "Cardiomyopathy",
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},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "18.1",
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},
{
"reactionmeddrapt": "Pulmonary oedema",
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},
{
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{
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],
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}
},
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"literaturereference": "MORTENSEN ME, DIETRICH A, WHELLER J. CARDIAC TOXICITY IN AN ADOLESCENT FOLLOWING CHRONIC LITHIUM AND IMIPRAMINE THERAPY. JOURNAL OF ADOLESCENT HEALTH. 1993;14 (5):394-97",
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},
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{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) can be familial or secondary, which is often triggered by infection or malignancy. HLH therapy includes dexamethasone and etoposide. However, therapy is associated with significant morbidity and mortality. Anakinra, a recombinant interleukin-1 receptor antagonist, has been reported to treat macrophage activation syndrome (MAS), rheumatic sHLH. We report our experience with anakinra to treat patients with nonrheumatic secondary HLH (sHLH).\n\n\n\nSix children were diagnosed with HLH from December 2014 to August 2016 and were treated with subcutaneous anakinra (6-10 mg/kg/day divided over four doses) with or without dexamethasone (10 mg/m2 /day). Therapy was either escalated or weaned based on clinical and laboratory response.\n\n\n\nFive of six patients were treated with anakinra and dexamethasone, and one with anakinra alone due to active cytomegalovirus (CMV) pneumonitis. The median age of diagnosis was 1.8 years (range 0.8-14.9 years). No pathogenic mutations associated with HLH were identified, but three of six possessed genetic variants of unknown significance. Infectious triggers were identified for four patients and two patients had malignancies. The average treatment duration was 8 weeks with 3.5-5.5 years of follow up. No patient needed escalation of therapy to include etoposide. All patients achieved remission. Anakinra was well tolerated without significant adverse effects.\n\n\n\nInitial treatment with anakinra (with or without dexamethasone) is a feasible treatment alternative for patients with secondary HLH and may allow for avoidance of etoposide. We recommend early initiation of anakinra when HLH is suspected. A broader investigation of the use of anakinra as a first-line agent for HLH is ongoing.",
"affiliations": "Hospitalist Medicine Program, St Jude Children's Research Hospital, Memphis, Tennessee.;Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, New York.;Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.;Division of Pediatric Hematology/Oncology, West Virginia University, Charleston, West Virginia.;Division of Pediatric Hematology/Oncology and Stem Cell Transplantation, Children's Hospital of Richmond, Virginia Commonwealth University, Richmond, Virginia.;Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, New York.;Division of Pediatric Rheumatology, Children's Hospital of Alabama, University of Alabama, Birmingham, Alabama.;Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, New York.",
"authors": "Bami|Sakshi|S|;Vagrecha|Anshul|A|;Soberman|Danielle|D|0000-0003-3763-9476;Badawi|Mohamad|M|0000-0001-5131-9861;Cannone|Daniel|D|;Lipton|Jeffrey M|JM|;Cron|Randy Q|RQ|;Levy|Carolyn Fein|CF|0000-0002-9285-2248",
"chemical_list": "D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28581",
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"issn_linking": "1545-5009",
"issue": "67(11)",
"journal": "Pediatric blood & cancer",
"keywords": "HLH; MA-HLH; anakinra; sHLH",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28581",
"pmc": null,
"pmid": "32725881",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis.",
"title_normalized": "the use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis"
}
|
[
{
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{
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"activesubstancename": "DEXAMETHASONE"
},
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"medicinalproduct": "DEXAMETHASONE."
},
{
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},
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"drugindication": "HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS",
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],
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{
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},
{
"reactionmeddrapt": "Acute erythroid leukaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
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{
"reactionmeddrapt": "Off label use",
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}
],
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},
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"literaturereference": "BAMI S, VAGRECHA A, SOBERMAN D, BADAWI M, CANNONE D, LIPTON J, ET AL.. THE USE OF ANAKINRA IN THE TREATMENT OF SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. PEDIATRIC BLOOD + CANCER. 2020?.",
"literaturereference_normalized": "the use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis",
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"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20201103"
}
] |
{
"abstract": "BACKGROUND\nIrreversible electroporation (IRE) is a non-thermal ablation technique recently used in pancreatic cancer. In our prospective study we evaluated safety, feasibility and efficacy of a neoadjuvant protocol based on CT-guided percutaneous IRE followed by chemotherapy in patients with locally advanced pancreatic cancer (LAPC).\n\n\nMETHODS\nWe performed CT-guided percutaneous IRE in 20 patients with LAPC, followed by a combination of gemcitabine (1000 mg/mq) and oxaliplatin (100 mg/mq) biweekly. Imaging follow-up was performed by a contrast enhanced CT scan at 1, 3, 6 months and then every 3 months.\n\n\nRESULTS\nNo major complications occurred. Two patients died 3 and 4 months after IRE because of rapidly progressive disease. In the remaining 18 patients 6-month imaging follow-up showed a mean lesions volumetric decrease percentage of 42.89% (95% Confidence Interval: 34.90-54.88%). Thanks to lesions downstaging, three patients underwent R0 resection. At last available follow-up (mean follow-up 91 months; range 6-14), imaging showed no disease progression or post-surgical relapse in all 18 cases. The mean estimated survival was 12,950 months (95% CI: 11,570-14,332).\n\n\nCONCLUSIONS\nOur preliminary study suggests that IRE followed by chemotherapy is safe, feasible and effective in producing local control of LAPC, with a possible downstaging effect to resectable lesions.",
"affiliations": "Department of Clinical and Experimental Medicine, \"F. Magrassi - A. Lanzara\" Second University of Naples, Piazza Miraglia 2, 80131 Naples, Italy. Electronic address: [email protected].;Department of Diagnostic Imaging, \"S. Anna-S. Sebastiano\" Hospital, Via F. Palasciano, 81100 Caserta, Italy.;Department of Informatics, Second University of Naples, Piazza Miraglia 2, 80131 Naples, Italy.;Department of Oncology, \"S. Anna-S. Sebastiano\" Hospital, Via F. Palasciano, 81100 Caserta, Italy.;Department of Oncology, \"S. Anna-S. Sebastiano\" Hospital, Via F. Palasciano, 81100 Caserta, Italy.;Department of Anaesthesiology and Rianimation, \"S. Anna-S. Sebastiano\" Hospital, Via F. Palasciano, 81100 Caserta, Italy.;Department of Anaesthesiology and Rianimation, \"S. Anna-S. Sebastiano\" Hospital, Via F. Palasciano, 81100 Caserta, Italy.;Department of Anesthesiological, Surgical and Emergency Sciences, Second University of Naples, Piazza Miraglia 2, 80131 Naples, Italy.;Department of Diagnostic Imaging, \"S. Anna-S. Sebastiano\" Hospital, Via F. Palasciano, 81100 Caserta, Italy.",
"authors": "Belfiore|Maria Paola|MP|;Ronza|Francesco Michele|FM|;Romano|Francesco|F|;Ianniello|Giovanni Pietro|GP|;De Lucia|Guido|G|;Gallo|Concetta|C|;Marsicano|Carmela|C|;Di Gennaro|Teresa Letizia|TL|;Belfiore|Giuseppe|G|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-9159",
"issue": "21 Suppl 1()",
"journal": "International journal of surgery (London, England)",
"keywords": "Downstaging; Gemcitabine; IRE; Irreversible electroporation; Oxaliplatin; Pancreatic cancer",
"medline_ta": "Int J Surg",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D018274:Electroporation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101228232",
"other_id": null,
"pages": "S34-9",
"pmc": null,
"pmid": "26118600",
"pubdate": "2015-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Percutaneous CT-guided irreversible electroporation followed by chemotherapy as a novel neoadjuvant protocol in locally advanced pancreatic cancer: Our preliminary experience.",
"title_normalized": "percutaneous ct guided irreversible electroporation followed by chemotherapy as a novel neoadjuvant protocol in locally advanced pancreatic cancer our preliminary experience"
}
|
[
{
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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": "Metastases to peritoneum",
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}
],
"summary": null
},
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"literaturereference": "MARIA PAOLA BELFIORE, FRANCESCO MICHELE RONZA, FRANCESCO ROMANO, GIOVANNI PIETRO IANNIELLO, GUIDO DE LUCIA, CONCETTA GALLO ET AL. PERCUTANEOUS CT-GUIDED IRREVERSIBLE ELECTROPORATION FOLLOWED BY CHEMOTHERAPY AS A NOVEL NEOADJUVANT PROTOCOL IN LOCALLY ADVANCED PANCREATIC CANCER: OUR PRELIMINARY EXPERIENCE. INTERNATIONAL JOURNAL OF SURGERY. 2015;21:S34-S39",
"literaturereference_normalized": "percutaneous ct guided irreversible electroporation followed by chemotherapy as a novel neoadjuvant protocol in locally advanced pancreatic cancer our preliminary experience",
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},
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},
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},
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},
{
"companynumb": "IT-CIPLA LTD.-2015IT07280",
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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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"drugdosagetext": "1000 MG/MQ BIWEEKLY",
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"drugindication": "PANCREATIC CARCINOMA",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "GEMCITABINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Metastatic neoplasm",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Metastases to peritoneum",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MARIA PAOLA BELFIORE, FRANCESCO MICHELE RONZA, FRANCESCO ROMANO, GIOVANNI PIETRO IANNIELLO, GUIDO DE LUCIA, CONCETTA GALLO ET AL. PERCUTANEOUS CT-GUIDED IRREVERSIBLE ELECTROPORATION FOLLOWED BY CHEMOTHERAPY AS A NOVEL NEOADJUVANT PROTOCOL IN LOCALLY ADVANCED PANCREATIC CANCER: OUR PRELIMINARY EXPERIENCE. INTERNATIONAL JOURNAL OF SURGERY. 2015;21:S34-S39",
"literaturereference_normalized": "percutaneous ct guided irreversible electroporation followed by chemotherapy as a novel neoadjuvant protocol in locally advanced pancreatic cancer our preliminary experience",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20150915",
"receivedate": "20150915",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11510881,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20151125"
}
] |
{
"abstract": "102 episodes of continuous ambulatory peritoneal dialysis (CAPD) peritonitis were studied prospectively during a 288-day period at The Queen Elizabeth Hospital, Birmingham. Organisms were isolated from 76% of the episodes, with coagulase-negative staphylococci, being the most commonly encountered organism (55%). Initial treatment consisted of intraperitoneal vancomycin and ceftazidime with subsequent adjustment on the basis of antibiotic sensitivities. With this regimen, 83% of the positive cultures became negative by 72 h, 9.8% of cases relapsed and removal of the CAPD catheter was necessary in 8 patients (7.8%). Overall, 92% of cases were cured. No adverse drug reactions were seen. This combination of antibiotics appears effective and safe in the treatment of CAPD peritonitis.",
"affiliations": "Department of Nephrology, Queen Elizabeth Hospital, Birmingham, UK.",
"authors": "Beaman|M|M|;Solaro|L|L|;McGonigle|R J|RJ|;Michael|J|J|;Adu|D|D|",
"chemical_list": "D014640:Vancomycin; D002442:Ceftazidime",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000185242",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1660-8151",
"issue": "51(1)",
"journal": "Nephron",
"keywords": null,
"medline_ta": "Nephron",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002442:Ceftazidime; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010538:Peritonitis; D014640:Vancomycin",
"nlm_unique_id": "0331777",
"other_id": null,
"pages": "51-5",
"pmc": null,
"pmid": "2644565",
"pubdate": "1989",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Vancomycin and ceftazidime in the treatment of CAPD peritonitis.",
"title_normalized": "vancomycin and ceftazidime in the treatment of capd peritonitis"
}
|
[
{
"companynumb": "GB-PFIZER INC-2021336029",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "033",
"drugauthorizationnumb": "062911",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "15 MG/L DIALYSATE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PERITONITIS",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VANCOMYCIN HCL"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CANDIDA INFECTION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "AMPHOTERICIN B."
},
{
"actiondrug": "5",
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"activesubstancename": "CEFTAZIDIME"
},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "100 MG/L DIALYSATE",
"drugenddate": null,
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"drugindication": "PERITONITIS",
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"medicinalproduct": "CEFTAZIDIME."
}
],
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"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
}
],
"summary": null
},
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"literaturereference": "BEAMAN, M.. VANCOMYCIN AND CEFTAZIDIME IN THE TREATMENT OF CAPD PERITONITIS. NEPHRON. 1989?51(1):51?55",
"literaturereference_normalized": "vancomycin and ceftazidime in the treatment of capd peritonitis",
"qualification": "3",
"reportercountry": "GB"
},
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},
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},
"serious": 1,
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"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210717"
}
] |
{
"abstract": "Cervical cancer is a human papilloma virus-related disease, whereas endometrial cancer and atypical endometrial hyperplasia (AEH) are hormone-related diseases, so co-occurrence of the two is possible. However, scientific studies about such cases are rare. We encountered a case of cervical adenocarcinoma and AEH in a 33-year-old nulliparous woman. Two fertility-sparing treatments were performed, a radical trachelectomy for the cervical cancer and high-dose medroxyprogesterone acetate treatment for the AEH. After remission of the diseases, the patient became pregnant by in vitro fertilization and delivered a baby at 36 weeks' gestation by cesarean section. Although the patient had two uterine malignancies, proper evaluation of the diseases, consultation with the patient and her husband, and appropriate management led to fertility preservation, and live birth was achieved.",
"affiliations": "Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, Toyoake, Japan.;Department of Gynecologic Oncology, Aichi Cancer Center, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Tamauchi|Satoshi|S|https://orcid.org/0000-0003-3130-3736;Moriyama|Yoshinori|Y|;Suzuki|Shiro|S|;Ikeda|Yoshiki|Y|;Yoshikawa|Nobuhisa|N|;Kajiyama|Hiroaki|H|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D017258:Medroxyprogesterone Acetate",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.15001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "47(11)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "atypical endometrial hyperplasia; cervical cancer; fertilization; malignancy; pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D002585:Cesarean Section; D016889:Endometrial Neoplasms; D005260:Female; D059247:Fertility Preservation; D006801:Humans; D050498:Live Birth; D017258:Medroxyprogesterone Acetate; D011247:Pregnancy; D000069339:Trachelectomy; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "4101-4105",
"pmc": null,
"pmid": "34463005",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy.",
"title_normalized": "achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy"
}
|
[
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-02523",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditional": "4",
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"drugauthorizationnumb": "209106",
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"drugdosagetext": "UNK, INJECTION",
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"drugindication": "Maternal therapy to enhance foetal lung maturity",
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"medicinalproduct": "BETAMETHASONE"
},
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"activesubstancename": "PROGESTERONE"
},
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"medicinalproduct": "PROGESTERONE"
},
{
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"activesubstancename": "MAGNESIUM SULFATE"
},
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"drugbatchnumb": "Unknown",
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"medicinalproduct": "MAGNESIUM SULFATE"
},
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITODRINE HYDROCHLORIDE"
},
"drugadditional": "4",
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": "Unknown",
"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": "RITODRINE HYDROCHLORIDE"
}
],
"patientagegroup": "1",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": "2.802",
"reaction": [
{
"reactionmeddrapt": "Premature baby",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Tamauchi S, Moriyama Y, Suzuki S, Ikeda Y, Yoshikawa N, Kajiyama H. Achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy. The Journal of Obstetrics and Gynaecology Research. 2021;47(11):4101-4105",
"literaturereference_normalized": "achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20220303",
"receivedate": "20220303",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20546986,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220424"
},
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-02342",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditional": "4",
"drugadministrationroute": "030",
"drugauthorizationnumb": "209106",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK, INJECTION",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Maternal therapy to enhance foetal lung maturity",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BETAMETHASONE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROGESTERONE"
},
"drugadditional": "4",
"drugadministrationroute": "067",
"drugauthorizationnumb": null,
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Suppository",
"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": "PROGESTERONE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": "4",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": "Unknown",
"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": "MAGNESIUM SULFATE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITODRINE HYDROCHLORIDE"
},
"drugadditional": "4",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": "Unknown",
"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": "RITODRINE HYDROCHLORIDE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEDROXYPROGESTERONE ACETATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "600 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Endometrial hyperplasia",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": "26",
"drugtreatmentdurationunit": "803",
"medicinalproduct": "MEDROXYPROGESTERONE ACETATE"
}
],
"patientagegroup": null,
"patientonsetage": "33",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Premature delivery",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Tamauchi S, Moriyama Y, Suzuki S, Ikeda Y, Yoshikawa N, Kajiyama H. Achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy. The Journal of Obstetrics and Gynaecology Research. 2021;47(11):4101-4105",
"literaturereference_normalized": "achievement of live birth after overcoming two gynecological malignancies treated with radical trachelectomy and medroxyprogesterone acetate therapy",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20220224",
"receivedate": "20220224",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20511531,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
}
] |
{
"abstract": "Herpes simplex encephalitis (HSE) occurring within 30 days after neurosurgery for solid CNS tumors is underrecognized and underreported but remains important because of high morbidity and mortality. We present the case of a 41-year-old woman who had HSE after craniopharyngioma surgery, and delayed recognition and treatment led to a poor outcome. Subsequently, we review reported HSE cases after neurosurgery for solid CNS tumors and describe outcomes after treatment with and without acyclovir.\nA literature search was performed for cases meeting the above criteria. Information was gathered regarding patient demographics, tumor types, symptoms, diagnostic workup, therapy, and outcomes.\nEighteen cases were studied. Encephalopathy, fever, and seizures were the most common symptoms. A majority of patients (78%) received IV acyclovir, with a 79% survival rate with treatment. Mortality rate was 100% in untreated cases. The median time to starting acyclovir was 17 postoperative days (range, 8-53 days). Most patients received steroids, but its use was not associated with a specific outcome.\nHSE may develop following neurosurgical resection, and the threshold for suspicion of this condition should be extremely low in a patient who shows compatible symptoms (encephalopathy, fever, or seizures) or does not recover as planned. Moreover, in case of suspicion of HSE, acyclovir should be promptly started until infection can be definitely ruled out. A delay in diagnosis of HSE and failure to treat may result in severe morbidity as well as mortality. This observation may warrant further study.",
"affiliations": "Department of Neurology, Baylor Scott & White Health, Temple, TX.;Department of Neurosurgery, Baylor Scott & White Health, Temple, TX.;Baylor Scott & White Research Institute, Temple, TX.;Department of Neurology, Tulane University School of Medicine, New Orleans, LA.;Department of Neurology, Baylor Scott & White Health, Temple, TX.",
"authors": "Yari|Niloofar|N|0000-0002-0312-6296;Benardete|Ethan Alexander|EA|;Chen|Wencong|W|;Ambe|Solomon Neba|SN|;Fonkem|Ekokobe|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/nop/npz007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2054-2577",
"issue": "6(4)",
"journal": "Neuro-oncology practice",
"keywords": "acyclovir; central nervous system tumors; herpes simplex encephalitis; neurosurgery; postoperative",
"medline_ta": "Neurooncol Pract",
"mesh_terms": null,
"nlm_unique_id": "101640528",
"other_id": null,
"pages": "259-263",
"pmc": null,
"pmid": "31386089",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "10407001;11596972;12185148;12652407;16175983;16301509;17945155;18976107;19533470;19631366;20862348;20941525;21637964;22467488;23289817;24649468;25192177;26543809;26724620;27216026;28509218;28587310;30083888;4335254;9496822",
"title": "Outcomes with acyclovir treatment in herpes simplex encephalitis after surgery for solid CNS tumors: a case report and systematic review of the literature.",
"title_normalized": "outcomes with acyclovir treatment in herpes simplex encephalitis after surgery for solid cns tumors a case report and systematic review of the literature"
}
|
[
{
"companynumb": "US-SA-2019SA224387",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HYDROCORTISONE SALT NOT SPECIFIED"
}
],
"patientagegroup": "5",
"patientonsetage": "40",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Herpes simplex",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Hemiparesis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Post procedural infection",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Encephalopathy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Meningoencephalitis herpetic",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Lethargy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Generalised tonic-clonic seizure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Muscular weakness",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YARI N, BENARDETE E.A, CHEN W, AMBE SN, FONKEM E.. OUTCOMES WITH ACYCLOVIR TREATMENT IN HERPES SIMPLEX ENCEPHALITIS AFTER SURGERY FOR SOLID CNS TUMORS: A CASE REPORT AND SYSTEMATIC REVIEW OF THE LITERATURE. NEURO-ONCOL PRACT.. 2019?6(4):259-63.",
"literaturereference_normalized": "outcomes with acyclovir treatment in herpes simplex encephalitis after surgery for solid cns tumors a case report and systematic review of the literature",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190822",
"receivedate": "20190822",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16727257,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191005"
}
] |
{
"abstract": "OBJECTIVE\nBotulinum toxin is used to treat a wide range of dystonias in the head and neck. Occasionally, patients receiving laryngeal botulinum toxin experience severe dysphagia, dyspnea, or even distant and autonomic symptoms. Rarely, these patients may require hospitalization with possible intubation and placement of nasogastric tubes. Botulinum antitoxin is not readily available and ineffective once symptoms have progressed, so patients must wait until the toxin wears off over weeks to months. Pyridostigmine prevents the breakdown of acetylcholine at the neuromuscular junction, thus making more neurotransmitter available for the muscles.\n\n\nMETHODS\nA retrospective case study of patients receiving botulinum toxin for dystonia in the head and neck from 1998 to 2012 who experienced adverse effects that were successfully treated with pyridostigmine.\n\n\nMETHODS\nTwenty cases were selected and reviewed to demonstrate how pyridostigmine was used to modulate severe dysphagia, breathiness, dyspnea, and some distant/autonomic symptoms.\n\n\nRESULTS\nPyridostigmine was well tolerated and resulted in significant symptom improvement. Only one significant adverse effect, bradycardia, occurred in a patient with severe cardiac disease.\n\n\nCONCLUSIONS\nGiven the safety and efficacy of this medication, pyridostigmine should be considered to modulate severe sequelae of botulinum toxin in select patients when conservative management is deemed insufficient. Also, physicians should be aware that patient complaints of symptoms at distant sites and temporally delayed from the injection may be a result of the botulinum toxin and relieved with pyridostigmine.",
"affiliations": "School of Medicine, Medical University of South Carolina, Charleston, South Carolina.;Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina. Electronic address: [email protected].",
"authors": "Young|David L|DL|;Halstead|Lucinda A|LA|",
"chemical_list": "D000931:Antidotes; D002800:Cholinesterase Inhibitors; D009465:Neuromuscular Agents; D001905:Botulinum Toxins; D011729:Pyridostigmine Bromide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0892-1997",
"issue": "28(6)",
"journal": "Journal of voice : official journal of the Voice Foundation",
"keywords": "Adverse reactions; Botox; Botulinum toxin; Pyrodostigmine; Reversal of botulinum toxin",
"medline_ta": "J Voice",
"mesh_terms": "D000328:Adult; D000368:Aged; D000931:Antidotes; D001905:Botulinum Toxins; D002800:Cholinesterase Inhibitors; D003680:Deglutition Disorders; D004417:Dyspnea; D004421:Dystonia; D005260:Female; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D009465:Neuromuscular Agents; D011729:Pyridostigmine Bromide; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8712262",
"other_id": null,
"pages": "830-4",
"pmc": null,
"pmid": "25008379",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pyridostigmine for reversal of severe sequelae from botulinum toxin injection.",
"title_normalized": "pyridostigmine for reversal of severe sequelae from botulinum toxin injection"
}
|
[
{
"companynumb": "US-BAUSCH-BL-2014-011411",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PYRIDOSTIGMINE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "009829",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DYSPNOEA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "3",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "60",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PYRIDOSTIGMINE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BOTULINUM TOXIN TYPE A"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OESOPHAGEAL ACHALASIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BOTULINUM TOXIN"
}
],
"patientagegroup": null,
"patientonsetage": "77",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Bradycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YOUNG D, HALSTEAD L. PYRIDOSTIGMINE FOR REVERSAL OF SEVERE SEQUELAE FROM BOTULINUM TOXIN INJECTION. JOURNAL OF VOICE. 2014;VOL.28 (6):830-834.",
"literaturereference_normalized": "pyridostigmine for reversal of severe sequelae from botulinum toxin injection",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20141230",
"receivedate": "20141230",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10683812,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150529"
}
] |
{
"abstract": "The optimal use of sacubitril/valsartan in clinical practice needs further investigation, in particular for patients with multiple comorbidities, as such patients are usually poorly represented in clinical trials. To this end, well-documented case reports may add further evidence to the bulk of \"field practice\" experience on sacubitril/valsartan. We report here the case of a patient with heart failure with reduced ejection refraction with multiple comorbidities treated with sacubitril/valsartan. Overall, sacubitril/valsartan led to a prompt (within a few months) improvement in LVEF (+15%, from 38 to 53%), without any noticeable adverse events. This therapy also allowed the patient to discontinue furosemide.",
"affiliations": "Internal Medicine Unit (Dir. C. Borghi), University of Bologna, Bologna, Italy.",
"authors": "Magri|Gianluigi|G|;Bentivenga|Crescenzio|C|;Cosentino|Eugenio Roberto|ER|;Degli Esposti|Daniela|D|;Borghi|Claudio|C|;Dormi|Ada|A|",
"chemical_list": "D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000484888",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-6312",
"issue": "138 Suppl 1()",
"journal": "Cardiology",
"keywords": "Comorbidity; Heart failure; Sacubitril; Valsartan",
"medline_ta": "Cardiology",
"mesh_terms": "D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006333:Heart Failure; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome; D008875:Middle Aged; D013777:Tetrazoles; D000068756:Valsartan",
"nlm_unique_id": "1266406",
"other_id": null,
"pages": "21-23",
"pmc": null,
"pmid": "29262405",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of a Multicomorbid Patient with Heart Failure.",
"title_normalized": "management of a multicomorbid patient with heart failure"
}
|
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"reactionmeddraversionpt": "21.0",
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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": "Hypercholesterolaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mitral valve incompetence",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Iron deficiency",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Inflammatory marker increased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Congestive cardiomyopathy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 200606"
}
},
"primarysource": {
"literaturereference": "MAGRI G., BENTIVENGA C., COSENTINO E.R., DEGLI ESPOSTI D., BORGHI C., DORMI A.. MANAGEMENT OF A MULTICOMORBID PATIENT WITH HEART FAILURE. CARDIOLOGY. 2017?138(1 SUPPL. 1):21-23",
"literaturereference_normalized": "management of a multicomorbid patient with heart failure",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20180207",
"receivedate": "20180201",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14474690,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Neuroleptic malignant-like syndrome is a rare but potentially fatal complication of sudden withdrawal of dopaminergic drugs. Clinical features are similar to that of neuroleptic malignant syndrome (NMS) like hyperthermia, autonomic dysfunction, altered sensorium, muscle rigidity; but instead of history of neuroleptic use, there is history of withdrawal of dopaminergic drugs. Laboratory examination generally show elevated creatine phosphokinase levels and may show elevated total leucocyte count. Thrombocytopaenia has been very rarely reported with NMS but it has not been reported with NM-like syndrome. Here, we discuss a case of Parkinson's disease which presented with typical clinical features and risk factors of NM-like syndrome associated with thrombocytopaenia and type 1 respiratory failure. He was treated with bromocriptine and supportive care. Thrombocytopaenia and respiratory failure resolved with above treatment. The patient improved clinically and was successfully discharged on day 12 of admission.",
"affiliations": "Medicine, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Medicine, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Medicine, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Medicine, All India Institute of Medical Sciences, New Delhi, Delhi, India.",
"authors": "Sahu|Harsh|H|;Manjunath|Mouna Bidarguppe|MB|;Ray|Animesh|A|http://orcid.org/0000-0001-7498-9112;Vikram|Naval Kishore|NK|",
"chemical_list": "D007980:Levodopa",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227089",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "Parkinson’s disease; medical management; neurology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D015600:Glasgow Coma Scale; D006801:Humans; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D010300:Parkinson Disease; D010349:Patient Compliance; D013921:Thrombocytopenia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567175",
"pubdate": "2018-12-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21601731;2951265;9798079;12920474;18712508;12573874;12735909;28492457;23983836;9375964;26968824;24591835;12952806;10928001;10798826;11330330;11991344;839449;9104438",
"title": "Neuroleptic malignant-like syndrome causing thrombocytopaenia: a rare association.",
"title_normalized": "neuroleptic malignant like syndrome causing thrombocytopaenia a rare association"
}
|
[
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"medicinalproduct": "PRAMIPEXOLE."
},
{
"actiondrug": "1",
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}
],
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"reaction": [
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Treatment noncompliance",
"reactionmeddraversionpt": "21.1",
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},
{
"reactionmeddrapt": "Neuroleptic malignant syndrome",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Respiratory fatigue",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "RAY A, SAHU H, MANJUNATH M, VIKRAM N. NEUROLEPTIC MALIGNANT-LIKE SYNDROME CAUSING THROMBOCYTOPAENIA: A RARE ASSOCIATION. BMJ CASE REPORTS. 2018?11:1:.",
"literaturereference_normalized": "neuroleptic malignant like syndrome causing thrombocytopaenia a rare association",
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},
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},
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"transmissiondate": "20190417"
},
{
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{
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},
{
"actiondrug": null,
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},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TELMISARTAN/HYDROCHLOROTHIAZIDE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RASAGILINE MESYLATE"
},
"drugadditional": null,
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"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "1",
"drugrecurrence": [
{
"drugrecuraction": "Thrombocytopenia"
},
{
"drugrecuraction": "Neuroleptic malignant syndrome"
},
{
"drugrecuraction": "Respiratory failure"
}
],
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"medicinalproduct": "RASAGILIN"
}
],
"patientagegroup": null,
"patientonsetage": "62",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Neuroleptic malignant syndrome",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAHU H, MANJUNATH M, RAY A, VIKRAM N. NEUROLEPTIC MALIGNANT-LIKE SYNDROME CAUSING THROMBOCYTOPAENIA: A RARE ASSOCIATION.. BMJ-CASE-REP. 2018?11:.",
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},
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},
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},
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},
{
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{
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],
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"literaturereference": "SAHU H, MANJUNATH M, RAY A, VIKRAM N. NEUROLEPTIC MALIGNANT-LIKE SYNDROME CAUSING THROMBOCYTOPAENIA: A RARE ASSOCIATION. BMJ CASE REPORTS. 2018?11(1):.",
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] |
{
"abstract": "Cortical spreading depression (CSD) has been directly observed in humans with malignant stroke, traumatic brain injury and subarachnoid haemorrhage and is also considered to be the correlate of migraine aura. We report on a 76-year-old woman with new-onset episodes of headache, paraesthesia, hemiparesis and dysarthria, in whom a small cortical subarachnoid haemorrhage was diagnosed with MRI. Repeated diffusion-weighted MRI scans shortly after transient focal neurological episodes as well as diagnostic workup were normal, which makes recurrent transient ischaemic attacks unlikely. Ictal electroencephalogram recordings showed no epileptic activity. Long-term follow-up revealed a diagnosis of probable cerebral amyloid angiopathy. We propose that CSD could be a pathophysiological correlate of transient focal neurological deficits in patients with cortical bleeding.",
"affiliations": "Department of Neurology, Clinic Hietzing, Wien, Austria.;Department of Neurology, Clinic Hietzing, Wien, Austria.;Department of Neurology, Clinic Hietzing, Wien, Austria.;Department of Neurology, Clinic Hietzing, Wien, Austria [email protected].",
"authors": "Glössmann|Kerstin|K|http://orcid.org/0000-0002-5536-1992;Baumgartner|Christoph|C|;Koren|Johannes Peter|JP|;Riederer|Franz|F|http://orcid.org/0000-0002-9722-9754",
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"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-241479",
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"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "headache (including migraines); pain (neurology); stroke",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D016657:Cerebral Amyloid Angiopathy; D013181:Cortical Spreading Depression; D004827:Epilepsy; D005260:Female; D006261:Headache; D006801:Humans; D020325:Migraine with Aura",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34226251",
"pubdate": "2021-07-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent migraine aura-like symptoms in an elderly woman: symptomatic cortical spreading depression?",
"title_normalized": "recurrent migraine aura like symptoms in an elderly woman symptomatic cortical spreading depression"
}
|
[
{
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"literaturereference": "Glossmann K, Baumgartner C, Koren JP, Riederer F. Recurrent migraine aura-like symptoms in an elderly woman: Symptomatic cortical spreading depression?. British Medical.Journal case reports. 2021;14(7):e241479.:1-4",
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{
"abstract": "Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event-free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS.",
"affiliations": "Department of Leukemia, The University of Texas M. D. Anderson Cancer Center , Houston, TX , USA.",
"authors": "Strati|Paolo|P|;Ferrajoli|Alessandra|A|;Lerner|Susan|S|;O'Brien|Susan|S|;Wierda|William|W|;Keating|Michael J|MJ|;Faderl|Stefan|S|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
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"issn_linking": "1026-8022",
"issue": "55(4)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "828-33",
"pmc": null,
"pmid": "23808813",
"pubdate": "2014-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "20888994;15921393;21617923;19224852;22331940;22080061;12217803;22853816;23264597;19050308;18843642;21874830;15767648;17941952;19347738;10785263;21765022;21750315;18216293;19117034;21220603;17707840;15927668;19701850;19646755;12153163;21212432;19843378;21153774;18411418",
"title": "Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia.",
"title_normalized": "fludarabine cyclophosphamide and rituximab plus granulocyte macrophage colony stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia"
}
|
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"literaturereference": "STRATI P, FERRAJOLI A, LERNER S, O^BRIEN S, WIERDA W, KEATING MJ, ET AL. FLUDARABINE, CYCLOPHOSPHAMIDE AND RITUXIMAB PLUS GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR AS FRONTLINE TREATMENT FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. LEUK-LYMPHOMA 2014; 55(4) 828-833",
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},
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},
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] |
{
"abstract": "OBJECTIVE\nThe prognostic value of kinetics of response to multiple myeloma (MM) therapy is controversial. We aimed to expand the knowledge on this topic by reviewing the kinetics of response to both first- and second-line MM therapy, utilizing a homogeneously treated cohort and analyzing separately both M-spike and light chain (LC) responses for each patient.\n\n\nMETHODS\nWe reviewed all patients who received first-line cyclophosphamide, bortezomib and dexamethasone induction followed by autologous transplant with melphalan and lenalidomide maintenance in our center between 2007 and 2019.\n\n\nRESULTS\nAnalyzing 360 patients, we observed no correlation between response kinetics to first- versus second-line therapy at the individual patient level. Time to best response to first-line therapy was not a predictor of outcome; however, longer time to best response was highly predictive of a favorable outcome in the second-line setting, independent of other factors. Patients with IgA-MM cleared their M-spike faster than IgG-MM, probably reflecting different half-lives of these isotypes rather than disease biology, as the clearance of LC in both subtypes was similar.\n\n\nCONCLUSIONS\nAnalyzing both M-spike and LC responses in a homogenously treated cohort, we identified important insights regarding the prognostic value of kinetic patterns. Prospective analysis may shed more light on unsolved questions.",
"affiliations": "Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, Toronto, Ontario, Canada.",
"authors": "Lebel|Eyal|E|https://orcid.org/0000-0001-5215-7278;Li|Xuan|X|;Paul|Harminder|H|;Masih-Khan|Esther|E|https://orcid.org/0000-0002-7271-0680;Bhella|Sita|S|;Chen|Christine|C|;Prica|Anca|A|;Reece|Donna|D|;Tiedemann|Rodger|R|;Trudel|Suzanne|S|;Kukreti|Vishal|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13726",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": null,
"journal": "European journal of haematology",
"keywords": "kinetics; light chains; multiple myeloma; paraproteins",
"medline_ta": "Eur J Haematol",
"mesh_terms": null,
"nlm_unique_id": "8703985",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34767270",
"pubdate": "2021-11-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Kinetics of response to first- and second-line therapies in multiple myeloma: Assessment by both M-spikes and light chains.",
"title_normalized": "kinetics of response to first and second line therapies in multiple myeloma assessment by both m spikes and light chains"
}
|
[
{
"companynumb": "CA-AMGEN-CANSP2022064064",
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"occurcountry": "CA",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
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"drugindication": "Plasma cell myeloma",
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"medicinalproduct": "CARFILZOMIB"
}
],
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"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "25.0",
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},
{
"reactionmeddrapt": "Plasma cell myeloma",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "Lebel E.. Kinetics of response to first- and second-line therapies in multiple myeloma: Assessment by both M-spikes and light chains. European Journal of Haematology. 2021;108:204-211",
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"abstract": "Reversible cerebral vasoconstriction syndrome (RCVS) is an uncommon disorder characterised by thunderclap headache and self-resolving angiographic vasospasm in the presence or absence of neurological deficit. We present the first case of RCVS likely precipitated by a complex array of confounding factors including a hyperosmolar hyperglycaemic state (HHS), induction chemotherapy with cyclophosphamide, non-Hodgkin's lymphoma, pancytopenia and previous blood transfusions. However, the clinical presentation in this case of altered conscious state followed by thunderclap headache was highly suggestive of HHS being the crucial inciting factor. This report of RCVS associated with HHS lends unique insight into key underlying pathophysiological mechanisms, and warns of the need to maintain a high index of suspicion for this elusive condition given the dynamic and transient nature of its clinical and radiological features.",
"affiliations": "Department of Neurosurgery, Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3000, Australia; National Trauma Research Institute, 85-89 Commercial Road, Melbourne, VIC 3004, Australia. Electronic address: [email protected].;Department of Neurosurgery, Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3000, Australia; National Trauma Research Institute, 85-89 Commercial Road, Melbourne, VIC 3004, Australia.;Department of Neurosurgery, Royal Melbourne Hospital, 300 Grattan Street, Parkville, Victoria 3000, Australia; Department of Surgery, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: [email protected].",
"authors": "Kweh|Barry Ting Sheen|BTS|;Tan|Terence|T|;Morokoff|Andrew|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; C543332:obinutuzumab",
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"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Cyclophosphamide; Hyperosmolar hyperglycaemic state; Reversible cerebral vasoconstriction syndrome; Thunderclap headache",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003907:Dexamethasone; D004317:Doxorubicin; D005260:Female; D051270:Headache Disorders, Primary; D006689:Hodgkin Disease; D006801:Humans; D006944:Hyperglycemic Hyperosmolar Nonketotic Coma; D060828:Induction Chemotherapy; D008875:Middle Aged; D020301:Vasospasm, Intracranial; D014750:Vincristine",
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"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Reversible cerebral vasoconstriction syndrome associated with hyperosmolar hyperglycaemic state: A case report and literature review.",
"title_normalized": "reversible cerebral vasoconstriction syndrome associated with hyperosmolar hyperglycaemic state a case report and literature review"
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{
"abstract": "Radiation-induced sarcoma is a known but rare complication of radiation treatment for skull base paraganglioma. We present the cases of a female patient with multiple paraganglioma syndrome treated with external beam radiation treatment who presented 4 years later with a malignant peripheral nerve sheath tumor of the vagus nerve.",
"affiliations": "Division of Neurosurgery, House Institute, Los Angeles, California, United States.;Division of Neurosurgery, House Institute, Los Angeles, California, United States.;Division of Neurotology, House Institute, Los Angeles, California, United States.;Division of Neurotology, House Institute, Los Angeles, California, United States.;Division of Neurotology, House Institute, Los Angeles, California, United States.",
"authors": "Lekovic|Gregory P|GP|;Mehta|Gautam U|GU|0000-0002-8009-6430;Maxwell|Anne K|AK|;Peng|Kevin A|KA|;Brackmann|Derald E|DE|",
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"fulltext": "\n==== Front\nJ Neurol Surg Rep\nJ Neurol Surg Rep\n10.1055/s-00000182\nJournal of Neurological Surgery Reports\n2193-6358 2193-6366 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany \n\n10.1055/s-0040-1718408\n200007\nCase Report\nRadiation-Induced Malignant Peripheral Nerve Sheath Tumor of the Vagus Nerve Following Radiation Treatment of Cervical Paraganglioma\nLekovic Gregory P. 1 http://orcid.org/0000-0002-8009-6430Mehta Gautam U. 1 Maxwell Anne K. 2 Peng Kevin A. 2 Brackmann Derald E. 2 1 Division of Neurosurgery, House Institute, Los Angeles, California, United States\n2 Division of Neurotology, House Institute, Los Angeles, California, United States\nAddress for correspondence Gregory P. Lekovic, MD, PhD House Clinic2100 West Third Street, Los Angeles, CA 90057United [email protected]\n10 2020 \n31 12 2020 \n81 4 e66 e70\n16 3 2020 02 9 2020 \nThe Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/\n).\n2020The Author(s).This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.Radiation-induced sarcoma is a known but rare complication of radiation treatment for skull base paraganglioma. We present the cases of a female patient with multiple paraganglioma syndrome treated with external beam radiation treatment who presented 4 years later with a malignant peripheral nerve sheath tumor of the vagus nerve.\n\nKeywords\nparagangliomaradiationvagus nervemalignant peripheral nerve sheath tumorradiation-induced sarcomaglomus vagaleFunding\nNone.\n==== Body\nCase Report\nA 28-year-old woman with a known history of multiple paraganglioma syndrome presented with enlarging mass in the right neck, dysphonia, cough, dysphagia, and severe neck pain. Weight loss was attributed to poor oral intake secondary to dysphagia and nausea. Four years previously, the patient was diagnosed with bilateral carotid body tumors. She completed a course of 6 weeks of external beam radiation therapy (EBRT) at that time for the right-sided tumor which was felt to be inoperable due to rostral extension to the skull base. The prescription dose was 5,400 cGy delivered in 180 cGy fractions. She subsequently had a left-sided carotid body tumor removed approximately 1 year later with no adverse sequelae. Both procedures were performed at an outside hospital. After radiation treatment, the patient had a partial imaging response and reported improvement in local symptoms until 4 years later, when she noticed progressive dysphonia, dysphagia, and pain. The patient was not evaluated for succinate dehydrogenase (SDH) mutation or other germline genetic analysis.\n\nOn physical examination, a firm mass was palpable in the upper neck. The patient had deviation of the soft palate/uvula to the left consistent with right-sided glossopharyngeal nerve deficit. On direct laryngoscopy, she was found to have an immobile right vocal cord consistent with vagus nerve palsy. The remainder of the patient's neurologic examination was unremarkable. In addition, the patient did not have café-au-lait macules, freckling of the axilla or groin, cutaneous or subcutaneous tumors, or other clinical stigmata of neurofibromatosis.\n\n\nMagnetic resonance imaging (MRI) of the neck demonstrated a homogeneously enhancing mass in the posterior parapharyngeal space of the neck on the right side with anterior displacement of the carotid artery and internal jugular vein, extending from the carotid bifurcation inferiorly to the jugular foramen rostrally (\nFig. 1\n). Based on this imaging and the patient's clinical history of multiple paraganglioma syndrome, the presumptive diagnosis was that of a glomus vagale, carotid body tumor, or possibly a “collision tumor” of both. Given that the patient was symptomatic with enlarging neck mass, new neurologic deficits (i.e., glossopharyngeal and vagus neuropathies), and prior failed radiation treatment, surgery was recommended.\n\n\nFig. 1 \nPreoperative T2-weighted axial (\na\n) and coronal (\nb\n) magnetic resonance imaging of the brain and neck showing a large mass in the carotid sheath with “popcorn”-type appearance of flow voids suggestive of paraganglioma; T1-weighted axial and coronal images following administration of gadolinium demonstrate avid contrast enhancement and splaying of the internal and external carotid arteries (\nc\nand\nd\n, respectively).\n\n\nSurgery Details\n\nPreoperative angiography with embolization was performed 1 week prior to surgery. The angiogram demonstrated a vascular blush typical of paraganglioma, but limited to only part of the tumor mass that enhanced on MRI (\nFig. 2\n). This was attributed to a partial response to radiation. A balloon test occlusion was performed, which the patient tolerated without evidence of ischemia. A gastrostomy tube was placed prior to surgery to assist with nutrition both before surgery and in anticipation of persistent postoperative dysphagia. The patient underwent a transjugular approach to the infratemporal fossa and cervical carotid artery, including blind sac closure of the external auditory canal, anterior transposition of the facial nerve, ligation of the internal jugular vein and sigmoid sinus, exenteration of the jugular foramen contents, and carotid artery sacrifice. A gross total resection of tumor was felt to have been obtained; however, surgical margins were not evaluated at the time of surgery. Four regional lymph nodes were excised for pathological evaluation of possible metastases.\n\n\nFig. 2 \nPreoperative anteroposterior (\na\n) and lateral (\nb\n) angiograms show two distinct patterns of vascularity: a prominent blush typical of paraganglioma and an avascular component with pronounced mass effect on the distal carotid artery.\n\n\nPathology\n\nPathology revealed two separate and distinct histologic components, including one comprised weakly eosinophilic large cuboidal and polygonal cells arranged in clusters, or “zellballen” with supporting sustentacular cells, and an infiltrating spindle cell lesion composed of large ovoid spindle-shaped cells with prominent nucleoli and amphophilic cytoplasm (\nFig. 3\n). No necrosis was seen. Additional immunohistochemistry was performed that demonstrated S100 positivity in the high-grade, spindle-cell component of the tumor and chromogranin A, and synaptophysin staining in the sustentacular cells of the paraganglioma component. K\ni\n-67 staining was present in 2% of the paraganglioma and 70% of the spindle cell lesion. The overall pathology impression was that of two separate contiguous tumors: a paraganglioma and also a spindle cell neoplasm consistent with high-grade malignant peripheral nerve sheath tumor (MPNST). There was no evidence of underlying plexiform neurofibroma on histopathology. Regional lymph nodes were negative for tumor.\n\n\nFig. 3 \nHematoxylin and eosin staining shows two distinct tumors: paraganglioma (\na\n) characterized by “zellballen” and a spindle cell neoplasm (\nb\n). This latter tumor had a high mitotic rate and demonstrated a high K\ni\n-67 staining rate (70%) (not shown).\n\n\nPostoperative Course\nPostoperatively, the patient developed new facial nerve weakness (House–Brackmann grade 6/6, which improved to grade 4/6 at last follow-up) but was otherwise neurologically intact. Her pain was improved, but she complained of persistent nausea and vomiting. She was discharged home and referred to speech and language pathology. Given the diagnosis of MPNST, staging computed tomography (CT) was obtained and multiple pulmonary nodules were identified. A CT-guided biopsy confirmed metastatic MPNST to the lung. The patient was referred to oncology and completed an initial regimen of vincristine, doxorubicin, and cyclophosphamide. Additional metastatic lesions were subsequently identified in the left ilium and at L2. A second round of chemotherapy with doxorubicin and ifosfamide was completed with partial response of systemic metastatic disease but with progression of locally recurrent disease in the jugular foramen and cerebellopontine angle. The patient had multiple chemotherapy-related complications, including neutropenia with opportunistic fungal infection and fungemia, and thrombocytopenia. Given the rapid local progression of disease and poor performance status, the patient was transitioned to palliative care. She expired 2 months thereafter (6 months after surgery).\n\nDiscussion\n\nRadiation therapy is an established treatment option for patients with skull base paragangliomas.\n1\n2\nTumor control (defined as cessation of tumor growth, including both stable and shrinking tumors) is achieved in 88 to 100% of patients following radiation therapy, with fewer cranial nerve complications compared with surgery.\n3\n4\n5\nRadiation treatment options for patients undergoing radiation therapy include both conventional EBRT and stereotactic radiosurgery (SRS), sometimes called stereotactic body radiation therapy (SBRT). EBRT for paraganglioma has decades of proven efficacy at achieving tumor control.\n6\n7\n8\n9\nAlthough most complications associated with conventional radiation therapy are not life threatening, induction of malignancy following EBRT for paraganglioma may also occur.\n1\n2\n10\n11\n\n\nRadiation-Induced Malignant Peripheral Nerve Sheath Tumor\n\nThe association between radiation therapy and subsequent development of sarcoma has been appreciated since Cahan et al's original report in 1948 of 11 sarcomas of bone following irradiation.\n12\nApproximately 6% of all head and neck sarcomas occur in patients with a history of prior irradiation,\n13\nwith leiomyosarcoma and other subtypes of sarcoma more commonly seen with a history of prior irradiation.\n14\nConversely, although MPNSTs are rare, roughly 10% of all MPNST occur in patients with a history of prior irradiation and are associated with high local recurrence and poorer overall prognosis.\n15\n\n\n\nOur case satisfies Cahan et al's criteria for radiation-induced sarcoma: (1) the malignancy arose from the irradiated field; (2) the malignancy was of a different histology than the neoplasm treated with irradiation; (3) sufficient delay exists between the radiation exposure and development of secondary malignancy; and (4) the secondary malignancy arose from normal in-field tissue. Latency in our case between radiation exposure and sarcoma development is just over 4 years, consistent with Cahan et al's original criteria but less than the median reported by others.\n13\n14\n16\n17\n18\n19\nThis may be attributable to the patient's relative young age and the possible presence of a genetic tumor predisposition syndrome. The final Cahan et al's criteria, that the induced neoplasm arises from tissue “normal” prior to treatment, are in this case speculative. Importantly, we do not have the patient's initial presenting imaging (i.e., prior to radiation therapy), and hence cannot unequivocally rule out the presence of a coexisting neurofibroma of the vagus nerve. At surgery, the tumor specimen consisted of both paraganglioma and MPNST both involving the vagus nerve. It is possible that the patient previously had both a carotid body tumor and glomus vagale on that side, although this may not have been appreciated at the time of initial treatment. In any event, the vagus nerve would be in contact with the paraganglioma from the skull base to carotid bifurcation. Although biopsy was not obtained prior to radiation treatment on the patient's right side, she had a history of prior surgery for carotid body tumor on the contralateral side, confirming the diagnosis of multiple paraganglioma syndrome. Furthermore, at the time of radiation treatment, the patient displayed no signs or symptoms of MPNST, only later developing (e.g., severe pain). Nevertheless, without preoperative imaging and genetic analysis (see later), it remains theoretically possible that the patient had either coexisting neurofibromatosis type 1 (NF1) and multiple paraganglioma syndrome or had a pathological mutation contributing to a mixed phenotype. If so, the induction of a secondary malignancy may not fully fulfill Cahan et al's criteria for malignant transformation of “normal” in field tissue.\n\n\nRole of Radiation Therapy Technique in Induction of Malignancy\n\nA dose–response relationship between radiation exposure and induction of malignancy has been well established in both experimental models and clinically, such as in survivors of atomic bomb exposure.\n17\n20\nWhether there is a threshold of exposure for cancer induction, and the shape of the dose–response curve for higher radiation exposures, however, is not well established. It has been postulated that for hematological malignancies, reduced cell survival seen with higher doses of therapeutic radiation leads to a decrease in malignancy induction with high doses, that is, that the dose–response relationship is “bell shaped.”\n17\n19\nIn contrast, sarcoma induction is more commonly seen after high radiation doses, with evidence of an increased risk of secondary malignancy with doses up to 60 Gy.\n13\n16\n21\nThis dose dependence may be clinically relevant when comparing SRS with EBRT: In a large study of sarcoma risk following breast irradiation, Rubino et al found the risk of sarcoma 30.6 times higher for doses more than 44 Gy compared with 15 Gy.\n22\nSRS allows for highly conformal treatment plans resulting in minimal dose to surrounding tissues and achieves rates of tumor control comparable to conventional (Guss et al, 2011).\n3\n23\n24\n25\n26\n27\nImportantly, the mean prescription dose for patients treated with SRS (median marginal doses between 1,400 and 1,730 cGy)\n14\nis significantly less than with traditional EBRT regimens such as were employed with our patient (5,400 cGy in 180 cGy fractions). As SRS achieves tumor control comparable to that obtained with EBRT with a significantly lower prescription dose, SRS might have a lower risk of induction of malignancy when treating head and neck paragangliomas. However, given the rarity of head and neck paraganglioma and the infrequency with which SRS has historically been used for these tumors, there is insufficient data in the literature to make any firm conclusions regarding the relative safety of SRS versus EBRT.\n\n\nRole of Mutational Analysis of Paraganglioma Syndrome\n\nOur patient did not have genetic testing performed prior to treatment. Multiple genes/genetic pathways have been shown to contribute to head and neck paraganglioma formation, including SDH, Von Hippel–Lindau, and RAS signaling pathway genes such as NF1.\n28\nSome SDH mutations (i.e., SDHB) are associated with a significantly increased risk of malignant paraganglioma,\n29\nwhereas NF1 mutations may predispose to MPNST, as seen in our patient. Whether a patient's specific genetic landscape poses a predictable risk factor with regard to the underlying radiation dose–response relationship of new tumor induction is however unknown. Specifically, whether patients' susceptibility to either malignant transformation or sarcoma induction is impacted by a given specific causative mutation (e.g., SDHB, NF1, etc.) is not established. Nevertheless, we believe that characterization of the causative genetic mutation(s) could have helped inform the patient's initial decision to proceed with radiation treatment (e.g., if an underlying NF1 mutation had been identified).\n\n\nSummary\nClinical suspicion for malignancy in head and neck paragangliomas previously treated with radiation is warranted. Pain is an unusual symptom with paraganglioma, and as is the case with peripheral nerve tumors should raise suspicion of malignant transformation. Radiation strategies aimed at lowering overall dose such as SRS/SBRT may be preferable to conventional EBRT for patients undergoing radiation of head and neck paraganglioma. Genetic analysis should be obtained prior to initiation of treatment in the management of head and neck paraganglioma.\n\nConflict of Interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this case report.\n\nEthical Approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Declaration of Helsinki 1964 and its later amendments or comparable ethical standards.\n\nPatient Consent\nThe patient's next of kin has given consent for submission of this case report.\n==== Refs\nReferences\n1 Galland-Girodet S Maire J P De-Mones E The role of radiation therapy in the management of head and neck paragangliomas: impact of quality of life versus treatment response\nRadiother Oncol 2014 111 03 463 467\n24996453 \n2 Gilbo P Morris C G Amdur R J Radiotherapy for benign head and neck paragangliomas: a 45-year experience\nCancer 2014 120 23 3738 3743\n25060724 \n3 Liscak R Urgosik D Chytka T Leksell Gamma Knife radiosurgery of the jugulotympanic glomus tumor: long-term results\nJ Neurosurg 2014 121 (Suppl):198 202\n25434953 \n4 Cole J M Beiler D Long-term results of treatment for glomus jugulare and glomus vagale tumors with radiotherapy\nLaryngoscope 1994 104 12 1461 1465\n7990634 \n5 Hansen H S Thomsen K A Radiotherapy in glomus tumours (paragangliomas). A 25 year-review\nActa Otolaryngol Suppl 1988 449 151 154\n2849282 \n6 Jackson A W Koshiba R Treatment of glomus jugulare tumours by radiotherapy\nProc R Soc Med 1974 67 04 267 270\n4375820 \n7 Krych A J Foote R L Brown P D Garces Y I Link M J Long-term results of irradiation for paraganglioma\nInt J Radiat Oncol Biol Phys 2006 65 04 1063 1066\n16682153 \n8 Lalwani A K Jackler R K Gutin P H Lethal fibrosarcoma complicating radiation therapy for benign glomus jugulare tumor\nAm J Otol 1993 14 04 398 402\n8238279 \n9 Lustig L R Jackler R K Lanser M J Radiation-induced tumors of the temporal bone\nAm J Otol 1997 18 02 230 235\n9093681 \n10 Na A F Lai L T Kaye A H Radiation induced brainstem glioblastoma in a patient treated for glomus jugulare tumour\nJ Clin Neurosci 2015 22 01 219 221\n25085729 \n11 Preissig S H Bohmfalk G L Reichel G W Smith M T Anaplastic astrocytoma following radiation for a glomus jugular tumor\nCancer 1979 43 06 2243 2247\n222421 \n12 Cahan W G Woodard H Q Higinbotham N L Stewart F W Coley B L Sarcoma arising in irradiated bone; report of 11 cases\nCancer 1948 1 01 3 29\n18867438 \n13 Mark R J Bailet J W Poen J Postirradiation sarcoma of the head and neck\nCancer 1993 72 03 887 893\n8334642 \n14 Williams L Tmanova L Mydlarz W K Radiation-associated sarcoma of the neck: case series and systematic review\nAnn Otol Rhinol Laryngol 2018 127 10 735 740\n30047787 \n15 Wong W W Hirose T Scheithauer B W Schild S E Gunderson L L Malignant peripheral nerve sheath tumor: analysis of treatment outcome\nInt J Radiat Oncol Biol Phys 1998 42 02 351 360\n9788415 \n16 Berrington de Gonzalez A Gilbert E Curtis R Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship\nInt J Radiat Oncol Biol Phys 2013 86 02 224 233\n23102695 \n17 Kumar S Second malignant neoplasms following radiotherapy\nInt J Environ Res Public Health 2012 9 12 4744 4759\n23249860 \n18 Rosko A J Birkeland A C Chinn S B Survival and margin status in head and neck radiation-induced sarcomas and de novo sarcomas\nOtolaryngol Head Neck Surg 2017 157 02 252 259\n28397585 \n19 Toda K Shibuya H Hayashi K Ayukawa F Radiation-induced cancer after radiotherapy for non-Hodgkin's lymphoma of the head and neck: a retrospective study\nRadiat Oncol 2009 4 21 19591686 \n20 Little M P Evidence for dose and dose rate effects in human and animal radiation studies\nAnn ICRP 2018 47 (3-4):97 112\n29652168 \n21 Kuttesch J F JrWexler L H Marcus R B Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas\nJ Clin Oncol 1996 14 10 2818 2825\n8874344 \n22 Rubino C Shamsaldin A Lê M G Radiation dose and risk of soft tissue and bone sarcoma after breast cancer treatment\nBreast Cancer Res Treat 2005 89 03 277 288\n15754127 \n23 Genç A Bicer A Abacioglu U Peker S Pamir M N Kilic T Gamma Knife radiosurgery for the treatment of glomus jugulare tumors\nJ Neurooncol 2010 97 01 101 108\n19707722 \n24 Guss Z D Batra S Limb C J Radiosurgery of glomus jugulare tumors: a meta-analysis\nInt J Radiat Oncol Biol Phys 2011 81 04 e497 e502\n21703782 \n25 Ibrahim R Ammori M B Yianni J Grainger A Rowe J Radatz M Gamma Knife radiosurgery for glomus jugulare tumors: a single-center series of 75 cases\nJ Neurosurg 2017 126 05 1488 1497\n27392265 \n26 Marchetti M Pinzi V Tramacere I Bianchi L C Ghielmetti F Fariselli L Radiosurgery for paragangliomas of the head and neck: another step for the validation of a treatment paradigm\nWorld Neurosurg 2017 98 281 287\n27825903 \n27 Winford T W Dorton L H Browne J D Chan M D Tatter S B Oliver E R Stereotactic radiosurgical treatment of glomus jugulare tumors\nOtol Neurotol 2017 38 04 555 562\n28121969 \n28 Guha A Musil Z Vicha A A systematic review on the genetic analysis of paragangliomas: primarily focused on head and neck paragangliomas\nNeoplasma 2019 66 05 671 680\n31307198 \n29 PGL.NET network Burnichon N Rohmer V Amar L The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas\nJ Clin Endocrinol Metab 2009 94 08 2817 2827\n19454582\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2193-6358",
"issue": "81(4)",
"journal": "Journal of neurological surgery reports",
"keywords": "glomus vagale; malignant peripheral nerve sheath tumor; paraganglioma; radiation; radiation-induced sarcoma; vagus nerve",
"medline_ta": "J Neurol Surg Rep",
"mesh_terms": null,
"nlm_unique_id": "101601540",
"other_id": null,
"pages": "e66-e70",
"pmc": null,
"pmid": "33403195",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "23102695;21703782;18867438;28121969;24996453;16682153;4375820;25085729;25060724;222421;2849282;15754127;19454582;9093681;30047787;28397585;8874344;29652168;19707722;25434953;8334642;27825903;9788415;19591686;23249860;31307198;7990634;8238279;27392265",
"title": "Radiation-Induced Malignant Peripheral Nerve Sheath Tumor of the Vagus Nerve Following Radiation Treatment of Cervical Paraganglioma.",
"title_normalized": "radiation induced malignant peripheral nerve sheath tumor of the vagus nerve following radiation treatment of cervical paraganglioma"
}
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"abstract": "Fibula free flap (FFF) is widely used in head and neck reconstructive surgery and is considered as a standard and therapy of choice after ablative cancer surgery. The aim of this retrospective monocenter study was to determine the success rates of fibula free flaps for jaw reconstruction after ablative tumor surgery. The disease course of patients who underwent jaw reconstructive surgery with FFF from January 2002 to June 2020 was evaluated regarding the flap success rate. Flap failure was analyzed in detail and categorized into two groups: partial flap failure (PFF) and total flap failure (TFF). A total of 180 free fibular flaps were performed over the last 19 years and a total of 36 flap failures were recorded. TFF occurred in n = 20 (56.6%) and PFF in n = 16 cases (44.4%) cases. No statistically significant differences were found concerning patients' age at flap transfer, sex, BMI, ASA-Score, preoperative non-virtual or virtual surgical planning (non-VSP vs. VSP), and time of reconstruction (immediately vs. delayed). Duration of hospitalization shows statistically significant differences between both groups (p = 0.038), but no differences concerning operating time and duration on Intensive Care Unit (ICU). Partial flap failure appears to be underreported in literature. Sub- and complete failure of the skin paddle leads to clinical complaints like uncovered bone segments and plate exposure. Partial or complete FFF failure lead to infections on the recipient site and prolonged wound healing and therefore may cause a delay of the beginning of adjuvant radiation therapy (RT). PFF of hard tissue can be induced by RT.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany.;Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany.;Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany.;Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany.;Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany.;Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany.;Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany.",
"authors": "Knitschke|Michael|M|0000-0002-2632-1799;Sonnabend|Sophia|S|;Bäcker|Christina|C|;Schmermund|Daniel|D|;Böttger|Sebastian|S|;Howaldt|Hans-Peter|HP|;Attia|Sameh|S|0000-0002-9174-6435",
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"country": "Switzerland",
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"doi": "10.3390/cancers13040865",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694 MDPI \n\n10.3390/cancers13040865\ncancers-13-00865\nArticle\nPartial and Total Flap Failure after Fibula Free Flap in Head and Neck Reconstructive Surgery: Retrospective Analysis of 180 Flaps over 19 Years\nhttps://orcid.org/0000-0002-2632-1799Knitschke Michael * Sonnabend Sophia Bäcker Christina Schmermund Daniel Böttger Sebastian Howaldt Hans-Peter https://orcid.org/0000-0002-9174-6435Attia Sameh Otto Sven Academic Editor Department of Oral and Maxillofacial Surgery, Justus-Liebig-University, Klinikstrasse 33, 35392 Giessen, Germany; [email protected] (S.S.); [email protected] (C.B.); [email protected] (D.S.); [email protected] (S.B.); [email protected] (H.-P.H.); [email protected] (S.A.)\n* Correspondence: [email protected]\n18 2 2021 \n2 2021 \n13 4 86519 1 2021 16 2 2021 © 2021 by the authors.2021Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Simple Summary\nMost data concerning fibula free flaps after cancer resection in the head and neck region are limited to small sample sizes and a short period of follow-up. This retrospective study aims to evaluate the flap success, failure, and complications at the recipient site in 180 cases over 19 years. The flap failure is classified as partial and total flap necrosis. A correlation between flap failure and patients’ medical status, age, sex, BMI, ASA-Score, planning type, and reconstruction time point was performed. Our findings help head and neck surgeons understand the factors that influence flap failure and assess risk factors. Our observations could optimize the treatment of cancer patients receiving a fibula free flap in the future.\n\nAbstract\nFibula free flap (FFF) is widely used in head and neck reconstructive surgery and is considered as a standard and therapy of choice after ablative cancer surgery. The aim of this retrospective monocenter study was to determine the success rates of fibula free flaps for jaw reconstruction after ablative tumor surgery. The disease course of patients who underwent jaw reconstructive surgery with FFF from January 2002 to June 2020 was evaluated regarding the flap success rate. Flap failure was analyzed in detail and categorized into two groups: partial flap failure (PFF) and total flap failure (TFF). A total of 180 free fibular flaps were performed over the last 19 years and a total of 36 flap failures were recorded. TFF occurred in n = 20 (56.6%) and PFF in n = 16 cases (44.4%) cases. No statistically significant differences were found concerning patients’ age at flap transfer, sex, BMI, ASA-Score, preoperative non-virtual or virtual surgical planning (non-VSP vs. VSP), and time of reconstruction (immediately vs. delayed). Duration of hospitalization shows statistically significant differences between both groups (p = 0.038), but no differences concerning operating time and duration on Intensive Care Unit (ICU). Partial flap failure appears to be underreported in literature. Sub- and complete failure of the skin paddle leads to clinical complaints like uncovered bone segments and plate exposure. Partial or complete FFF failure lead to infections on the recipient site and prolonged wound healing and therefore may cause a delay of the beginning of adjuvant radiation therapy (RT). PFF of hard tissue can be induced by RT.\n\nfibula free flaphead and neck cancerreconstructive surgeryFFF success rateFFF failure rate\n==== Body\n1. Introduction\nSince the first mandibular reconstruction with a fibula free flap (FFF) by Hidalgo in 1989, it has been shown that FFF is a reliable and versatile graft [1,2]. Currently, FFF is considered as standard therapy in head and neck reconstructive surgery, providing the optimal precondition for dental implant success and therefore for oral and dental rehabilitation [3,4]. Long-term complications on the donor-site are relatively low. Most patients have been satisfied with the functional and aesthetic results [5,6]. The number of free tissue transfers of soft and/or bone tissue defects have increased significantly in recent years [7]. The flap provides the opportunity to include a septo-cutaneous skin paddle of up to 200 cm2. Cadaver studies investigating skin perfusion through selective injection have shown that a skin area of 12 × 7 cm can be perfused by a single perforating vessel [8]. A recent milestone in operative techniques is the possibility of computer-assisted surgery (CAS) and virtual surgical planning (VSP) in reconstructions of jaws [9,10,11]. VSP initially focused on bone grafts. The innovative potential lies in the design of a cutting guide that takes into account the course of the cutaneous perforating vessels based on preoperative CT and sonographic measurements [12,13]. For skin paddle harvesting, the support of perforator vessels is crucial. Fibular flaps have been reported to allow a success rate of up to 95% [7,14,15,16]. The causes of flap failure are anastomosis insufficiency, more frequent venous congestion (e.g., edema, hematoma), rare arterial occlusion (e.g., embolism, thrombus, kinking), vasospasms, postoperative bleeding, and coagulopathies [17,18,19,20]. \n\nHowever, detailed data about partial FFF loss are rare and seem to be underreported in literature. An analysis of risk factors for flap failure and complications in a low-level center of 129 FFFs over a time span of 20 years reported a PFF rate of 7.8%. By definition, (sub-)total flap loss describes the failure of the skin paddle and/or the loss of one or more bone graft segments in poly-segmental reconstructions [21]. The data published to date lack a differentiation concerning soft and/or hard tissue loss. A comparative investigation on computer-assisted versus conventional FFF technique for craniofacial reconstruction found six skin paddle and two segmental graft failures, which corresponded to a PFF rate of 11.76% (n = 8 out of 68) and a TFF rate of 4.41% (n = 3) [22]. Comparative results of partial loss were reported with a range of 3–14% [16,23]. This should be considered when the often-described advantage of the skin paddle as a vital monitor is advocated [24,25]. Gennaro et al. mentioned that a thin muscle cuff around bone, e.g., the fibula or vascularized iliac crest bone flap, is needed for flap harvesting. In these cases, a direct clinical assessment even without the use of a Doppler probe is advisable [26]. However, if PFF or TFF occurs, therapeutic options and decisions must be made to reduce local infection, functional impairment, and increase the patient’s quality of life. In this study, we have assessed and discussed the therapeutic options in the setting of TFF.\n\nThe aims of this study are:to estimate the rate of partial flap loss ((sub-)total loss of skin paddle and/or failure of graft segments) and total flap failure over a long time period of 19 years, and to suggest further therapy procedures according to localization and defect type;\n\nto examine a correlation between age at flap transfer, BMI, ASA-Score, and risk factors in terms of partial and total flap failure; and\n\nto investigate whether there is a correlation between non-VSP vs. VSP and time of reconstruction (immediate vs. delayed).\n\n\n\n2. Materials and Methods\n2.1. Study Design and Patient Population\nThe study was conducted as a monocentric, retrospective study. Medical records of all patients who underwent FFF in the head and neck region from January 2002 to June 2020 were analyzed in respect of success of the flap transfer procedure. Flap failure was stratified into two groups: partial flap failure (PFF) and total flap failure (TFF) (Figure 1). PFF was defined as any loss of parts of the skin paddle (Skin) (Figure 2), parts or segments (poly-segmental reconstruction) of bone grafts (Bone) (Figure 3), or a combination of both (Both). The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to PFF, TFF is characterized by discontinued perfusion of the graft (i.e., thrombosis). Intra- or extraoral wound dehiscences around the skin paddle alone did not match the criteria for PFF and were not included. \n\nAll patients underwent a preoperative CT or MRI angiography to ensure the presence of a three fibular vessel anatomy and the absence of significant arteriosclerotic changes in the lower leg. Free fibula flap dissection was performed by Gilbert’s lateral approach [27]. To preserve knee and ankle stability, respectively, a bone length of 8 cm proximal to the harvest site and a distal bone length of 6–8 cm of distal to the harvest site were left in situ. When an osseo-cutaneous free flap was harvested, a muscle cuff with parts of soleus and flexor hallucis longus muscle was included to protect the perforators. Before donor-site wounds were closed, a vacuum drainage (Redon) was installed. Wound closure at the lower limb was performed using a split skin graft over the harvested skin flap or primarily in all cases of sole bone flaps without skin paddles.\n\nExamples for the clinical course of a subtotal bone graft loss (PFF) were illustrated in Figure 3, Figure 4 and Figure 5 and an example of TFF is demonstrated in Figure 6.\n\n2.2. Study Parameters and Evaluator Calibration\nThe following parameters were collected: Patient age at the time of flap transfer, sex, primary diagnosis, planning procedure, location, type of defect classified according to Brown et al. [29,30], number of fibula segments, reconstruction time (immediately vs. delayed), flap condition, part of flap loss, and reason for flap loss. Patients’ medical records were analyzed independently for flap outcomes. \n\n2.3. Inclusion and Exclusion Criteria for Study Subjects\nIn this study, we enrolled all patients who underwent a reconstruction of the maxilla or mandible (immediately or delayed) with a FFF. Only cases with incomplete data sets and/or medical records were excluded (n = 2).\n\n2.4. Statistical Analyses\nFischer test and Freeman–Halton extension [31] were used to compare flap outcome with sex, ASA-Score, alcohol and tobacco abuse, time and method of reconstruction, and the number of fibular bone segments. Students t-test was performed to compare the mean age at FFF-transfer, operating time, duration in the ICU, and time of hospitalization between the three flap outcome groups after verification of normality. p < 0.05 was defined as statistically significant. The statistical analysis was carried out with SPSS 25 (SPSS Inc., Chicago, IL, USA).\n\n2.5. Ethics Statement/Confirmation of Patients’ Permission \nThe study was approved by the local Ethics Committee of the Justus-Liebig University Giessen (AZ35/20) and patients’ consent was not necessary for this retrospective study. The patients consented that their intraoral pictures and X-ray images may be used anonymously in the publication. All data in the Microsoft Excel spreadsheet were pseudonymized.\n\n3. Results\nA total of 180 fibula free flaps (FFF) were performed over a period from January 2002 to June 2020. Complete flap success was recorded in 144 cases (80.0%). The remaining 36 flap failures were categorized into the two major groups partial (PFF) and total flap failure (TFF). PFF occurred in n = 16 (44.4%) and TFF in n = 20 (56.6%) cases (Table 1). No statistically significant difference concerning the age at flap transfer, sex, time, and method of reconstruction was apparent. Furthermore, no significant differences were detected in relation to surgical parameters (neck dissection, tracheostomy, radiation therapy) and general risk factors (alcohol and tobacco abuse). There is a significant difference concerning the duration of hospitalization between the groups PFF (mean 22.6 ± 9.7 days) and TFF (mean 33.8 ± 18.8 days) (p = 0.038). No statistically significant differences concerning operating time and duration in the ICU between PFF and TFF were detected. \n\nWhile TFF occurred in a median 8.5 days, PFF was clinically incident later. All TFF were an early complication. Out of 20 TFF (100%), four arterial and four venous thrombosis were found during anastomosis revision. The aetiology of the flap failure of the remaining 12 cases (60%) are unknown. PFF of the skin paddle (n = 11) was observed in a median time of 22.5 days and therefore considered as a late complication. The onset of PFF of bone segments without skin paddles (n = 4) was detected much later at a median time of 101.5 days. \n\nPFF was analyzed in detail. After maxillary reconstruction, two partial and three total flap failures were found in the investigation. This corresponds to 13.5% (n = 5) of the study collective. Two cases of PFF of the skin paddle was found after maxilla reconstructions (Brown Class II and III) with uni-segmental fibular, and three TFF were observed in uni- (n = 2) and bi-segmental reconstruction (n = 1). \n\nIn mandible reconstruction, PFF was observed in 87.5% of cases. A total number of 14 partial flap failures—nine losses of the skin paddle, four isolated bone graft losses, and one combination of both—were found in mandible reconstructions after tumor recurrence (Table 2). Out of 11 skin paddle losses (PFF), 81.81% (n = 9) occurred in the conventional non-VSP group. \n\nTFF was observed mostly in Brown class I (n = 7) and II (n = 6) defects. Subtotal loss of the skin paddle was incident in 68.7% of cases (n = 11 out of 16). Isolated loss of fibular bone segments was found in 25.0% (n = 4) and a combination of both was reported in only one case (6.3%). PFF was found in 50.0% (8 out of 16 cases) of uni-segmental, 25.0% (n = 4) of bi-segmental, and 25.0% (n = 4) of tri-segmental jaw reconstructions. A total flap loss occurred in 55.0% of cases after bi-segmental and in 40.0% of cases after uni-segmental reconstructions (Figure 7). There was a non-significant trend towards TFF in poly-segmental reconstructions (p = 0.114).\n\nA total loss of the skin paddle (n = 11) was observed at a mean of 27 days (median 22 days, range 2–67 days) and an isolated loss of bone graft segments at 181 days (n = 4; median: 101.5 days, range 37–499 days) post surgery. Kaplan–Meier survival function was calculated and visualizes the different periods of partial soft and hard tissue failure (Figure 8).\n\nIn comparison to the beginning of radiation therapy in the complete success group (n = 40, mean 52.9 days, median 49 days, range 21–98 days), PFF of the skin paddle generates a delay (Figure 9). Radiation therapy started at a mean of 63.5 days (n = 4, median 50.5 days, range 39–114 days). The difference remains without any statistical significance (p = 0.358).\n\nClinical flap necrosis and time of bone graft removal were compared with the number of bone segments used. Statistical analysis showed no significant differences between the uni- and bi-segmental graft losses. Overall, clinical flap loss was observed at a mean of 12 days after surgery (Median 8.5 days, range 0–40 days) and surgical removal of the avital grafts at a mean of 86.4 postoperative days (Median 22.5 days, range 2–503 days) (Figure 10).\n\nComparing TFF after maxillary and mandibular reconstruction, it is noticeable that maxillary TFF cases were a mean of 73.3 years old, and thus older than mandibular TFF cases (62.5 years). Therefore, with unequal variance, there is a statistically highly significant difference, which can be explained by the composition of the collective (p < 0.001). Regarding the first clinical sign of impending TFF, signs of TFF were documented after 3.3 days in the upper jaw and after 14.4 days in the lower jaw (Table 3). This observation is statistically significant (p = 0.007). Concerning further surgical procedure and removal of the necrotic graft, no statistically significant difference between maxilla and mandible was observed (Figure 11). \n\n4. Discussion\n4.1. Rate of PFF and TFF \nThrombosis, kinking, and spasm of the vessels have been reported as common causes of total free-flap failure in the early phase after microvascular anastomosis [32]. Venous thrombosis is more common than arterial thrombosis due to the low-flow and low-pressure venous system. Unrecognized venous thrombosis can lead to backward perfusion failure up to total stasis in the arterial system. This is followed by flap ischemia, no-reflow, and subsequent flap loss [33,34]. Fibular flaps are reported with success rates of up to 95.0% [7,14,15,16]. Study findings have shown a cumulative success rate of 88.9% (80.0% complete success and 8.9% partial flap failure). The total failure rate in the presented study is 11.1% over the last 19 years and over all types of indications for reconstruction, time of reconstruction, and method of planning (Non-VSP vs. VSP). In comparison to the here reported investigations, other reconstructive centers report total fibular flap failure rates of up to 12.4% (Table 4). Comparability of the results must be ensured concerning the chosen definition of flap success and PFF/TFF. In the presented study, strict criteria for PFF and TFF was defined. Only clear definitions will engage the collection of comparable data. Retrospective study design without standardization is often of poor data quality due to incomplete follow up data and different investigators. However, data collection over 19 years by a single investigator appears to be impractical. Loss and removal of the whole graft are clear parameters for TFF. From the clinical course and as a result of perfusion disorder through its vascular pedicle, TFF is an early flap failure. Therefore, minor, insufficient perfusion of flap elements leads to malnutrition, and thus to consecutive (sub-)total loss of skin paddle and/or bone segments. This was defined as PFF. PFF therefore does include the functional use of the flap and appears as a late flap failure. Most published data lack a differentiation between soft and hard tissue loss. Partial flap failure was reported with an incidence of 3–14% but has not been further differentiated in most cases (Table 4).\n\nA retrospective single-center study on 129 FFF transfers over the last 20 years found TFF in 12.4% and PFF in 7.8% of cases [21]. An investigation on 20 virtual planned FFF showed that preoperative planning based on preoperative CT-scan allows to include the preoperatively planned skin paddle area [13]. Another clinical trial included preoperatively marked perforator vessels for skin paddle in digital planning and noted a survival rate of 92% (n = 24) in FFF transfer with three total and two partial skin paddle losses [12]. Other investigators observed seven total flap losses and three losses of skin paddle in a total of 99 FFFs [16].\n\nIn the present study, there were four losses of fibular bone segments and only two of them occurred after radiation therapy (RT). Loss of the skin paddle occurred in two cases of maxillary reconstruction and in nine cases of uni- and poly-segmental reconstruction of the mandible. After an average time of 27 days (median: 22 days, range 2–67 days), partial loss of the skin paddle was observed whereas partial bone loss occurred after mean 181 days (Median: 101.5 days, range 37–499 days). Swelling and edema are results of ongoing inflammatory processes and wound healing immediately after surgery. A critically reduced perfusion of the septo-cutaneous perforators could be the consequence. Its maximum dimension can be expected 2–3 days after surgery. The unusually late appearance of visible (sub-)total dysfunction of the skin paddle perfusion after more than the median time of 3 weeks should be interpreted with caution and as result of documentation bias. Any influence of RT in this respect can be excluded, since RT always started after PFF was already observed. The onset of adjuvant RT in the group PFF skin was at median 50.5 days (range 39–114 days) after surgery in comparison to the control group comprising complete flap success (n = 40), in which RT began in median 49 days (range 21–98 days) after surgery. A statistically significant difference could not be observed. However, an adjuvant RT for oncologic reasons was not to be delayed by a PFF. The results must be interpreted with caution due to the small number of cases. In the literature, the effect of prior irradiation on partial or complete loss of FFF compared with unirradiated grafts has often been reported to be statistically insignificant [38,39,40,41,42]. The effect of postoperative irradiation on partial flap failure in microvascular head and neck reconstruction has not been well described in literature and indicates that further studies are needed in this area. Verhelst et al. focused on perioperative irradiation but it was not identified as a statistically insignificant risk factor for flap failure [21]. In a study by He et al., 9 of 17 patients were irradiated postoperatively and all grafts sustained [43]. In this study, no cases of PFF were detected during or after RF. Under RT conditions, PFF could be similar to radiogenic oral mucositis, which is associated with an early inflammatory response [44,45]. These factors provide a target for biology-based mucositis-prevention strategies [46,47], and thus for PFF prevention. Further, the option of an additional skin paddle for defect closure after oncologic resection is without doubt one of the major advantages of the FFF in addition to its clinical and technical function of flap monitoring. On the other site, wound healing disorder of the donor site after skin paddle harvesting appears at a rate of 1.07–31.2% [23,48,49]. In literature, different techniques for closure of the donor site have been described [50]. Focused only on monitor function, the price for an unreliable monitor skin paddle seems to be high and should be critically reflected. Nevertheless, some authors believe that the reliability of the skin paddle for the closure of recipient site defects is insufficient in non-irradiated [51] and especially in irradiated patients [52]. In a retrospective investigation, Thome et al. observed 20% of skin paddle failures (n = 27) and came to a similar conclusion [53]. Other authors found a stable and sufficient vascular supply of the septo-cutaneous skin paddle by the septum intermusculare posterius and perforator vessels around the musculus soleus [54,55,56]. They emphasize the necessity of a muscle cuff around the posterior septum, which contains vessels that are crucial for skin paddle survival [24]. \n\nPartial bone loss may occur more frequently than previously observed and described in the literature as a result of malnutrition. Sufficient neovascularization to allow free-flap survival independent of the vascular pedicle has been reported to occur within 7 to 10 days in myo-cutaneous flaps [57,58,59]. In contrast, a comparative prospective clinical study measured hemoglobin oxygenation and capillary flow in 50 flaps (25 forearm flaps, 15 osseo-cutaneous fibular flaps, and 10 anterolateral thigh flaps) at 4 and 12 postoperative weeks. The authors found that flap autonomization rates were significantly higher in the lower jaw and non-irradiated defect sites. In addition, fascio-cutaneous flaps were found to be autonomized faster than osseo-myo-cutaneous free flaps. Myo-cutaneous flaps were never found to be autonomized after 4 weeks [60]. Kumar et al. studied blood supply of fascio-septo-cutaneous free flaps several months after surgery and found no significant blood flow through vessels across the flap inset [59]. Mücke et al. found that osseo-myo-cutaneous free flaps are significantly dependent on vascularity of the original anastomoses even 1 year after surgery [60]. According to their data, our findings should be interpreted as an adverse effect of radiation therapy (n = 2) and two “real” partial bone segment failures. The risk to develop osteoradionecrosis is decreased in patients with high body mass indices and on steroid therapy [61] through adequate soft-tissue bulk paired with the high-quality vascularized fibula bone [62]. Data published in the literature show that osteoradionecrosis of the original mandible occurred after a median time of 10.9 months (range 1.8–89.7 months) after RT and 90% occurred within 37.4 months [63]. In contrast, our data show bone loss after a median time of 3.38 months (range 1.23–16.63 months) and more than 6 months earlier. This observation should be interpreted with caution due to the low number of cases and should be further studied in larger study groups. \n\nEarly TFF was incident in n = 3 maxillary and n = 17 mandible reconstructions. TFF was found after mandible reconstruction in anterior defects (Classes III-IV, 3 out of 17 cases, 17.6%) and more frequently in lateral defects (Classes I–II, n = 14, 82.4%). Uni- and bi-segmental were commonly used for these Classes I–II reconstructions. Reasons for increased TFF in class I and II were critical pedicle course (inner surface of mandible and mouth floor), kinking of the vascular bundle [64] and length [21,65,66]. In addition to known general risk and complicating factors, further risk factors for flap failure include postoperative swelling and edema, hematoma, movement of the neck, circular tracheal tube fixation loop, and course of the vessel through the neck [33]. \n\nThe therapeutic procedure for partial skin or isolated bone loss depends on the jaw affected. If PFF of the skin paddle occurs in the maxilla, it is usually an uncritical situation and wound healing from peri-osseous tissue can be expected. When bone loss in the maxilla occurs, a “simple” prosthetic rehabilitation by obturator prosthetic is a therapeutic alternative [67,68] if another microvascular bone graft is not desired. Large defects can be downsized with local tissue advancement. Functional impairment (eg. scars) might be addressed in a two-staged procedure. Safe flaps routinely used in our department are the temporal myo-fascial [69], pectoralis major [70,71], and deltopectoral flaps [72]. \n\nIn the mandible, skin paddle loss is often noncritical when the primary bone graft is vital. After wound healing local flaps and staged scars, loosing procedures can be necessary to improve dysfunction such as trismus [73]. Flaps of choice in this situation are often radial forearm [74], pectoralis major [70,71], and deltopectoral flaps [72]. When PFF of bone segments or TFF after mandible reconstructions appear, there are different strategies available that need to be evaluated in light of the patient’s condition. If patient’s condition is poor and the avital graft showed no signs of inflammation, it was left in the oral cavity (Figure 6). If inflammation and/or loosening of osteosynthesis material occurred around the avital segment, removal is necessary. Sometimes further use of osteosynthesis is possible, especially if patient-specific osteosynthesis was used. However, in the majority of cases, removal of the osteosynthesis will become necessary (Table 3). Re-osteosyntheses could be useful in combination with distant flaps like pectoralis major flaps, deltopectoral flaps, and bone hip grafts. The staged procedure of second attempts microvascular bone graft is possible after critical evaluation. The removal of the avital graft and the anticipation of stable scars building and “functional” pseudarthrosis is a further option (Figure 6).\n\n4.2. Influence of Age at Flap Transfer, BMI, ASA-Score and Risk Factors in Terms of Flap Success in Relation to PFF and TFF\nIn this study, no significant differences between patients’ age at flap transfer and flap outcome were observed. This confirms other investigations that patients’ age at flap transfer is not crucial for flap success [75,76]. It is a surrogate parameter for the general condition of the patient [77,78]. A prospective study on 215 patients found that age ≥ 70 years had a significantly higher ASA-Score and shorter duration of surgery. Age was a risk factor for longer ICU stay and complication rate. They found no influence of age on the length of hospital stay and overall success of microvascular reconstructions [79]. In this study, more than 92% were rated ASA 2 or 3. All partial flap failures and all but one total flap occurred in both groups. ASA score and duration of the operation were found to be independent risk factors for operative revisions [76]. In literature, ASA-Rating is correlated with a higher number of postoperative complications after microvascular reconstructions [80,81] and the overall survival [82]. We calculated the relation between ‘Age at flap transfer’ and BMI and found an evenly distributed pattern. \n\nConcerning alcohol and tobacco abuse in the investigated group, no statistically significant differences were found. In published literature, alcohol abuse was identified as a risk factor for postoperative adverse events [82]. Tobacco abuse was shown to reduce overall survival time compared with non- and never-smokers [83,84]. A review by Van Imhoff et al. stated that survival rates are lower and recurrence rates are higher in patients who continued to smoke after having being diagnosed with Head and Neck SCC in comparison to patients who stopped smoking [85].\n\nBMI had no statistically significant influence on flap success in this study. Low BMI or underweight at diagnosis was an independent, unfavorable prognostic factor [86,87]. Obesity was associated with better outcome and was not an independent risk factor for postoperative complications of free tissue transfer [88,89]. Other investigators found that higher BMI/obesity is a risk factor for peri- and postoperative medical complications [90].\n\nThe duration of hospitalization was calculated with a mean of 22.6 days in the PFF group and a mean of 33.8 days in the TFF group. Statistically significant differences (p = 0.038) were found in the occurrence of partial or total flap failures (Table 1). While the majority (68.75%, n= 11 out of 16) of all partial flap failures are a dysfunction of the skin paddle failures (mean duration of hospitalization partial flap loss group 20.71 days), we conclude that loss of that skin loss does not result in significantly longer hospital stay than in total flap losses. Stepwise removing of avital flap parts, deperiostizing of the bone graft, and covering with oral mucosa is an attempt for flap salvage. However, the initial stay at the ICU seems to have no statistical influence concerning upcoming PFF or TFF. It was calculated in both groups with a mean of approximately 2.0 days. \n\nNo statistically significant difference concerning mean operating time (PFF: meantime 546 min, TFF: meantime 524 min) and flap outcome was found. Surgery time is described as a risk factor for postoperative complications [91,92,93]. Increased operating time may also be the result of a younger surgeon learning and being taught by an older instructing surgeon. However, operating time should be reduced whenever possible [92]. The study could not include ischemia time in the risk analysis because this parameter was not recorded or was incomplete.\n\n4.3. PFF and TFF in Non-VSP vs. VSP and Reconstruction Methods (Immediate vs. Delayed)\nThe majority of isolated skin paddle losses occurred in the non-VSP group. Reasons can be seen in mechanical trauma and manipulation during free-hand transplant forming i.e., preparation of bone segments and revised application of osteosynthesis. Individually custom-made cutting guides stabilize and preserve intersegmental connectors for stabilization of several bone segments, which provide a valuable support on the vascular pedicle during transplant preparation and shaping.\n\nNo statistically significant differences were found concerning patients’ preoperative planning procedure (non-VSP vs. VSP) and time of reconstruction (immediately vs. delayed). The results confirmed the findings of other clinical investigations [94]. A retrospective study of 128 osseous free flaps with a minimum follow-up of 12 months evaluated plate-related complications in patient-specific versus conventional fixation systems. They found more complications with patient-specific plates (e.g., wound healing disorders, plate exposure, fixation failure, and subtotal osseous union) in comparison to conventional reconstruction plates, but the differences were statistically insignificant.\n\nOne possible reason for (sub-)total bone loss despite maintained perfusion of the vascular pedicle might be trauma during preparation, segmentation, and shaping of the fibula graft. Preoperatively planned and fabricated saw guides and patient-specific implants ease and accelerate the surgical procedure itself, which should be helpful in avoiding mistakes and facilitating the handling of the fibula graft. More complex shaping and osteotomization of bone segments leads to manipulation of the vascular pedicle during dissection and puts it at risk [22]. Furthermore, the impact of VSP and patient-specific plates in terms of wound healing abnormalities, plate exposure, and subtotal osseous union shows a trend towards increased complication rates compared with non-VSP with hand-bended plates. Plate-related complications were increased with radiotherapy and multi-segment flaps [95]. \n\nFurther investigations on partial flap loss of osseomyocutaneous FFF are needed.\n\n5. Conclusions\nThe fibula free flap constitutes a standard therapy for jaw reconstructive surgery. The present results of 180 fibula free flap over a period of 19 years shows a cumulative success rate of 88.9%, which is well comparable with other studies. The findings of our long term monocenter retrospective investigation are a position statement about flap success and partial and total loss rates, which was achieved by careful patient selection and a two team approach to reduce operating time. In partial or total flap failure, no statistically significant correlation was observed between patient age, sex, ASA, BMI, alcohol and tobacco abuse, time, and method of reconstruction (virtual versus non-virtual surgical planning). Total flap failure caused significantly prolonged hospitalization time. Partial flap failure affected mainly the skin paddle. Two-thirds of these cases were found in the non-VSP group and only two cases were observed in the virtual surgical planning group. This could be attributed to protective effects of the cutting-guide template, which possibly decrease the mechanical trauma during surgery.\n\nAcknowledgments\nThe authors are grateful for the consent of the patient for presented X-rays and clinical images. This publication is part of the second author’s dental doctoral thesis (SS).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nConceptualization, M.K.; methodology, S.S., M.K., C.B.; formal analysis, M.K.; investigation, M.K., and S.S; data curation, M.K. and S.S.; writing—original draft preparation, M.K., S.S., S.A. and S.B.; writing—review and editing, M.K., S.S., S.A., C.B., D.S., H.-P.H. and S.B.; visualization, M.K., D.S., H.-P.H. and S.A.; supervision, M.K., H.-P.H., S.B. and S.A.; project administration, M.K. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nInstitutional Review Board Statement\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Justus-Liebig University Giessen (AZ35/20, approval 25.5.2020). \n\nInformed Consent Statement\nPatient consent was waived as the study is a retrospective data analysis.\n\nData Availability Statement\nThe data presented in this study are available upon request from the corresponding author.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Schematic illustration of reconstructive workflow and stratification in partial and total flap failure groups. The major characteristic of PFF is the remaining blood supply by the vascular pedicle. In contrast to this, TFF is characterized by interrupted graft perfusion.\n\nFigure 2 Example of ‘PFF skin’ after maxilla reconstruction.\n\nFigure 3 The clinical course of PFF. (OPT 1) Due to the recurrence of an ossifying fibroma (odontogenic tumor) in the ramus ascendens mandibulae in a 22-year-old patient, (OPT 2) a continuity resection and simultaneous reconstruction with a bi-segmental fibula and CAD/CAM plate was planned. (OPT 3) The clinical submandibular fistula had a connection to the plate (Figure 4A). (OPT 4) An OPT image was obtained after removal of the avital fibular segments and re-stabilization of the remaining graft. There is initial evidence of incipient bone healing on the proximal resection-site. (OPT 5) Follow-up visit at 9 weeks after re-stabilization. In the condylar segment, bone healing is pictured, and at the distal segment, progressive resorption is visible. (OPT 6) Progressive bone healing and callus formation originating from the resection site is visible 19 weeks after re-stabilization.\n\nFigure 4 (A) Clinical aspect 4 weeks after reconstruction. After reopening the submandibular approach and excision of the skin fistula, there was no evidence of screw loosening. Temporary unscrewing of the screw (No. 5) leads to bleeding. (B) With a new fistula, the site was reentered 8 weeks after surgery and the screw was removed again. There was no clear bleeding from the screw hole. In addition, the anterior-caudal edge of the bone was removed.\n\nFigure 5 (C1) The CAD/CAM plate was removed 14 weeks after surgery when the fistula was productive again. (C1–C3) A sharp demarcation line caudal to the crestal edge of the plate became visible and was conspicuous. (C2) Between the fibula segments, an incipient ossification of the gap was observed. The underlying bone was pale. (C3) The bone was removed caudally. The bone marrow was replaced by granulation tissue and was removed. (C4) The intersegmental ossification was not yet sufficient so that stabilization again was necessary.\n\nFigure 6 The following OPTs outline the clinical course of TFF in a 76-year-old patient in good general condition who suffered from osseous metastasis of prostate cancer and underwent FFF. (OPT 1) A pathologic fracture occurred after the removal of necrotic bone in the right lower jaw in the setting of bisphosphonate induced MRONJ stage III (treatment with Zoledronacid/Denosumab in prostate cancer) [28]. (OPT 2) Virtual planning of double-barrel fibula was performed. CAD/CAM plate was used for stabilization and the simultaneous insertion of two dental implants was performed. (OPT 3) At 3 weeks post-surgery, the skin paddle was lost. A surgical exploration ended with the removal of an avital distal graft segment and modification of the plate in situ. The vascular pedicle of the remaining FFF still rendered a clear signal in the Doppler ultrasonic probe. (OPT 4) At 16 weeks after surgery, the remaining graft segment also had to be removed in the setting of continued inflammation and the absence of a Doppler signal. (OPT 5) At 22 weeks after surgery: The screws loosened in the anterior mandible segment so that the remaining plate with teeth 32–42 and a bone sequester had to be taken out.\n\nFigure 7 Partial or total flap failure in relation to the number of fibula segments (p = 0.114).\n\nFigure 8 Kaplan–Meier function was drawn for the three sub-groups of PFF. The abscissa axis “time” (days) is drawn on a logarithmic scale.\n\nFigure 9 Comparison of the onset of adjuvant radiation therapy between the groups of complete flap success (n = 40) and PFF skin (n = 4).\n\nFigure 10 TFF concerning the first clinical signs of flap necrosis and time of removal of the avital graft was visualized by Kaplan–Meier function. The abscissa axis “time” (days) is drawn on a logarithmic scale.\n\nFigure 11 TFF analysis. Clinically diagnosed flap necrosis and further surgical interventions (removal of graft) are shown according to jaw location (maxilla or mandible) in the postoperative time course. The ordinate axis “time” (days) is drawn on a logarithmic scale.\n\ncancers-13-00865-t001_Table 1Table 1 Clinical details of partial (PFF; n = 16) and total flap failures (TFF; n = 20) after jaw reconstruction with fibular free flaps.\n\nN = 36\tPFF\nN = 16 (44.4%)\tTFF\nN = 20 (56.6%)\tp-Value\t\nAge (years), SD\t59.9 ± 14.4\t62.5 ± 9.5\tp = 0.520\t\nFollow-up (months), SD\t48 ± 42.9\t31.5 ± 31.6\tp = 0.193\t\nType of flap loss\t\n\t\n\t\n\t\nPFF, Skin paddle\t11\t\n\t\n\t\nPFF, Bone segment\t4\t\n\t\n\t\nPFF, Both\t1\t\n\t\n\t\nTotal flap loss (TFF)\t\n\t20\t\n\t\nSex\t\n\t\n\t\n\t\nFemale\t5\t6\tp = 0.609\t\nMale\t11\t14\t\n\t\nDiagnosis\t\n\t\n\t\n\t\nBenign tumor\nMalignant tumor\nMRONJ\nORN\t1\n15\n\n\n\t\n15\n2\n3\t\n\t\nReconstruction\t\n\t\n\t\n\t\nImmediate\t14\t17\tp = 0.610\t\nDelayed\t2\t3\t\n\t\nReconstruction\t\n\t\n\t\n\t\nNon-VSP\t10\t10\tp = 0.341\t\nVSP\t6\t10\t\n\t\nNeck dissection\t\n\t\n\t\n\t\nUnilateral\t11\t13\tn.s.\t\nBilateral\t3\t3\t\n\t\nNone\t2\t4\t\n\t\nTracheostomy\t\n\t\n\t\n\t\nNone\t6\t8\tn.s.\t\nPrimary\t9\t11\t\n\t\nSecondary\t1\t1\t\n\t\nIrradiation\t\n\t\n\t\n\t\nPreoperative\t1\t3\tn.s.\t\nPostoperative\t8\t4\t\n\t\nNone\t7\t13\t\n\t\nRisk factors\t\n\t\n\t\n\t\nAlcohol abuse\t5\t9\tp = 0.348\t\nTobacco abuse\t9\t13\tp = 0.546\t\nOperating time (min)\t546.2 ± 94.9\t524.4 ± 97.2\tp = 0.504\t\nDuration ICU (days)\t2 ± 1.3\t2.1 ± 1.7\tp = 0.847\t\nHospitalization (days)\t22.6 ± 9.7\t33.8 ± 18.8\tp = 0.038\t\nBMI\n≤18\n18 ≤ 25\n25 ≤ 30\n30 ≤ 35\n>35\t\n\n9\n3\n4\n\t\n1\n9\n7\n2\n1\t\n\t\nASA-Score\t\n\t\n\t\n\t\nASA 2\t10\t7\t\n\t\nASA 3\t6\t12\t\n\t\nASA 4\t\n\t1\t\n\t\nn.s. = not significant; ORN, Osteoradionecrosis; MRONJ, Medication-related osteonecrosis of the jaw; VSP, virtual surgical planning; BMI, Body mass index; SD, standard deviation.\n\ncancers-13-00865-t002_Table 2Table 2 Table depicting the locations according to the classification by Brown et al. where PFF (n=16) and TFF (n=20) occurred [29,30].\n\nType of Defect\tPFF Skin (n = 11)\tPFF Bone (n = 4)\tPFF Both (n = 1)\tTFF (n = 20)\t\nMaxilla\t\n\t\n\t\n\t\n\t\nII\t1\t-\t-\t2\t\nIII\t1\t-\t-\t1\t\nMandible\t\n\t\n\t\n\t\n\t\nI\t\n4\n\t-\t\n1\n\t\n7\n\t\nIc\t-\t-\t-\t\n1\n\t\nII\t\n2\n\t\n2\n\t-\t\n6\n\t\nIIc\t-\t1\t-\t-\t\nIII\t\n3\n\t\n1\n\t-\t2\t\nIV\t-\t-\t-\t\n1\n\t\ncancers-13-00865-t003_Table 3Table 3 Clinical details of total flap failures (n = 20).\n\nN = 20\tMaxilla (n = 3)\tMandible (n = 17)\tOverall (n = 20)\t\np\n\t\nAge (years), SD\t73.3 ± 1.8\t60.6 ± 8.9\t62.5 ± 9.5\tp = 0.001 ^\t\nFollow-up (months), SD\t10.3 ± 9.7\t35.2 ± 32.8\t31 ± 31.6\t\n\t\nThe earliest sign of flap dysfunction (days)\t3. 3 ± 3.5\n (Median 3)\t14.4 ± 11.1\n(Median 10)\t12 ± 10.9 \n(Median 8.5)\tp = 0.007 ^\t\nSurgical validation and avital flap treatment procedure (days)\t54 ± 60.1\n(Median 36)\t92.1 ± 132.0\n(Median 21)\t86.5 ± 123.6\n(Median 22.5)\tp = 0.449 ^\t\nAnastomosis revisions\t2\t6\t8\t\n\t\nArterial thrombosis ‡\t2\t2\t4\t\n\t\nVenous thrombosis ‡\t-\t4\t4\tn.s\t\nUnknown\t1\t11\t12\t\n\t\nExplantation of bone graft\t2\t16\t18\t\n\t\nOsteosynthesis (PSI) removal\t1\t11\t12\t\n\t\nRe-osteosynthesis\t-\t3\t3\t\n\t\nSecond flap\t1\t8\t9\t\n\t\nTemporalis muscle flap\t1\t1\t2\t\n\t\nDeltopectoral flap\t-\t1\t1\t\n\t\nPectoralis major flap\t-\t2\t2\t\n\t\nRFF\t-\t1\t1\t\n\t\nFFF\t-\t2\t2\t\n\t\nHip graft (non-DCIA)\t-\t1\t1\t\n\t\n‡ Kind of thrombosis was evaluated during microsurgical revision. (n.s. = not significant; ^ Equal variances not assumed; DCIA, deep circumflexia iliac artery; PSI, patient-specific implant; SD, standard deviation; RFF, radial forearm flap).\n\ncancers-13-00865-t004_Table 4Table 4 Overview of FFF total and partial flap failure rates in the literature.\n\nAuthors\tInvestigation Period\t\nn\n\tTotal Flap Failure\tPartial Flap Failure\t\nThis study\t2002–2020\t180\t11.1%\t8.9%\t\nColletti et al. [16]\t2002–2010\t99\t7%\t3%\t\nGallegos-Hernandez et al. [35]\t1996–2006\t87\t16.1%\t-\t\nGötze et al. [12]\t2013–2015\t24\t12.5%\t8.3%\t\nLopez-Arcas et al. [36]\t1992–2006\t117\t-\t8.5%\t\nMomoh et al. [23]\t2005–2009\t157\t1%\t14%\t\nMücke et al. [37]\t2009–2013\t76\t9.2%\t-\t\nSeruya et al. [22]\t2003–2012\t68\t4.41%\t11.76%\t\nShroff et al. [14]\t2009–2013\t30\t6.66%\t-\t\nVerhelst et al. [21]\t1996–2016\t129\t12.4%\t7.8%\n==== Refs\nReferences\n1. Hidalgo D.A. Fibula free flap: A new method of mandible reconstruction Plast. Reconstr. 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Vascular Complications and Free Flap Salvage in Head and Neck Reconstructive Surgery Ann. Plast. Surg. 2017 78 S83 S88 10.1097/sap.0000000000001011 28166137 \n67. Costa H. Zenha H. Sequeira H. Coelho G. Gomes N. Pinto C. Martins J. Santos D. Andresen C. Microsurgical reconstruction of the maxilla: Algorithm and concepts J. Plast. Reconstr. Aesthetic Surg. 2015 68 e89 e104 10.1016/j.bjps.2014.12.002 \n68. Cao Y. Yu C. Liu W. Miao C. Han B. Yang J. Li L. Li C. Obturators versus flaps after maxillary oncological ablation: A systematic review and best evidence synthesis Oral Oncol. 2018 82 152 161 10.1016/j.oraloncology.2018.05.019 29909890 \n69. Colmenero C. Martorell V. Colmenero B. Sierra I. Temporalis myofascial flap for maxillofacial reconstruction J. Oral Maxillofac. Surg. 1991 49 1067 1073 10.1016/0278-2391(91)90141-8 1653825 \n70. Ariyan S. The Pectoralis Major Myocutaneous Flap A Versatile Flap for Reconstruction in the Head and Neck Plast. Reconstr. Surg. 1979 63 73 81 10.1097/00006534-197901000-00012 372988 \n71. Ariyan S. Pectoralis Major, Sternomastoid, and Other Musculocutaneous Flaps for Head and Neck Reconstruction Clin. Plast. Surg. 1980 7 89 109 10.1016/s0094-1298(20)31995-7 6988149 \n72. Bakamjian V. Poole M. Maxillo-facial and palatal reconstructions with the deltopectoral flap Br. J. Plast. Surg. 1977 30 17 37 10.1016/s0007-1226(77)90029-7 319850 \n73. de Pablo A. Chen Y.-T. Chen J.-K. Tsao C.-K. Trismus surgical release and free flap reconstruction after radiation therapy in oral and oropharyngeal squamous cell carcinoma J. Surg. Oncol. 2018 117 142 149 10.1002/jso.24806 28833146 \n74. Chang T.S. Wang W. Hsu C.Y. The free forearm flap--a report of 25 cases Ann. Acad. Med. Singap. 1982 11 236 240 7137902 \n75. Ludolph I. Lehnhardt M. Arkudas A. Kneser U. Pierer G. Harder Y. Horch R.E. Plastisch rekonstruktive Mikrochirurgie beim alten Patienten Handchir. · Mikrochir. · Plast. Chir. 2017 50 118 125 10.1055/s-0043-115730 29045998 \n76. Wolfer S. Wohlrath R. Kunzler A. Foos T. Ernst C. Schultze-Mosgau S. Scapular free flap as a good choice for mandibular reconstruction: 119 out of 280 cases after resection of oral squamous cell carcinoma in a single institution Br. J. Oral Maxillofac. Surg. 2020 58 451 457 10.1016/j.bjoms.2020.02.020 32201048 \n77. Hwang K. Lee J.P. Yoo S.Y. Kim H. Relationships of comorbidities and old age with postoperative complications of head and neck free flaps: A review J. Plast. Reconstr. Aesthetic Surg. 2016 69 1627 1635 10.1016/j.bjps.2016.08.018 \n78. Sierakowski A. Nawar A. Parker M. Mathur B. Free flap surgery in the elderly: Experience with 110 cases aged ≥70 years J. Plast. Reconstr. Aesthetic Surg. 2017 70 189 195 10.1016/j.bjps.2016.11.008 \n79. Kesting M.R. Hölzle F. Wolff K.-D. Wagenpfeil S. Hasler R.J. Wales C.J. Steinstraesser L. Rohleder N.H. Use of microvascular flap technique in older adults with head and neck cancer: A persisting dilemma in reconstructive surgery? J. Am. Geriatr. Soc. 2011 59 398 405 10.1111/j.1532-5415.2011.03315.x 21391930 \n80. Grill F.D. Wasmaier M. Mücke T. Ritschl L.M. Wolff K.-D. Schneider G. Loeffelbein D.J. Kadera V. Identifying perioperative volume-related risk factors in head and neck surgeries with free flap reconstructions—An investigation with focus on the influence of red blood cell concentrates and noradrenaline use J. Cranio Maxillofac. Surg. 2020 48 67 74 10.1016/j.jcms.2019.12.001 \n81. Clark J.R. McCluskey S.A. Hall F. Lipa J. Neligan P. Brown D. Irish J. Gullane P. Gilbert R. Predictors of morbidity following free flap reconstruction for cancer of the head and neck Head Neck 2007 29 1090 1101 10.1002/hed.20639 17563889 \n82. Loeffelbein D. Ritschl L. Güll F. Roth M. Wolff K.-D. Mücke T. Influence of possible predictor variables on the outcome of primary oral squamous cell carcinoma: A retrospective study of 392 consecutive cases at a single centre Int. J. Oral Maxillofac. Surg. 2017 46 413 421 10.1016/j.ijom.2016.11.014 28007325 \n83. Chen A.M. Chen L.M. Vaughan A. Farwell D.G. Luu Q. Purdy J.A. Vijayakumar S. Head and Neck Cancer Among Lifelong Never-Smokers and Ever-Smokers Am. J. Clin. Oncol. 2011 34 270 275 10.1097/coc.0b013e3181dea40b 20622648 \n84. Fortin A. Wang C.S. Vigneault É. Influence of Smoking and Alcohol Drinking Behaviors on Treatment Outcomes of Patients With Squamous Cell Carcinomas of the Head and Neck Int. J. Radiat. Oncol. 2009 74 1062 1069 10.1016/j.ijrobp.2008.09.021 \n85. Van Imhoff L.C. Kranenburg G.G. Macco S. Nijman N.L. van Overbeeke E.J. Wegner I. Grolman W. Pothen A.J. Prognostic value of continued smoking on survival and recurrence rates in patients with head and neck cancer: A systematic review Head Neck 2015 38 E2214 E2220 10.1002/hed.24082 25900211 \n86. Crippen M.M. Brady J.S. Mozeika A.M. Eloy J.A. Baredes S. Park R.C.W. Impact of Body Mass Index on Operative Outcomes in Head and Neck Free Flap Surgery Otolaryngol. Neck Surg. 2018 159 817 823 10.1177/0194599818777240 \n87. Gama R.R. Song Y. Zhang Q. Brown M.C. Wang J. Habbous S. Tong L. Huang S.H. O’Sullivan B. Waldron J. Body mass index and prognosis in patients with head and neck cancer Head Neck 2017 39 1226 1233 10.1002/hed.24760 28323362 \n88. de La Garza G. Militsakh O.N. Panwar A. Galloway T.L. Jorgensen J.B. Ledgerwood L.G. Kaiser K. Bs C.K. Shnayder Y. Neumann C.A. Obesity and perioperative complications in head and neck free tissue reconstruction Head Neck 2016 38 E1188 E1191 10.1002/hed.24189 26268587 \n89. Khan M.N. Russo J. Spivack J. Pool C. Likhterov I. Teng M. Genden E.M. Miles B.A. Association of Body Mass Index With Infectious Complications in Free Tissue Transfer for Head and Neck Reconstructive Surgery JAMA Otolaryngol. Neck Surg. 2017 143 574 579 10.1001/jamaoto.2016.4304 \n90. Thai L. McCarn K. Stott W. Watts T. Wax M.K. Andersen P.E. Gross N.D. Venous thromboembolism in patients with head and neck cancer after surgery Head Neck 2012 35 4 9 10.1002/hed.22920 22302625 \n91. Eskander A. Kang S. Tweel B. Sitapara J. Old M. Ozer E. Agrawal A. Carrau R. Rocco J.W. Teknos T.N. Predictors of Complications in Patients Receiving Head and Neck Free Flap Reconstructive Procedures Otolaryngol. Neck Surg. 2018 158 839 847 10.1177/0194599818757949 \n92. Cannady S.B. Hatten K.M. Bur A.M. Brant J. Fischer J.P. Newman J.G. Chalian A.A. Use of free tissue transfer in head and neck cancer surgery and risk of overall and serious complication(s): An American College of Surgeons-National Surgical Quality Improvement Project analysis of free tissue transfer to the head and neck Head Neck 2017 39 702 707 10.1002/hed.24669 28000297 \n93. Offodile A.C. Aherrera A. Wenger J. Rajab T.K. Guo L. Impact of increasing operative time on the incidence of early failure and complications following free tissue transfer? A risk factor analysis of 2,008 patients from the ACS-NSQIP database Microsurgery 2015 37 12 20 10.1002/micr.22387 25752264 \n94. Tang N.S. Ahmadi I. Ramakrishnan A. Virtual surgical planning in fibula free flap head and neck reconstruction: A systematic review and meta-analysis J. Plast. Reconstr. Aesthetic Surg. 2019 72 1465 1477 10.1016/j.bjps.2019.06.013 \n95. Rendenbach C. Steffen C. Hanken H. Schluermann K. Henningsen A. Beck-Broichsitter B. Kreutzer K. Heiland M. Precht C. Complication rates and clinical outcomes of osseous free flaps: A retrospective comparison of CAD/CAM versus conventional fixation in 128 patients Int. J. Oral Maxillofac. Surg. 2019 48 1156 1162 10.1016/j.ijom.2019.01.029 30792087\n\n",
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"title": "Partial and Total Flap Failure after Fibula Free Flap in Head and Neck Reconstructive Surgery: Retrospective Analysis of 180 Flaps over 19 Years.",
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"abstract": "COVID-19 was declared to be a pandemic due to the rapid increase of cases around the world, including the number of pregnant women. Data about vertical transmission of COVID-19 are still limited and controversial: in most cases, although a positive mother, the virus could not be isolated in amniotic fluid, cord blood, breast milk or neonatal throat swab in these patients. No data have been published about possible intrauterine sonographic signs of infection. A pregnant woman was diagnosed with SARS-CoV-2 at 35+5 weeks of gestation and managed conservatively at home. At transabdominal ultrasound at 38+3 weeks, fetal bowel and gallbladder calcifications were noted. CMV and other infectious agents were ruled out; an iterative caesarean section was performed at 38+5 weeks without complications. Placenta resulted negative for SARS-CoV-2; the umbilical cord blood sample was IgG positive and IgM negative as per maternal infection. The baby developed respiratory distress syndrome requiring endotracheal surfactant administration and nasal-CPAP for one day but nasopharyngeal swabs at birth and after 48 hours were SARS-CoV-2 negative. Neonatal abdominal ultrasound showed normal liver, acalculous gallbladder with mild parietal thickening. The baby was discharged in good conditions. Although gallbladder calcifications and echogenic bowel are highly suspicious of viral infection and were thought to be due to the vertical transmission of SARS-CoV-2, these findings were not corroborated by the results of our diagnostic tests; these sonographic findings might represent a false positive of fetal infection in mother affected by COVID-19 since vertical transmission appears to be rare.",
"affiliations": "Unit of Prenatal Medicine, Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Prenatal Medicine, Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Prenatal Medicine, Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Clinical Microbiology, University Hospital of Modena, Modena, Italy.;Laboratory of Microbiology and Virology, University Hospital of Modena, Modena, Italy.;Unit of Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Prenatal Medicine, Obstetrics and Gynecology, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Modena, Italy - [email protected].",
"authors": "Sileo|Filomena G|FG|;Tramontano|Anna L|AL|;Leone|Chiara|C|;Meacci|Marisa|M|;Gennari|William|W|;Ternelli|Giliana|G|;LA Marca|Antonio|A|;Lugli|Licia|L|;Berardi|Alberto|A|;Facchinetti|Fabio|F|;Bertucci|Emma|E|",
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"mesh_terms": "D000653:Amniotic Fluid; D000086382:COVID-19; D002114:Calcinosis; D002585:Cesarean Section; D000072700:Conservative Treatment; D005189:False Positive Reactions; D005260:Female; D005312:Fetal Blood; D005315:Fetal Diseases; D005705:Gallbladder Diseases; D006801:Humans; D007231:Infant, Newborn; D007410:Intestinal Diseases; D008297:Male; D000076723:Negative Results; D010920:Placenta; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012127:Respiratory Distress Syndrome, Newborn; D000086402:SARS-CoV-2; D016216:Ultrasonography, Prenatal",
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"title": "Pregnant woman infected by Coronavirus disease (COVID-19) and calcifications of the fetal bowel and gallbladder.",
"title_normalized": "pregnant woman infected by coronavirus disease covid 19 and calcifications of the fetal bowel and gallbladder"
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"literaturereference": "Sileo FG, Tramontano AL, Leone C, Meacci M, Gennari W, Ternelli G et al.. Pregnant woman infected by Coronavirus disease (COVID-19) and calcifications of the fetal bowel and gallbladder.. Minerva Obstetrics and Gynecology. 2021;73 (1):121-124",
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{
"abstract": "Iron deficiency anemia is often listed among potential adverse effects of gastric acid-suppressive medications, given that gastric acidity promotes intestinal absorption of nonheme iron. Additionally, the antacid calcium carbonate can inhibit iron absorption. However, there is little direct clinical evidence that proton-pump inhibitors, histamine-2 receptor antagonists, or calcium carbonate cause iron deficiency anemia. Most case reports have had substantial limitations (e.g., minimal follow-up and presence of other causes of iron deficiency), and retrospective cohort studies have lacked sufficient patient-specific detail to make strong causal inferences. We present 2 cases-both with detailed, prospective 10-year follow-up-in which combinations of proton-pump inhibitors, histamine-2 receptor antagonists and calcium carbonate were clearly associated with development of iron deficiency anemia. Overt iron-deficiency anemia is probably uncommon in patients who use acid-modifying medications and who have no other conditions that predispose to iron deficiency. Nevertheless, clinicians should be aware of this potential complication, given widespread use of these agents.",
"affiliations": "Department of Medicine, University of South Carolina School of Medicine, Columbia, South Carolina.;Department of Medicine, University of South Carolina School of Medicine, Columbia, South Carolina. Electronic address: [email protected].",
"authors": "Vinnakota|Ramya Deepthi|RD|;Brett|Allan S|AS|",
"chemical_list": "D006635:Histamine H2 Antagonists; D054328:Proton Pump Inhibitors; D002119:Calcium Carbonate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2018.10.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "357(2)",
"journal": "The American journal of the medical sciences",
"keywords": "Anemia; Calcium carbonate; Histamine H2 antagonists; Iron deficiency; Proton pump inhibitors",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000368:Aged; D018798:Anemia, Iron-Deficiency; D002119:Calcium Carbonate; D006635:Histamine H2 Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D054328:Proton Pump Inhibitors",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "160-163",
"pmc": null,
"pmid": "30528320",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Iron Deficiency Anemia Associated With Acid-Modifying Medications: Two Cases and Literature Review.",
"title_normalized": "iron deficiency anemia associated with acid modifying medications two cases and literature review"
}
|
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"abstract": "Anti-NMDA receptor encephalitis is a rare and often therapy-responsive autoimmune disease that usually affects young adults and causes neuropsychiatric symptoms. Here, we describe a 69-year-old patient who developed anti-NMDA receptor encephalitis while being under adequate immunosuppressive therapy following liver transplantation. Although a broad spectrum of different immunotherapies was applied and anti-NMDA receptor antibody titers gradually decreased, the clinical course could not be affected positively. Autoimmune encephalitis after transplantation is only described in a few cases and not well-recognized. Our case adds further evidence for anti-NMDA receptor encephalitis as the cause of neuropsychiatric symptoms even under immunosuppressive therapy in a post-transplant setting.",
"affiliations": "Department of Neurology, Hannover Medical School, Hanover, Germany.;Department of Neurology, Hannover Medical School, Hanover, Germany.;Department of Neurology, Hannover Medical School, Hanover, Germany.;Department of Neurology, Hannover Medical School, Hanover, Germany.;Department of Neurology, Hannover Medical School, Hanover, Germany.;Department of Neurology, Hannover Medical School, Hanover, Germany.;Department of Neurology, Hannover Medical School, Hanover, Germany.;Department of Neurology, Hannover Medical School, Hanover, Germany.",
"authors": "Konen|Franz Felix|FF|;Schwenkenbecher|Philipp|P|;Jendretzky|Konstantin Fritz|KF|;Hümmert|Martin Werner|MW|;Wegner|Florian|F|;Stangel|Martin|M|;Sühs|Kurt-Wolfram|KW|;Skripuletz|Thomas|T|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3389/fneur.2019.00987",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2019.00987NeurologyCase ReportSevere Anti-N-Methyl-D-Aspartate Receptor Encephalitis Under Immunosuppression After Liver Transplantation Konen Franz Felix Schwenkenbecher Philipp Jendretzky Konstantin Fritz Hümmert Martin Werner Wegner Florian Stangel Martin Sühs Kurt-Wolfram Skripuletz Thomas *Department of Neurology, Hannover Medical School, Hanover, GermanyEdited by: Fabienne Brilot, University of Sydney, Australia\n\nReviewed by: Takahiro Iizuka, Kitasato University, Japan; Anna Fogdell-Hahn, Karolinska Institute (KI), Sweden; Marianna Spatola, Massachusetts General Hospital and Harvard Medical School, United States\n\n*Correspondence: Thomas Skripuletz [email protected] article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n25 9 2019 2019 10 98712 7 2019 29 8 2019 Copyright © 2019 Konen, Schwenkenbecher, Jendretzky, Hümmert, Wegner, Stangel, Sühs and Skripuletz.2019Konen, Schwenkenbecher, Jendretzky, Hümmert, Wegner, Stangel, Sühs and SkripuletzThis 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.Anti-NMDA receptor encephalitis is a rare and often therapy-responsive autoimmune disease that usually affects young adults and causes neuropsychiatric symptoms. Here, we describe a 69-year-old patient who developed anti-NMDA receptor encephalitis while being under adequate immunosuppressive therapy following liver transplantation. Although a broad spectrum of different immunotherapies was applied and anti-NMDA receptor antibody titers gradually decreased, the clinical course could not be affected positively. Autoimmune encephalitis after transplantation is only described in a few cases and not well-recognized. Our case adds further evidence for anti-NMDA receptor encephalitis as the cause of neuropsychiatric symptoms even under immunosuppressive therapy in a post-transplant setting.\n\nEpstein-Barr virusanti-NMDA receptor encephalitisimmunosuppressionliver-transplantationautoimmune encephalitis\n==== Body\nBackground\nThe anti-N-methyl-D-aspartate (NMDA) receptor encephalitis was first described in female patients under 50 years who developed neuropsychiatric symptoms after a non-obligate prodromal phase with flu-like symptoms (1–3). The core symptoms of the disease are cognitive deficiency, behavioral changes, dyskinesia, and seizures (2). Some patients may develop autonomic dysfunctions and reduced consciousness leading to the need of intensive care (2). This spectrum of encephalitis is associated with antibodies that target extracellular epitopes of cell-surface or synaptic proteins such as the GluN1 subunit of the NMDA receptor (2). Associated neurological syndromes often respond to immunotherapy, achieving substantial, or complete recovery in >75% of the patients (2).\n\nSince a strict immunosuppressive treatment after solid organ transplantation is mandatory, it could be assumed that those patients have only marginal risk in developing autoimmune encephalitis. However, anti-NMDA receptor encephalitis was described in five post-transplant cases (4–8). Here, we report the first case of anti-NMDA receptor encephalitis after liver transplantation during sufficient anti-rejection immunosuppressive therapy.\n\nCase Presentation\nA 69-year-old woman presented with a 10-day history of progressive mental impairment to the emergency department of a community hospital. Acquaintances of her had observed that she withdraw from social life, barely spoke, and appeared mentally absent. The clinical examination showed that she was aphasic and not oriented. The remaining neurological examination was unremarkable.\n\nA decade before onset of the neurological symptoms, she was diagnosed with liver cirrhosis due to chronic hepatitis c virus infection of which she suffered for 13 years and received an allogenic transplant. The cause of hepatitis c virus infection remained unclear. From then on, she was permanently on immunosuppressive therapy with tacrolimus and mycophenolate mofetil. At the time of onset of neurological symptoms, tacrolimus was administered with 1.5 mg/day and mycophenolate mofetil with 1,000 mg/day. Blood dosage of tacrolimus was 2.2 μg/L, and blood dosage of mycophenolate mofetil was not examined. White blood cell count and distribution revealed normal values for leukocytes (8,300/μl) and lymphocytes (1,300/μl).\n\nAfter first admission, contrast enhanced magnetic resonance imaging (MRI) of the brain demonstrated leukoencephalopathy but no signs of a brain tumor or encephalitis. Basic cerebrospinal fluid (CSF) diagnostic revealed pleocytosis (58 cells/μl) and an elevated protein level (695 mg/L), while the lactate concentration was within the normal range (2.1 mmol/L). A viral encephalitis was assumed and the patient was treated intravenously with acyclovir. In the course of disease, she suffered from generalized epileptic seizures and an anticonvulsive therapy with levetiracetam 2 × 500 mg/day was initiated. The patient was then transferred to our university hospital. Follow-up MRI showed no change (Figure 1, A1) and electroencephalogram (EEG) was unremarkable. Due to a rapid progressive disturbance of consciousness within a week that led to a vegetative state, she had to be treated on the intensive care unit. The immunosuppressive therapy was changed from tacrolimus and mycophenolate mofetil to intravenous hydrocortisone. One month after immunosuppression with intravenous hydrocortisone, blood dosage of tacrolimus was 2.5 μg/L and that of mycophenolate mofetil was 3.2 mg/L, while the according white blood cell count and distribution revealed values within the reference range for leukocytes (6,600/μl) and lymphocytes (1,200/μl). Since C-reactive protein (CRP) and leucocytes were increasing, the anti-infectious therapy was changed to ganciclovir and piperacillin/tazobactam was added. CSF analysis was repeated 1 day after admission in our clinic and revealed pleocytosis (25 cells/μl, thereof 80% lymphocytes, 15% monocytes, 4% granulocytes, and 1% plasma cells), a disturbed blood–CSF barrier function (Qalbumin 12.3; protein 791 mg/L), and a lactate concentration of 2.6 mmol/L. Oligoclonal bands (OCB) restricted to CSF were found. Laboratory tests for autoimmune causes such as connective tissue diseases (antinuclear antibodies, anti-DNA antibodies, and antiphospholipid antibodies) were unremarkable. A broad diagnostic screening for infectious agents was performed. Analysis for bacterial (conventional cultural growth, mycobacterial cultures, Treponema pallidum, and Borrelia burgdorferi antibody tests), viral [antibody-specific index (AI) for herpes-simplex virus, varicella zoster virus, Epstein-Barr virus (EBV), measles virus, and rubella virus; polymerase-chain-reaction (PCR) for DNA of herpes-simplex virus, varicella zoster virus, Epstein–Barr virus, entero-virus, parecho-virus, adeno-virus, JC-virus, and human herpesvirus-6], and fungal (cultural growth and antigen test to Aspergillus and Cryptococcus neoformans) pathogens at different time points revealed only signs of CNS infection with Epstein–Barr virus. Polymerase-chain-reaction (PCR) analysis detected Epstein–Barr virus DNA in CSF (<3,200 copies/ml) and an elevated antibody-specific index for Epstein–Barr virus (45.3) suggesting intrathecal synthesis of EBV-specific IgG. In addition, anti-NMDAR-IgG antibodies in serum (titer 1:200) and CSF (titer 1:100) were found (Figure 1, B1) by using the commercially available cell-based assay of Euroimmune, confirming the diagnosis of anti-NMDAR encephalitis.\n\nFigure 1 Timeline of patient's disease course. (A1) Exemplary axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain demonstrated leukoencephalopathy but no signs of inflammation. Immune-fluorescence microscopy of anti-NMDA receptor staining with high (B1) and low titers (B2) in serum (depicted) and CSF. Bright green cells represent an antibody-antigen-interaction (B1) while dim cells do not reveal such interaction (B2). CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MP, methylprednisolone; IA, immunoadsorption-therapy; IG, intravenous immunoglobulins; RTX, rituximab; CP, cyclophosphamide; Anti-NMDA receptor, Anti-N-methyl-D-aspartate receptor.\n\nAdditionally, flow cytometry of the CSF was performed to exclude post-transplant lymphoproliferative disorders (9, 10).\n\nCorticoid treatment with 1 g of intravenous methylprednisolone was administered for 5 days followed by five courses of immunoadsorption therapy.\n\nThe patient's symptoms did not improve and thus a therapy with two cycles of intravenous immunoglobulins (60 g in total) was performed followed by a second course of methylprednisolone (1 g daily for 5 days) and two applications of rituximab (2 × 1,000 mg within 14 days). Because of the devastating disease course without any improvement, an additional immunosuppressive therapy with cyclophosphamide (750 mg/m2) was performed. White blood cell population count after extended immunosuppressive therapy revealed a decrease of leukocytes (2,400/μl) and lymphocytes (700/μl). As the patient experienced further epileptic seizures, the anticonvulsive treatment was expanded with valproate and lacosamid. Due to persisting epileptic seizures, lacosamid was changed to phenytoin.\n\nMeanwhile, the gynecologic diagnostic including ovarian ultrasound remained unremarkable. Whole-body PET-CT screening showed no signs of a paraneoplastic etiology of the autoimmune encephalitis. Nevertheless, the patient underwent oophorectomy of both sides, as a rescue option that can be considered in imaging-negative anti-NMDA receptor encephalitis patients without obvious ovarian teratoma (11). Histological examination of the ovarian tissue did not detect a teratoma.\n\nIn the course of the disease, the patient slightly regained consciousness. Follow-up CSF diagnostic 8 weeks after first symptoms and 5 weeks after the first dose of steroids showed decreasing pleocytosis (10 cells/μl, thereof 90% lymphocytes and 10% monocytes) and reduced anti-NMDAR-IgG antibodies titers (1:100 in serum, 1:50 in CSF, Figure 1, B2). The immunosuppressive therapy was switched back to oral treatment with tacrolimus and mycophenolate mofetil and the patient was transferred to a rehab facility. The patient regained consciousness and orientation but showed a reduced general condition with cachexia and was not able to walk.\n\nAfter 6 weeks, she was readmitted to our hospital for another course of cyclophosphamide and after 6 months for rituximab treatment. In the course, repeated tumor screening including cerebral, abdominal, and thoracic imaging showed no evidence of concomitant malignant diseases. However, the patient did not fully recover and died 2 years after disease onset due to septicemia (see timeline figure for overview).\n\nDiscussion\nHere, we present the first case of anti-NMDA receptor encephalitis developing despite immunosuppressive therapy after liver transplantation. Mycophenolate mofetil and tacrolimus are both highly effective drugs and were developed to prevent autoimmunity in patients after transplantation of solid organs (12–14). Mycophenolate mofetil has inhibitory effects on B- and T-cells, while tacrolimus reduces activation of T-cells (14, 15). Since the pathomechanisms of anti-NMDA receptor encephalitis are considered to be driven by complement-independent antibody effects, it could be assumed that this autoimmune disease should not occur under adequate immunosuppressive therapy with mycophenolate mofetil and tacrolimus (7). However, similar cases have been described in three patients after kidney transplantation (4, 5, 8), in one patient after repeated stem-cell transplantations in childhood and kidney transplantation in the course (7), and in one patient after heart transplantation (6). In all five published cases, immunosuppressive therapy at the time of encephalitis onset consisted of mycophenolate mofetil in addition to either tacrolimus or prednisolone (4–8). Furthermore, several reports showed that patients after allogeneic or autologous stem cell transplantation developed autoimmune diseases such as polymyositis, myasthenia gravis, Guillain–Barré syndrome, and anti-LGI1 and anti-GABAAR encephalitis, concluding that the inhibitory effect of mycophenolate mofetil on B- and T-cells and tacrolimus on T-cells might not be sufficient to prevent additional neuroimmunological diseases (16–18).\n\nIn all reported cases of anti-NMDAR encephalitis, symptoms began at least 6 years after transplantation (4–8). The symptom onset in our patient occurred even 10 years after liver transplantation. Dysfunctional immune tolerance and autoimmune phenomena are described as long-term effects of immunosuppressive therapy (16–18). It can be hypothesized that after several years of immunosuppression therapy, immune cell populations might be imbalanced, causing the breakdown of immune tolerance, in particular on the side of B-cells since chronic immunosuppression is rather T-cell targeting (12, 14).\n\nAnother interesting observation in our case is the concomitant presentation of Epstein–Barr virus DNA in CSF. In four of the five published cases, Epstein–Barr virus DNA was also found in the CSF of patients with autoimmune encephalitis (4–8). The authors suggested either reactivation of latent virus infection or first infection under immunosuppressive therapy (5, 7). An involvement of Epstein–Barr virus in autoimmune diseases such as multiple sclerosis is the subject of ongoing discussion. Casiraghi et al. propose that Epstein–Barr virus infection of brain endothelial cells could cause an upregulation of inflammatory mediators, which then induces a local breach in the brain–blood barrier and attraction of autoreactive lymphocytes into the brain (19). In analogy to this hypothesis, a similar pathomechanism with diffusion of peripheral autoreactive lymphocytes across a dysfunctional blood–brain barrier and subsequent intrathecal production of anti-NMDAR-IgG antibodies could be assumed (19).\n\nOn the other side, in another infectious disease, the herpes-simplex virus encephalitis, the herpes-simplex virus is regarded to trigger processes of autoimmunity in the CNS directly, which was demonstrated in a study involving patients with herpes-simplex encephalitis who subsequently developed autoimmune encephalitis (20, 21).\n\nThere are several other hypotheses about a possible relationship between virus infection and autoimmune encephalitis. As it is known, that EBV acquires its definite envelope by budding through the plasma membrane of infected host cells, the virus might incorporate specific components of their membrane like expressed receptors in its envelope (22). Possible targets for infection with Epstein–Barr virus are B- and T-lymphocytes, NK-cells, and epithelial cells of the nasopharyngeal and gastrointestinal area (23). If the infected host cells express the specific NMDA receptor on their surfaces as it is shown for different neuronal and extra-neuronal cells, for example, of the gastrointestinal tract, the envelope of the Epstein–Barr virus might include this receptor (24). The specific immune response against Epstein–Barr virus might also lead to an immune reaction against the virus envelope-associated NMDA receptor.\n\nFurthermore, it might be possible that the Epstein–Barr virus infection of already primed B-lymphocytes against the NMDA receptor promotes the proliferation of this specific B-cell type and thus increases the synthetization of anti-NMDA receptor antibodies (25).\n\nAnother remarkable aspect of our case is the clinical poor response to the broad spectrum of immunosuppressive therapeutics. Although clinical trials are not yet available, clinical experience in the therapy of anti-NMDA receptor encephalitis suggests intravenous methylprednisolone followed by plasma exchange or immunoadsorption therapy and/or intravenous immunoglobulins and an escalation therapy with rituximab and/or cyclophosphamide (26–28). In our case, all the recommended therapies were performed but did not improve the patient's symptoms. White blood cell count showed laboratory efficacy of the immunosuppressive therapy and even anti-NMDAR antibody titers in serum and CSF decreased. However, a correlating positive clinical effect could not be achieved. Even oophorectomy of both sides did not lead to clinical improvement as described in some cases (11, 28).\n\nEarly treatment in autoimmune encephalitis patients without previous immunosuppressive therapy has been shown to have a better prognosis (2). Our patient was diagnosed already 3 weeks after the onset of symptoms and had a fatal outcome. In contrast, the other published cases of post-transplant patients with autoimmune encephalitis and full recovery were diagnosed even later (3 and 5 months) after clinical manifestation (5, 7). Thus, the duration of symptoms and onset of a sufficient therapy was rather not the reason for the fatal outcome in our patient.\n\nConclusion\nAnti-NMDA receptor encephalitis can develop fatally despite previous immunosuppressive therapy. The etiology of anti-NMDA receptor encephalitis is still not fully understood but seems to involve autoimmune mechanisms that are not sufficiently inhibited by mycophenolate mofetil and tacrolimus. In addition, an EBV infection of the cells forming the blood–brain barrier might play a role in the pathogenesis of anti-NMDA receptor encephalitis. An autoimmune encephalitis should be considered in post-transplant patients with neuropsychiatric symptoms.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nFK participated in the design of the study, collected and analyzed the data, and drafted the manuscript. PS collected the data, analyzed the data, and drafted the manuscript. KJ, MH, FW, and K-WS contributed in drafting the manuscript. MS analyzed the data and contributed in drafting the manuscript. TS conceived the study, analyzed the data, and drafted the manuscript. All authors read and approved the final 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\nThe authors thank Karin Fricke, Kathrin Scheiwe, Sabine Lang, Katharina Dorsch, and Ilona Cierpka-Leja for excellent technical assistance.\n\nAbbreviations\nAnti-NMDA receptoranti-N-methyl-D-aspartate receptor\n\nMRImagnetic resonance imaging\n\nCSFcerebrospinal fluid\n\nEEGelectroencephalogram\n\nPCRpolymerase chain reaction\n\nEBVEpstein–Barr virus\n\nCRPC-reactive protein\n\nOCBCSF-specific oligoclonal bands\n\nQalbuminCSF-serum albumin quotients\n\nPETpositron emission tomography\n\nCTcomputed tomography.\n==== Refs\nReferences\n1. Dalmau J Tüzün E Wu HY Masjuan J Rossi JE Voloschin A . Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma . Ann Neurol. (2007 ) 61 :25 –36 . 10.1002/ana.21050 17262855 \n2. Titulaer MJ McCracken L Gabilondo I Armangué T Glaser C Iizuka T . Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study . Lancet Neurol. (2013 ) 12 :157 –65 . 10.1016/S1474-4422(12)70310-1 23290630 \n3. Dalmau J Lancaster E Martinez-Hernandez E Rosenfeld MR Balice-Gordon R . Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis . Lancet Neurol. (2011 ) 10 :63 –74 . 10.1016/S1474-4422(10)70253-2 21163445 \n4. Randall A Saif H Anu J Larner AJ . Autoimmune encephalitis (NMDAR antibody) in a patient receiving chronic post-transplant immunosuppression . Pract Neurol. (2018 ) 18 :320 –2 . 10.1136/practneurol-2018-001923 29588384 \n5. Derksen SJ Goraj B Molenaar JG van der Hoeven JG \nSevere anti NMDA encephalitis and EBV infection . Neth J Crit Care. (2013 ) 17 :19 –21 .\n6. Cohen DA Lopez-Chiriboga AS Pittock SJ Gadoth A Zekeridou A Boilson BA . Posttransplant autoimmune encephalitis . Neurol Neuroimmunol Neuroinflamm. (2018 ) 5 :e497 . 10.1212/NXI.0000000000000497 30175169 \n7. Zhao CZ Erickson J Dalmau J . Clinical reasoning: agitation and psychosis in a patient after renal transplantation . Neurology. (2012 ) 79 :e41 –4 . 10.1212/WNL.0b013e3182616fad 22851723 \n8. Garré J Sprengers M Van Melkebeke D Laureys G . EBV-NMDA double positive encephalitis in an immunocompromised patient . J Neurol Sci. (2019 ) 396 :76 –7 . 10.1016/j.jns.2018.11.001 30419370 \n9. Agnihotri SP . Central nervous system opportunistic . Infect Semin Neurol. (2019 ) 39 :383 –90 . 10.1055/s-0039-1687842 31378873 \n10. Lieberman F Yazbeck V Raptis A Felgar R Boyiadzis M . Primary central nervous system post-transplant lymphoproliferative disorders following allogeneic hematopoietic stem cell transplantation . J Neurooncol. (2012 ) 107 :225 –32 . 10.1007/s11060-011-0739-6 22037801 \n11. Boeck AL Logemann F Krauß T Hussein K Bültmann E Trebst C . Ovarectomy despite negative imaging in anti-NMDA receptor encephalitis: effective even late . Case Rep Neurol Med. (2013 ) 2013 :843192 . 10.1155/2013/843192 23533859 \n12. Allison AC Eugui EM . Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection . Transplantation. (2005 ) 80 (2 Suppl ):S181 –90 . 10.1097/01.tp.0000186390.10150.66 16251851 \n13. Staatz CE Tett SE . Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update . Arch Toxicol. (2014 ) 88 :1351 –89 . 10.1007/s00204-014-1247-1 24792322 \n14. Staatz CE Tett SE . Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation . Clin Pharmacokinet. (2004 ) 43 :623 –53 . 10.2165/00003088-200443100-00001 15244495 \n15. Allison AC Eugui EM . Mycophenolate mofetil and its mechanisms of action . Immunopharmacology. (2000 ) 47 :85 –118 . 10.1016/S0162-3109(00)00188-0 10878285 \n16. Saiz A Graus F . Neurologic complications of hematopoietic cell transplantation . Semin Neurol. (2010 ) 30 :287 –95 . 10.1055/s-0030-1255218 20577935 \n17. Spatola M Petit-Pedrol M Simabukuro MM Armangue T Castro FJ Barcelo Artigues MI . Investigations in GABAA receptor antibody-associated encephalitis . Neurology. (2017 ) 88 :1012 –20 . 10.1212/WNL.0000000000003713 28202703 \n18. Rathore GS Leung KS Muscal E . Autoimmune encephalitis following bone marrow transplantation . Pediatr Neurol. (2015 ) 53 :253 –6 . 10.1016/j.pediatrneurol.2015.05.011 26220353 \n19. Casiraghi C Dorovini-Zis K Horwitz MS \nEpstein–Barr virus infections of human brain microvessel endothelial cells: a novel role in multiple sclerosis . J Neuroimmunol. (2011 ) 230 :173 –7 . 10.1016/j.jneuroim.2010.08.003 20826008 \n20. Armangue T Leypoldt F Málaga I Raspall-Chaure M Marti I Nichter C . Herpes simplex virus encephalitis is a trigger of brain autoimmunity . Ann Neurol. (2014 ) 75 :317 –23 . 10.1002/ana.24083 24318406 \n21. Armangue T Spatola M Vlagea A Mattozzi S Cárceles-Cordon M Martinez-Heras E \nSpanish herpes simplex encephalitis study group. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis . Lancet Neurol. (2018 ) 17 :760 –72 . 10.1016/S1474-4422(18)30244-8 30049614 \n22. Gong M Kieff E . Intracellular trafficking of two major Epstein–Barr virus glycoproteins, gp350/220 and gp110 . J Virol. (1990 ) 64 :1507 –16 .2157039 \n23. Kasahara Y Yachie A . Cell type specific infection of Epstein–Barr virus (EBV) in EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection . Crit Rev Oncol Hematol. (2002 ) 44 :283 –94 . 10.1016/S1040-8428(02)00119-1 12467968 \n24. Gill SS Pulido OM . Glutamate receptors in peripheral tissues: current knowledge, future research, and implications for toxicology . Toxicol Pathol. (2001 ) 29 :208 –23 . 10.1080/019262301317052486 11421488 \n25. Kilger E Kieser A Baumann M Hammerschmidt W . Epstein–Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor . EMBO J. (1998 ) 17 :1700 –9 . 10.1093/emboj/17.6.1700 9501091 \n26. Irani SR Vincent A . NMDA receptor antibody encephalitis . Curr Neurol Neurosci Rep. (2011 ) 11 :298 –304 . 10.1007/s11910-011-0186-y 21331529 \n27. Tüzün E Dalmau J . Limbic encephalitis and variants: classification, diagnosis and treatment . Neurologist. (2007 ) 13 :261 –71 . 10.1097/NRL.0b013e31813e34a5 17848866 \n28. Dalmau J Gleichman AJ Hughes EG Rossi JE Peng X Lai M . Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies . Lancet Neurol. (2008 ) 7 :1091 –8 . 10.1016/S1474-4422(08)70224-2 18851928\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "10()",
"journal": "Frontiers in neurology",
"keywords": "Epstein-Barr virus; anti-NMDA receptor encephalitis; autoimmune encephalitis; immunosuppression; liver-transplantation",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "987",
"pmc": null,
"pmid": "31608003",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "23290630;30419370;12467968;31378873;29588384;24792322;21331529;22037801;30049614;28202703;16251851;9501091;11421488;24318406;21163445;17262855;10878285;20826008;23533859;15244495;22851723;30175169;26220353;17848866;2157039;18851928;20577935",
"title": "Severe Anti-N-Methyl-D-Aspartate Receptor Encephalitis Under Immunosuppression After Liver Transplantation.",
"title_normalized": "severe anti n methyl d aspartate receptor encephalitis under immunosuppression after liver transplantation"
}
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{
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},
{
"reactionmeddrapt": "Apallic syndrome",
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},
{
"reactionmeddrapt": "Central nervous system viral infection",
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},
{
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},
{
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},
{
"reactionmeddrapt": "Sepsis",
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},
{
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},
{
"reactionmeddrapt": "Gait inability",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
},
{
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"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
}
],
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},
"primarysource": {
"literaturereference": "KONEN FF, SCHWENKENBECHER P, JENDRETZKY KF, HUMMERT MW, WEGNER F, STANGEL M, ET AL. SEVERE ANTI-N-METHYL-D-ASPARTATE RECEPTOR ENCEPHALITIS UNDER IMMUNOSUPPRESSION AFTER LIVER TRANSPLANTATION. FRONT-NEUROL 2019?10:987.",
"literaturereference_normalized": "severe anti n methyl d aspartate receptor encephalitis under immunosuppression after liver transplantation",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20191220",
"receivedate": "20191220",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17181105,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "Clopidogrel is an antiplatelet drug widely used for treatment and prevention of a variety of cardiovascular diseases. We report a successful desensitization to clopidogrel in a 70-year-old Caucasian man with delayed hypersensitivity (HS) reaction. He developed lip, hand and foot swelling, erythematous papular non-pruritic lesions and arthralgias 2 weeks after starting treatment with clopidogrel 75 mg/d. A 3-hour desensitization protocol was started, achieving a cumulative dose of 154 mg without any reaction, and a daily dose of 75 mg was recommended. On the 4th day, the patient developed skin lesions similar to the previously described. He was treated with topical steroids and oral antihistamines, and the daily dose of clopidogrel was reduced to 20 mg. A new desensitization protocol was established, with a slow dose increment, according to the patient's response. It was only possible to achieve the dose of 75 mg/d after 2 months. Although well tolerated by most patients, HS reactions with clopidogrel may occur and desensitization is rising as a safe alternative in those patients. In delayed reactions with cutaneous lesions, a slower desensitization protocol may be necessary, as in this case.",
"affiliations": "Drug Allergy Unit, Allergy and Clinical Immunology Department, Centro Hospitalar de Vila Nova de Gaia / Espinho - EPE, Vila Nova de Gaia, Portugal. [email protected].;Drug Allergy Unit, Allergy and Clinical Immunology Department, Centro Hospitalar de Vila Nova de Gaia / Espinho - EPE, Vila Nova de Gaia, Portugal.;Drug Allergy Unit, Allergy and Clinical Immunology Department, Centro Hospitalar de Vila Nova de Gaia / Espinho - EPE, Vila Nova de Gaia, Portugal.;Drug Allergy Unit, Allergy and Clinical Immunology Department, Centro Hospitalar de Vila Nova de Gaia / Espinho - EPE, Vila Nova de Gaia, Portugal.",
"authors": "Barreira|P|P|;Cadinha|S|S|;Malheiro|D|D|;Moreira da Silva|J P|JP|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1764-1489",
"issue": "46(1)",
"journal": "European annals of allergy and clinical immunology",
"keywords": "Clopidogrel; desensitization; hypersensitivity reaction",
"medline_ta": "Eur Ann Allergy Clin Immunol",
"mesh_terms": "D000368:Aged; D000077144:Clopidogrel; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine",
"nlm_unique_id": "101466614",
"other_id": null,
"pages": "53-5",
"pmc": null,
"pmid": "24702878",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Desensitization to clopidogrel: a tailor-made protocol.",
"title_normalized": "desensitization to clopidogrel a tailor made protocol"
}
|
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
}
] |
{
"abstract": "BACKGROUND\nIt is unclear whether anti-tumour necrosis factor alpha and biological agents with different mechanisms of action have similar safety. This study evaluated the incidence of hospitalised infections among rheumatoid arthritis (RA) patients starting or switching various biological agents.\n\n\nMETHODS\nUsing a database from a large US healthcare organisation from January 2005 to August 2009, the authors identified enrollees with RA and their treatment episodes entailing the new use of a biological agent, stratified by no biological use in the previous year ('biological-free') or switching from a different biological agent ('switchers'). Outcomes were hospitalised infections identified using previously validated algorithms. Proportional hazards models estimated the hazard ratio of hospitalised infections, comparing each biological agent with infliximab.\n\n\nRESULTS\nAmong 7847 biological treatment episodes, 63% were for biological-free patients and 37% for switchers. There were 364 hospitalised infections. Rates of hospitalised infection among biological-free patients and switchers were 4.6 and 7.0 per 100 person-years, respectively (p<0.0001). After multivariable adjustment controlling for biological-free/switcher status and other infection-related factors and compared with infliximab, users of abatacept (HR 0.68, 95% CI 0.48 to 0.96), adalimumab (HR 0.52, 0.39 to 0.71), etanercept (HR 0.64, 0.49 to 0.84) and rituximab (HR 0.81, 0.55 to 1.20) had lower rates of hospitalised infection. Patient risk factors contributed more to the risk of infection than did the risk associated with specific biological therapies.\n\n\nCONCLUSIONS\nThe rate of hospitalised infections among RA patients was highest for infliximab. Most of the variability in patients' risk of infection was driven by factors other than biological agent exposure.",
"affiliations": "Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA. [email protected]",
"authors": "Curtis|Jeffrey R|JR|;Xie|Fenglong|F|;Chen|Lang|L|;Baddley|John W|JW|;Beukelman|Timothy|T|;Saag|Kenneth G|KG|;Spettell|Claire|C|;McMahan|Raechele M|RM|;Fernandes|Joaquim|J|;Winthrop|Kevin|K|;Delzell|Elizabeth|E|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1136/ard.2010.146365",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "70(8)",
"journal": "Annals of the rheumatic diseases",
"keywords": null,
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001424:Bacterial Infections; D001688:Biological Products; D016208:Databases, Factual; D057915:Drug Substitution; D005260:Female; D006760:Hospitalization; D006801:Humans; D016867:Immunocompromised Host; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D014409:Tumor Necrosis Factor-alpha; D014481:United States",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1401-6",
"pmc": null,
"pmid": "21586439",
"pubdate": "2011-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17763441;18055472;19821440;15840622;12355475;19884297;18834713;12355476;21177290;14585769;21097801;17393394;9603539;20223500;998608;18717997;18050253;18512708;16255017;20674669;19757416;19854715;19565495;17261532",
"title": "The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents.",
"title_normalized": "the comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents"
}
|
[
{
"companynumb": "US-JNJFOC-20120909844",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "LYOPHILIZED POWDER",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RHEUMATOID ARTHRITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INFLIXIMAB, RECOMBINANT"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CURTIS JR, XIE F, CHEN L, BADDLEY JW, BEUKELMAN T, SAAG KG, ET AL. THE COMPARATIVE RISK OF SERIOUS INFECTIONS AMONG RHEUMATOID ARTHRITIS PATIENTS STARTING OR SWITCHING BIOLOGICAL AGENTS. ANN RHEUM DIS 2011;70:1401-1406.",
"literaturereference_normalized": "the comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150525",
"receivedate": "20150404",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10987636,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "Endobronchial metastasis (EBM) from extrapulmonary primary malignancy is a rare entity. Although the most common site of metastasis of osteosarcoma is the lungs, EBM remains a rare occurrence. Cough and dyspnea are the most common symptoms. A significant number of patients are asymptomatic, making the diagnosis without any radiographic imaging challenging. CT scan of the lung, along with bronchoscopy and biopsy, is the mainstay of diagnosis and staging. A 36-year-old man presented with small cell osteosarcoma of the left maxillary region and was treated with surgery and adjuvant chemotherapy. The patient presented 8 years later with axillary metastasis and was found to have lung metastasis on further workup. Bronchoscopy and biopsy proved an EBM that was debulked by hot snare technique. The patient was then started on chemotherapy for recurrent small cell osteosarcoma.",
"affiliations": "Internal Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.;Internal Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.;Cleveland Clinic, Cleveland, Ohio, USA.;Cancer Treatment Centers of America Chicago, Zion, Illinois, USA.",
"authors": "Kadamkulam Syriac|Arun|A|http://orcid.org/0000-0003-2425-4622;Bhaskarla|Amrit Ved|AV|;Elrifai|Mohamed|M|;Alraiyes|Abdul Hamid|AH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229779",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "head and neck cancer; lung cancer (oncology); respiratory cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001984:Bronchial Neoplasms; D001999:Bronchoscopy; D017024:Chemotherapy, Adjuvant; D006801:Humans; D008297:Male; D012516:Osteosarcoma; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31366615",
"pubdate": "2019-07-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7359928;24681280;23364974;11243955;16475029;15068323;10845436;2066757;1742126;2805842",
"title": "Endobronchial metastasis as an uncommon pattern of metastatic dissemination from small cell osteosarcoma.",
"title_normalized": "endobronchial metastasis as an uncommon pattern of metastatic dissemination from small cell osteosarcoma"
}
|
[
{
"companynumb": "US-ACCORD-153692",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "206774",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OSTEOSARCOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OSTEOSARCOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ADRIAMYCIN"
}
],
"patientagegroup": null,
"patientonsetage": "36",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Mucosal inflammation",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KADAMKULAM SYRIAC A, BHASKARLA AV, ELRIFAI M, ALRAIYES AH. ENDOBRONCHIAL METASTASIS AS AN UNCOMMON PATTERN OF METASTATIC DISSEMINATION FROM SMALL CELL OSTEOSARCOMA. BMJ CASE REPORTS. 2019?12(7):ARTICLE NUMBER E229779.",
"literaturereference_normalized": "endobronchial metastasis as an uncommon pattern of metastatic dissemination from small cell osteosarcoma",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190904",
"receivedate": "20190904",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16770463,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191005"
}
] |
{
"abstract": "Methylphenidate (MPH) is an indirect-acting sympathomimetic drug and structurally related to amphetamine. It is widely used to treat children aged 6 years and older, as well as adolescents who have attention-deficit/hyperactivity disorder (ADHD). We report on a 6-year-old boy who presented with typical angina symptoms occurring several hours after intake of an increased dose of MPH, which had been initiated for ADHD treatment 2 days earlier. Despite typical angina symptoms, the diagnosis of myocardial infarction due to spontaneous coronary artery dissection of the right coronary artery was delayed. Most epidemiological studies could not detect an increased risk for cardiovascular events in association with ADHD medications. However, the direct temporal relationship in our case indicates the possibility that MPH may trigger spontaneous coronary artery dissection in predisposed patients. Since myocardial infarction in children is rare but comprises various etiologies, awareness of this possible catastrophic event among medical staff may be lower and may delay immediate life-saving diagnostic and therapeutic measures.",
"affiliations": "Drug Commission of the German Medical Association, Berlin, Germany. [email protected].;Drug Commission of the German Medical Association, Berlin, Germany.;Drug Commission of the German Medical Association, Berlin, Germany.;Clinic for Cardiology, Nephrology and Internal Intensive Care Medicine, Rhein-Maas Klinikum, Würselen, Germany.;Clinic for Pediatric and Adolescent Medicine, St. Marien Hospital, Düren, Germany.;Department of Pediatric Cardiology, University Clinic Aachen, Aachen, Germany.;Department of Pediatric Cardiology, University Clinic Aachen, Aachen, Germany.",
"authors": "Stammschulte|Thomas|T|http://orcid.org/0000-0003-3830-3843;Pitzer|Martina|M|;Rascher|Wolfgang|W|;Becker|Michael|M|;Pohlmann|Ulrich|U|;Ostermayer|Stefan|S|;Kerst|Gunter|G|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00787-021-01729-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8827",
"issue": null,
"journal": "European child & adolescent psychiatry",
"keywords": "Adverse drug reaction; Attention deficit hyperactivity disorder; Methylphenidate; Myocardial infarction; Spontaneous coronary artery dissection",
"medline_ta": "Eur Child Adolesc Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "9212296",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33537905",
"pubdate": "2021-02-03",
"publication_types": "D016428:Journal Article",
"references": "29428394;18957001;27747690;26221559;18024065;16190800;22395014;25073534;21576311;22043968;22682429;27245699;27245078;31275818;25294399;27522384;9596438;26320110",
"title": "Acute myocardial infarction due to spontaneous coronary artery dissection in a 6-year-old boy with ADHD on the third day of treatment with methylphenidate.",
"title_normalized": "acute myocardial infarction due to spontaneous coronary artery dissection in a 6 year old boy with adhd on the third day of treatment with methylphenidate"
}
|
[
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2021-00860",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 GRAM",
"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": "1",
"drugstructuredosageunit": "002",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BUPROPION."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "211779",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "30 MILLIGRAM",
"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": "30",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPHENIDATE HYDROCHLORIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERYTHROMYCIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "200 MILLIGRAM",
"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": "200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ERYTHROMYCIN."
}
],
"patientagegroup": null,
"patientonsetage": "16",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Myocardial infarction",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "STAMMSCHULTE T, PITZER M, RASCHER W, BECKER M, ET AL.. ACUTE MYOCARDIAL INFARCTION DUE TO SPONTANEOUS CORONARY ARTERY DISSECTION IN A 6?YEAR?OLD BOY WITH ADHD ON THE THIRD DAY OF TREATMENT WITH METHYLPHENIDATE. EUROPEAN CHILD + ADOLESCENT PSYCHIATRY. 2021?UNK:UNK",
"literaturereference_normalized": "acute myocardial infarction due to spontaneous coronary artery dissection in a 6 year old boy with adhd on the third day of treatment with methylphenidate",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20210226",
"receivedate": "20210226",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18944374,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210420"
},
{
"companynumb": "DE-TEVA-2021-DE-1890549",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": "210924",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MILLIGRAM DAILY; AFTER 3 DAYS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPHENIDATE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": "210924",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "5 MILLIGRAM DAILY; 0.14 MG/KG BODY WEIGHT",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ATTENTION DEFICIT HYPERACTIVITY DISORDER",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPHENIDATE."
}
],
"patientagegroup": "3",
"patientonsetage": "6",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": "36",
"reaction": [
{
"reactionmeddrapt": "Acute myocardial infarction",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Coronary artery dissection",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Mitral valve incompetence",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "STAMMSCHULTE T, PITZER M, RASCHER W, BECKER M, POHLMANN U, OSTERMAYER S, ET AL. ACUTE MYOCARDIAL INFARCTION DUE TO SPONTANEOUS CORONARY ARTERY DISSECTION IN A 6?YEAR?OLD BOY WITH ADHD ON THE THIRD DAY OF TREATMENT WITH METHYLPHENIDATE. EUR?CHILD?ADOLESC?PSYCHIATRY 2021?:.",
"literaturereference_normalized": "acute myocardial infarction due to spontaneous coronary artery dissection in a 6 year old boy with adhd on the third day of treatment with methylphenidate",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20210318",
"receivedate": "20210318",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19023834,
"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"
},
{
"companynumb": "NO-ALKEM LABORATORIES LIMITED-NO-ALKEM-2021-00862",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "211779",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MILLIGRAM, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
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"abstract": "A 59-year-old woman with small-cell lung carcinoma achieved tumor disappearance after cisplatin-based chemotherapy (CBC) and radiation treatment but subsequently experienced right hemiparesis and aphasia. Brain magnetic resonance imaging revealed a left middle cerebral artery territory acute infarction and left internal carotid artery occlusion. Ultrasonography revealed a mobile thrombus in the left common and internal carotid arteries, and contrast computed tomography revealed a mural thrombus in the ascending aorta. Based on these findings, embolic stroke due to aortic mural thrombus following CBC was diagnosed. Aortic mural thrombus is a rare complication of CBC but carries a risk of embolic stroke.",
"affiliations": "Department of Neurology and Stroke Medicine, Tokyo Metropolitan Tama Medical Center, Japan.;Department of Neurology and Stroke Medicine, Tokyo Metropolitan Tama Medical Center, Japan.;Department of Neurology and Stroke Medicine, Tokyo Metropolitan Tama Medical Center, Japan.",
"authors": "Ochiai|Yukiko|Y|;Tsunogae|Marie|M|;Ueda|Masayuki|M|",
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"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33087671\n10.2169/internalmedicine.5761-20\nCase Report\nEmbolic Stroke Due to a Mural Thrombus in the Ascending Aorta Following Cisplatin-based Chemotherapy\nOchiai Yukiko 1\nTsunogae Marie 1\nUeda Masayuki 1\n1 Department of Neurology and Stroke Medicine, Tokyo Metropolitan Tama Medical Center, Japan\nCorrespondence to Dr. Masayuki Ueda, [email protected]\n\n21 10 2020\n15 3 2021\n60 6 945951\n2 7 2020\n8 9 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 59-year-old woman with small-cell lung carcinoma achieved tumor disappearance after cisplatin-based chemotherapy (CBC) and radiation treatment but subsequently experienced right hemiparesis and aphasia. Brain magnetic resonance imaging revealed a left middle cerebral artery territory acute infarction and left internal carotid artery occlusion. Ultrasonography revealed a mobile thrombus in the left common and internal carotid arteries, and contrast computed tomography revealed a mural thrombus in the ascending aorta. Based on these findings, embolic stroke due to aortic mural thrombus following CBC was diagnosed. Aortic mural thrombus is a rare complication of CBC but carries a risk of embolic stroke.\n\ncisplatin\naortic mural thrombus\nembolic stroke\nsmall-cell lung carcinoma\n==== Body\nIntroduction\n\nSmall-cell lung carcinoma (SCLC) is generally thought to be the most malignant subtype of lung cancer. The standard treatment is cisplatin-based chemotherapy (CBC) combined with radiation therapy for the limited stage and CBC alone for the extensive stage (1). However, cisplatin use carries a potential risk of thromboembolism (2, 3).\n\nFigure 1. Computed tomography (CT) of the chest before and after cisplatin-based chemotherapy. Contrast chest CT prior to chemotherapy (A) shows the lung cancer in the right middle lobe (white arrowhead). Non-contrast chest CT immediately after the final chemoradiotherapy course (B) shows that the tumor in the right middle lobe has completely vanished. R indicates right side A through B.\n\nWe herein report a patient with SCLC who was successfully treated with CBC and radiation but subsequently experienced an ischemic stroke due to a mural thrombus in the ascending aorta. Aortic mural thrombus, especially in the ascending aorta, is a rare complication of CBC but poses a risk of serious embolic stroke.\n\nCase Report\n\nA 59-year-old right-handed woman with stage IIIB (T3N2M0) SCLC in the right middle lobe (Fig. 1A) was successfully treated with 4 standard courses of cisplatin-etoposide therapy (cisplatin 80 mg/m2/day on day 1 and etoposide 100 mg/m2/day on days 1-3 every 3 weeks for 4 cycles) combined with a total of 60 Gy of radiation, which achieved complete disappearance of the tumor (Fig. 1B). However, right hemiparesis and aphasia developed two days after the final chemotherapy course. She was admitted to a local hospital but was transferred the next day to our hospital, where she had received her chemotherapy.\n\nA neurological examination revealed left conjugate deviation, right complete hemiparesis, including the face, and motor-dominant aphasia; her National Institute of Health stroke scale (NIHSS) score was 20. Tendon reflexes in the right upper and lower extremities were slightly increased, and Babinski reflex was positive on the right side. Vital signs were normal; blood pressure was 136/42 mmHg, heart rate was regular and 72/min, respiratory rate was 14/min, and body temperature was 37.1℃. Brain magnetic resonance imaging (MRI) performed in the local hospital (day 1) showed an acute infarction in the left middle cerebral artery (MCA) territory (Fig. 2A-F), non-terminal occlusion of the left internal carotid artery (ICA) and probable main trunk occlusion of the left MCA (Fig. 2G, H). An imaging mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) was evident at the time. Previous contrast-enhanced brain MRI examined before the CBC revealed that the left ICA and left MCA appeared to be normal (Fig. 3). This suggested that the tandem ICA-MCA occlusions might be embolic.\n\nFigure 2. Magnetic resonance imaging of the brain on day 1. Note the acute brain infarction in the left middle cerebral artery (MCA) territory, showing a high signal intensity on diffusion-weighted imaging (A, B) and low signal intensity on apparent diffusion coefficient maps (C, D). The ischemic area does not show obvious signal changes on fluid-attenuated inversion recovery, except for the left insula cortex (E, F). Magnetic resonance angiography indicates non-terminal occlusion of the left internal carotid artery and probable main trunk occlusion of the left MCA (G, H). R indicates right side A through H.\n\nFigure 3. Contrast-enhanced magnetic resonance imaging of the brain before chemotherapy. Contrast-enhanced T1-weighted coronal (A) and axial (B) images show that the left internal carotid (black arrow) and middle cerebral (white arrow) arteries appear to be normal. R indicates right side A through B.\n\nBrain MRI on admission (day 2) showed an acute infarction in the anterior territory of the left MCA (Fig. 4A-F) and complete occlusion of the left ICA-MCA (Fig. 4G, H). The DWI-FLAIR mismatch was not observed anymore. A blood cell count on admission showed moderate anemia and the following findings: white blood cells (WBCs) 3,900/μL, red blood cells (RBCs) 282×104/μL, hemoglobin 8.6 g/dL and platelets 15.8×104/μL. Blood biochemistry revealed slightly elevated levels of glucose (141 mg/dL), HbA1c (7.6%) and triglyceride (206 mg/dL), low levels of high-density lipoprotein cholesterol (30 mg/dL), almost normal levels of low-density lipoprotein cholesterol (122 mg/dL) and normal levels of N-terminal pro-brain natriuretic peptide (72 pg/mL). D-dimer levels were slightly increased (2.4 μg/mL), but protein C levels were normal: protein C antigen 100% (normal range: 70-150%) and protein C activity 114% (normal range: 64-146%). Protein S levels were also normal: protein S antigen 98% (normal range: 65-135%), protein S free antigen 104% (normal range: 60-104%) and protein S activity 99% (normal range: 56-126%). Antithrombin-III levels were unremarkable: 93.5% (normal range: 70-130%). Antiphospholipid antibodies were negative.\n\nPhysiological function tests were performed on days 3-4. A Holter electrocardiogram showed no atrial fibrillation. Transthoracic echocardiography indicated neither valvular abnormalities nor left atrial enlargement (left atrial diameter: 24 mm), and an additional microbubble test with abdominal compression in substitution for the Valsalva maneuver revealed no right-left shunt. Transesophageal echocardiography was not performed in order to avoid any risk of aspiration pneumonia because of her post-chemotherapy condition. Venous ultrasonography revealed asymptomatic distal deep vein thrombosis in the right fibular vein. Carotid ultrasonography showed a mobile thrombus extending from the left common carotid artery to the ICA. Contrast computed tomography (CT) on day 4 revealed a massive thrombus within the left common carotid and internal carotid arteries (Fig. 5A) and a mural thrombus attached to the calcified lesion of the ascending aorta (Fig. 5B, C), which had not been observed before chemotherapy (Fig. 5D). Brain CT on day 8 demonstrated hemorrhagic infarction in the left MCA territory (Fig. 5E). Based on these findings, cardiogenic embolism, including paradoxical embolism, was unlikely, and aortic mural thrombus was considered a potential embolic source in the patient. Embolic stroke due to an aortic mural thrombus following CBC was therefore diagnosed.\n\nFigure 4. Magnetic resonance imaging of the brain on day 2. Note the acute brain infarction in the anterior territory of the left middle cerebral artery (MCA), showing a high signal intensity on diffusion-weighted imaging (A, B) and low signal intensity on apparent diffusion coefficient maps (C, D). The ischemic lesion also exhibits a high signal intensity on fluid-attenuated inversion recovery (E, F). Magnetic resonance angiography indicates complete occlusion of the left internal carotid artery and the left MCA, but cross flow through anterior communicating artery supplies the left anterior cerebral artery (G, H). R indicates right side A through H.\n\nFigure 5. Computed tomography (CT) of the brain, neck and chest. Contrast neck CT on day 4 (A) shows the massive thrombus in the left internal carotid artery (white arrow). Contrast chest CT on day 4 (B, C) demonstrates the aortic mural thrombus (black arrow) attached to the calcified lesion of the ascending aorta (white arrowhead). There is no mural thrombus in the ascending aorta on contrast chest CT examined before chemotherapy (D). Brain CT on day 8 (E) displays hemorrhagic infarction in the left middle cerebral artery territory. Contrast chest CT on day 17 (F) shows the disappearance of the aortic mural thrombus. R indicates right side A through F.\n\nAfter admission she received 60 mg/day of intravenous edaravone, a free radical scavenger, and intravenous heparin was begun in order to achieve 1.5-fold prolongation of the activated partial thromboplastin time over the baseline for the aortic mural thrombus. Due to progressive pancytopenia on day 4 (WBCs 1,600/μL, RBCs 253×104/μL, hemoglobin 7.6 g/dL, platelets 7.9×104/μL) resulting from the final course of chemotherapy, surgical thrombectomy was not performed. Contrast CT on day 17 revealed complete disappearance of the aortic mural thrombus (Fig. 5F) with no additional whole-body embolisms observed, and the antithrombotic therapy was changed to aspirin 81 mg/day.\n\nShe was transferred to a rehabilitation facility on day 42. After six months of rehabilitation, she still exhibited right hemiparesis and motor-dominant aphasia (NIHSS score 13 and modified Rankin scale 4). Brain MRI at 12 months after the stroke onset showed an old infarction in the left MCA territory (Fig. 6A, B), which was basically similar to the previously observed lesion, and occlusion of the left ICA-MCA (Fig. 6C, D). She showed no cancer recurrence or further thromboembolic events for at least 18 months and had a normal D-dimer level despite no anticoagulant use.\n\nFigure 6. Magnetic resonance imaging at 12 months after stroke. T2-weighted images (A, B) show old infarction in the left middle cerebral artery (MCA) territory. Magnetic resonance angiography shows occlusions of the left internal carotid artery and the left MCA (C, D). R indicates right side A through D.\n\nDiscussion\n\nMachleder et al. reviewed 10,671 consecutive autopsies and identified 48 cases of nonaneurysmal aortic mural thrombus, of which 38 were in the abdominal aorta, 1 was in the thoracic aorta, and 9 were in both (4). Pagni et al. analyzed 14 patients with symptomatic thoracic aortic mural thrombus and found that only 1 patient had a mural thrombus in the ascending aorta (5). These findings point to the rarity of a nonaneurysmal mural thrombus in the ascending aorta.\n\nAn ischemic stroke, particularly an embolic stroke, in patients with active cancer may be a sign of Trousseau syndrome, which is thought to arise from the hypercoagulability associated with cancer (6). This disorder generally has a poor prognosis, as seen in the median survival time of 4.5 months (7). Although the present patient suffered from cancer and eventually experienced an ischemic stroke, Trousseau syndrome was unlikely to be the cause of the stroke for the following reasons: first, chemoradiotherapy had achieved complete resolution of the lung tumor prior to the stroke onset; second, no thromboembolic events had occurred for more than 18 months during aspirin therapy following the disappearance of the aortic mural thrombus although the initial treatment began with heparin; finally, the D-dimer level had remained normal despite the discontinuation of anticoagulants.\n\nStandard chemotherapy for SCLC consists of a cisplatin-based regimen (1), but cisplatin is known to be a risk factor of thromboembolism. Lee et al. analyzed 277 patients with SCLC who received chemotherapy, of whom 218 received cisplatin, and found that CBC was an independent risk factor of thromboembolism, as indicated by a hazard ratio of 4.36 (2). Moore et al. also analyzed 932 cancer patients treated with CBC and discovered an extremely high incidence of 18.1% for thromboembolisms, most of which were deep vein thromboses and pulmonary embolisms; arterial embolisms were rare (3). Although the pathogenesis of cisplatin-related arterial embolisms remains uncertain, endothelial cell damage, as indicated by von Willebrand factor release, may be a contributing factor (8). Endothelial damage was not confirmed in the present patient, because the von Willebrand factor level was not examined. However, the aortic calcified lesion might suggest atherosclerotic endothelial impairment, and CBC together with atherosclerosis might have generated mural thrombus in the present patient.\n\nThus far, only two cases of aortic mural thrombus associated with CBC in the ascending aorta have been reported (9, 10), and the characteristics of the patients are summarized in Table. A patient reported by Moorjani et al. was undergoing CBC for bladder carcinoma and was incidentally found to have an asymptomatic aortic mural thrombus on three-dimensional CT of the chest (9). Surgical thrombectomy disclosed mobile thrombus adherent to the ascending aorta along with a separate aortic ulcer (9). Similar to our patient, the atherosclerotic endothelial impairment together with cisplatin-induced endothelial damage may have caused the aortic mural thrombus in that patient. Another patient reported by Yagyu et al. also had an asymptomatic aortic mural thrombus after pre-operative CBC for gastric cancer, which was incidentally found on enhanced CT for an evaluation of the response to chemotherapy. That patient also had protein C deficiency, a risk factor of hypercoagulability (10). Both patients were asymptomatic, and neither had an ischemic stroke. Atherosclerosis risk factors were not mentioned in either case. The present patient did not have any coagulation disorders as far as we found but was suggested to have potential atherosclerotic endothelial damage of the ascending aorta. Although arterial thrombosis is a rare complication after CBC, cisplatin-induced endothelial damage in combination with additional factors, such as coagulation disorder and atherosclerosis, may cause aortic mural thrombus.\n\nTable. Clinical Characteristics of Patients with Mural Thrombus in the Ascending Aorta Following Cisplatin-based Chemotherapy.\n\n\tAge\tSex\tCancer\tSymptoms\tCoagulation disorder\tAtherosclerosis\tInitial treatment\tLong-term treatment\t\nCase 1 (9)\t53 yo\tM\tBC\tNone\tNot described\tAortic ulcer\tSurgical thrombectomy\tWarfarin\t\nCase 2 (10)\t70 yo\tM\tGC\tNone\tProtein C deficiency\tNot described\tHeparin/Warfarin\tNone\t\nPresent case\t59 yo\tF\tSCLC\tIS\tNone\tAortic calcification\tHeparin\tAspirin\t\nyo: years old, M: male, F: female, BC: bladder carcinoma, GC: gastric carcinoma, SCLC: small cell lung carcinoma, IS: ischemic stroke\n\nThe present report is the first to describe an embolic stroke due to a mural thrombus attached to the ascending aorta following CBC. Physicians should be aware of aortic mural thrombus as a rare cause of ischemic stroke in patients treated with CBC, given the wide use of cisplatin against various cancers aside from SCLC.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nThe authors are grateful to Mr. James R. Valera for his assistance in editing the manuscript.\n==== Refs\n1. Byers LA , Rudin CM . Small cell lung cancer: where do we go from here? Cancer 121 : 664-672, 2015.25336398\n2. Lee YG , Lee E , Kim I , et al . Cisplatin-based chemotherapy is a strong risk factor for thromboembolic events in small-cell lung cancer. Cancer Res Treat 47 : 670-675, 2015.25672586\n3. Moore RA , Adel N , Riedel E , et al . High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J Clin Oncol 29 : 3466-3473, 2011.21810688\n4. Machleder HI , Takiff H , Lois JF , Holburt E . Aortic mural thrombus: an occult source of arterial thromboembolism. J Vasc Surg 4 : 473-478, 1986.3773130\n5. Pagni S , Trivedi J , Ganzel BL , et al . Thoracic aortic mobile thrombus: is there a role for early surgical intervention? Ann Thorac Surg 91 : 1875-1881, 2011.21529769\n6. Varki A . Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 110 : 1723-1729, 2007.17496204\n7. Cestari DM , Weine DM , Panageas KS , Segal AZ , DeAngelis LM . Stroke in patients with cancer: incidence and etiology. Neurology 62 : 2025-2030, 2004.15184609\n8. Licciardello JT , Moake JL , Rudy CK , Karp DD , Hong WK . Elevated plasma von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy. Oncology 42 : 296-300, 1985.3875817\n9. Moorjani N , Rubens M , Price S , DeSouza A . Mobile thrombus in the ascending aorta following cisplatin-based chemotherapy. J Card Surg 28 : 48-49, 2013.23199294\n10. Yagyu T , Naito M , Kumada M , Nakagawa T . Aortic mural thrombus in the non-atherosclerotic aorta of patients with multiple hypercoagulable factors. Intern Med 58 : 381-385, 2019.30210102\n\n",
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"issue": "60(6)",
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"keywords": "aortic mural thrombus; cisplatin; embolic stroke; small-cell lung carcinoma",
"medline_ta": "Intern Med",
"mesh_terms": "D001011:Aorta; D002343:Carotid Artery, Internal; D002945:Cisplatin; D000083262:Embolic Stroke; D005260:Female; D006801:Humans; D008875:Middle Aged; D020521:Stroke; D013927:Thrombosis; D016896:Treatment Outcome",
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},
{
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},
{
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{
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}
],
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "3"
}
],
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},
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}
] |
{
"abstract": "We report a case of fatal disseminated varicella zoster virus (VZV) with delayed-onset rash in a 66-year-old female more than 2 years following uncomplicated deceased donor renal transplantation. Whilst on a stable regimen of maintenance immunosuppression, the patient presented with chest and abdominal pain with concomitant hepatitis and pancreatitis. After pursuing multiple other potential causes of her symptoms, the correct diagnosis of VZV was only suspected after the development of a widespread vesicular rash-11 days after her initial symptoms. Despite antiviral therapy and inotropic support in the intensive care unit, the patient died. Simultaneous VZV hepatitis and pancreatitis in solid organ transplant recipients is uncommon. The new inactivated VZV vaccines have the potential to prevent post-transplant infections, with promising early clinical data on safety and efficacy in renal transplant recipients. VZV is an important preventable infection that should be considered in immunocompromised patients, even in the absence of rash.",
"affiliations": "Department of Infectious Diseases, Alfred Health, Melbourne, Victoria, Australia.;Department of Infectious Diseases, Alfred Health, Melbourne, Victoria, Australia.;Central Clinical School, Monash University, Melbourne, Victoria, Australia.;Department of Infectious Diseases, Alfred Health, Melbourne, Victoria, Australia.",
"authors": "Loftus|Michael J|MJ|https://orcid.org/0000-0001-6672-0578;Yong|Michelle K|MK|;Wilson|Scott|S|;Peleg|Anton Y|AY|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "immunocompromised; kidney transplantation; varicella zoster virus",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D005076:Exanthema; D017809:Fatal Outcome; D005260:Female; D006505:Hepatitis; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D010195:Pancreatitis",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13062",
"pmc": null,
"pmid": "30756453",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal disseminated visceral varicella zoster virus infection in a renal transplant recipient.",
"title_normalized": "fatal disseminated visceral varicella zoster virus infection in a renal transplant recipient"
}
|
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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": "Product use in unapproved indication",
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}
],
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{
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],
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"reaction": [
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hepatitis viral",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Confusional state",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Pancreatitis viral",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Agitation",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Somnolence",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LOFTUS MJ, YONG MK, WILSON S, PELEG AY. FATAL DISSEMINATED VISCERAL VARICELLA ZOSTER VIRUS INFECTION IN A RENAL TRANSPLANT RECIPIENT. TRANSPL-INFECT-DIS 2019?21(3):E13062.",
"literaturereference_normalized": "fatal disseminated visceral varicella zoster virus infection in a renal transplant recipient",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20190709",
"receivedate": "20190709",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16548507,
"safetyreportversion": 1,
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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}
] |
{
"abstract": "The relationship between acute pancreatitis and the administration of glucocorticoids is unclear because most reported cases have been diagnosed with systemic vascular diseases, such as systemic lupus erythematosus, which may be responsible for pancreatitis. A 22-year-old woman with eye involvement of a newly diagnosed systemic lupus erythematosus was admitted to our hospital. Pulse intravenous methylprednisolone therapy was given at 1mg/kg day for 3 days, and oral prednisolone at 40 mg/day thereafter. During pulse steroid therapy, she had abdominal pain, back pain, distention, nausea, and vomiting. Her physical examination was compatible with acute abdomen and peritonitis. Abdomen Computerized Tomography scan revealed diffuse liquid perihepatic and perisplenic area with heterogeneity around the mesentery. Due to the symptoms of acute abdomen, explorative laparotomy was performed. There was diffuse free fluid in the abdomen and edematous changes were observed around the pancreas. Amylase and lipase from intraabdominal fluid were studied and found to be high. The postoperative prednol dose was reduced carefully. On the sixth postoperative day, the drain was removed, and the patient was discharged without any problem. Physicians should keep in mind that acute pancreatitis may also be a cause of differential diagnosis of newly developed abdominal pain in patients receiving pulse steroid therapy with a normal level of serum amylase and lipase.",
"affiliations": "University of Health Sciences, Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey.;University of Health Sciences, Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey.;University of Health Sciences, Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey.;University of Health Sciences, Tepecik Training and Research Hospital, Department of General Surgery, İzmir, Turkey.",
"authors": "Atıcı|Semra Demirli|SD|http://orcid.org/0000-0002-8287-067X;Engin|Ömer|Ö|http://orcid.org/0000-0002-6597-1970;Akpınar|Göksever|G|http://orcid.org/0000-0002-0648-7767;Tuğmen|Cem|C|http://orcid.org/0000-0002-2668-5197",
"chemical_list": "D000305:Adrenal Cortex Hormones; D008775:Methylprednisolone",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1806-9282.66.10.1414",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0104-4230",
"issue": "66(10)",
"journal": "Revista da Associacao Medica Brasileira (1992)",
"keywords": null,
"medline_ta": "Rev Assoc Med Bras (1992)",
"mesh_terms": "D000208:Acute Disease; D000305:Adrenal Cortex Hormones; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008775:Methylprednisolone; D010195:Pancreatitis; D055815:Young Adult",
"nlm_unique_id": "9308586",
"other_id": null,
"pages": "1414-1416",
"pmc": null,
"pmid": "33174936",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Corticosteroid associated lupus pancreatitis.",
"title_normalized": "corticosteroid associated lupus pancreatitis"
}
|
[
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{
"abstract": "Prosthetic valve thrombosis is a severe complication, which usually occurs in inadequately anticoagulated patients. Mechanical valve thrombosis is more common than bioprosthetic valve thrombosis (BVT). Oral contraceptive drugs are associated with increased risk of thromboembolism in women. The possible association between oral contraceptive drug use and BVT has never been reported before. We present a case of obstructive BVT occurring after the use of an oral contraceptive drug and successful management with ultra-slow thrombolytic therapy.",
"affiliations": "aDepartment of Cardiology, Kars Karakani State Hospital, Kars bDepartment of Cardiology, İskilip Atif Hoca State Hospital, Çorum cDepartment of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul dDepartment of Cardiology, Evliya Çelebi Training and Research Hospital, Kütahya eDepartment of Cardiology, Gaziemir State Hospital, İzmir fDepartment of Cardiology, Kars Kafkas University, Faculty of Medicine, Kars gDivision of Health Sciences, Ardahan University, Ardahan, Turkey.",
"authors": "Yesin|Mahmut|M|;Kalçik|Macit|M|;Gündüz|Sabahattin|S|;Astarcioğlu|Mehmet Ali|MA|;Gürsoy|Mustafa Ozan|MO|;Karakoyun|Süleyman|S|;Özkan|Mehmet|M|",
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"issue": "27(2)",
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"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000328:Adult; D003276:Contraceptives, Oral; D005260:Female; D005343:Fibrinolytic Agents; D006350:Heart Valve Prosthesis; D006801:Humans; D008943:Mitral Valve; D015912:Thrombolytic Therapy; D013927:Thrombosis; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
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"pages": "220-2",
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"pmid": "26378817",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Bioprostethic mitral valve thrombosis due to oral contraceptive drug use and management with ultra-slow thrombolytic therapy.",
"title_normalized": "bioprostethic mitral valve thrombosis due to oral contraceptive drug use and management with ultra slow thrombolytic therapy"
}
|
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},
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] |
{
"abstract": "OBJECTIVE\nErythromelalgia is a rare clinical syndrome characterized by episodic attacks of burning pain, erythema, and increased temperature, primarily affecting the extremities, and in rare instances, involving the ear, face, neck, and the scrotum. The dermatoscopic features of erythromelalgia in a case with solely facial involvement have never been described previously.\n\n\nMETHODS\nWe describe a 14-year-old female who presented with erythema, burning sensation, and warmth on her face only, which mimic the features of erythromelalgia. Physical examination showed higher temperature on the involved cheeks than on axillas during the episode, while the temperature on both areas was the same between episodes. Dermatoscope showed more dilated vessels inside the erythema during the episodes than between the episodes. The symptoms had excellent response to the combination treatment of gabapentin, indomethacin, and topical lidocaine compounds.\n\n\nCONCLUSIONS\nThe present case is considered to be a variant of erythromelalgia. Its erythema may be resulted from the dilated vessels. Combination of modalities may provide effective management for erythromelalgia. \"Erythermalgia\" may be better than \"erythromelalgia\" to describe such conditions.",
"affiliations": "Department of Dermatology, Huangpu Hospital of The First Affiliated Hospital.",
"authors": "Luo|Di-Qing|DQ|;Zhao|Yu-Kun|YK|;Xu|Qing-Fang|QF|;He|Xiang-Qun|XQ|;Wu|Liang-Cai|LC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/pme.12343",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-2375",
"issue": "15(6)",
"journal": "Pain medicine (Malden, Mass.)",
"keywords": "Dermatoscope; Erythermalgia; Erythromelalgia; Face; Pain; Treatment",
"medline_ta": "Pain Med",
"mesh_terms": "D000293:Adolescent; D004890:Erythema; D004916:Erythromelalgia; D005157:Facial Pain; D005260:Female; D006801:Humans; D010146:Pain; D012008:Recurrence",
"nlm_unique_id": "100894201",
"other_id": null,
"pages": "1007-10",
"pmc": null,
"pmid": "24433512",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent facial erythema with burning sensation and increased temperature: a variant of erythromelalgia or a new entity?",
"title_normalized": "recurrent facial erythema with burning sensation and increased temperature a variant of erythromelalgia or a new entity"
}
|
[
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"actiondrug": "5",
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"abstract": "Pneumonia is the leading infectious killer of children. We conducted a double-blind, randomised controlled non-inferiority trial comparing placebo to amoxicillin treatment for fast breathing pneumonia in HIV-negative children aged 2-59 months in Malawi. Occurrence of serious adverse events (SAEs) during the trial were examined to assess disease progression, co-morbidities, recurrence of pneumonia and side effects of amoxicillin.\n\n\n\nEnrolled children with fast breathing for age and a history of cough <14 days or difficult breathing were randomised to either placebo or amoxicillin for 3 days, and followed for 14 days to track clinical characteristics and outcomes. Medical history, physical exam, laboratory results and any chest radiographs collected at screening, enrolment and during hospitalisation were evaluated. All SAE reports were reviewed for additional information regarding hospitalisation, course of treatment and outcome.\n\n\n\nIn total, 102/1126 (9.0%) enrolled children with fast breathing pneumonia were reported to have a SAE. Seventy-five per cent (n=77) of SAEs were pneumonia-related (p<0.01). Children<2 years of age represented the greatest proportion (61/77, 79.2%) of those with a pneumonia-related SAE. In the amoxicillin group, there were 46 SAEs and 5 (10.9%) cases were identified as possibly related to study drug (4 gastroenteritis and 1 fever). There were no life-threatening pneumonia SAEs or deaths in either group, and by the time of exit from the study, all children recovered without sequelae.\n\n\n\nIn this fast breathing pneumonia clinical trial, SAEs occurred infrequently in both the amoxicillin and placebo groups, and amoxicillin was well tolerated.\n\n\n\nNCT02760420. https://clinicaltrials.gov/ct2/show/NCT02760420?term=ginsburg&rank=9.",
"affiliations": "International Programs, Save the Children Federation Inc, Fairfield, Connecticut, USA.;Department of Biostatistics, University of Washington, Seattle, Washington, USA.;Department of Pediatrics, University of North Carolina Project, Lilongwe Medical Relief Fund Trust, Lilongwe, Malawi.;Department of Pediatrics, University of North Carolina Project, Lilongwe Medical Relief Fund Trust, Lilongwe, Malawi.;Department of Pediatrics and Child Health, University of Malawi College of Medicine, Blantyre, Malawi.;International Programs, Save the Children Federation Inc, Fairfield, Connecticut, USA.;Eudowood Division of Pediatric Respiratory Sciences, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.;International Programs, Save the Children Federation Inc, Fairfield, Connecticut, USA.",
"authors": "Nkwopara|Evangelyn|E|0000-0002-1078-7375;Schmicker|Robert|R|;Mvalo|Tisungane|T|;Phiri|Melda|M|;Phiri|Ajib|A|;Couasnon|Mari|M|;McCollum|Eric D|ED|0000-0002-1872-5566;Ginsburg|Amy Sarah|AS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D010919:Placebos; D000658:Amoxicillin",
"country": "England",
"delete": false,
"doi": "10.1136/bmjresp-2019-000415",
"fulltext": "\n==== Front\nBMJ Open Respir ResBMJ Open Respir ResbmjrespbmjopenrespresBMJ Open Respiratory Research2052-4439BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bmjresp-2019-00041510.1136/bmjresp-2019-000415Paediatric Lung Disease15062226Analysis of serious adverse events in a paediatric fast breathing pneumonia clinical trial in Malawi http://orcid.org/0000-0002-1078-7375Nkwopara Evangelyn 1Schmicker Robert 2Mvalo Tisungane 3Phiri Melda 3Phiri Ajib 4Couasnon Mari 1http://orcid.org/0000-0002-1872-5566McCollum Eric D. 5Ginsburg Amy Sarah 11 International Programs, Save the Children Federation Inc, Fairfield, Connecticut, USA2 Department of Biostatistics, University of Washington, Seattle, Washington, USA3 Department of Pediatrics, University of North Carolina Project, Lilongwe Medical Relief Fund Trust, Lilongwe, Malawi4 Department of Pediatrics and Child Health, University of Malawi College of Medicine, Blantyre, Malawi5 Eudowood Division of Pediatric Respiratory Sciences, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USACorrespondence to Evangelyn Nkwopara; [email protected] 3 9 2019 6 1 e00041530 1 2019 01 7 2019 09 8 2019 © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.Introduction\nPneumonia is the leading infectious killer of children. We conducted a double-blind, randomised controlled non-inferiority trial comparing placebo to amoxicillin treatment for fast breathing pneumonia in HIV-negative children aged 2–59 months in Malawi. Occurrence of serious adverse events (SAEs) during the trial were examined to assess disease progression, co-morbidities, recurrence of pneumonia and side effects of amoxicillin.\n\nMethods\nEnrolled children with fast breathing for age and a history of cough <14 days or difficult breathing were randomised to either placebo or amoxicillin for 3 days, and followed for 14 days to track clinical characteristics and outcomes. Medical history, physical exam, laboratory results and any chest radiographs collected at screening, enrolment and during hospitalisation were evaluated. All SAE reports were reviewed for additional information regarding hospitalisation, course of treatment and outcome.\n\nResults\nIn total, 102/1126 (9.0%) enrolled children with fast breathing pneumonia were reported to have a SAE. Seventy-five per cent (n=77) of SAEs were pneumonia-related (p<0.01). Children<2 years of age represented the greatest proportion (61/77, 79.2%) of those with a pneumonia-related SAE. In the amoxicillin group, there were 46 SAEs and 5 (10.9%) cases were identified as possibly related to study drug (4 gastroenteritis and 1 fever). There were no life-threatening pneumonia SAEs or deaths in either group, and by the time of exit from the study, all children recovered without sequelae.\n\nDiscussion\nIn this fast breathing pneumonia clinical trial, SAEs occurred infrequently in both the amoxicillin and placebo groups, and amoxicillin was well tolerated.\n\nTrial registration number\nNCT02760420. https://clinicaltrials.gov/ct2/show/NCT02760420?term=ginsburg&rank=9.\n\npneumoniahttp://dx.doi.org/10.13039/100000865Bill and Melinda Gates FoundationOPP1105080special-featureunlocked\n==== Body\nKey messages\nWhat are the safety implications when conducting a paediatric fast breathing pneumonia clinical trial involving placebo in a malaria-endemic setting in Africa?\n\nBy carefully adhering to strict eligibility criteria and conducting frequent and careful clinical monitoring of enrolled children with fast breathing pneumonia, our study population in Lilongwe, Malawi experienced no deaths, no life-threatening events and an overall low incidence of serious adverse events.\n\nThis secondary analysis of safety outcomes demonstrates that it is possible to safely conduct a large-scale paediatric pneumonia clinical trial in which placebo is involved.\n\nIntroduction\nGlobally, pneumonia remains the leading infectious cause of death in children aged less than 5 years.1 Although the number of child deaths due to pneumonia has dropped significantly in the last 15 years, more work is needed to improve the diagnosis and treatment of pneumonia, particularly in sub-Saharan Africa.2 WHO Integrated Management of Childhood Illness (IMCI) guidelines were developed to be pragmatic and to assist with identifying and treating acutely ill children in low resource settings using mainly clinical signs rather than invasive testing or imaging.3 Current WHO IMCI guidelines diagnose pneumonia by identifying fast breathing and/or chest indrawing in a child with cough or difficult breathing, and recommend outpatient treatment with amoxicillin for those without accompanying clinical danger signs. However, it has been questioned whether fast breathing as an isolated clinical sign in a child with cough or difficult breathing is due to bacteria and requires antibiotics.4 We recently completed a double-blind randomised controlled non-inferiority trial in HIV-uninfected children aged 2–59 months with WHO IMCI-defined fast breathing pneumonia in a malaria-endemic region of Malawi which showed treatment with placebo was inferior to 3 days of treatment with amoxicillin.5 Given the opportunity to assess clinical outcomes in both a placebo group and a group receiving antibiotic treatment, we examined the incidence of serious adverse events (SAEs) within each group as a secondary analysis.\n\nWhile the safety of amoxicillin use in children with pneumonia has been established, amoxicillin has important side effects including diarrhoea, nausea, vomiting, fever and rash as well as rarer but more serious side effects such as abnormal liver function tests, interstitial nephritis, seizures and Stevens-Johnson syndrome, all of which could lead to SAEs.6 7 In the absence of antibiotic treatment, there is concern for clinical deterioration and SAEs in children with bacterial infections like pneumonia. While this secondary analysis is not a reassessment of amoxicillin’s safety or effectiveness, there is value in assessing both the harms and benefits of amoxicillin, particularly in a randomised controlled trial that includes a placebo group. We also investigate the impact, if any, on disease progression in the placebo group since these children did not receive antibiotics for WHO-defined pneumonia despite having clinical signs.\n\nMethods\nHIV-uninfected children aged 2–59 months who presented with fast breathing for age in the presence of a cough <14 days or difficult breathing were enrolled (table 1). The study was conducted at Kamuzu Central Hospital (KCH) and Bwaila District Hospital in Lilongwe, Malawi. Final eligibility determination for enrolment depended on the results of the medical history, physical examination, laboratory testing, appropriate understanding of the study and completion of the written informed consent process. Enrolled children were randomised to either 3 days of amoxicillin or placebo dispersible tablet treatment, and then followed for 14 days to track clinical outcomes. At follow-up visits, children were assessed for treatment failure (primary endpoint, day 4) or clinical relapse.\n\nTable 1 Study terms and definitions\n\nFast breathing for age\tRespiratory rate >50 breaths per minute for children t2 to <12 months of age, or >40 breaths per minute for children>12 months of age\t\nSevere respiratory distress\tGrunting, nasal flaring, head nodding and/or chest indrawing\t\nHypoxaemia\tArterial oxyhaemoglobin saturation (SpO2) <90% in room air, as assessed non-invasively by a pulse oximeter\t\nWHO IMCI general danger signs\tLethargy or unconsciousness, convulsions, vomiting everything or inability to drink or breastfeed\t\nSevere acute malnutrition\tWeight for height/length <-3 SD, MUAC <11.5 cm, or peripheral oedema\t\nSevere malaria\tPositive malaria rapid diagnostic test with any WHO IMCI general danger sign, stiff neck, abnormal bleeding, clinical jaundice, or haemoglobinuria\t\nHIV exposure\tChildren<24 months of age with a HIV-infected mother\t\nSerious adverse event\t Adverse event that: Results in death\n\n Is life threatening\n\n Requires inpatient hospitalisation or prolongation of existing hospitalisation\n\n Results in persistent or significant disability/incapacity\n\n Is a medical event, based on appropriate medical judgement, that may jeopardise the health of the participating child or require medical or surgical intervention to prevent one of the outcomes listed\n\n\t\nEligibility criteria\t\nInclusion criteria\t 2–59 months of age\n\n Cough <14 days or difficulty breathing\n\n Fast breathing for age\n\n\t\nExclusion criteria\t Severe respiratory distress\n\n Hypoxaemia\n\n Resolution of fast-breathing after bronchodilator challenge, if wheezing at screening examination\n\n WHO IMCI general danger signs\n\n Stridor when calm\n\n HIV seropositivity or HIV exposure\n\n Severe acute malnutrition\n\n Possible tuberculosis (coughing >14 days)\n\n Anaemia with haemoglobin <80 g/L\n\n Severe malaria\n\n Known allergy to penicillin or amoxicillin\n\n Receipt of an antibiotic treatment in the 48 hours prior to the study\n\n Hospitalised within 14 days prior to the study\n\n Living outside the study area\n\n Any medical or psychosocial condition or circumstance that, in the opinion of the investigators, would interfere with the conduct of the study or for which study participation might jeopardise the child’s health\n\n Any non-pneumonia acute medical illness which requires antibiotic treatment as per local standard of care\n\n Participation in a clinical study of another investigational product within 12 weeks prior to randomisation or planning to begin participation during this study\n\n Prior participation in the study during a previous pneumonia diagnosis\n\n\t\nTreatment failure\t\nAny time on or before day 4\t Severe respiratory distress\n\n Hypoxaemia\n\n WHO IMCI danger signs\n\n Missing >2 study drug doses due to vomiting\n\n Change in antibiotics prescribed by a study clinician\n\n Hospitalisation due to pneumonia (if not initially admitted)\n\n Prolonged hospitalisation or re-admission due to pneumonia (if initially admitted)\n\n Death\n\n\t\nOn day 4 only\t Axillary temperature >38°C in the absence of a diagnosed co-infection with fever symptoms (eg, malaria)\n\n\t\nClinical relapse\t \t\nAny time after day 4\t Recurrence of signs of pneumonia\n\n Signs of severe disease\n\n\t\nNIH DAIDS severity grading\t\nGrade 1\tMild event\t\nGrade 2\tModerate event\t\nGrade 3\tSevere event\t\nGrade 4\tPotentially life-threatening event\t\nGrade 5\tDeath\t\nDAIDS, Division of AIDS; IMCI, Integrated Management of Childhood Illness; MUAC, mid-upper arm circumference; NIH, National Institutes of Health.\n\nOn administration of the initial study drug dose on day 1, all children were observed by study staff for at least 2–8 hours before considering discharge. Children with no fever and a respiratory rate below the enrolment respiratory rate threshold were discharged after 2 hours of observation. Children aged less than 6 months, with moderate malnutrition, or febrile with a negative malaria rapid diagnostic test were monitored inpatient overnight and assessed by study staff for discharge on the morning of day 2. At any time between 2 hours post-enrolment and the morning of day 2, if a child’s condition deteriorated, s/he was hospitalised, the study drug was discontinued and treatment was provided as per local standard of care. If a child showed signs of deterioration resulting in a SAE, a detailed SAE report was completed. The United States National Institutes of Health (NIH) Division of AIDS (DAIDS) adverse event (AE) grading system was used to assess severity of the event (table 1).8 All enrolled children requiring hospitalisation for their pneumonia any time between days 1 and 14 were initially treated with benzyl penicillin and gentamycin intravenously as per standard of care at KCH. The study drug was discontinued for any enrolled children who were hospitalised between days 1 and 4. Chest radiographs were obtained at the discretion of study clinicians, and the local principal investigator made the final clinical interpretation. A data safety monitoring board was established to routinely and independently assess child safety throughout the trial. Participants had regular follow-up visits at the study clinic, and if a child missed a visit, the clinical team conducted a home visit to assess the health status of the child.\n\nMedical history, physical exam information, laboratory results and chest radiographs collected at screening, enrolment and during hospitalisation were evaluated. We reviewed all SAE reports for any additional information regarding the child’s hospitalisation, course of treatment and outcome. Reported possible side effects of amoxicillin (ie, fever, gastroenteritis, skin conditions and candidiasis) were also reviewed.\n\nPatient and public involvement\nThe University of North Carolina Project Lilongwe community advisory board assisted with community outreach during study recruitment. However, neither the study participants nor the community advisory board were involved in the development of the research question, study design or outcome measures.\n\nResults\nA total of 1126 HIV-uninfected children with fast breathing pneumonia were enrolled with 102 SAEs reported. Among those enrolled, 98 (8.7%) children experienced at least 1 SAE (figure 1), and 4 children had more than 1 SAE. SAEs were evenly distributed between males and females (table 2). Children aged 2–11, 12–23 and 24–59 months accounted for 39.7% (n=39), 35.7% (n=35) and 24.5% (n=24) of all SAEs, respectively. Baseline clinical characteristics at enrolment for those with at least 1 SAE included runny nose (n=47), fever (n=25), diarrhoea by caregiver report (n=9) and malaria (n=5). Only three children were moderately malnourished by MUAC. Of the 98 children with at least 1 SAE, 53 (54.0%) who should have received all three pneumococcal conjugate vaccine doses based on age did receive all three doses and 54 (55.1%) who should have received all three pentavalent vaccine doses based on age did receive all three doses (table 3). Fifty-five (4.9%) SAEs occurred during days 1–4 while receiving study drug, and the remaining 47 (4.2%) SAEs occurred after day 4.\n\nFigure 1 Serious adverse events.\n\nTable 2 Baseline clinical presentation at enrolment\n\n\tAmoxicillin\tPlacebo\t\nAge 2–6\nmonths\tAge 7–11\nmonths\tAge 12–23\nmonths\tAge 24–59\nmonths\tAge 2–6\nmonths\tAge 7–11\nmonths\tAge 12–23\nmonths\tAge 24–59\nmonths\t\nNo of children\t9\t7\t18\t10\t14\t9\t17\t14\t\nMale gender, n (%)\t6 (66.7)\t4 (57.1)\t10 (55.6)\t7 (70.0)\t6 (42.9)\t4 (44.4)\t6 (35.3)\t6 (42.9)\t\nMalaria present, n (%)\t0 (0.0)\t1 (14.3)\t1 (5.6)\t2 (20.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t1 (7.1)\t\nDiarrhoea (by caretaker assessment), n (%)\t1 (11.1)\t1 (14.3)\t1 (5.6)\t0 (0.0)\t0 (0.0)\t2 (22.2)\t2 (11.8)\t2 (14.3)\t\nRespiratory rate (breaths/min)\n40–49, n (%)\t0 (0.0)\t0 (0.0)\t8 (44.4)\t7 (70.0)\t0 (0.0)\t0 (0.0)\t10 (58.8)\t10 (71.4)\t\nRespiratory rate (breaths/min)\n>49, n (%)\t9 (100.0)\t7 (100.0)\t10 (55.6)\t3 (30.0)\t14 (100.0)\t9 (100.0)\t7 (41.2)\t4 (28.6)\t\nOxygen saturation\n90%–93%, n (%)\t0 (0.0)\t0 (0.0)\t1 (5.6)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nOxygen saturation\n>93%, n (%)\t9 (100.0)\t7 (100.0)\t17 (94.4)\t10 (100.0)\t14 (100.0)\t9 (100.0)\t17 (100.0)\t14 (100.0)\t\nAxillary temperature\n>38°C, n (%)\t1 (11.1)\t1 (14.3)\t5 (27.8)\t4 (40.0)\t1 (7.1)\t1 (11.1)\t3 (17.6)\t9 (64.3)\t\nAxillary temperature\n<38°C, n (%)\t8 (88.9)\t6 (85.7)\t13 (72.2)\t6 (60.0)\t13 (92.9)\t8 (88.9)\t14 (82.4)\t5 (35.7)\t\nHeart rate (beats/min) Median\t156\t149\t150\t136\t147\t150\t145\t153\t\nHeart rate (beats/min)\nMin, Max\t129, 170\t117, 162\t126, 192\t130, 156\t129, 168\t120, 162\t133, 163\t125, 170\t\nHeight/weight Z-score, n\t9\t7\t18\t10\t14\t9\t17\t14\t\nHeight/weight Z-score\n> −2, n (%)\t9 (100.0)\t7 (100.0)\t17 (94.4)\t10 (100.0)\t13 (92.9)\t9 (100.0)\t17 (100.0)\t13 (92.9)\t\nHeight/weight Z-score\n−2 and −3, n (%)\t0 (0.0)\t0 (0.0)\t1 (5.6)\t0 (0.0)\t1 (7.1)\t0 (0.0)\t0 (0.0)\t1 (7.1)\t\nHeight/weight Z-score\nMean (SD)\t1.5 (1.2)\t0.0 (1.4)\t0.9 (1.5)\t0.0 (1.3)\t0.9 (1.9)\t0.4 (1.0)\t0.8 (0.6)\t−0.2 (1.1)\t\nMid-upper arm circumference, n\t9\t7\t18\t10\t14\t9\t17\t14\t\nMid-upper arm circumference\n>125 mm, n (%)\t8 (88.9)\t7 (100.0)\t18 (100.0)\t10 (100.0)\t12 (85.7)\t9 (100.0)\t17 (100.0)\t14 (100.0)\t\nMid-upper arm circumference\n115–125 mm, n (%)\t1 (11.1)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t2 (14.3)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nMid-upper arm circumference\nMedian (IQR)\t140.6 (8.9)\t144.6 (6.4)\t153.4 (11.5)\t156.2 (14.0)\t139.3 (10.6)\t146.2 (9.5)\t150.4 (9.6)\t151.4 (6.9)\t\nEvidence of discharge from ear, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nRunny nose, n (%)\t6 (66.7)\t6 (85.7)\t8 (44.4)\t5 (50.0)\t6 (42.9)\t4 (44.4)\t6 (35.3)\t6 (42.9)\t\nOral thrush, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nTender, enlarged lymph node(s) on neck, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nStiff neck, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nTable 3 Pneumococcal conjugate and pentavalent vaccines history\n\n\tAmoxicillin\tPlacebo\t\n2–3 months*\t4–59 months*\t2–3 months*\t4–59 months*\t\nNo of children\t4\t40\t6\t48\t\nPneumococcal conjugate vaccine\t\t\t\t\t\n Received three doses, n (%)\t1 (25.0)\t24 (60.0)\t0 (0.0)\t29 (60.4)\t\n Received two doses, n (%)\t0 (0.0)\t3 (7.5)\t1 (16.7)\t0 (0.0)\t\n Received one dose, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n Received 0 doses, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n All doses unknown, n (%)\t0 (0.0)\t13 (32.5)\t0 (0.0)\t19 (39.6)\t\n Some doses unknown, n (%)\t\t\t\t\t\n Received two doses\t2 (50.0)\t0 (0.0)\t5 (83.3)\t0 (0.0)\t\n Received one dose\t1 (25.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n Received 0 doses\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nPentavalent vaccine\t\t\t\t\t\n Received three doses, n (%)\t1 (25.0)\t25 (62.5)\t0 (0.0)\t29 (60.4)\t\n Received two doses, n (%)\t0 (0.0)\t2 (5.0)\t1 (16.7)\t0 (0.0)\t\n Received one dose, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n Received 0 doses, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n All doses unknown, n (%)\t0 (0.0)\t13 (32.5)\t0 (0.0)\t19 (39.6)\t\n Some doses unknown, n (%)\t\t\t\t\t\n Received two doses\t2 (50.0)\t0 (0.0)\t5 (83.3)\t0 (0.0)\t\n Received one dose\t1 (25.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n Received 0 doses\t0 (0.0)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\n*Age groups reflect recommended vaccine dosing schedules:<3 months should have received one dose;>3 months should have received all three doses.\n\nOf the 102 SAEs, 77 (75.5%; p=<0.01) were pneumonia-related SAEs (table 4). Of the 77 pneumonia-related SAEs, 39 (27 in the placebo group and 12 in the amoxicillin group) occurred during days 1–4 while receiving study drug, and 38 (16 in the placebo group and 22 in the amoxicillin group) occurred after day 4 (figure 2). Types of pneumonia-related SAEs included progression to chest indrawing pneumonia (n=35; 45.5%), persistence of fast breathing pneumonia (n=19; 24.7%), progression to pneumonia with respiratory distress or WHO general danger signs (n=14; 18.2%), chest radiograph confirmed pneumonia (n=8; 10.4%) and one pneumonia case with no additional data regarding type of pneumonia. Of the 77 pneumonia-related SAEs, 61 (79.2%) cases occurred in children aged <2 years (table 5). Fifty (64.9%) of the pneumonia-related SAEs were NIH DAIDs severity grade 3 (severe) and 27 (35.0%) were severity grade 2 (moderate) (S1 Appendix, supporting material). There were no grade 4 (life-threatening) SAEs. All children recovered without sequelae. There were no deaths.\n\n10.1136/bmjresp-2019-000415.supp1Supplementary data \n\n Table 4 Serious adverse events by treatment group\n\n\tAmoxicillin\tPlacebo\tOverall\t\nSerious adverse events per group\t46\t56\t102\t\nSerious adverse events (can be multiple events per child)\t\nPneumonia-related, n (%)*\t34 (73.9)\t43 (76.8)\t77 (75.5)\t\n Chest indrawing pneumonia\t17 (50.0)\t18 (41.9)\t35 (45.5)\t\n Fast breathing pneumonia\t7 (20.6)\t12 (27.9)\t19 (24.7)\t\n Pneumonia with respiratory distress or WHO general danger signs\t5 (14.7)\t9 (20.9)\t14 (18.1)\t\n Chest radiograph confirmed pneumonia†\t4 (11.8)\t4 (9.3)\t8 (10.4)\t\n Pneumonia‡\t1 (3.0)\t0 (0.0)\t1 (1.3)\t\nNon-pneumonia related, n (%)*\t12 (26.0)\t13 (23.2)\t25 (24.5)\t\n Acute gastroenteritis\t4 (33.3)\t4 (30.8)\t8 (32.0)\t\n Fever\t1 (8.3)\t4 (30.8)\t5 (20.0)\t\n Malaria\t2 (16.7)\t1 (7.7)\t3 (12.0)\t\n Convulsion\t1 (8.3)\t1 (7.7)\t2 (8.0)\t\n Urinary tract infection\t0 (0.0)\t2 (15.4)\t2 (8.0)\t\n Vomiting\t2 (16.7)\t0 (0.0)\t2 (8.0)\t\n Anaemia\t0 (0.0)\t1 (7.7)\t1 (4.0)\t\n Epistaxis\t1 (8.3)\t0 (0.0)\t1 (4.0)\t\n Febrile convulsion\t1 (8.3)\t0 (0.0)\t1 (4.0)\t\n*Percentages for ‘Amoxicillin’ and ‘Placebo’ columns reflect total number of children within each category by treatment group. Percentages for ‘Overall’ column reflect total number of serious adverse event cases.\n\n†Chest radiograph performed due to persistent fever leading to identification of pneumonia.\n\n‡Event reported from an outside hospital and hospital records did not specify type of pneumonia.\n\nFigure 2 Serious adverse events by visit day and treatment group.\n\nTable 5 Serious adverse event by age and treatment group\n\nAge group (months)\tAmoxicillin\tPlacebo\t\n2–6\t7–11\t12–23\t24–59\t2–6\t7–11\t12–23\t24–59\t\nSerious adverse events, n\t9\t7\t19\t11\t14\t10\t17\t15\t\nFast breathing pneumonia, n (%)\t0 (0.0%)\t1 (0.2%)\t4 (0.7%)\t2 (0.4%)\t3 (0.5%)\t1 (0.2%)\t5 (0.9%)\t3 (0.5%)\t\nChest indrawing pneumonia, n (%)\t6 (1.1%)\t1 (0.2%)\t7 (1.2%)\t3 (0.5%)\t10 (1.8%)\t1 (0.2%)\t6 (1.1%)\t1 (0.2%)\t\nPneumonia with respiratory distress or general danger signs, n (%)\t0 (0.0%)\t1 (0.2%)\t3 (0.5%)\t1 (0.2%)\t1 (0.2%)\t3 (0.5%)\t3 (0.5%)\t2 (0.4%)\t\nChest radiograph confirmed pneumonia, n (%)*\t1 (0.2%)\t1 (0.2%)\t2 (0.4%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t4 (0.7%)\t\nPneumonia, n (%)\t1 (0.2%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t\nAcute gastroenteritis, n (%)\t1 (0.2%)\t1 (0.2%)\t2 (0.4%)\t0 (0.0%)\t0 (0.0%)\t3 (0.5%)\t1 (0.2%)\t0 (0.0%)\t\nFever, n (%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t2 (0.4%)\t0 (0.0%)\t2 (0.4%)\t\nMalaria, n (%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t\nConvulsion, n (%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t\nUrinary tract infection, n (%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t2 (0.4%)\t\nVomiting, n (%)\t0 (0.0%)\t0 (0.0%)\t1 (0.2%)\t1 (0.2%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t\nAnaemia, n (%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t1 (0.2%)\t\nEpistaxis, n (%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t\nFebrile convulsion, n (%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t1 (0.2%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t\n*Chest radiograph performed due to persistent fever leading to identification of pneumonia.\n\nThere were 25 non-pneumonia-related SAEs: acute gastroenteritis (n=8); fever (n=5); malaria (n=3); convulsion (n=3); and other (n=6; urinary tract infections (n=2), vomiting (n=2); epistaxis (n=1); anaemia (n=1)). Of the 25 non-pneumonia-related SAEs, 16 occurred between days 1 and 4 (7 in the placebo group and 9 in the amoxicillin group), and 9 occurred after day 4 (6 in the placebo group and 3 in the amoxicillin group). The NIH DAIDs severity grade for 15 of the non-pneumonia-related SAEs was grade 3; 8 were grade 2 SAEs. All recovered without sequelae. There were no deaths. The average duration of hospitalisation for both pneumonia-related and non-pneumonia-related SAEs was 10 days, and was similar in both the placebo and amoxicillin groups (S2 Appendix, supporting material).\n\nWhen reviewing the relationship of SAE to study drug, 4 gastroenteritis cases and 1 fever were noted as “possibly related” in the amoxicillin group (10.9%). All other SAEs were assessed as not related to study drug (S3 Appendix, supporting material). A total of 200 AEs in the amoxicillin group (n=564) were reviewed and 77 (13.7%) AEs were identified as possibly amoxicillin-related side effects, of which 52 (67.5%) were gastroenteritis. These cases did not require hospitalisation and were not reported as SAEs. Rash was reported in 8 (10.4%) children, and candidiasis in 4 (5.2%) children in the amoxicillin group (S3 Appendix, supporting material). For comparison, in the placebo group (n=562), there were 241 (42.9%) AEs, 47 (19.5%) of which were gastroenteritis, 12 (5.0%) rash and 1 (0.4%) candidiasis. In contrast to children with SAEs, the 1028 children (520 in the amoxicillin group, 508 in the placebo group) without SAEs were predominantly greater than 1 year of age (65.7%, 675/1028) and had slightly higher rates of malaria (13.2%, 136/1028) (S4 Appendix, supporting material). There were no significant differences in all other baseline characteristics between children with SAEs compared with those without.\n\nDiscussion\nIn this fast breathing pneumonia clinical trial, SAEs were infrequent. In addition, the number of children who required hospitalisation due to a SAE while receiving study drug or placebo was low, even among children aged <2 years. None of the SAEs were life-threatening or resulted in death. The low rate of SAEs in our trial may be attributed to the high level of supportive care and close monitoring of children during the study, particularly between days 1 and 4. It could also be argued that the low rate of SAEs may be a consequence of the trial’s strict study eligibility criteria that included relatively low-risk children and excluded HIV-seropositive children as well as any child exhibiting signs of severe disease, anaemia or acute malnourishment. Another fast breathing pneumonia clinical trial, also comparing 3 days of amoxicillin to placebo in children, recently completed in Karachi, Pakistan and a similar secondary analysis of their SAEs may provide additional insight into the generalisability of our results.\n\nA key aim in reviewing SAEs within this trial was to assess potential adverse impacts of amoxicillin use for treatment of childhood pneumonia, particularly since the diagnosis of pneumonia was based solely on clinical signs and did not involve any laboratory or radiographic confirmation. Common harms from antibiotics are poorly quantified and often are not well reported in clinical trials.6 Within our trial there were 5 SAEs, 4 cases of gastroenteritis and 1 fever, determined to be possibly related to receiving amoxicillin. Non-pneumonia-related SAEs were almost evenly distributed between the placebo and amoxicillin groups (placebo 13/25 vs amoxicillin 12/25), with the most common non-pneumonia-related SAE being acute gastroenteritis. The low number of SAEs in the amoxicillin group supports the general safety of amoxicillin use in children.7 In a meta-analysis reviewing randomised trials of amoxicillin and/or amoxicillin–clavulanic acid, diarrhoea and candidiasis were identified as the most common associated harms.6 Our secondary analysis is limited because it focuses primarily on SAEs. We did review AEs; however, we did not look at all AEs, but rather only those that could be possible side effects of amoxicillin. Gastroenteritis was the most commonly reported side effect in the amoxicillin group but attribution to amoxicillin was not examined. A more comprehensive review of all AEs may provide additional information confirming which diarrhoea and vomiting events might be attributed to amoxicillin use, as well as other reported possible side effects, during the trial.\n\nThe number of children with 2 or more SAEs was low; only 4 out of 98 children with at least 1 SAE had multiple SAEs. Although most initial SAE hospitalisations were due to progression or recurrent pneumonia, only 4% of children were readmitted for additional treatment of pneumonia or other severe disease. In low resource settings, the months following hospital discharge carry significant risk for morbidity and mortality, with pneumonia identified as one of the baseline variables associated with post-discharge mortality.9 This highlights a major limitation in this analysis. Follow-up of children post-discharge was restricted to the study participation period of 2 weeks, with a 2-day visit window if the child missed day 14. We do not have additional outcome data after day 14 and are therefore unable to assess if any children were readmitted or died within 30 days of enrolment at KCH or other local healthcare facilities. We also are not able to assess any long-term potential adverse impacts of amoxicillin use (eg, microbiome, growth, antimicrobial resistance). Additional limitations of this secondary analysis include our small sample size and the strict eligibility criteria of the trial. Our results may not be generalisable across other settings or non-trial conditions and should be interpreted within that context. The children enrolled in this trial were non-severe pneumonia cases without HIV and very few comorbidities or complications. This may have ultimately biased the number of SAEs.\n\nConclusion\nThe overall incidence of SAEs among children in this fast breathing pneumonia clinical trial was low. This also held true among the children receiving placebo for their fast breathing pneumonia. Only 5 SAEs were possibly related to receipt of amoxicillin. Enrolled children aged 2–23 months represented the greatest proportion of those with any SAE or a pneumonia-related SAE. Our analysis and findings help to underscore the importance of adequate and complete safety monitoring and reporting in phase 4 clinical trials, particularly those involving children. The results of this analysis demonstrate that it is possible to safely conduct a clinical trial of this magnitude with placebo in a paediatric group. While this could be credited in part to the trial eligibility criteria and close monitoring by the clinical research site, it should be noted that there were no life-threatening pneumonia SAEs or deaths, even among those in the placebo group. The dissemination of this data is useful to better understand the balance of risks versus benefits of antibiotic treatment in young children, even with a well-established and commonly used antibiotic such as amoxicillin.\n\nWe thank the dedicated study staff at the University of North Carolina (UNC) Project, Lilongwe Medical Relief Fund Trust for providing patient care and data collection; the UNC Project Lilongwe community advisory board for their work as participant advocates and their assistance with community outreach; Triclinium Clinical Development for facilitating data review and management; and the Malawi Ministry of Health. We also thank the trial participants, their caregivers and the local community in Lilongwe, Malawi for their participation and support.\n\nContributors: EN: conceptualisation, project administration, supervision, methodology, data curation, formal analysis, writing (original draft, review and editing). RS: conceptualisation, methodology, data curation, formal analysis, writing (review and editing). TM: project administration and implementation, methodology, data curation, writing (review and editing). MP: project administration and implementation, data curation. AP: project administration and implementation. MC: project administration, data curation. EDM: conceptualisation, methodology, data curation, formal analysis, writing (review and editing). ASG: funding acquisition, conceptualisation, project administration, supervision, methodology, data curation, formal analysis, writing (review and editing).\n\nFunding: This research is supported by a grant from the Bill and Melinda Gates Foundation.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Not required.\n\nEthics approval: The study was conducted in accordance with the International Conference on Harmonisation, Good Clinical Practice and the Declaration of Helsinki 2008. The study was approved by the Western Institutional Review Board in the state of Washington, USA; the College of Medicine Research and Ethics Committee, Blantyre, Malawi; and the Malawi Pharmacy, Medicines and Poisons Board.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: Data are available in a public, open access repository.\n==== Refs\nReferences\n1. Liu L , Oza S , Hogan D , et al \nGlobal, regional, and national causes of child mortality in 2000–13, with projections to inform post-2015 priorities: an updated systematic analysis . The Lancet 2015 ;385 :430 –40 . 10.1016/S0140-6736(14)61698-6 \n2. UNICEF \nOne is too many. ending child deaths from pneumonia and diarrhea . New York : UNICEF , 2016 .\n3. WHO \nRevised WHO classification and treatment of pneumonia in children at health facilities: evidence summaries . Geneva : World Health Organization , 2014 .\n4. Hazir T , Nisar YB , Qazi SA , et al \nChest radiography in children aged 2-59 months diagnosed with non-severe pneumonia as defined by World Health organization: descriptive multicentre study in Pakistan . BMJ 2006 ;333 \n10.1136/bmj.38915.673322.80 \n5. Ginsburg AS , Mvalo T , Nkwopara E , et al \nPlacebo vs amoxicillin for nonsevere Fast-Breathing pneumonia in Malawian children aged 2 to 59 months: a double-blind, randomized clinical Noninferiority trial . JAMA Pediatr 2018 ;3407 .\n6. Gillies M , Ranakusuma A , Hoffmann T , et al \nCommon harms from amoxicillin: a systematic review and meta-analysis of randomized placebo-controlled trials for any indication . CMAJ 2015 ;187 :E21 –31 . 10.1503/cmaj.140848 25404399 \n7. FDA \nAmoxil . Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050760s11,050761s11,050754s12,050542s25lbl.pdf [Accessed 20 Dec 2018 ].\n8. Division of AIDS (DAIDS) \nTable for grading the severity of adult and pediatric adverse events, corrected version 2.1 , 2017 Available: http://rsc.tech-res.com/docs/default-source/safety/daidsgradingcorrecetedv21.pdf?sfvrsn=6 [Accessed 20 Dec 2018 ].\n9. Wiens MO , Pawluk S , Kissoon N , et al \nPediatric post-discharge mortality in resource poor countries: a systematic review . PLoS One 2013 ;8 :e66698\n10.1371/journal.pone.0066698 23825556\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-4439",
"issue": "6(1)",
"journal": "BMJ open respiratory research",
"keywords": "pneumonia",
"medline_ta": "BMJ Open Respir Res",
"mesh_terms": "D000284:Administration, Oral; D000367:Age Factors; D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D005334:Fever; D005759:Gastroenteritis; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D007223:Infant; D008295:Malawi; D008297:Male; D010919:Placebos; D011014:Pneumonia; D012307:Risk Factors; D059246:Tachypnea; D016896:Treatment Outcome",
"nlm_unique_id": "101638061",
"other_id": null,
"pages": "e000415",
"pmc": null,
"pmid": "31548894",
"pubdate": "2019",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "16923771;25280870;25404399;23825556;30419120",
"title": "Analysis of serious adverse events in a paediatric fast breathing pneumonia clinical trial in Malawi.",
"title_normalized": "analysis of serious adverse events in a paediatric fast breathing pneumonia clinical trial in malawi"
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"abstract": "Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in DPYD, which encodes dihydropyrimidine dehydrogenase, a key enzyme of 5-FU catabolism and deactivation. Although the association of germline DPYD alterations with toxicity is well-described, the potential contribution of somatic DPYD alterations to 5-FU sensitivity has not been explored. In a patient with metastatic HNSCC, in-depth genomic and transcriptomic integrative analysis on a biopsy from a metastatic neck lesion revealed alterations in genes that are associated with 5-FU uptake and metabolism. These included a novel somatic structural variant resulting in a partial deletion affecting DPYD, a variant of unknown significance affecting SLC29A1, and homozygous deletion of MTAP There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity, indicating a potential vulnerability of the tumor to 5-FU therapy. The discovery of the novel DPYD variant led to the initiation of 5-FU treatment that resulted in a rapid response lasting 17 wk, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumor may serve as markers for tumor sensitivity to 5-FU, aiding in the selection of personalized treatment strategies.",
"affiliations": "Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.;Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.;Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.;Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.;Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.;Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada.;Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada.;Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada.;Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.;Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.;Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada.;Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada.",
"authors": "Majounie|Elisa|E|;Wee|Kathleen|K|;Williamson|Laura M|LM|;Jones|Martin R|MR|;Pleasance|Erin|E|;Lim|Howard J|HJ|;Ho|Cheryl|C|;Renouf|Daniel J|DJ|;Yip|Stephen|S|0000-0002-8514-9861;Jones|Steven J M|SJM|;Marra|Marco A|MA|;Laskin|Janessa|J|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a004713",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 10.1101/mcs.a004713MCS004713MajResearch ReportFluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic DPYD structural variant DPYD variant and 5-FU sensitivity in a HNSCC caseDPYD variant and 5-FU sensitivity in a HNSCC caseMajounie Elisa 1Wee Kathleen 1Williamson Laura M. 1Jones Martin R. 1Pleasance Erin 1Lim Howard J. 2Ho Cheryl 2Renouf Daniel J. 23http://orcid.org/0000-0002-8514-9861Yip Stephen 4Jones Steven J.M. 156Marra Marco A. 16Laskin Janessa 21 Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 4S6, Canada;2 Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada;3 Pancreas Centre BC, Vancouver, British Columbia V5Z 1L8, Canada;4 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada;5 Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia V5A 1S6, Canada;6 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, CanadaCorresponding author: [email protected] 2020 6 1 a00471316 8 2019 18 11 2019 © 2020 Majounie et al.; Published by Cold Spring Harbor Laboratory Press2020This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in DPYD, which encodes dihydropyrimidine dehydrogenase, a key enzyme of 5-FU catabolism and deactivation. Although the association of germline DPYD alterations with toxicity is well-described, the potential contribution of somatic DPYD alterations to 5-FU sensitivity has not been explored. In a patient with metastatic HNSCC, in-depth genomic and transcriptomic integrative analysis on a biopsy from a metastatic neck lesion revealed alterations in genes that are associated with 5-FU uptake and metabolism. These included a novel somatic structural variant resulting in a partial deletion affecting DPYD, a variant of unknown significance affecting SLC29A1, and homozygous deletion of MTAP. There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity, indicating a potential vulnerability of the tumor to 5-FU therapy. The discovery of the novel DPYD variant led to the initiation of 5-FU treatment that resulted in a rapid response lasting 17 wk, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumor may serve as markers for tumor sensitivity to 5-FU, aiding in the selection of personalized treatment strategies.\n\nsquamous cell carcinoma of the skin\n==== Body\nINTRODUCTION\nHead and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors originating from the squamous epithelium of the oral cavity, oropharynx, larynx, and hypopharynx. Human papillomavirus (HPV) infection is associated with 60%–70% of head and neck cancers. HPV-negative HNSCC tumors, however, tend to have a worse prognosis and response to treatment compared with HPV-positive tumors (Berman and Schiller 2017; Fung et al. 2017). Irrespective of HPV status, the majority of HNSCC patients are treated with a combination of surgery, radiation, and chemotherapy (Adelstein et al. 2017). Fluoropyrimidine (5-FU) and its prodrug capecitabine are a frequently prescribed systemic therapy in the treatment of several solid tumor types including HNSCC (Diasio and Harris 1989). Importantly, 5-FU-related toxicity is observed in ∼30% of treated patients (Meulendijks et al. 2015). Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme of 5-FU catabolism and deactivation (Diasio and Harris 1989). Consequently, DPD activity moderates response to 5-FU, and DPD deficiency as a result of germline polymorphism is considered a major cause of 5-FU-associated toxicity (van Kuilenburg 2004). Deleterious variants in DPYD, the large gene encoding DPD, have been described as significantly impacting enzymatic activity (Etienne-Grimaldi et al. 2017; van Kuilenburg et al. 2017; Henricks et al. 2018).\n\nTo date, few studies have fully characterized the somatic or germline genomic landscape of DPYD in cancer patients (Etienne-Grimaldi et al. 2017). Here, we present the case study of a patient with HNSCC who had a biopsy that underwent in-depth genomic and transcriptomic integrative analysis. We identified a number of alterations that are associated with 5-FU uptake and metabolism, including a novel somatic structural variant resulting in a partial deletion affecting the DPYD gene as well as a homozygous variant of unknown significance affecting SLC29A1 and homozygous deletion of MTAP. There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity. Given the well-described toxicity to 5-FU associated with deleterious germline variants affecting DPYD, we hypothesized that the somatic DPYD structural variant may have rendered the tumor to be sensitive to 5-FU and report the subsequent response to treatment.\n\nRESULTS\nClinical Presentation\nThe patient was a 69-yr-old gentleman of East-Asian extraction who presented with a 4 mo history of oral discomfort and was found to have an ulcer on his right maxillary palate. The patient was a lifelong never-smoker, drank alcohol approximately once per month, and had no other significant medical history. Pathology evaluation of the resected ulcer (with a right hemimaxillectomy and right-sided neck dissection) identified a 3.5-cm well-differentiated squamous cell carcinoma involving the alveolar ridge and maxillary sinus with bone invasion; level I and II (but not III/IV) nodes were involved. Perineural and lymphovascular invasion was noted. He underwent adjuvant radiation therapy with 6000 cGy over 6 wk, which included the adjacent lymph nodes. Initially, he made a good recovery, but unfortunately after 3 mo of follow-up he presented with a 4-cm neck mass and a fine needle aspirate–confirmed cancer recurrence. The mass was considered surgically unresectable and was within the previous radiation field. Thus, he was referred for palliative systemic therapy.\n\nAt that time he was consented for participation in the Personalized Oncogenomics (POG) study at BC Cancer in Vancouver, British Columbia (see Methods), and a biopsy of his neck mass was taken for genomic and transcriptomic analysis as per study protocol. He was also enrolled on a clinical trial of avelumab plus an OX40 agonist as his first systemic therapy. After 3 mo of treatment, he had markedly progressed (Fig. 1), and this treatment was discontinued. Based on the findings of the POG analysis, treatment with weekly 5-FU (500 mg/m2) and leucovorin (20 mg/m2) was initiated. He had a rapid response (Fig. 1) both clinically and radiographically that was sustained for 17 wk. He did require a dose modification because of side effects (specifically mucositis and hand–foot syndrome) and was maintained on 80% dose receiving a total of 14 wk of treatment. A treatment break was initiated, but 3 wk following treatment cessation, a small cancer nodule reappeared. A repeat biopsy was taken for POG sequencing and analysis that did not reveal marked changes in the genome or transcriptome compared with the initial biopsy. The patient was started on capecitabine (oral 5-FU), but unfortunately he did not respond to the reinitiation of this line of therapy. The mechanisms underlying the acquired resistance remain unclear. He was subsequently treated with cisplatin (progression as best response) and palbociclib (mixed response) on a clinical trial; unfortunately, he passed away because of tumor rupture and massive bleeding after 9 wk on trial.\n\nFigure 1. Clinical images of the metastatic deposits of this squamous cell carcinoma, originally surgically resected from the alveolar ridge. Images are organized chronologically starting from the baseline image (A) when the metastatic nodule presented clinically and the biopsy for the POG analysis was taken. Following this, B demonstrates the interim growth and representing the baseline image for the initiation of the clinical trial protocol of avelumab plus an OX40 agonist. C depicts the growth of the cancer despite this systemic therapy. Finally, D demonstrates the marked improvement after only 4 wk of weekly 5-FU/folinic acid therapy.\n\nGenomic Analysis\nHPV genetic material was not detected in this tumor, further confirming the HPV-negative status identified in pathology. All relevant mutations and variants identified in the initial biopsy were confirmed in both the initial and repeat biopsies.\n\nSingle-Nucleotide Variants\nWe identified 85 somatic nonsynonymous protein-coding single-nucleotide variants (SNVs) from the sequencing data (Supplemental Table 1). Although none of these were deemed to be clinically actionable, three were of biological interest (Table 1). A homozygous promoter mutation (g.1295228G>A) at a recurrent hotspot was detected in the human telomerase reverse transcriptase (TERT) gene, an enzyme that maintains telomere length and genomic integrity. Routine comparative analysis of gene expression revealed the TERT gene was moderately overexpressed compared with the Cancer Genome Atlas (TCGA) HNSCC data set (78th percentile). TERT promoter mutations occur in patients with oral cavity squamous cell carcinoma (SCC) at a high frequency and may be associated with aggressive disease (Killela et al. 2013; Zhao et al. 2015; Barczak et al. 2017; Chang et al. 2017). Additionally, there was a heterozygous variant (p.R234W) in KEAP1, a gene that is recurrently inactivated and associated with reduced survival in HNSCC (Network CGA 2015). Finally, a novel homozygous variant (p.P7L) was identified in nucleoside transporter SLC29A1 (hENT1). The functional and clinical impact of this mutation has not been characterized. However, hENT1 is important in 5-FU transport, and low levels of mRNA expression have been associated with response to 5-FU in pancreatic cancer cell lines (Tsujie et al. 2007). In this case, the somatic variant was also associated with a low level of SLC29A1 expression (5th percentile compared with TCGA HNSCC).\n\nTable 1. Somatic nonsynonymous single-nucleotide variant (SNV) and indels\n\nGene\tChr\tPosition\tRef\tAlt\tType\tHGVS CDS\tHGVS protein\tGenotype\tPredicted effect\tdbSNP\t\nKEAP1\t19\t10602878\tG\tA\tSNV\tc.700C>T\tp.Arg234Trp\tHeterozygous\tMissense\t—\t\nSLC29A1\t6\t44195070\tC\tT\tSNV\tc.20C>T\tp.Pro7Leu\tHomozygous\tMissense\t—\t\nTERT\t5\t1295228\tC\tT\tSNV\tc.−124C>T\t—\tHomozygous\t—\trs1242535815\t\n(HGVS CDS) Human Genome Variation Society coding sequence, (dbSNP) Single Nucleotide Polymorphism Database.\n\nCopy-Number Variants\nBased on the tumor/normal sequencing ratio and loss of heterozygosity, the tumor content was estimated to be 78% and a triploid model was used to describe the observed copy-number changes. Of particular interest, the genome-wide copy-number analysis revealed a homozygous CDKN2A/CDKN2B/MTAP codeletion. CDKN2A (p16) is a tumor suppressor that regulates the cell cycle and is the second most commonly inactivated gene in HNSCC (Beck and Golemis 2016). Disruption of p16 allows for activation of CDK4 and CDK6 and phosphorylation of RB1, leading to cell cycle progression (Asghar et al. 2015). MTAP is also thought to function as a tumor suppressor and is a key enzyme in the formation of adenine, influencing response to 5-FU therapy (Tang et al. 2012).\n\nDPYD Structural Variant\nStructural variants were identified using de novo sequence assembly followed by variant detection. A somatic fusion deletion event in the DPYD gene predicted to result in an in-frame deletion of exons 11–19 was detected in the genome and transcriptome (Fig. 2). The expression of the DPYD gene was moderate compared with the TCGA HNSCC data set (35th percentile). To our knowledge, our case is the first description of a somatic multiexon deletion in DPYD in a HNSCC cancer patient.\n\nFigure 2. Somatic fusion deletion event in the DPYD gene. The plot depicts the breakpoints affecting the DPYD gene that was predicted to result in an in-frame deletion of exons 11–19. (Top) Deletion breakpoints B1 and B2 shown in relation to the chromosome. (Middle) Model of DPYD transcript ENST00000370192 (T1) depicting exons 1–23. DPYD contains three Pfam domains, which are depicted by D1 (PF01180: dihydro-orotate dehydrogenase), D2 (PF01207: TRNA-dihydrouridine synthase), and D3 (PF07992: Pyridine nucleotide-disulphide oxidoreductase). (Bottom) Resulting variant DPYD transcript lacking exons 11–19. Black blocks below the exons depict the protein-coding region of the transcript.\n\nEvaluation of normal DNA revealed that the patient did not harbor any of the three SNP alleles associated with 5-FU toxicity (rs55886062; rs67376798; rs3918290) nor evidence of germline deletion in DPYD.\n\nDISCUSSION\nHere, we describe a case study of a patient with HNSCC who demonstrated a notable response to 5-FU. Alterations affecting multiple genes that play a role in nucleotide transport and metabolism were identified in this case study and may have contributed to the response to therapy, including a novel somatic structural variant affecting DPYD. Discrete germline DPYD polymorphisms and deletions have been identified in cancer patients with severe 5-FU-associated toxicity (van Kuilenburg 2004; Etienne-Grimaldi et al. 2017; van Kuilenburg et al. 2017; Henricks et al. 2018). Thus, testing for DPYD variants known to affect DPD enzyme activity is becoming more prominent in patients undergoing 5-FU chemotherapy (Deenen et al. 2016). Our case was found to be negative for described germline alterations associated with 5-FU toxicity. However, the somatic structural variant analysis resulted in the identification of a rearrangement in the DPYD gene leading to a partial in-frame deletion of exons 11–19. This region of the gene contains part of the FAD-binding domain and the majority of the FMN/pyrimidine binding domain (van Kuilenburg 2004), which likely results in the translation of a nonfunctional protein that is unable to metabolize 5-FU. We, therefore, speculated that the tumor may be sensitive to 5-FU/capecitabine because of the somatic DPYD structural variant. Indeed, this patient demonstrated a rapid and dramatic reduction in tumor size following initiation of treatment with 5-FU, which lasted for 17 wk. This notable response was of particular interest as his cancer was resistant to other standard treatments. In support of the hypothesis that the somatic DPYD loss may contribute to 5-FU response, another study that conducted a retrospective analysis of triple-negative breast cancer patients revealed patients with somatic DPYD copy-number variants (CNVs) demonstrated a trend for a longer time to progression on 5-FU (Gross et al. 2013). Unfortunately, the patient relapsed within 3 wk of ending 5-FU therapy and was subsequently reinitiated on oral 5-FU, capecitabine, but did not respond. Repeat biopsy prior to initiation of capecitabine did not reveal any further alterations of note, and the mechanism of resistance remains unclear.\n\nAdditional genomic findings that may also contribute to 5-FU response include a variant of unknown significance affecting SLC29A1 and homozygous deletion of MTAP. High expression of SLC29A1 has been associated with resistance to 5-FU in pancreatic cancer cell lines (Tsujie et al. 2007) by either facilitating bilateral transport of 5-FU or by preferential transport of nucleosides over 5-FU into cells (Wang et al. 2014). Although the low expression of SLC29A1 in the tumor has been associated with a clinical response to 5-FU (Tsujie et al. 2007; Phua et al. 2013), the homozygous single nucleotide variant (p.P7L) has not been observed in any public databases to date and is located on the amino terminus of the protein with no associated functional domain. Therefore, the precise clinical impact of this variant on 5-FU response remains unclear. Additionally, MTAP deletion is commonly found in a number of different cancer types (Tang et al. 2012) including oral SCCs (Chen et al. 2004). Adenine derived from MTAP activity could compete with purine analogs such as 5-FU for phosphoribosyl-5-pyrophosphate substrate utilization, thereby decreasing the amount of toxic nucleotide produced (Tang et al. 2012). Thus, the deletion of MTAP could result in increased amounts of toxic analog. In line with this hypothesis, several in vitro studies have shown that the deletion of MTAP in various cell lines resulted in the enhanced cytotoxicity in response to 5-FU treatment (Lubin and Lubin 2009; Lubin and Lubin 2010; Tang et al. 2012). However, there is no clinical evidence of its impact on 5-FU treatment to date. Altogether, the genomic findings point to the inability of the tumor to catabolize and deactivate 5-FU and therefore increase its therapeutic efficacy.\n\nStructural variants and inactivating mutations in DPYD are rare events, with only nine cases cataloged in TCGA and COSMIC databases (cBioportal; Cerami et al. 2012; Gao et al. 2013). DPYD alterations were found in a variety of different cancer types, highlighting the potential impact that somatic mutations can have on treatment choices and outcomes. By sequencing the whole genome, we were positioned to find novel variants, including the DPYD structural variant described here, that informed personalized patient management that may otherwise be missed in targeted sequencing approaches.\n\nCONCLUSION\nComprehensive genomic and transcriptomic analysis of a metastatic HNSCC was performed. A somatic structural variant affecting DPYD was detected that lead to the patient receiving 5-FU therapy. The patient had a rapidly growing cancer that was resistant to radiation, immunotherapy, and cisplatin and yet he demonstrated an impressive clinical response to 5-FU therapy, which we hypothesize to be in part due to the DPYD structural variant. This analysis shows for the first time that somatic lesions in DPYD may be used as a potential biomarker in prospectively evaluating for somatic variants that point to treatment sensitivity in patients with HNSCC and other cancer types in which 5-FU is commonly used.\n\nMETHODS\nSample Collection and Processing\nThe patient was enrolled in the ongoing POG project at BC Cancer in Vancouver, Canada (NCT02155621). This study was approved by the University of British Columbia Research Ethics Board (REB#H14-006817). Patient identity is de-identified for the research team and information is communicated to the clinicians through unique patient identifiers. Patients consent to the potential publication of findings. Raw sequence data, analytics, and clinical data are maintained in secure computing environments.\n\nAs per study protocol, each patient undergoes a study-specific biopsy. In this case, an ultrasound-guided core-needle biopsy of the neck and blood samples were collected for paired-end whole-genome sequencing (WGS) and transcriptome sequencing. RNA and DNA libraries were prepared and sequenced on the Illumina platform as previously described (Grewal et al. 2017).\n\nSequencing Data Analysis\nIn total, 150 bp paired-end normal and tumor reads were aligned to the human reference genome (hg19) using the Burrows–Wheeler alignment tool (Li and Durbin 2010) (v0.7.6a). Somatic point mutations and small insertion and deletions were detected using Strelka (v1.0.6) (Saunders et al. 2012). Somatic copy-number alterations that were present in the tumor DNA but not in the germline were identified using CNAseq (v0.0.6) (Jones et al. 2010) and loss of heterozygosity was determined using APOLLOH (v0.1.1) (Ha et al. 2012). De novo assembly of genomic and transcriptomic data using ABySS v1.3.4 (Simpson et al. 2009) and TransABySS (v1.4.10) (Birol et al. 2009; Simpson et al. 2009) was carried out to detect rearrangements. Mutations were annotated to Ensembl v69 (Flicek et al. 2014) using SNPEff (v4.1) (Cingolani et al. 2012). Tumor content and sequencing coverage are outlined in Table 2.\n\nTable 2. Sequencing coverage\n\nSample\tTumor DNA coverage (WGS)\tNormal DNA coverage (WGS)\tTumor RNA coverage (RNA-seq)\t\nHNSCC case\t101×\t39×\t360M reads\t\nRNA-seq reads were aligned using Jaguar (v2.0.3) (Butterfield et al. 2014) to the human reference (hg19) with a database of exon junctions based on Ensembl v69 (Flicek et al. 2014), and normalized expression levels were computed in reads per kilobase per million mapped reads (Mortazavi et al. 2008). Publicly available transcriptome sequencing data from HNSCC from TCGA (https://tcga-data.nci.nih.gov/tcga/; Network CGA 2015) and a compendium of adjacent normal tissue samples from the Illumina Human BodyMap 2.0 project (www.illumina.com; ArrayExpress ID: E-MTAB-513) were used to explore the expression profile of human genes and transcripts.\n\nADDITIONAL INFORMATION\nDatabase Deposition and Access\nThe whole-genome and transcriptome sequencing data for this case are available as .bam files from the European Genome-phenome Archive (EGA; www.ebi.ac.uk/ega/home) as part of the study EGAS00001001159, accession ID EGAD00001004934. The DPYD structural variant and variants affecting KEAP1 and SLC29A1 are deposited in ClinVar (https:www.ncbi.nlm.nih.gov/clinvar/) under accession numbers SCV000996023, SCV000996021, and SCV000996022, respectively.\n\nEthics Statement\nThe patient provided written informed consent for metastatic biopsies, sequencing, and publication of results as part of the Personalized Oncogenomics Program of British Columbia (NCT02155621, University of British Columbia Clinical Research Ethics Board approval no. H14-006817).\n\nAcknowledgments\nThis work would not be possible without the participation of our patients and families, the POG team, and the generous support of the BC Cancer Foundation and Genome British Columbia (project B20POG). We also acknowledge contributions toward equipment and infrastructure from Genome Canada and Genome BC (projects 202SEQ, 212SEQ, 12002), Canada Foundation for Innovation (projects 20070, 30981, 30198, 33408), and the BC Knowledge Development Fund. The results published here are in part based on data generated by the following projects and obtained from dbGaP (http://www.ncbi.nlm.nih.gov/gap): The Cancer Genome Atlas managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) (http://cancergenome.nih.gov) and the Genotype-Tissue Expression (GTEx) Project, supported by the Common Fund of the Office of the Director of the National Institutes of Health (https://commonfund.nih.gov/GTEx).\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nAdelstein \nD , Gillison \nML , Pfister \nDG , Spencer \nS , Adkins \nD , Brizel \nDM , Burtness \nB , Busse \nPM , Caudell \nJJ , Cmelak \nAJ , \n2017 \nNCCN guidelines insights: head and neck cancers, Version 2.2017 . 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Fly (Austin) \n6 : 80 –92 . 10.4161/fly.19695 22728672 \nDeenen \nMJ , Meulendijks \nD , Cats \nA , Sechterberger \nMK , Severens \nJL , Boot \nH , Smits \nPH , Rosing \nH , Mandigers \nCM , Soesan \nM , \n2016 \nUpfront genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis . J Clin Oncol \n34 : 227 –234 . 10.1200/JCO.2015.63.1325 26573078 \nDiasio \nRB , Harris \nBE . 1989 \nClinical pharmacology of 5-fluorouracil . Clin Pharmacokinet \n16 : 215 –237 . 10.2165/00003088-198916040-00002 2656050 \nEtienne-Grimaldi \nM-C , Boyer \nJ-C , Beroud \nC , Mbatchi \nL , van Kuilenburg \nA , Bobin-Dubigeon \nC , Thomas \nF , Chatelut \nE , Merlin \nJ-L , Pinguet \nF , \n2017 \nNew advances in DPYD genotype and risk of severe toxicity under capecitabine . PLoS One \n12 : e0175998 \n10.1371/journal.pone.0175998 28481884 \nFlicek \nP , Amode \nMR , Barrell \nD , Beal \nK , Billis \nK , Brent \nS , Carvalho-Silva \nD , Clapham \nP , Coates \nG , Fitzgerald \nS , \n2014 \nEnsembl 2014 . Nucleic Acids Res \n42 : D749 –D755 . 10.1093/nar/gkt1196 24316576 \nFung \nN , Faraji \nF , Kang \nH , Fakhry \nC . 2017 \nThe role of human papillomavirus on the prognosis and treatment of oropharyngeal carcinoma . Cancer Metastasis Rev \n36 : 449 –461 . 10.1007/s10555-017-9686-9 28812214 \nGao \nJ , Aksoy \nBA , Dogrusoz \nU , Dresdner \nG , Gross \nB , Sumer \nSO , Sun \nY , Jacobsen \nA , Sinha \nR , Larsson \nE , \n2013 \nIntegrative analysis of complex cancer genomics and clinical profiles using the cBioPortal . 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Proc Natl Acad Sci USA \n110 : 6021 –6026 . 10.1073/pnas.1303607110 23530248 \nLi \nH , Durbin \nR . 2010 \nFast and accurate long-read alignment with Burrows–Wheeler transform . Bioinformatics \n26 : 589 –595 . 10.1093/bioinformatics/btp698 20080505 \nLubin \nM , Lubin \nA . 2009 \nSelective killing of tumours deficient in methylthioadenosine phosphorylase: a novel strategy . PLoS One \n4 : e5735 \n10.1371/journal.pone.0005735 19478948 \nLubin \nM , Lubin \nA . 2010 \nCorrection: selective killing of tumours deficient in methylthioadenosine phosphorylase: a novel strategy . PLoS One \n4 : e5735 \n10.1371/annotation/54fad81d-c975-4b30-bb2b-249650ec3d66 \nMeulendijks \nD , Henricks \nLM , Sonke \nGS , Deenen \nMJ , Froehlich \nTK , Amstutz \nU , Largiader \nCR , Jennings \nBA , Marinaki \nAM , Sanderson \nJD , \n2015 \nClinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data . Lancet Oncol \n16 : 1639 –1650 . 10.1016/S1470-2045(15)00286-7 26603945 \nMortazavi \nA , Williams \nBA , McCue \nK , Schaeffer \nL , Wold \nB . 2008 \nMapping and quantifying mammalian transcriptomes by RNA-Seq . Nat Methods \n5 : 621 –628 . 10.1038/nmeth.1226 18516045 \nNetwork CGA . 2015 \nComprehensive genomic characterization of head and neck squamous cell carcinomas . Nature \n517 : 576 –582 . 10.1038/nature14129 25631445 \nPhua \nLC , Mal \nM , Koh \nPK , Cheah \nPY , Chan \nEC , Ho \nHK . 2013 \nInvestigating the role of nucleoside transporters in the resistance of colorectal cancer to 5-fluorouracil therapy . Cancer Chemother Pharmacol \n71 : 817 –823 . 10.1007/s00280-012-2054-0 23271323 \nSaunders \nCT , Wong \nWS , Swamy \nS , Becq \nJ , Murray \nLJ , Cheetham \nRK . 2012 \nStrelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs . Bioinformatics \n28 : 1811 –1817 . 10.1093/bioinformatics/bts271 22581179 \nSimpson \nJT , Wong \nK , Jackman \nSD , Schein \nJE , Jones \nSJ , Birol \nI . 2009 \nABySS: a parallel assembler for short read sequence data . Genome Res \n19 : 1117 –1123 . 10.1101/gr.089532.108 19251739 \nTang \nB , Testa \nJR , Kruger \nWD . 2012 \nIncreasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumour cells . Cancer Biol Ther \n13 : 1082 –1090 . 10.4161/cbt.21115 22825330 \nTsujie \nM , Nakamori \nS , Nakahira \nS , Takahashi \nY , Hayashi \nN , Okami \nJ , Nagano \nH , Dono \nK , Umeshita \nK , Sakon \nM , \n2007 \nHuman equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer . Anticancer Res \n27 : 2241 –2249 . PMID:1769550917695509 \nvan Kuilenburg \nAB . 2004 \nDihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil . Cancer \n40 : 939 –950 . 10.1016/j.ejca.2003.12.004 \nvan Kuilenburg \nAB , Meijer \nJ , Maurer \nD , Dobritzsch \nD , Meinsma \nR , Los \nM , Knegt \nLC , Zoetekouw \nL , Jansen \nRL , Dezentje \nV , \n2017 \nSevere fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing . Biochim Biophys Acta Mol Basis Dis \n1863 : 721 –730 . 10.1016/j.bbadis.2016.12.010 28024938 \nWang \nWB , Yang \nY , Zhao \nYP , Zhang \nTP , Liao \nQ , Shu \nH . 2014 \nRecent studies of 5-fluorouracil resistance in pancreatic cancer . World J Gastroenterol \n20 : 15682 –15690 . 10.3748/wjg.v20.i42.15682 25400452 \nZhao \nT , Hu \nF , Qiao \nB , Chen \nZ , Tao \nQ . 2015 \nTelomerase reverse transcriptase potentially promotes the progression of oral squamous cell carcinoma through induction of epithelial-mesenchymal transition . Int J Oncol \n46 : 2205 –2215 . 10.3892/ijo.2015.2927 25775973\n\n",
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"issue": "6(1)",
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"keywords": "squamous cell carcinoma of the skin",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D000964:Antimetabolites, Antineoplastic; D001706:Biopsy; D042943:Dihydrouracil Dehydrogenase (NADP); D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil; D014644:Genetic Variation; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
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"pmid": "31871216",
"pubdate": "2020-02",
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"references": "24104963;17695509;22825330;28346680;19478948;22588877;22728672;26603945;23550210;28877932;22637570;20696054;25631445;28535013;29034103;28481884;28812214;20080505;28929491;26573078;15093568;25062255;25633797;19528083;24316576;18516045;28024938;15372456;23271323;19251739;22581179;28596256;25775973;28230921;23530248;2656050;25400452",
"title": "Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic DPYD structural variant.",
"title_normalized": "fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic dpyd structural variant"
}
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},
{
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},
{
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{
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],
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},
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"literaturereference": "PRIVACY P, WEE K, WILLIAMSON LM, JONES MR, PLEASANCE E, LIM HJ ET AL. FLUOROURACIL SENSITIVITY IN A HEAD AND NECK SQUAMOUS CELL CARCINOMA WITH A SOMATIC DPYD STRUCTURAL VARIANT. COLD SPRING HARBOR MOLECULAR CASE STUDIES 2020?6(A004713):1?9.",
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},
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},
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"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
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},
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] |
{
"abstract": "A case of uterine bleeding after intake of rifampicin is reported in a 35-year-old female. Provocation test was also positive. The underlying mechanism whether it was a hypersensitivity phenomenon like fixed drug eruption or due to induction of uterine acyl-hydrolase enzyme, is not clear. Uterine bleeding has not been observed as a side-effect of rifampicin in the past.",
"affiliations": "Department of Dermatology, Institute of Medical Sciences, B.H.U., Varanasi.",
"authors": "Nigam|P K|PK|;Singh|P K|PK|;Singh|G|G|;Kumar|M|M|",
"chemical_list": "D003622:Dapsone; D012293:Rifampin",
"country": "India",
"delete": false,
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"fulltext_license": null,
"issn_linking": "0254-9395",
"issue": "60(2)",
"journal": "Indian journal of leprosy",
"keywords": null,
"medline_ta": "Indian J Lepr",
"mesh_terms": "D000328:Adult; D003622:Dapsone; D004359:Drug Therapy, Combination; D004717:Endometrium; D005260:Female; D006801:Humans; D015441:Leprosy, Tuberculoid; D012293:Rifampin; D014592:Uterine Hemorrhage",
"nlm_unique_id": "8409173",
"other_id": null,
"pages": "303-5",
"pmc": null,
"pmid": "3192980",
"pubdate": "1988-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rifampicin induced uterine bleeding.",
"title_normalized": "rifampicin induced uterine bleeding"
}
|
[
{
"companynumb": "IN-SA-2021SA152801",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "5",
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"activesubstancename": "RIFAMPIN"
},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Uterine haemorrhage",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "NIGAM PK, SINGH PK, SINGH G, KUMAR M.. RIFAMPICIN INDUCED UTERINE BLEEDING. INDIAN JOURNAL OF LEPROSY. 1988?60(2):303?5",
"literaturereference_normalized": "rifampicin induced uterine bleeding",
"qualification": "3",
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},
"primarysourcecountry": "IN",
"receiptdate": "20210512",
"receivedate": "20210512",
"receiver": {
"receiverorganization": "FDA",
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210717"
}
] |
{
"abstract": "We aimed to evaluate early recanalization postintravenous (i.v.) tissue plasminogen activator (t-PA) by digital subtraction angiography (DSA) in acute ischemic stroke (AIS) with large vessel occlusion (LVO).\n\n\n\nWe performed baseline CT angiography to identify LVO in AIS. Recanalization pre- and post-intra-arterial therapy (IAT) was categorized to none, partial, and global recanalization (GR). Modified Rankin Scale score ≤2 at 3 months was considered a favorable outcome.\n\n\n\nAmong 1610 patients with AIS, 286 received IV t-PA. Of these, 55 patients with LVO were included. The median time from IV t-PA to DSA was 120 min (interquartile range, 79-152). Recanalization post-IV t-PA was observed in seven patients (12.7%). By occlusion sites, the recanalization rates were as follows: extracranial internal carotid artery 2 of 14 (14.3%); intracranial internal carotid artery 3 of 24 (12.5%); M1 of middle cerebral artery 3 of 39 (7.7%); M2 of middle cerebral artery 1 of 40 (2.5%); vertebral artery 0 of 4; and basilar artery 0 of 7. GR post-IAT was associated with favorable outcomes (odds ratio: 8.6; 95% confidence interval, 1.5-48.0; P = 0.014).\n\n\n\nEarly recanalization assessed by DSA post-IV t-PA is rarely observed in acute ischemic stroke patients with LVO.",
"affiliations": "Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Radiology, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic., Australia.;Florey Institute of Neuroscience and Mental Health, Melbourne, Vic., Australia.;Department of Radiology, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic., Australia.;Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Neurology, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Vic., Australia.",
"authors": "Mao|Yi-Ting|YT|;Mitchell|Peter|P|;Churilov|Leonid|L|;Dowling|Richard|R|;Dong|Qiang|Q|;Yan|Bernard|B|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.1111/cns.12549",
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"fulltext_license": null,
"issn_linking": "1755-5930",
"issue": "22(8)",
"journal": "CNS neuroscience & therapeutics",
"keywords": "Digital subtraction angiography; Ischemic stroke; Large vessel occlusion; Recanalization; Thrombolysis",
"medline_ta": "CNS Neurosci Ther",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015901:Angiography, Digital Subtraction; D002545:Brain Ischemia; D002536:Cerebral Arteries; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020521:Stroke; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "101473265",
"other_id": null,
"pages": "643-7",
"pmc": null,
"pmid": "27165451",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": "10884471;12297567;14970040;15095555;1579252;15891154;1642475;16498189;17110611;17200490;17258667;19147716;19713704;19850525;20829513;21860234;21990808;22241381;23306320;23599933;23920012;24481332;24916912;25517348;25671797;25671798;25882376;25882510;7563451",
"title": "Early Recanalization Postintravenous Thrombolysis in Ischemic Stroke with Large Vessel Occlusion: A Digital Subtraction Angiography Study.",
"title_normalized": "early recanalization postintravenous thrombolysis in ischemic stroke with large vessel occlusion a digital subtraction angiography study"
}
|
[
{
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],
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},
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"literaturereference": "MAO Y, MITCHELL P, CHURILOV L, DOWLING R, DONG Q AND YAN B. EARLY RECANALIZATION POSTINTRAVENOUS THROMBOLYSIS IN ISCHEMIC STROKE WITH LARGE VESSEL OCCLUSION: A DIGITAL SUBTRACTION ANGIOGRAPHY STUDY.. CNS NEUROSCIENCE AND THERAPEUTICS 2016;:1-5.",
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},
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},
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"transmissiondate": "20161109"
}
] |
{
"abstract": "The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.",
"affiliations": "California National Primate Research Center, University of California, Davis, Davis, CA 95616; [email protected].;California National Primate Research Center, University of California, Davis, Davis, CA 95616.;California National Primate Research Center, University of California, Davis, Davis, CA 95616.;Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.;Center for Bioinformatics and Molecular Biostatistics, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94107.;Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.;Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.;Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.;Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612.;Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143.;Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.;Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.;California National Primate Research Center, University of California, Davis, Davis, CA 95616.",
"authors": "Méndez-Lagares|Gema|G|0000-0002-6297-5693;Lu|Ding|D|;Chen|Connie|C|0000-0001-5016-6584;Terrault|Norah|N|;Segal|Mark R|MR|;Khalili|Mandana|M|;Monto|Alexander|A|;Shen|Hui|H|;Manos|M Michele|MM|;Lanier|Lewis L|LL|0000-0003-1308-3952;Ryan|James C|JC|;McCune|Joseph M|JM|;Hartigan-O'Connor|Dennis J|DJ|",
"chemical_list": "D000914:Antibodies, Viral; D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D020825:T-Box Domain Proteins; C406820:T-box transcription factor TBX21; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; C100416:peginterferon alfa-2a",
"country": "United States",
"delete": false,
"doi": "10.4049/jimmunol.1701364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1767",
"issue": "200(3)",
"journal": "Journal of immunology (Baltimore, Md. : 1950)",
"keywords": null,
"medline_ta": "J Immunol",
"mesh_terms": "D056704:Adaptive Immunity; D000914:Antibodies, Viral; D000998:Antiviral Agents; D015496:CD4-Positive T-Lymphocytes; D049109:Cell Proliferation; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007113:Immunity, Innate; D007156:Immunologic Memory; D016898:Interferon-alpha; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011392:Proline; D011446:Prospective Studies; D011994:Recombinant Proteins; D012254:Ribavirin; D020825:T-Box Domain Proteins; D016896:Treatment Outcome",
"nlm_unique_id": "2985117R",
"other_id": null,
"pages": "1124-1132",
"pmc": null,
"pmid": "29263212",
"pubdate": "2018-02-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23197535;10790425;21685955;14673093;21371579;17659573;24325966;17114419;19330875;14605368;19759533;22425747;19749758;26787172;21930973;23455505;17082589;12001996;25032686;27084592;19596234;27537841;14576438;16273099;20408862;12218168;15841456;12407584;15738952;24905492;23808990;10960457;25225458;21623380;19625712;12360469;16129706;12810686;10761931;9021963;10802716;17919489;25754160;19118522;15032595;11714747;27349488;19434929;14499244",
"title": "Memory T Cell Proliferation before Hepatitis C Virus Therapy Predicts Antiviral Immune Responses and Treatment Success.",
"title_normalized": "memory t cell proliferation before hepatitis c virus therapy predicts antiviral immune responses and treatment success"
}
|
[
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"companynumb": "US-009507513-1805USA004662",
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},
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"reaction": [
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"reactionmeddrapt": "Therapy non-responder",
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},
{
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}
],
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},
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"literaturereference": "MENDEZ?LAGARES G, LU D, CHEN C, TERRAULT N, SEGAL MR, KHALILI M, ET AL.. MEMORY T CELL PROLIFERATION BEFORE HEPATITIS C VIRUS THERAPY PREDICTS ANTIVIRAL IMMUNE RESPONSES AND TREATMENT SUCCESS. JOURNAL OF IMMUNOLOGY. 2018?200(3):1124?32",
"literaturereference_normalized": "memory t cell proliferation before hepatitis c virus therapy predicts antiviral immune responses and treatment success",
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},
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},
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},
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},
{
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},
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},
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"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "MENDEZ?LAGARES G, LU D, CHEN C, TERRAULT N, SEGAL MR, KHALILI M, ET AL.. MEMORY T CELL PROLIFERATION BEFORE HEPATITIS C VIRUS THERAPY PREDICTS ANTIVIRAL IMMUNE RESPONSES AND TREATMENT SUCCESS. JOURNAL OF IMMUNOLOGY. 2018?200(3):1124?32",
"literaturereference_normalized": "memory t cell proliferation before hepatitis c virus therapy predicts antiviral immune responses and treatment success",
"qualification": "1",
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},
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"receiptdate": "20180718",
"receivedate": "20180511",
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},
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},
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"transmissiondate": "20181010"
}
] |
{
"abstract": "Identification of the manifestations, assessment and follow up of children with hypertrophic cardiomyopathy (HCM) by transthoracic echocardiography may be important for clinical management and our understanding of pathogenesis.\n\n\n\nWe present a comprehensive analysis of 43 children seen in Kosovo, 23 were male, aged between 4 months and 9 years at first presentation (median of 2 years and 3 months).\n\n\n\nCardiac failure, seen in almost half of them, was the most common presenting feature. At admission, the chest x-ray revealed an increased cardiothoracic ratio, to a mean of 72% in 6 infants and to 65% in 37 older children. Measured by transthoracic echocardiography, 28 children had asymmetric hypertrophy of left ventricle while 15 had concentric hypertrophy. Left ventricular ejection fraction was depressed in 21 children. Patients with cardiac failure received various combinations of diuretics, B-blockers, ACE inhibitors and anticoagulant therapy (aspirin). Death occurred in 8 children, in 4 of them shortly after admission, the other 4 left Kosovo and continued examination and treatment abroad Kosovo; their death has been confirmed by family members. The remaining 32 were followed- up for a mean 42 months, with a range from 5 to 115 months. Surgical intervention was not performed to any of them, despite the clinical and echocardiography indications due to a limitation of resources. Recovery was noted in 14 children but still requiring anti-heart failure medications. Slightly over two-fifths died. Of those with asymmetric form, 45% died, half of those presenting in infancy, and 89% of those who presented at admission with signs of cardiac failure.\n\n\n\nThe results of our study show that similar to many centers, the etiology of HCM is often uncertain. In the absence of etiology, treatment aimed at the cause is either impossible or, at best, empirical.",
"affiliations": "Pediatric Clinic, University Clinical Center of Kosovo, Prishtina.;Pediatric Clinic, University Clinical Center of Kosovo, Prishtina.;Pediatric Clinic, University Clinical Center of Kosovo, Prishtina.;Pediatric Clinic, University Clinical Center of Kosovo, Prishtina.;Pediatric Clinic, University Clinical Center of Kosovo, Prishtina.;University of Gjakova \"Fehmi Agani\", Gjakova, Republic of Kosovo.",
"authors": "Bejiqi|Ramush A|RA|;Retkoceri|Ragip|R|;Zeka|Naim|N|;Vuçiterna|Armend|A|;Mustafa|Aferdita|A|;Maloku|Arlinda|A|;Bejiqi|Rinor|R|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "62(2)",
"journal": "The Turkish journal of pediatrics",
"keywords": "heart failure; hypertrophic cardiomyopathy; left ventricular hypertrophy; myectomy transthoracic echocardiography",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000293:Adolescent; D002312:Cardiomyopathy, Hypertrophic; D002648:Child; D006801:Humans; D007223:Infant; D063826:Kosovo; D008297:Male; D057193:Medical Tourism; D013318:Stroke Volume; D016277:Ventricular Function, Left",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "215-223",
"pmc": null,
"pmid": "32419413",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical manifestation and outcomes of children with hypertrophic cardiomyopathy in Kosovo.",
"title_normalized": "clinical manifestation and outcomes of children with hypertrophic cardiomyopathy in kosovo"
}
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{
"abstract": "The primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) has a poor prognosis. R-CHOP with or without radiotherapy is the available recommendations for first-line treatment. Relapses/refractory cases are frequent with no standardized therapeutic guidelines. Lenalidomide seems to be an excellent therapeutic option as a second-line treatment of relapsed PCDLBCL-LT.",
"affiliations": "Department of Dermatology Bichat Hospital Paris France.;Department of Hematology Saint-Louis Hospital Paris France.;Department of Anatomopathology Bichat Hospital Paris France.;Department of Anatomopathology Bichat Hospital Paris France.;Department of Dermatology Lausanne University Hospital Lausanne Switzerland.;Department of Dermatology Bichat Hospital Paris France.;Department of Dermatology Bichat Hospital Paris France.",
"authors": "Al Dhafiri|Mahdi|M|https://orcid.org/0000-0001-7370-1877;Sicre de Fontbrune|Flore|F|;Marinho|Eduardo|E|;Deschamps|Lydia|L|;Di-Lucca|Julie|J|;Crickx|Beatrice|B|;Descamps|Vincent|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2137",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2137CCR32137Case ReportCase ReportsEffectiveness of lenalidomide in relapsed primary cutaneous diffuse large B‐cell lymphoma, leg type AL DHAFIRI et al.Al Dhafiri Mahdi https://orcid.org/[email protected] \n1\n\n2\nSicre de Fontbrune Flore \n3\nMarinho Eduardo \n4\nDeschamps Lydia \n4\nDi‐Lucca Julie \n5\nCrickx Beatrice \n1\nDescamps Vincent \n1\n\n1 \nDepartment of Dermatology\nBichat Hospital\nParis\nFrance\n\n2 \nDepartment of Dermatology, College of Medicine\nKing Faisal University\nAl‐Ahsa\nSaudi Arabia\n\n3 \nDepartment of Hematology\nSaint‐Louis Hospital\nParis\nFrance\n\n4 \nDepartment of Anatomopathology\nBichat Hospital\nParis\nFrance\n\n5 \nDepartment of Dermatology\nLausanne University Hospital\nLausanne\nSwitzerland\n* Correspondence\n\nMahdi Al Dhafiri, Department of Dermatology, College of Medicine, King Faisal University, Al-Ahsa Saudi Arabia.\n\nEmail: [email protected]\n05 4 2019 5 2019 7 5 10.1002/ccr3.2019.7.issue-5964 967 24 1 2019 22 2 2019 12 3 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nThe primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT) has a poor prognosis. R‐CHOP with or without radiotherapy is the available recommendations for first‐line treatment. Relapses/refractory cases are frequent with no standardized therapeutic guidelines. Lenalidomide seems to be an excellent therapeutic option as a second‐line treatment of relapsed PCDLBCL‐LT.\n\nchemotherapyleg typelenalidomideprimary cutaneous diffuse large B‐cell lymphoma source-schema-version-number2.0component-idccr32137cover-dateMay 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:10.05.2019\n\n\nAl Dhafiri \nM \n, \nSicre de Fontbrune \nF \n, \nMarinho \nE \n, et al. Effectiveness of lenalidomide in relapsed primary cutaneous diffuse large B‐cell lymphoma, leg type . Clin Case Rep . 2019 ;7 :964 –967 . 10.1002/ccr3.2137\n==== Body\n1 INTRODUCTION\nPrimary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT) is one of the major four subtypes of cutaneous B‐cell lymphoma 1 and characterized by its aggressive nature, poor prognosis, and occurrence in advanced age, with five‐years survival estimations of approximately 50%‐60%. 2, 3\n\n\nClinically it is represented as red to purple nodules that arise mainly in the lower extremities. Histologically it is characterized by the presence of confluent sheets of large cells with round nuclei, with strong expression of Bcl‐2, as well as intermediate or positive staining for MUM‐1 protein.1, 4, 5\n\n\nThe initial treatment is based on rituximab associated with polychemotherapy,2, 3, 6 with no ideal therapy for relapsing or refractory forms. To date, there are two previously reported cases showing a promising effect of lenalidomide in relapsed cases,6, 7 with one recent phase II study on the efficacy of lenalidomide in relapsing or refractory PCDLBCL‐LT.4\n\n\nHerein, we exhibit a case successfully treated with lenalidomide (Revlimid®) in second‐line treatment.\n\n2 CASE REPORT\nAn 80‐year‐old female patient was referred to our hospital for a relapse of PCDLBCL‐LT. She was previously treated by systemic immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). The first cutaneous lesions of her left leg developed on March 2009. Initial screening by total body computed tomography (CT) showed, other than the multiple nodules of the left leg (Figure 1A), a mediastinal mass of 70 × 37 mm associated with pleural effusion. The initial histological investigations confirmed the diagnosis of PCDLBCL‐LT in both skin lesions and mediastinal mass, with the positivity of CD20, Ki67, and bcl2 (Figure 2). After the completion of 5 cycles of treatment, the clinical examination, and total body CT scan showed complete control of PCDLBCL‐LT on June 2010 with clearance of the cutaneous and mediastinal lesions. However, the patient developed neutropenia, and the sixth cycle was not performed.\n\nFigure 1 A, Progressing lymphoma at left leg with multiple growing tumors. B, Cutaneous relapse after second R‐CHOP cycle\n\nFigure 2 Histological examination of a biopsy of the mediastinal mass (original magnification × 400): numerous large cells with predominant immunoblasts (A) with CD20+ (B), and Ki‐67 (C) staining\n\nThe patient then developed a relapse of both cutaneous and mediastinal lesions in September 2010 (Figure 1B). The second course of R‐ CHOP did not control the disease and was responsible for hematological toxicity, including severe neutropenia. Lenalidomide (10 mg/day for 21 days of every 28‐day cycle) was proposed on November 2010, associated with a dexamethasone 20 mg on days 1‐7‐14 monthly.\n\nThis treatment was well tolerated and permitted a good control with a complete disappearance of the cutaneous nodules with control of 5 months of her lymphoma. The lymphoma then progressed by the 6th month (on May 2011) with a rapid progression of the mediastinal mass. She deceased on June 2011.\n\n3 DISCUSSION\nPCDLBCL‐LT is rare non‐Hodgkin's lymphoma (2.6% of primary cutaneous non‐Hodgkin's lymphomas), affecting elderly people (median age of 76 years),1 and known by its aggressive behavior and poor prognosis. It is represented by solitary or multiple rapidly growing nodule localized mainly on lower limb unilaterally or bilaterally. Ulceration of these lesions is possible.2, 3, 4 Unlike other primary cutaneous B‐cell lymphomas, secondary extracutaneous dissemination is common,3, 4 including lymph nodes, central nervous system, bone, and liver.1, 8 PCDLBCL‐LT is characterized by the positivity of MUM‐1, CD20, and high Bcl‐2 expression with lack of CD10.2, 9 Dual expression of both bcl‐2 and c‐myc is also common and associated with inferior overall survival.3, 10 However, up to 10% of PCDLBCL‐LT presents lack of bcl‐2 and Mum‐1 staining.1 Genetically, NF‐κB pathway‐activating mutations were observed in PCDLBCL‐LT, and this includes CD79B, CARD11, and the mutation of MYD88 which was confirmed to be the most prevalent mutation (~75%).3, 9, 11 Moreover, MYD88 mutation can be used as a diagnostic feature to differentiate PCDLBCL‐LT from the primary cutaneous follicular large B‐cell lymphoma.9\n\n\nThe main adverse prognostic factors include multiple lesions, old age, MYD88 mutation, advanced T stage of the tumor, and leg localization of the lesion.2, 4, 5 First‐line treatment in the diffuse or multifocal form of PCDLBCL‐LT is as in diffuse large B‐cell lymphomas (DLBCL)3 depends on polychemotherapy associating rituximab (R‐CHOP) with or without radiotherapy.12, 13 This combined therapy could be replaced by less‐aggressive treatment of rituximab and polychemotherapy (R‐PCT) in oldest or frailest patients.2, 4 However, for the solitary lesion, radiotherapy should be considered as a first‐therapeutic choice. It could also be treated by surgical resection.8, 12, 13 Additionally, it has been observed that the 5‐year survival rate has been increased by about 65% to 75% over time since the use of rituximab‐PCT with or without anthracyclines.2 Nevertheless, neutropenia and consecutive infection are the main adverse effect and cause of morbidity and mortality in this treatment.2\n\n\nSpontaneous remission of PCDLBCL‐LT is extremely rare, and it was reported in five cases.1, 14, 15 The cause of this spontaneous regression in unknown, and it has been described as a result of probable response of immune system to bacterial or viral infection, or traumatic causes including biopsies, or apoptosis or particular condition of the tumor microenvironment as well.1, 14, 17 All biopsies taken after regression of the published cases showed superficial and deep dermal inflammatory T‐cell infiltrate suggesting that un inadequate T‐cell immune response may play a role in the disease pathogenesis.\n\nRefractory cases to R‐PCT are possible, and rapid recurrence after initial treatment is still frequent and remains a challenging issue due to lack of standardized therapeutic protocol.2, 4, 7 Lenalidomide (Revlimid®) is a derivative of thalidomide,18 and it is an oral immunomodulatory agent with multiple mechanisms of action that interfere with the growth of aggressive non‐Hodgkin's lymphomas through alteration of the tumor microenvironment and enhancing the cytotoxic activity of T cells and natural killer cells.19 It performs an inhibition of cell signaling engaging NF‐κB and IFN‐β, through its antiproliferative and antiangiogenic effects.4\n\n\nLenalidomide was approved in December 2005 by the FDA for the treatment of red blood cell transfusion‐dependent anemia due to myelodysplastic syndrome (MDS) associated with a chromosome 5q31 deletion. It is also indicated in the treatment of other conditions, including plasma cell malignancy, mantel cell lymphoma, cutaneous T‐cell lymphoma, and multiple myeloma.20 The most common adverse events are neutropenia and thrombocytopenia.19\n\n\nThe efficacy of lenalidomide was demonstrated on relapsing and refractory DLBCL, and it looks to be a good candidate for PCDLBCL‐LT.4 Thus its effectiveness was discussed previously in two case reports of relapsed PCDLBCL‐LT, showing partial remission of the disease with excellent tolerance of the treatment in an 83‐year‐old woman.6 And the complete resolution was obtained after combined therapy of lenalidomide with rituximab in a 78‐year‐old woman.7 The efficacy of single‐agent lenalidomide in relapsed/refractory PCDLBCL‐LT was recently discussed in a small phase II study (n = 19), and the 6‐month overall response rate was 26%. However, the response was significantly higher with the absence of the MYD88 mutation.4\n\n\nThis observation underlines the interest of the association lenalidomide‐dexamethasone in the management of PCDLBCLs‐LT.\n\n4 CONCLUSION\nPCDLBCL‐LT has a poor prognosis with no standardized treatment recommendations available in relapsed forms. The adverse therapeutic effects are most likely related to the advanced age and poor general condition of patients. A combined lenalidomide therapy, as well as more targeting monotherapy, deserves to be evaluated as a second‐line treatment for this affection.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nMA: provided scientific and bibliographic feature and wrote the paper. FSDF: participation in the therapeutic plan and patient monitoring. EM&LD: provided histopathologic work‐up. JDL&BC: provided clinical follow‐up and control of the patient as well as participation in the therapeutic plan and evaluation. VD: supervision and involvement in the scientific work‐up and writing the paper, as well as patient follow‐up.\n==== Refs\nREFERENCES\n1 \n\nGraham \nPM \n, \nRichardson \nAS \n, \nSchapiro \nBL \n, \nSaundres \nMD \n, \nStewart \nDM \n. Spontaneous regression of primary cutaneous diffuse large B‐cell lymphoma, leg type with significant T‐cell immune response . JAAD Case Rep . 2018 ;31;4(4) :305 ‐309 .\n2 \n\nGrange \nF \n, \nJoly \nP \n, \nBarbe \nC \n, et al. Improvement of survival in patients with primary cutaneous diffuse large B‐cell lymphoma, leg type, in France . JAMA Dermatol . 2014 ;150 (5 ):535 ‐541 .24647650 \n3 \n\nWilcox \nRA \n. Cutaneous B‐cell lymphomas: 2019 update on diagnosis, risk stratification, and management . Am J Hmatol . 2018 ;93 (11 ):1427 ‐1430 .\n4 \n\nBeylot‐Barry \nM \n, \nMermin \nD \n, \nMaillard \nA \n, et al. A single phase II trial of lenalidomide in relapsing or refractory primary cutaneous large B‐cell lymphoma, leg type . 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Medicine . 2017 ;96 (8 ):e6161 .28225499 \n9 \n\nMareschal \nS \n, \nPham‐Ledard \nA \n, \nViailly \nPJ \n, et al. Identification of somatic mutations in primary cutaneous diffuse large B‐cell lymphoma, leg type by massive parallel sequencing . I Invest Dermatol . 2017 ;137 (9 ):1984 ‐1994 .\n10 \n\nMenguy \nS \n, \nFrison \nE \n, \nProchazkova‐Carlotti \nM \n, et al. Double‐hit or dual expression of MYC and BCL2 in primary cutaneous large B‐cell lymphomas . Mod Pathol . 2018 ;31 (8 ):1332 ‐1342 .29581544 \n11 \n\nPham‐Ledard \nA \n, \nBeylot‐Barry \nM \n, \nBarbe \nC \n, et al. High frequency and clinical prognostic value of MYD88 L265P mutation in primary cutaneous diffuse large B‐cell lymphoma‐leg type . JAMA Dermatol . 2014 ;150 (11 ):1173 ‐1179 .25055137 \n12 \n\nSenff \nNj \n, \nNoordijk \nEm \n, \nKim \nYh \n, et al. European organization for research and treatment of cancer and international society for cutaneous lymphoma consensus recommendations for the management of cutaneous B‐cell lymphomas . Blood . 2008 ;112 (5 ):1600 ‐1609 .18567836 \n13 \n\nSenff \nNJ \n, \nHoefnagel \nJJ \n, \nNeelis \nKJ \n, et al. Results of radiotherapy in 153 primary cutaneous B‐cell lymphomas classified according to the WHO‐EORTC classification . Arch Dermatol . 2007 ;143 :1520 ‐1526 .18087001 \n14 \n\nMarrero‐Aleman \nG \n, \nMontenegro‐Damaso \nT \n, \nPenate \nY \n. Primary cutaneous diffuse large B‐cell lymphoma, leg type, with spontaneous regression after biopy . Am J Dermatopathol . 2017 ;39 (10 ):785 ‐787 .28926365 \n15 \n\nAlcántara‐González \nJ \n, \nGonzález‐García \nC \n, \nFernández‐Guarino \nM \n, \nJaén‐Olasolo \nP \n. Spontaneous regression of primary diffuse large B‐cell lymphoma, leg type . 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Ann Oncol . 2011 ;22 (7 ):1622 ‐1627 .21228334 \n20 \n\nZeldis \nJB \n, \nKnight \nR \n, \nHussein \nM \n, \nChopra \nR \n, \nMuller \nG \n. A review of the history, properties, and use of the immunomodulatory compound lenalidomide . Ann N Y Acad Soci . 2011 ;1222 :76 ‐82 .\n\n",
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"keywords": "chemotherapy; leg type; lenalidomide; primary cutaneous diffuse large B‐cell lymphoma",
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"title": "Effectiveness of lenalidomide in relapsed primary cutaneous diffuse large B-cell lymphoma, leg type.",
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{
"abstract": "Investigators from Child Neurology and Pediatrics, University of Texas Health Science Center, Houston, report extrapyramidal symptoms in a 13-year-old boy with a psychiatric history of schizophrenia, bipolar disorder, ADHD, and autism, responsive to combination risperidone, oxcarbazepine, and MPH.",
"affiliations": "Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.;Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.",
"authors": "Millichap|J Gordon|JG|0000-0002-0173-7931;Yee|Michelle M|MM|",
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"fulltext": "\n==== Front\nPediatr Neurol BriefsPediatr Neurol Briefs1043-3155pedneurbriefsPediatr Neurol BriefsPediatric Neurology Briefs2166-64821043-31551043-3155Pediatric Neurology Briefs Publishers Chicago, IL, USA PNB-30-0710.15844/pedneurbriefs-30-1-6Behavior DisordersNeurologyPediatricsNervous System DiseasesChild DevelopmentBrain DiseasesNeurosurgeryChildInfantDystonia with MPH/Risperidone Combined Therapy for ADHD http://orcid.org/0000-0002-0173-7931Millichap J. Gordon MD12*Yee Michelle M. CPNP121 Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL2 Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL* Correspondence: Dr. J. Gordon Millichap, E-mail: [email protected] 2016 11 3 2016 30 1 7 7 02 3 2016 07 3 2016 Copyright: © 2016 The Author(s)2016This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nExtrapyramidal symptoms as a result of risperidone discontinuation during combination therapy with methylphenidate in a pediatric patient \nInvestigators from Child Neurology and Pediatrics, University of Texas Health Science Center, Houston, report extrapyramidal symptoms in a 13-year-old boy with a psychiatric history of schizophrenia, bipolar disorder, ADHD, and autism, responsive to combination risperidone, oxcarbazepine, and MPH.\n\nRisperidoneMethylphenidateADHDDystoniaDyskinesia\n==== Body\nInvestigators from Child Neurology and Pediatrics, University of Texas Health Science Center, Houston, report extrapyramidal symptoms in a 13-year-old boy with a psychiatric history of schizophrenia, bipolar disorder, ADHD, and autism, responsive to combination risperidone, oxcarbazepine, and MPH. Risperidone was started at age 4 for aggressive behavior and titrated to 1.5 mg. twice daily. Because of significant weight gain, risperidone was tapered and, at a dose of 0.5 mg twice daily, he developed severe painful cervical dystonia and dyskinesia consisting of involuntary movements of the upper extremities, and uncontrollable sense of restlessness and agitation. Treatment with quetiapine, diphenhydramine, benztropine, clonidine, or lorazepam was ineffective and symptoms worsened. Risperidone was reinstated at 0.5 mg twice daily and increased to his previous dose of 1.5 mg twice daily within 3 days, after which the dystonia, akathisia, and tardive dyskinesia resolved. The authors consider this the first case of acute onset of extrapyramidal symptoms as a result of discontinuation of risperidone during combination therapy with MPH in a child. [1]\n\nCOMMENTARY. Although pediatric neurologists do not generally prescribe the antipsychotic risperidone as primary treatment for ADHD, patients taking risperidone are sometimes referred to neurology from psychiatry for a second opinion regarding refractory symptoms or untoward side-effects. The addition of a psychostimulant, methylphenidate (MPH) is a frequent recommendation and, in our experience, using conservative dosages, extrapyramidal side effects have not occurred. The present report of extrapyramidal symptoms during discontinuation of risperidone in a child taking combination RIS/MPH therapy we consider unusual and worthy of further study.\n\nA Pubmed search in the past two years uncovered five reports of dyskinesia associated with combination RIS/MPH therapy prescribed for ADHD and comorbid disorders. An analysis of 44 cases treated in psychiatry where children received either MPH (n=28) or risperidone (n=16) as primary treatment and the majority combination treatment, symptoms of ADHD and conduct disorder were benefited, and only one case of dyskinesia occurred that resolved with the discontinuation of treatment [2]. MPH/risperidone therapy was considered particularly effective in ADHD with conduct disorder. An acute dystonic reaction in an adolescent followed the abrupt discontinuation of MPH from a combination drug regimen risperidone/MPH; the patient experienced acute dystonia on 3 occasions when he forgot to take his MPH [3]. An acute and transient dyskinesia occurred on starting long-acting MPH in a 7-year-old boy who had recently stopped taking risperidone [4]. A further report concerns three children with ADHD who developed severe hyperactivity and agitation on starting MPH after discontinuing risperidone [5]. The adverse reaction resolved after withdrawal of MPH, and following a drug-free interval, MPH was re-administered without adverse effect. In treating ADHD with the drug combination risperidone/MPH, particular care is advised when switching, starting, or discontinuing either treatment, and particularly when changing MPH. Conservative dosages are often better than mega, and to festina-lente is advised in dosage increments.\n\nDisclosures\nThe author has declared that no competing interests exist.\n==== Refs\n1 Pérez CA Garcia SS Yu RD Extrapyramidal symptoms as a result of risperidone discontinuation during combination therapy with methylphenidate in a pediatric patient J Child Adolesc Psychopharmacol 2016 2 [Epub ahead of print] 10.1089/cap.2015.0225 26871198 \n2 Javelot H Glay-Ribau C Ligier F Weiner L Didelot N Messaoudi M Methylphenidate-risperidone combination in child psychiatry: A retrospective analysis of 44 cases Ann Pharm Fr 2014 5 72 3 164 77 10.1016/j.pharma.2013.12.009 24780832 \n3 Guler G Yildirim V Kutuk MO Toros F Dystonia in an adolescent on risperidone following the discontinuation of methylphenidate: a case report Clin Psychopharmacol Neurosci 2015 4 13 1 115 7 10.9758/cpn.2015.13.1.115 25912546 \n4 Hollis CP Thompson A Acute dyskinesia on starting methylphenidate after risperidone withdrawal Pediatr Neurol 2007 10 37 4 287 8 10.1016/j.pediatrneurol.2007.05.017 17903675 \n5 Sabuncuoglu O Risperidone-to-methylphenidate switch reaction in children: three cases J Psychopharmacol 2007 3 21 2 216 9 10.1177/0269881107069466 17329303\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1043-3155",
"issue": "30(1)",
"journal": "Pediatric neurology briefs",
"keywords": "ADHD; Dyskinesia; Dystonia; Methylphenidate; Risperidone",
"medline_ta": "Pediatr Neurol Briefs",
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"pmid": "27004141",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": "17903675;24780832;25912546;26871198;17329303",
"title": "Dystonia with MPH/Risperidone Combined Therapy for ADHD.",
"title_normalized": "dystonia with mph risperidone combined therapy for adhd"
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"abstract": "BACKGROUND\nWhen exogenous testosterone or treatments to elevate testosterone (human chorionic gonadotropin [HCG] or Clomid) are prescribed for men who have antecedent thrombophilia, deep venous thrombosis and pulmonary embolism often occur and may recur despite adequate anticoagulation if testosterone therapy is continued.\n\n\nMETHODS\nA 55-year-old white male was referred to us because of 4 thrombotic events, 3 despite adequate anticoagulation over a 5-year period. We assessed interactions between thrombophilia, exogenous testosterone therapy, and recurrent thrombosis. In 2009, despite low-normal serum testosterone 334 ng/dL (lower normal limit [LNL] 300 ng/dL), he was given testosterone (TT) cypionate (50 mg/week) and human chorionic gonadotropin (HCG; 500 units/week) for presumed hypogonadism. Ten months later, with supranormal serum T (1385 ng/dL, upper normal limit [UNL] 827 ng/dL) and estradiol (E2) 45 pg/mL (UNL 41 pg/mL), he had a pulmonary embolus (PE) and was then anticoagulated for 2 years (enoxaparin, then warfarin). Four years later, on TT-HCG, he had his first deep venous thrombosis (DVT). TT was stopped and HCG continued; he was anticoagulated (enoxaparin, then warfarin, then apixaban, then fondaparinux). One year after his first DVT, on HCG, still on fondaparinux, he had a second DVT (5/315), was anticoagulated (enoxaparin + warfarin), with a Greenfield filter placed, but 8 days later had a second PE. Thrombophilia testing revealed the lupus anticoagulant. After stopping HCG, and maintained on warfarin, he has been free of further DVT-PE for 9 months.\n\n\nCONCLUSIONS\nWhen DVT-PE occur on TT or HCG, in the presence of thrombophilia, TT-HCG should be stopped, lest DVT-PE reoccur despite concurrent anticoagulation.",
"affiliations": "Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Jewish Hospital of Cincinnati, Cincinnati, OH, USA.;Jewish Hospital of Cincinnati, Cincinnati, OH, USA.",
"authors": "Glueck|Charles J|CJ|;Lee|Kevin|K|;Prince|Marloe|M|;Jetty|Vybhav|V|;Shah|Parth|P|;Wang|Ping|P|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1177/2324709616661833",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961666183310.1177_2324709616661833Case ReportFour Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant Glueck Charles J. MD1Lee Kevin MD1Prince Marloe MD1Jetty Vybhav MD1Shah Parth MD1Wang Ping PhD11 Jewish Hospital of Cincinnati, Cincinnati, OH, USAKevin Lee, MD, Cholesterol Center, Jewish Hospital of Cincinnati, Suite 430, 2135 Dana Avenue, Cincinnati, OH 45207, USA. Email: [email protected] 8 2016 Jul-Sep 2016 4 3 232470961666183321 5 2016 29 6 2016 02 7 2016 © 2016 American Federation for Medical Research2016American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any 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).Background: When exogenous testosterone or treatments to elevate testosterone (human chorionic gonadotropin [HCG] or Clomid) are prescribed for men who have antecedent thrombophilia, deep venous thrombosis and pulmonary embolism often occur and may recur despite adequate anticoagulation if testosterone therapy is continued. Case Presentation: A 55-year-old white male was referred to us because of 4 thrombotic events, 3 despite adequate anticoagulation over a 5-year period. We assessed interactions between thrombophilia, exogenous testosterone therapy, and recurrent thrombosis. In 2009, despite low-normal serum testosterone 334 ng/dL (lower normal limit [LNL] 300 ng/dL), he was given testosterone (TT) cypionate (50 mg/week) and human chorionic gonadotropin (HCG; 500 units/week) for presumed hypogonadism. Ten months later, with supranormal serum T (1385 ng/dL, upper normal limit [UNL] 827 ng/dL) and estradiol (E2) 45 pg/mL (UNL 41 pg/mL), he had a pulmonary embolus (PE) and was then anticoagulated for 2 years (enoxaparin, then warfarin). Four years later, on TT-HCG, he had his first deep venous thrombosis (DVT). TT was stopped and HCG continued; he was anticoagulated (enoxaparin, then warfarin, then apixaban, then fondaparinux). One year after his first DVT, on HCG, still on fondaparinux, he had a second DVT (5/315), was anticoagulated (enoxaparin + warfarin), with a Greenfield filter placed, but 8 days later had a second PE. Thrombophilia testing revealed the lupus anticoagulant. After stopping HCG, and maintained on warfarin, he has been free of further DVT-PE for 9 months. Conclusion: When DVT-PE occur on TT or HCG, in the presence of thrombophilia, TT-HCG should be stopped, lest DVT-PE reoccur despite concurrent anticoagulation.\n\ntestosteronehuman chorionic gonadotropinClomiddeep venous thrombosispulmonary embolusanticoagulationcover-dateJuly-September 2016\n==== Body\nCase Report\nA white male, age 55, was referred to us (June 8, 2015) because of 4 thrombotic events, 3 despite adequate anticoagulation over a 5-year period. We assessed interactions between thrombophilia, exogenous testosterone therapy, and recurrent thrombosis.\n\nA previously healthy 55-year-old skilled welder developed acromegaly and had removal of a growth-hormone secreting pituitary adenoma in 2002. Seven years later (July 2009), after complaints of fatigue and increasing muscle weakness, he was found to have low-normal serum testosterone 334 ng/dL (lower normal limit [LNL] 300 ng/dL) and high estradiol [E2] 45 pg/mL (upper normal limit [UNL] 41 pg/mL), and despite these findings, he was started on 50 mg intramuscular testosterone therapy (TT) cypionate/week and intramuscular human chorionic gonadotropin (HCG) 250 IU twice/week. On TT-HCG, both serum total T and E2 became supranormal (T: 1385 ng/dL, UNL 827 ng/dL; E2: 45 pg/mL, UNL 41).\n\nTen months after starting TT-HCG, in May 2010, he sustained multiple pulmonary embolus PE (Figure 1). Sonography for deep venous thrombosis (DVT) was negative, and he was treated with enoxaparin and then warfarin, which was continued for 2 years (Figure 1). At the time of the PE, the injected testosterone cypionate was replaced by testosterone gel 50 mg/day, which was continued along with the HCG for 10 months, after which the gel was changed back to the injections (testosterone cypionate 50 mg/week; (Figure 1).\n\nFigure 1. Recurrent pulmonary embolism (PE) and deep venous thrombosis (DVT) despite anticoagulation when testosterone-human chorionic hormone (HCG) therapy was continued in a patient later shown to have the lupus anticoagulant. No further DVT or PE in 9 months after stopping HCG.\n\nOn TT-HCG (March 18, 2014), his serum E2 was high (54 pg/mL, UNL 41), and total T was normal (543 ng/dL, laboratory normal range 300-827).\n\nIn May 2014, 4 years from the initial PE, on TT-HCG but no anticoagulation, DVT #1 in the right leg was diagnosed. TT was stopped, but HCG was continued (Figure 1). Anticoagulation with enoxaparin and warfarin (8 months) was given, then apixaban (20 mg/day for 7 days, then 5 mg BID) and then fondaparinux 10 mg/day for another 4 months (Figure 1).\n\nOn May 3, 2015, 1 year after his first DVT, despite having been on enoxaparin, then warfarin, then apixaban, and then fondaparinux, while still on HCG, his second DVT occurred (Figure 1). Venous Doppler revealed a 20″ long nonocclusive thrombus in the right leg. A Greenfield filter was placed (May 4, 2015), enoxaparin and warfarin were re-instituted, and the HCG was stopped on our consultation (May 10, 2015). However, his second PE occurred 8 days after placement of the Greenfield filter (Figure 1) while still receiving both enoxaparin and warfarin (Figure 1). After stopping the HCG, and maintained on enoxaparin and warfarin together, and then warfarin alone for 9 months, he has had no recurrent DVT-PE (Figure 1).\n\nWe evaluated the patient for the first time in Cincinnati on May 28, 2015. Five years from his first PE, our tests of thrombophilia and hypofibrinolysis revealed the presence of the lupus anticoagulant, measured while on warfarin, with DRVVT 57.9 seconds (reference <55) and hexagonal phospholipid neutral 14.\n\nBeing off the HCG for 2 weeks and off TT for a year, serum T was normal (622 ng/dL; laboratory normal range 348-1197 ng/dL), and E2 was normal (19.1 pg/mL; laboratory normal range 7.6-42.6 pg/mL).\n\nDiscussion\nTT is often indiscriminately prescribed1 without consideration of risks.2 As in this case, many men given TT do not meet well-defined diagnostic and therapeutic criteria.3 Before TT-HCG, our patient was found to have low-normal serum T (334 ng/dL; LNL 300 ng/dL) and high E2 (45 pg/mL, UNL 41 pg/mL). Despite these findings, he was started on 50 mg testosterone cypionate and HCG 500 IU per week. On TT-HCG serum total T became supranormal (1385 ng/dL, UNL 827), and serum E2 was high (45 pg/mL; UNL 41), both speculatively contributing to his DVT-PE events, interacting with his lupus anticoagulant.\n\nIn 36 hypogonadal patients in our center studied before and on conventional TT (50-60 mg gel/day) 11% developed supranormal serum T (>800 ng/mL) on TT.4 In these 36 patients, E2 was supranormal (>42.6 pg/mL) before TT in 6%, and on TT in 14%. Conventional TT can lead to supranormal T and E2 in hypogonadal patients.\n\nWe have previously described 11 of 67 patients with thrombophilia given exogenous TT5,6 who sustained a first venous thromboembolic event (VTE) and then, while continuing TT, and despite adequate anticoagulation, sustained a second VTE. Moreover, of these 11 patients, with TT further continued, 6 men4-6 had a third VTE, despite continuing adequate anticoagulation. Recurrent PEs and DVTs despite anticoagulation in our current case when TT-HCG or HCG alone were continued parallels our previous 11 patients’4-6 recurrent thrombotic events. After stopping HCG, with continuation of warfarin, in the current study, the subject had no further DVT-PE over the subsequent 9 months of follow-up.\n\nIn the current case, the sole thrombophilia identified was the lupus anticoagulant, which was present during warfarin anticoagulation. Recent studies have suggested that despite concurrent warfarin, the lupus anticoagulant can be detected by dilute Russel’s Viper Venom time.7,8 However, the lupus anticoagulant can be transient and should be remeasured over time for optimal confirmation.\n\nIn 2014, both the US Food and Drug Administration9 and Canada Health,10 based on postmarketing data, required manufacturers to add a warning to testosterone product labels about the potential risks of VTE, including DVT and PE. As a result, there is now broad public concern regarding this issue.\n\nTT and/or HCG are conventionally used in the treatment of hypogonadism.11 High serum E2 is common during TT therapy5,6,12,13 via aromatization from exogenous T and may provide a direct stimulus to thrombosis, particularly when, as in the current case, TT supplementation leads to supranormal serum T, and subsequently to supranormal E2. TT can also promote VTE via increased blood pressure,14 polycythemia,15,16 decrements in high-density lipoprotein cholesterol,14,16 blood hyperviscosity, and platelet aggregation.16-18 Intramuscular TT increases platelet thromboxane A2 receptor density and platelet aggregation,19 increasing adhesion to the coronary artery endothelium and thrombus formation, with subsequent plaque rupture and acute coronary syndrome.20 Dihydrotestosterone can promote acute coronary events through enhanced monocyte activation.21,22\n\nFrom 2001 to 2011, androgen use in men age ≥40 has increased more than 3-fold.23 Despite the example of thrombotic and cardiovascular events related to sex-hormone therapy in postmenopausal women from the Women’s Health Initiative,24,25 TT is rapidly increasing, often indiscriminately, without understanding of its long-term effects.1,26\n\nUse of TT in young men with classic forms of hypogonadism is considered effective and there is little disagreement regarding its use in this patient population.3 However, T levels fall with age,27,28 with chronic disease,29,30 and with obesity29 but not with smoking.31,32 With aging, accumulation of obesity, and development of diabetes, more and more men have lower T, but do not meet diagnostic criteria3 for hypogonadism. Moreover, most normal ranges come from healthy younger men.33 Differences in T assay methods34,35 and adverse muscle symptoms at different T levels further interfere with efficient diagnosis.36\n\nUse of TT in men affected by late onset hypogonadism (LOH),37,38 where low T has no definable etiology beyond aging and/or chronic disease, is controversial, with concerns over its effectiveness and safety.2,39-42 Indiscriminate use of TT for LOH is a real issue,2,4,5,43-45 as this form of therapy is administered to almost 1 in 25 American men over the age of 60.46\n\nIncreasing use of TT may have thrombotic12,13,47-50 and cardiovascular ramifications.2,51,52 Adverse or intermediate cardiovascular disease (CVD) outcomes have been widely reported after TT was started.2,14,16,41-43,51,53,54 In contrast, 2 studies demonstrated significant CVD event reduction on TT.39,40 A placebo-controlled clinical trial demonstrated that in patients age 65 or older, raising low testosterone to mid-normal range improved sexual function, mood, and symptoms of depression, but failed to improve vitality and walking distance.55 The sample size was too small provide conclusions about TT risks.55\n\nWe have compared 67 patients who sustained VTE4 after starting TT to 76 controls, not taking TT, who sustained DVT/PE. Of the 67 VTE TT patients, 16 (24%) were found to be heterozygous for the factor V Leiden mutation versus 7 of the 76 (7%) VTE controls not on TT, P = .004. The 67 patients with VTE on TT also were more likely than the 76 VTE no-TT controls to have the lupus anticoagulant, 9/64 (14%) versus 2/76, 3%, P = .023.4 When screening men4 for thrombophilia before starting TT, we suggest that minimal tests include the factor V Leiden mutation and the lupus anticoagulant, while more extensive tests would also include PCR for the G20210A prothrombin gene mutation, factors VIII and XI, and homocysteine.\n\nIn contrast to our clinical case-control series,4 in an observational population study by Baillargeon et al,56 TT use was not associated with increased VTE events. Having filled a prescription for TT was not significantly associated with increased risk of VTE.56 In a retrospective study of male adults with low serum T at a low-moderate baseline risk of DVT/PE, and after excluding men with prior history of DVT/PE, cancer, hypercoagulable state, and chronic anticoagulation, Sharma et al57 did not detect a significant association between TT and risk of DVT/PE. However, almost all of our 67 subjects4 with VTE after starting TT would have been excluded by Sharma et al57 because of antecedent DVT/PE, hypercoagulable state, and chronic anticoagulation, biasing against recognizing a significant association4 between TT and DVT-PE events.57\n\nParticularly since our recent retrospective study of men and women hospitalized for VTE44 revealed that personal and family history were nonspecific and insensitive to effectively identify subjects in whom TT and estrogen replacement therapy should not be given, prescreening for thrombophilia is realistic. However, it is expensive, with average laboratory costs in our center $1200. On the other hand, direct hospital costs for VTE events are about $15 000,58 and higher for re-admission, and there are high direct and indirect costs of post–phlebitic syndrome. It would be valuable to do a pharmacoeconomic study of the number of quality of life years realized by prescreening for coagulation factors before starting TT, and the balance between the cost of hospitalization for VTE and dollars saved by prescreening. This analysis should provide an incremental cost-effectiveness ratio within a society willingness-to-pay threshold.\n\nWhy TT induces VTE in thrombophilic patients despite correct use of anticoagulation is unknown, but we speculate that testosterone with subsequent aromatization to estradiol must interact with underlying coagulation factors to overwhelm the expected protection from the anticoagulant.\n\nA limitation of our study is that there is only one set of lupus anticoagulant data. The lupus anticoagulant may be transient,59 and therefore we do not know that it was present during the entire time frame that the patient was studied. Even if the lupus anticoagulant was only transient, based on this case and in 11 similar cases (of 67 previously reported),4 we would never continue TT despite concurrent anticoagulants in patients with previous VTE, particularly if they had familial thrombophilia or repetitively demonstrated lupus anticoagulant.\n\nConclusions\nWhen DVT-PE occurs in men or women48 given exogenous TT and/or HCG, and especially in the presence of thrombophilia-hypofibrinolysis,4-6 we believe that continued or subsequent use of TT is contraindicated. As in this case, and in the presence of thrombophilia, continuation of anticoagulation therapy during TT repetitively fails to prevent recurrent DVT-PE, and to date, the only solution is to stop the TT. Moreover, we suggest that screening for thrombophilia be done before starting TT in order to avoid interaction of TT with underlying thrombophilia with resultant VTE. If thrombophilia is found before starting TT, this substantially changes estimations of risk-benefit ratios related to TT.\n\nAuthors’ Note: This study followed a protocol approved by our institutional review board. Signed informed consent was obtained.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported in part by the Lipoprotein Research Fund of the Jewish Hospital of Cincinnati.\n==== Refs\nReferences\n1 \nAnawalt BD \nGuidelines for testosterone therapy for men: how to avoid a mad (t)ea party by getting personal . 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J Endocrinol Invest . 2016 ;39 :473 -484 .26733213 \n39 \nWallis CJ Lo K Lee Y \nSurvival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study . Lancet Diabetes Endocrinol . 2016 ;4 :498 -506 .27165609 \n40 \nSharma R Oni OA Gupta K \nNormalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men . Eur Heart J . 2015 ;36 :2706 -2715 .26248567 \n41 \nLayton JB Meier CR Sharpless JL Sturmer T Jick SS Brookhart MA \nComparative safety of testosterone dosage forms . JAMA Intern Med . 2015 ;175 :1187 -1196 .25962056 \n42 \nAnderson JL May HT Lappe DL \nImpact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated health care system . Am J Cardiol . 2016 ;117 :794 -799 .26772440 \n43 \nBasaria S Harman SM Travison TG \nEffects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial . JAMA . 2015 ;314 :570 -581 .26262795 \n44 \nPrince M Glueck CJ Shah P \nHospitalization for pulmonary embolism associated with antecedent testosterone or estrogen therapy in patients found to have familial and acquired thrombophilia . BMC Hematol . 2016 ;16 :6 .26958344 \n45 \nGlueck CJ Riaz R Prince M Freiberg RA Wang P \nTestosterone therapy can interact with thrombophilia, leading to osteonecrosis . Orthopedics . 2015 ;38 :e1073 -e1078 .26652327 \n46 \nStanworth RD Jones TH \nTestosterone for the aging male; current evidence and recommended practice . Clin Interv Aging . 2008 ;3 :25 -44 .18488876 \n47 \nGlueck CJ Richardson-Royer C Schultz R \nTestosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: an exploratory, hypothesis-generating study . Clin Appl Thromb Hemost . 2014 ;20 :244 -249 .23925401 \n48 \nGlueck CJ Bowe D Valdez A Wang P \nThrombosis in three postmenopausal women receiving testosterone therapy for low libido . Womens Health (Lond Engl) . 2013 ;9 :405 -410 .23826780 \n49 \nGlueck CJ Richardson-Royer C Schultz R \nTestosterone, thrombophilia, and thrombosis . Clin Appl Thromb Hemost . 2014 ;20 :22 -30 .23615294 \n50 \nPandit RS Glueck CJ \nTestosterone, anastrozole, factor V Leiden heterozygosity and osteonecrosis of the jaws . Blood Coagul Fibrinolysis . 2014 ;25 :286 -288 .24674881 \n51 \nBasaria S Coviello AD Travison TG \nAdverse events associated with testosterone administration . N Engl J Med . 2010 ;363 :109 -122 .20592293 \n52 \nFinkle WD Greenland S Ridgeway GK \nIncreased risk of non-fatal myocardial infarction following testosterone therapy prescription in men . PLoS One . 2014 ;9 (1 ):e85805 .24489673 \n53 \nAnderson RA Ludlam CA Wu FC \nHaemostatic effects of supraphysiological levels of testosterone in normal men . Thromb Haemost . 1995 ;74 :693 -697 .8585008 \n54 \nXu L Freeman G Cowling BJ Schooling CM \nTestosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials . BMC Med . 2013 ;11 :108 .23597181 \n55 \nSnyder PJ Bhasin S Cunningham GR \nEffects of testosterone treatment in older men . N Engl J Med . 2016 ;374 :611 -624 .26886521 \n56 \nBaillargeon J Urban RJ Morgentaler A \nRisk of venous thromboembolism in men receiving testosterone therapy . Mayo Clin Proc . 2015 ;90 :1038 -1045 .26205547 \n57 \nSharma R Oni OA Chen G \nAssociation between testosterone replacement therapy and the incidence of deep vein thrombosis and pulmonary embolism: a retrospective cohort study of the Veterans Administration database [published online 5 \n11 , 2016 ]. Chest . doi:10.1016/j.chest.2016.05.007 .\n58 \nFernandez MM Hogue S Preblick R Kwong WJ \nReview of the cost of venous thromboembolism . Clinicoecon Outcomes Res . 2015 ;7 :451 -462 .26355805 \n59 \nPahus SH Hansen AT Hvas AM \nThrombophilia testing in young patients with ischemic stroke . Thromb Res . 2016 ;137 :108 -112 .26585761\n\n",
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"keywords": "Clomid; anticoagulation; deep venous thrombosis; human chorionic gonadotropin; pulmonary embolus; testosterone",
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"title": "Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant.",
"title_normalized": "four thrombotic events over 5 years two pulmonary emboli and two deep venous thrombosis when testosterone hcg therapy was continued despite concurrent anticoagulation in a 55 year old man with lupus anticoagulant"
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{
"abstract": "Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. Newly acquired and reactivation of latent infection are the major causes of infection, with typical later-onset and mainly as disseminated infection. The type and intensity of immunosuppression, diabetes mellitus and other co-morbidities as well as uremia seem to be important determinants on clinical presentation and outcome. Moreover, the diagnosis is not always apparent since it usually presents subacutely, as well as mimicking bacterial infections, which may be responsible for a delay in the diagnosis. Thus, a high degree of suspicion and need of invasive procedures for microbiological and histological evaluation are critical for definitive diagnosis and prompt institution of adequate treatment. We report two cases of disseminated cryptococcosis with different presentations and with an early-onset after renal transplantation.",
"affiliations": "Nephrology, Research and Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal. [email protected]",
"authors": "Castro-Ferreira|I|I|;Carvalho|C|C|;Coentrão|L|L|;Gaião|S|S|;Bustorff|M|M|;Santos|J|J|;Sampaio|S|S|;Portugal|R|R|;Pestana|M|M|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Germany",
"delete": false,
"doi": "10.5414/cn106772",
"fulltext": null,
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"issn_linking": "0301-0430",
"issue": "75(6)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D003453:Cryptococcosis; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D012307:Risk Factors",
"nlm_unique_id": "0364441",
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"pages": "542-6",
"pmc": null,
"pmid": "21612758",
"pubdate": "2011-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early-onset of disseminated cryptococcal infection in two renal transplant recipients.",
"title_normalized": "early onset of disseminated cryptococcal infection in two renal transplant recipients"
}
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{
"reactionmeddrapt": "Disseminated cryptococcosis",
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}
],
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},
"primarysource": {
"literaturereference": "CASTRO?FERREIRA, I.. EARLY?ONSET OF DISSEMINATED CRYPTOCOCCAL INFECTION IN TWO RENAL TRANSPLANT RECIPIENTS.. CLINICAL NEPHROLOGY. 2011?75 (6): JAN 01:542?546",
"literaturereference_normalized": "early onset of disseminated cryptococcal infection in two renal transplant recipients",
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},
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},
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},
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}
] |
{
"abstract": "BACKGROUND\nEarly initiated antiretroviral therapy (ART) in HIV infected infants leads to improved long-term viral suppression and survival. Guidelines recommend initiating therapy with a triple ART consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either one additional non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Compared to older children and adults, viral relapse is seen more frequently in infants receiving triple ART. We now address the possibility of a more potent ART with a quadruple induction and triple maintenance therapy.\n\n\nMETHODS\nWe examine the longitudinal course in four HIV infected infants, who were referred from other centers and could not be recruited to multicentre trials. We introduced ART initially consisting of two NRTIs, one NNRTI and one PI and later discontinued the PI at the age of 12 months maintaining a triple regime consisting of two NRTIs and one NNRTI.\n\n\nRESULTS\nProvided that therapy adherence was maintained we observed an effective sustained decline of viral load and significant CD4 cell reconstitution even after switching to a triple regime. No drug associated toxicity was seen.\n\n\nCONCLUSIONS\nWe suggest that a four drug therapy might be a possible initial therapy option in HIV infected infants, at least in those with a high viral load, followed by a maintenance triple regime after 12 months of therapy.",
"affiliations": "Department of Pediatric Oncology, Hematology and Clinical Immunology, University Hospital Düsseldorf, Medical Faculty, 40225 Duesseldorf, Germany. [email protected]",
"authors": "Ghosh|Sujal|S|;Neubert|J|J|;Niehues|T|T|;Adams|O|O|;Morali-Karzei|N|N|;Borkhardt|A|A|;Laws|H J|HJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/2047-783x-16-6-243",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0949-2321",
"issue": "16(6)",
"journal": "European journal of medical research",
"keywords": null,
"medline_ta": "Eur J Med Res",
"mesh_terms": "D000367:Age Factors; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D019562:Viral Load",
"nlm_unique_id": "9517857",
"other_id": null,
"pages": "243-8",
"pmc": null,
"pmid": "21810557",
"pubdate": "2011-06-21",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": "14610491;19878352;19020325;21288774;10601506;9134873;19194272;16511413;12038889;15608053;15075541;16905783;20029271;15190139;19709432",
"title": "Induction maintenance concept for HAART as initial treatment in HIV infected infants.",
"title_normalized": "induction maintenance concept for haart as initial treatment in hiv infected infants"
}
|
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],
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"reaction": [
{
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"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood triglycerides increased",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gamma-glutamyltransferase increased",
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},
{
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],
"summary": null
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"literaturereference": "GHOSH S, NEUBERT J, NIEHUES T, ADAMS O, MORALI-KARZEI N, BORKHARDT A, LAWS H. INDUCTION MAINTENANCE CONCEPT FOR HAART AS INITIAL TREATMENT IN HIV INFECTED INFANTS. EUROPEAN JOURNAL OF MEDICAL RESEARCH. 2011;16:243-248.",
"literaturereference_normalized": "induction maintenance concept for haart as initial treatment in hiv infected infants",
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"abstract": "Nonepileptic seizures (NES) apparently look like epileptic seizures, but are not associated with ictal electrical discharges in the brain. NES constitute one of the most important differential diagnoses of epilepsy. They have been recognized as a distinctive clinical phenomenon for centuries, and video/electroencephalogram monitoring has allowed clinicians to make near-certain diagnoses. NES are supposedly unrelated to organic brain lesions, and despite the preponderance of a psychiatric/psychological context, they may have an iatrogenic origin. We report a patient with NES precipitated by levetiracetam therapy; in this case, NES was observed during the disappearance of epileptiform discharges from the routine video/electroencephalogram. We discuss the possible mechanisms underlying NES with regard to alternative psychoses associated with the phenomenon of the forced normalization process.",
"affiliations": "Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d'Annunzio University Foundation, Gabriele d'Annunzio University, Chieti, Italy.;Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d'Annunzio University Foundation, Gabriele d'Annunzio University, Chieti, Italy.;Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d'Annunzio University Foundation, Gabriele d'Annunzio University, Chieti, Italy.;Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d'Annunzio University Foundation, Gabriele d'Annunzio University, Chieti, Italy.;Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d'Annunzio University Foundation, Gabriele d'Annunzio University, Chieti, Italy.;Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d'Annunzio University Foundation, Gabriele d'Annunzio University, Chieti, Italy.",
"authors": "Anzellotti|Francesca|F|;Franciotti|Raffaella|R|;Zhuzhuni|Holta|H|;D'Amico|Aurelio|A|;Thomas|Astrid|A|;Onofrj|Marco|M|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S60089",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S60089ndt-10-959Case ReportNonepileptic seizures under levetiracetam therapy: a case report of forced normalization process Anzellotti Francesca Franciotti Raffaella Zhuzhuni Holta D’Amico Aurelio Thomas Astrid Onofrj Marco Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d’Annunzio University Foundation, Gabriele d’Annunzio University, Chieti, ItalyCorrespondence: Francesca Anzellotti, Department of Neuroscience and Imaging, Aging Research Centre, Gabriele d’Annunzio University, 33 Via dei Vestini, Chieti 66013, Italy, Tel +39 0871 358 525, Email [email protected] 23 5 2014 10 959 964 © 2014 Anzellotti et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Nonepileptic seizures (NES) apparently look like epileptic seizures, but are not associated with ictal electrical discharges in the brain. NES constitute one of the most important differential diagnoses of epilepsy. They have been recognized as a distinctive clinical phenomenon for centuries, and video/electroencephalogram monitoring has allowed clinicians to make near-certain diagnoses. NES are supposedly unrelated to organic brain lesions, and despite the preponderance of a psychiatric/psychological context, they may have an iatrogenic origin. We report a patient with NES precipitated by levetiracetam therapy; in this case, NES was observed during the disappearance of epileptiform discharges from the routine video/electroencephalogram. We discuss the possible mechanisms underlying NES with regard to alternative psychoses associated with the phenomenon of the forced normalization process.\n\nKeywords\nnonepileptic seizuresforced normalizationlevetiracetambehavioral side effects\n==== Body\nIntroduction\nNonepileptic seizures (NES), also known as pseudoseizures or hysterical fits,1 are included in epileptic psychotic manifestations. NES are paroxysmal, time-limited episodes of abnormal behavior or obtunded consciousness, movements, sensations, and psychic states that may be mistaken for epilepsy, but are not accompanied by electroencephalogram (EEG) changes. In accordance with O’Hanlon et al,2 we prefer the acronym NES to the term pseudoseizures. NES are a common clinical problem for family physicians, internists, psychiatrists, neurologists, and neurosurgeons. This type of behavioral disturbance has a poorly defined epidemiology, reflecting difficulties in establishing its prevalence and incidence. Various estimates suggest that 5%–25%3 of patients being evaluated for epileptic seizures actually have NES, and thus NES are a significant health care problem.4 Although concepts concerning the etiology of NES are still in evolution, psychological explanations currently predominate: NES are considered a learned pattern of behavior due to environmental stressors.5 Improved diagnostic capabilities (especially video EEG) have shown that NES are more common than once believed,6 and are not exclusively associated with temporal lobe epilepsy.7,8 Patients with NES are often misdiagnosed as suffering from intractable epilepsy, and are thus potentially exposed to unnecessary anticonvulsant medications and other iatrogenic consequences.6\n\nAlthough there is variability in the data, there is a general consensus that psychiatric disorders are more prevalent in patients with epilepsy than in the general population.7 Psychosis encompasses a broad and subtle mental condition. Common features include impaired content and coherence of thought, reduced connection to reality, hallucinations, delusions, disorganized speech and behavior, and extremes of affect and motivation. The detection of psychosis can be difficult, as many patients actively hide their aberrant behavior and delusional beliefs, and others are quietly psychotic, showing only quirky mannerisms.9 As in other chronic disorders, the prevalence rates of psychiatric symptoms in epilepsy vary widely among the different studies published in the literature, with higher prevalence among patients with poorly controlled seizures.9–12 Psychoses can occur during seizure freedom and during or after epileptic seizures. Epileptic psychoses include also the phenomenon of the forced normalization process (FN) and de novo psychosis following epilepsy surgery. FN is characterized by a subacute/acute onset of psychosis associated with dramatic reduction of epileptiform activity.\n\nNeurologists and psychiatrists have debated the existence of the phenomenon of forced normalization since its description by Landolt in 1953,13 who introduced the concept with two cases who both developed personality and mood changes in association with normalization of their EEGs. Landolt13 defined FN as “the phenomenon characterized by the fact that, with the occurrence of psychotic states, the EEG becomes more normal or entirely normal, as compared with previous and subsequent EEG findings”. The literature in the nineteenth century reveals a growing interest in this relationship, particularly in France and Germany, and there are clear descriptions of specific psychopathological states and epilepsy.14 At this time, such terms as epileptic equivalents, larval epilepsy, and transformed epilepsy seem to have crept into the literature, and generally indicate an alteration in the seizure status and/or the development of a behavioral disorder.\n\nThe emergence of new anticonvulsant drugs in the past decade and the increased reporting of behavioral disturbances with several of these drugs, associated with an improvement in seizure status, however, have brought FN again into the focus of scientific attention and curiosity. Patients taking ethosuximide, vigabatrin, levetiracetam (LEV), and topiramate (TPM) with multiple daily seizures (mostly if focal and originating from the limbic lobe), sleep disturbances, and previous psychiatric disorders seem to be more vulnerable.15 FN has only been rarely reported in children and adolescents.16\n\nWe describe for the first time NES as expression of the FN process based on Krishnamoorthy and Trimble criteria (Table 1).17,18 The patient was taking TPM and LEV. NES after LEV administration has also been reported in a previous study.19\n\nCase report\nA 53-year-old right-handed woman suffered from focal epilepsy,20 with seizures characterized by abrupt loss of consciousness and tonic and clonic phases. Her clinical history was significant for a family history of febrile seizures, a poor therapeutic compliance associated with recurrences of epileptic seizures, a diagnosis of fibromyalgia, and a recent reactive depression with psychosomatic symptoms and insomnia; the Hamilton rating scale assessed a score of moderate depression. She denied previous pseudoseizures, but her relatives referred to behavioral disturbances in the past (she presented anxiety and irritability often in seizure-free periods). Magnetic resonance imaging findings were normal. Interictal EEG abnormalities in left frontocentrotemporal channels were characterized by repetitive nonperiodic sharp waves at 100 mV with reversal phase on F7 and sporadic anterior synchronous and asynchronous theta activity (6–7 Hz, 50–60 mV). Due to thrombocytopenia, previous treatment with valproic acid was progressively reduced with recurrences of seizures. Considering the obesity of the patient, TPM was titrated up to a total dose of 300 mg/day. Good seizure control was obtained, but 3 months later the patient was admitted to our neurology clinic, due to abnormal behavior and confusion; she presented with spatial/temporal disorientation, she aimlessly moved her hands, and she was slowly turning her head right and left. She presented with postictal aphasia. Video EEG monitoring revealed incoming seizures with a left frontotemporal focus (Figure 1A; Supplementary video). She received 10 mg of diazepam intravenously. The background EEG improved, showing generalized theta activities at a frequency of 6–7 Hz. Subsequently, her therapy was changed: LEV was added and titrated rapidly until 1,000 mg twice daily. After 10 days, new episodes occurred: the patient appeared confused, she did not want to get out of bed, and when she answered our questions appropriately, she lamented about abdominal pain and asthenia. In addition, she had brief and repetitive tonic jerks of the trunk unaccompanied by loss of consciousness. During these episodes, which lasted about 50 seconds, her eyes were closed. Then she appeared drowsy for 10–15 minutes and could not recall these events. Immediately, EEG monitoring (Figure 1B) was performed, and it revealed no ictal abnormalities during these episodes, but only sporadic interictal sharp waves noted at baseline, supporting a diagnosis of NES. We observed a reduction of the epileptic activity in more than 50% of the waking EEG recording. The reduction of TPM to 100 mg twice daily, the withdrawal of LEV and the introduction of lacosamide titrated to a dose of 300 mg/day led to immediate resolution of NES. During follow-up examinations, neither seizures nor NES were reported anymore by patients and relatives.\n\nDiscussion\nNonepileptic seizures\nNES are classified by the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) as a somatoform disorder.21 The condition is poorly understood, and is under-recognized by clinicians. The estimated incidence in an epilepsy outpatient clinic is 5%–25%.3 The correct diagnosis of NES, further complicated by the frequent coexistence of epilepsy, can be difficult if simply based on clinical criteria; a video EEG is always necessary. Several studies have described various semiological features of NES.22–24 Physical symptoms are suspected to result from psychosocial stress, and are only rarely intentional, as in malingering. NES are often suspected in patients with a history of somatization, abuse, or psychiatric comorbidity,25 or when the following clinical signs are identified:26 long duration, fluctuating course, asynchronous movements, pelvic thrusting, side-to-side head or body movement, ictal crying, memory recall, closed eyes, the uncommon ictal stuttering, and the “teddy-bear sign”. Our knowledge of the clinical picture and context of NES has made only modest progress since Gowers27 summarized his understanding of “hysteroid” seizures in 1885, presenting criteria for distinguishing organic from inorganic seizures; at the end of the nineteenth century, Charcot was the first to describe “hysteroepilepsy” as a clinical disorder.28 The lack of consensus to define and categorize the illness underlies the complexity encountered in establishing effective treatment methodologies, and raises questions regarding the current diagnostic criteria. To address some of these issues, the broad expression “functional neurological disorder” is used for the Diagnostic and Statistical Manual of Mental Disorders (fifth edition).29 The etiology of NES is not entirely understood. Our case shows that it might have an iatrogenic origin, and could be resolved after drug discontinuation. LEV is an anticonvulsant with a favorable safety profile, but behavioral side effects are frequently reported, and were found to be independent of dose or seizure frequency.30 Possible mechanisms underlying behavioral disorders are idiosyncratic dose-unrelated drug effects, significantly increased by antiepileptic drugs, and alternative psychoses (or behavioral disturbances) associated with the phenomenon of FN. Dose-related toxicity and withdrawal syndromes have less importance. The existence of NES as a reversible drug-induced side effect has been identified. Barbiturates, benzodiazepines, and vigabatrin with significant γ-aminobutyric acid (GABA)-ergic properties and LEV with atypical mechanism of action produce behavioral side effects; NES are a behavioral problem. A case of NES appearing as an LEV side effect has previously been reported.19\n\nForced normalization\nThere was a mutual antagonism between seizures and psychiatric problems: as the seizures improved, the psychiatric problem emerged. Neidermeyer et al1 suggested that preexisting “cerebral dysfunction” predisposes certain individuals to exhibit NES, and diffuse electroencephalographic slow-wave activity arising from anticonvulsant toxicity facilitates their expression. Since FN often occurs after an effective antiepileptic drug is added, the psychosis could be a side effect of medication, with EEG improvement an epiphenomenon. The concept of FN, first described by Landolt,13 refers to conditions where the disappearance of epileptiform discharges from the routine EEG is accompanied by some kind of behavioral disorder. The pathogenesis of this condition is debated. The most interesting hypotheses have been discussed by Wolf,31 who assumed that during “paradoxical normalization”, a term that he preferred, the epilepsy is still active subcortically: the spread of discharge along unusual pathways is supposed to induce some of the acute psychotic symptoms. More recently, Bob32 analyzed the FN concept, hypothesizing that dissociative and somatoform symptoms mainly occur as a consequence of traumatic events. Even though FN has been recognized for a long time, the majority of published papers are case reports, probably as a result of the lack of validated diagnostic criteria. Only Krishnamoorthy and Trimble17 have proposed primary and supportive diagnostic criteria (Table 1), which have been revisited more recently.18 Ideally, such criteria should be tested, suitably modified if required, and adopted by scientific organizations that promote epilepsy research. Uniform diagnostic criteria such as these are the first step in systematic research. Our patient fulfills all the primary and supportive criteria; therefore, she was more susceptible to the occurrence of FN, regardless of other provoking factors. Although a past history of psychosomatic symptoms and moderate depression are significant risk factors for NES, we showed the occurrence of behavioral abnormalities when a reduction of epileptic activity was observed in more than 50% of the waking EEG recording (compared to a similar recording performed during a normal state of behavior over 60 minutes) in a patient with an established diagnosis of epilepsy, with subacute onset of behavioral disturbance and a report of complete absence of seizures for at least 1 week (Table 1, Primary criteria). Furthermore the drug regimen was recently changed and parents referred to behavioral disturbances in the past (Table 1, Supportive criteria). Therefore, for the first time we have described and documented NES during a forced normalization process, pointing out that NES can be one of the multiple expressions of psychosis in FN. We obtained a resolution of the NES after LEV discontinuation, TPM reduction, and lacosamide introduction. For ethical reasons, we could not remove drug therapy to prove the disappearance of NES concomitant with the reappearance of the epileptic activity.\n\nConclusion\nWe hypothesized that in our case, FN was induced by LEV fast titration. Probably, lacosamide therapy controlled seizures without inducing FN, due to its different mechanism of action, although the impact of drug type and its mechanism of action is unclear.33 It is known that alterations in the balance of glutaminergic, dopaminergic, and GABA activity may cause seizures and behavioral disorder and can also play a role in the development of FN.17 The emergence of new anticonvulsant drugs in the past decade and the increased reporting of behavioral disturbances with several of these drugs, associated with an improvement in seizure status, underlines the complexity of interaction between several potential pathogenic factors as the possible cause of FN. It is of interest that Landolt13 himself commented on the increase in the number of cases of FN with the introduction of succinimide drugs. Other researchers also observed this with barbiturates and hydantoins.33 No data have reported behavioral side effects or FN cases with lacosamide, whereas both LEV and TPM might have induced NES: the patient had already been taking a stable dose of TPM for 3 months; therefore, it is likely that the psychotic episode could be ascribed to LEV introduction. In fact, during add-on therapy, we obtained EEG normalization. An interesting trial with LEV and TPM15 showed that some patients are prone to develop psychiatric drug-induced adverse events, regardless of pharmacological properties, and that an early limbic injury predisposes people to this type of psychiatric vulnerability. In our opinion, sudden seizure control obtained with fast titration and drug mechanism of action are in some selective cases the relevant factors for the development of psychosis in the FN process, while the association with a specific epilepsy syndrome may represent a bias connected to the probability of achieving complete seizure suppression: patients with symptomatic or multifocal epilepsy are less likely to be seizure-free than patients with idiopathic generalized epilepsy, which is usually associated with a better prognosis. Systematic research that identifies patients who meet Trimble’s criteria in hospital-, institutional-, and community-based population groups, grafted onto modern techniques in molecular genetics and functional imaging,34 may well be the way forward in understanding this fascinating condition. Effective research in this area requires a combined attempt to establish international protocols and databases, while respecting patient privacy and rights.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 (A) Seizure with a left frontotemporal focus. Ictal electroencephalography (EEG) showed rhythmic and reluctant fast (12–13 Hz) activity primarily involving the left frontotemporal area consisting of polyspikes of about 100 mV amplitude with reversal phase in the F7 lead, then epileptic discharge involved all channels and showed a reduction in frequency (6 Hz). The patient was unconscious. Discharges consisting of high-amplitude sharp waves (90–100 μV) and slow waves (prominent on the frontotemporal areas) (high 30 Hz, low 0.1 second; rate 15 mm/second). (B) EEG during pseudoseizures. Normal background activity with interictal abnormalities in left frontocentrotemporal channels: sporadic and nonperiodic sharp waves at 100 mV with reversal phase on F7 and sporadic anterior synchronous and asynchronous theta activity (6–7 Hz, 50–60 mV). Muscular artifacts on right frontal derivations and two abrupt movement artifacts were concomitant with fictitious spasms of the patient. No epileptic seizures were recorded. This recording showed a significant reduction of interictal activity in comparison with her previous EEGs.\n\nTable 1 Primary and supportive diagnostic criteria for FN\n\nPrimary criteria\t\n 1. Diagnosis of epilepsy supported by clinical history, EEG, and neuroimaging\t\n 2. Occurence of acute/subacute behavioral disturbances\t\n3A. Reduction in the total number of epileptiform abnormalities counted in a 60-min awake EEG recording by over 50% compared to a similar recording performed during a normal state of behavior or\t\n3B. Absence of seizures for at least one week corroborated by a relative or carer\t\nSupportive criteria\t\n 1. Recent change (within 15 days) of the drug regimen\t\n 2. Similar behavioral disturbances in the past corroborated by a relative, carer, or general practitioner.\t\nNote: To make the diagnosis of FN, it is necessary to identify primary criteria 1, 2, and 3A or primary criteria 1, 2, and 3B and one supportive criterion.\n\nAbbreviations: EEG, electroencephalography; FN, forced normalization.\n==== Refs\nReferences\n1 Neidermeyer E Blumer D Holscher E Walker BA Classical hysterical seizures facilitated by anticonvulsant toxicity Psychiatr Clin (Basel) 1970 3 71 84 5424766 \n2 O’Hanlon S Liston R Delanty N Psychogenic nonepileptic seizures: time to abandon the term pseudoseizures Arch Neurol 2012 69 1349 1350 23044592 \n3 Szaflarski JP Ficker DM Cahill WT Privitera MD Four-year incidence of psychogenic nonepileptic seizures in adults in Hamilton County, OH Neurology 2000 55 1561 1563 11094115 \n4 Betts TA Boden S Pseudoseizures (non-epileptic attack disorder) Trimble M Women and Epilepsy New York Wiley 1991 243 258 \n5 Ramani SV Quesney LF Olson D Gumnit RJ Diagnosis of hysterical seizures in epileptic patients Am J Psychiatry 1980 137 705 709 7377391 \n6 Reuber M Psychogenic nonepileptic seizures: Answers and questions Epilepsy Behav 2008 12 622 635 18164250 \n7 Kogeorgos J Fonagy P Scott DF Psychiatric symptom patterns of chronic epileptics attending a neurological clinic: a controlled investigation Br J Psychiatry 1982 140 236 243 6807385 \n8 Kanner AM Psychosis of epilepsy: a neurologist’s perspective Epilepsy Behav 2000 1 219 227 12609438 \n9 Adams SJ O’Brien TJ Lloyd J Kilpatrick CJ Salzberg MR Velakoulis D Neuropsychiatric morbidity in focal epilepsy Br J Psychiatry 2008 192 464 469 18515901 \n10 Cockerell OC Moriarty J Trimble M Sander JW Shorvon SD Acute psychological disorders in patients with epilepsy: a nation-wide study Epilepsy Res 1996 25 119 131 8884170 \n11 Sperli F Rentsch D Despland PA Psychiatric comorbidity in patients evaluated for chronic epilepsy: a differential role of the right hemisphere? Eur Neurol 2009 61 350 357 19365127 \n12 Torta R Keller R Behavioral, psychotic, and anxiety disorders in epilepsy: etiology, clinical features, and therapeutic implications Epilepsia 1999 40 Suppl 10 S2 S20 10609602 \n13 Landolt H Serial EEG investigations during psychotic episodes in epileptic patients and during schizophrenic attacks Lorentz De Haas AM Lectures on Epilepsy Amsterdam Elsevier 1958 91 133 \n14 Schmitz B Forced normalization: history of a concept Trimble MR Schmitz B Forced Normalization and Alternative Psychosis of Epilepsy Petersfield, UK Wrightson Biomedical 1998 7 24 \n15 Mula M Trimble MR Sander JW Are psychiatric adverse events of antiepileptic drugs a unique entity? A study of topiramate and levetiracetam Epilepsia 2007 48 2322 2326 17711462 \n16 Amir N Gross-Tsur V Paradoxical normalization in childhood epilepsy Epilepsia 1994 35 1060 1064 7925152 \n17 Krishnamoorthy ES Trimble MR Forced normalization: clinical and therapeutic relevance Epilepsia 1999 40 10 57 64 \n18 Krishnamoorthy ES Trimble MR Sander JW Kannerc AM Controversies in epilepsy and behavior: forced normalization at the interface between epilepsy and psychiatry Epilepsy Behav 2002 3 303 308 12609326 \n19 Ignatenco A Arzy S Ghika J Nonepileptic seizures under levetiracetam therapy Epilepsy Behav 2010 19 526 527 20934390 \n20 Berg AT Berkovic SF Brodie MJ Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009 Epilepsia 2010 51 676 685 20196795 \n21 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders fourth edition American Psychiatric Press Washington, DC, USA 1994 \n22 Chung SS Gerber P Kirlin KA Ictal eye closure is a reliable indicator of psychogenic nonepileptic seizures Neurology 2006 66 1730 1731 16769949 \n23 DeToledo JC Ramsay RE Patterns of involvement of facial muscles during epileptic and nonepileptic events: review of 654 events Neurology 1996 47 621 625 8797454 \n24 Vossler DG Haltiner AM Schepp SK Ictal stuttering: a sign suggestive of psychogenic nonepileptic seizures Neurology 2004 63 516 519 15304584 \n25 Anzellotti F Franciotti R Bonanni L Persistent genital arousal disorder associated with functional hyperconnectivity of an epileptic focus Neuroscience 2010 167 88 96 20144694 \n26 Avbersek A Sisodiya S Does the primary literature provide support for clinical signs used to distinguish psychogenic nonepileptic seizures from epileptic seizures? J Neurol Neurosurg Psychiatry 2010 81 719 725 20581136 \n27 Gowers WR Epilepsy and Other Chronic Diseases New York William Wood 1885 \n28 Havens LL Charcot and hysteria J Nerv Ment Dis 1965 141 505 516 \n29 Stone J LaFrance WC Jr Brown R Spiegel D Levenson JL Sharpe M Conversion disorder: current problems and potential solutions for DSM-5 J Psychosom Res 2011 71 369 376 22118377 \n30 Helmstaedter C Fritz NE Kockelmann E Kosanetzky N Elger CE Positive and negative psychotropic effects of levetiracetam Epilepsy Behav 2008 13 535 541 18583196 \n31 Wolf P Acute behavioral symptomatology at disappearance of epileptiform EEG abnormality. Paradoxical or “forced” normalization Adv Neurol 1991 55 127 142 2003402 \n32 Bob P Dissociation, forced normalization and dynamic multi-stability of the brain Neuro Endocrinol Lett 2007 28 231 246 17627254 \n33 Trimble MR New antiepileptic drugs and psychopathology Neuropsychobiology 1998 38 149 151 9778603 \n34 van der Kruijs SJ Bodde NM Vaessen MJ Functional connectivity of dissociation in patients with psychogenic non-epileptic seizures J Neurol Neurosurg Psychiatry 2012 83 239 247 22056967\n\n",
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"keywords": "behavioral side effects; forced normalization; levetiracetam; nonepileptic seizures",
"medline_ta": "Neuropsychiatr Dis Treat",
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"title": "Nonepileptic seizures under levetiracetam therapy: a case report of forced normalization process.",
"title_normalized": "nonepileptic seizures under levetiracetam therapy a case report of forced normalization process"
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"abstract": "OBJECTIVE\nSpontaneous spinal epidural haematomas (SSEH) are rare nosological units wherein acute collections of blood develop in the spinal canal. SSEH are usually manifested by sudden severe back pain accompanied by the development of neurological symptoms. In this study, we retrospectively describe management and the main risk factors of SSEH in a series of 14 cases.\n\n\nMETHODS\nBetween 2010 and 2019, we examined 14 patients (age range 17-89 years, 10 women) diagnosed with SSEH. Eight cases were patients using anticoagulant therapies (six warfarin, one dabigatran, one apixaban) and two others were using ASA of 100 mg/day. The exact localisation and extent of changes was determined from acute magnetic resonance imaging. Three people using warfarin had INR values higher than 3.0 at the time of their diagnosis.\n\n\nRESULTS\nTen patients (71%) were taking oral anticoagulants or antiplatelet agents. In seven patients, SSEH were localised in the lower cervical/thoracic spine. Ten patients (71%) had arterial hypertension. Six patients underwent acute surgery due to rapidly developing spinal cord compression. Eight patients (57%) with slight or mild neurological symptoms were successfully managed without surgery.\n\n\nCONCLUSIONS\nSSEH should be suspected in any patient receiving anticoagulant/antiplatelet agents who complains of sudden, severe back pain accompanied by neurological symptoms. SSEH is mostly localised in the lower cervical/thoracic spine. Arterial hypertension appears to be a risk factor of SSEH. Early decompression is an important therapeutic approach; in cases with minor neurological deficits, conservative treatment may be chosen.",
"affiliations": "Department of Neurology, Third Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady, Czech Republic, Srobarova 50, 100 34 Prague 10, Czech Republic. [email protected].;Neurological Department, Faculty of Health Studies, Pardubice University and Pardubice Regional Hospital, Pardubice, Czech Republic.;Department of Neurology, Third Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady, Czech Republic, Srobarova 50, 100 34 Prague 10, Czech Republic.;Department of Neurology, Third Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady, Czech Republic, Srobarova 50, 100 34 Prague 10, Czech Republic.;Department of Neurology, Third Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady, Czech Republic, Srobarova 50, 100 34 Prague 10, Czech Republic.;Department of Radiology, Third Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic.;Department of Radiology, Faculty of Health Studies, Pardubice University and Pardubice Regional Hospital, Pardubice, Czech Republic.;Department of Neurology, Third Faculty of Medicine, Charles University and Faculty Hospital Kralovske Vinohrady, Czech Republic, Srobarova 50, 100 34 Prague 10, Czech Republic.",
"authors": "Stetkarova|Ivana|I|0000-0003-2699-1124;Ehler|Edvard|E|;Brabec|Karel|K|;Jelinkova|Lenka|L|;Chylova|Miroslava|M|;Weichet|Jiri|J|;Ungermann|Leos|L|;Peisker|Tomas|T|",
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"journal": "Neurologia i neurochirurgia polska",
"keywords": "anticoagulant therapy; spinal cord compression; spontaneous spinal epidural haematoma; surgical and non-surgical management; warfarin",
"medline_ta": "Neurol Neurochir Pol",
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"pmid": "34637134",
"pubdate": "2021-10-12",
"publication_types": "D016428:Journal Article",
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"title": "Spontaneous spinal epidural haematoma: management and main risk factors in era of anticoagulant / antiplatelet treatment.",
"title_normalized": "spontaneous spinal epidural haematoma management and main risk factors in era of anticoagulant antiplatelet treatment"
}
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{
"abstract": "The use of anti-tumor necrosis factor-a (TNF-a) therapies has led to improved outcomes in the treatment of rheumatoid arthritis (RA). However, the use of these new therapeutic agents requires careful monitoring for adverse effects. We describe 3 patients who developed neurological disease closely associated with the use of infliximab, a monoclonal antibody that binds to and inactivates TNF-a. All had evidence of polyneuropathy, demyelinating in one and axonal in 2. One patient had a central nervous system syndrome. Physicians should be aware of these potential adverse effects when treating patients with infliximab.",
"affiliations": "Department of Medicine, University of Calgary, Calgary, Alberta T2N 4NI.",
"authors": "Jarand|Julie|J|;Zochodne|Douglas W|DW|;Martin|Liam O|LO|;Voll|Christopher|C|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "33(5)",
"journal": "The Journal of rheumatology",
"keywords": null,
"medline_ta": "J Rheumatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003711:Demyelinating Diseases; D005260:Female; D006801:Humans; D000069285:Infliximab; D008875:Middle Aged; D009420:Nervous System; D011115:Polyneuropathies",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "1018-20",
"pmc": null,
"pmid": "16511935",
"pubdate": "2006-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neurological complications of infliximab.",
"title_normalized": "neurological complications of infliximab"
}
|
[
{
"companynumb": "CA-CELLTRION INC.-2017CA001546",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
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}
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"reaction": [
{
"reactionmeddrapt": "Polyneuropathy",
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},
{
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"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Hypoaesthesia",
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"reactionoutcome": "2"
}
],
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},
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"literaturereference": "JARAND, J.. NEUROLOGICAL COMPLICATIONS OF INFLIXIMAB. JOURNAL OF RHEUMATOLOGY. 2006;33 (5):1018-1020",
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},
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},
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] |
{
"abstract": "Children treated for retinoblastoma with carboplatin have an increased risk for ototoxicity. Impaired hearing may have major consequences for these children, because they often suffer from reduced vision. Previous studies have shown limited information on the incidence and severity of carboplatin-induced ototoxicity and the used audiologic methods. The frequency of audiological testing is often limited and the audiologic follow-up time is relatively short.\n\n\n\nThe aim of this study was to determine the long-term effects of carboplatin ototoxicity in children with retinoblastoma.\n\n\n\nIn this retrospective non-randomized single center cohort study, we reviewed audiologic results of 25 patients. Experienced audiologists analyzed the pure-tone audiograms.\n\n\n\nAll patients had normal hearing prior to therapy and had a mean age of 11 months at first carboplatin administration. The mean audiologic follow-up was 12.0 years with a median of 11.6 (IQR 4.8) years. Three patients were excluded: two passed away and one could not participate in the audiologic tests. One of the 22 included patients developed sustained low-grade bilateral high-frequency hearing loss between 2 and 7 years after the last carboplatin dose. In one patient it was not possible to make a reliable conclusion due to a conductive hearing loss component. Twenty patients had normal hearing.\n\n\n\nWe observed no clear effect between carboplatin administration in young children and clinical significant ototoxicity in the long term. One child showed low-grade bilateral high-frequency hearing loss.",
"affiliations": "a Department of Pediatric Oncology , VU University Medical Center , Amsterdam , The Netherlands.;a Department of Pediatric Oncology , VU University Medical Center , Amsterdam , The Netherlands.;b Department of Ophthalmology , VU University Medical Center , Amsterdam , The Netherlands.;c Department of Otolaryngology, Head and Neck Surgery, Section of Ear & Hearing , and EMGO Institute for Health Care Research, VU University Medical Center , Amsterdam , The Netherlands.",
"authors": "Geurtsen|Madelon L|ML|;Kors|Wijnanda A|WA|;Moll|Annette C|AC|;Smits|Cas|C|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.3109/13816810.2015.1137325",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1381-6810",
"issue": "38(1)",
"journal": "Ophthalmic genetics",
"keywords": "Audiometry; carboplatin; hearing; ototoxicity; retinoblastoma",
"medline_ta": "Ophthalmic Genet",
"mesh_terms": "D000970:Antineoplastic Agents; D001301:Audiometry, Pure-Tone; D016190:Carboplatin; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006319:Hearing Loss, Sensorineural; D006801:Humans; D007223:Infant; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies",
"nlm_unique_id": "9436057",
"other_id": null,
"pages": "74-78",
"pmc": null,
"pmid": "27050825",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term audiologic follow-up of carboplatin-treated children with retinoblastoma.",
"title_normalized": "long term audiologic follow up of carboplatin treated children with retinoblastoma"
}
|
[
{
"companynumb": "NL-TEVA-751078ROM",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
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"drugindication": "CONGENITAL RETINOBLASTOMA",
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"medicinalproduct": "CARBOPLATIN."
}
],
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"reaction": [
{
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}
],
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},
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"literaturereference": "GEURTSEN M,KORS W,MOLL A,SMITS C. LONG-TERM AUDIOLOGIC FOLLOW-UP OF CARBOPLATIN-TREATED CHILDREN WITH RETINOBLASTOMA. OPHTHALM-GENET. 2017 JAN 01;38(1):74-78.",
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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": [
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},
{
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}
],
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},
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},
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{
"abstract": "Ganciclovir and its prodrug valganciclovir are elective treatments for cCMV. Neonates with important symptoms undergo 6 months of therapy to ameliorate/prevent symptoms and late sequelae, but evidence of resistance is emerging. Over the last 5 years, we took care of 59 cCMV infants and experienced two cases of resistance among nine cCMV infants receiving long-term valganciclovir therapy. In the first case, valganciclovir therapy was prolonged beyond 6 months due to severity of symptoms, control of viral load, and absence of adverse events. Resistance was detected in the 8th month of therapy. In the second case, after a significant reduction following valganciclovir administration and no adverse events, CMV viral load suddenly increased in the 6th month of therapy due to resistance. Both events were associated with UL97 gene mutation. The cCMV infants, affected by severe symptoms, remained in a steady state during treatment, and their later neurological development was coherent with initial seriousness of diagnosis. Prolonged therapeutic exposure may therefore be a risk for resistance, suggesting that constant dosage/weight adjustments, monthly surveillance of viral load, and therapeutic drug monitoring could be proposed to monitor resistance onset and optimize the therapy regime. The risk-benefit ratio for long-term therapy, including the possibility of resistance onset, alongside SNHL and neurodevelopmental improvement, should also be evaluated.",
"affiliations": "Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address: [email protected].;Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Neonatal Unit and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Italy.",
"authors": "Garofoli|Francesca|F|;Lombardi|Giuseppina|G|;Angelini|Micol|M|;Campanini|Giulia|G|;Zavattoni|Maurizio|M|;Baldanti|Fausto|F|",
"chemical_list": "D000998:Antiviral Agents; D000077562:Valganciclovir; D015774:Ganciclovir",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2020.06.087",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "98()",
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"keywords": "Congenital cytomegalovirus; Long-term therapy; Resistance",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D024882:Drug Resistance, Viral; D005260:Female; D015774:Ganciclovir; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D008297:Male; D009154:Mutation; D000077562:Valganciclovir; D019562:Viral Load",
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"pmid": "32615325",
"pubdate": "2020-09",
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"title": "Onset of valganciclovir resistance in two infants with congenital cytomegalovirus infection.",
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"abstract": "This postmarketing study aims to evaluate the safety and effectiveness of oral administration of risedronate at 75 mg once monthly for 36 months in patients with osteoporosis in Japan.\nParticipants were ambulatory outpatients with osteoporosis who were ≥ 50 years old and had prevalent vertebral fractures. Outcomes were the incidence rate of adverse drug reaction (ADR), cumulative incidence of vertebral, nonvertebral, and hip fractures, the percent changes of lumbar spinal L2-4 bone mineral density (BMD), and low back pain. In addition, medication compliance was examined.\nSafety, vertebral fractures, and other outcomes were analyzed in 542, 328, and 535 patients, respectively. In the safety analysis set, 88.38% of the patients were women and the mean age was 75.9 years. The monthly medication compliance rate ranged from 83.24% to 95.38%. The incidence rate of ADRs, including 4 severe ADRs, was 10.52% (n = 57). The common ADRs were gastrointestinal disorders, musculoskeletal, and connective tissue disorders. No osteonecrosis of the jaw was reported. The cumulative incidences (95% CI) of vertebral, nonvertebral, and hip fractures at 36 months were 12.58% (8.61-18.18), 6.59% (4.31-10.01), and 1.58% (0.64-3.88), respectively. The L2-4 BMD increased by 10.59% compared with baseline value (P < 0.01), and the proportion of patients with low back pain decreased to 30.77%, at 36 months.\nAdministering 75 mg of risedronate once a month remains a favorable compliance rate and may be useful for the treatment of patients, even the elderly, with osteoporosis in daily practice.",
"affiliations": "Soen Orthopaedics, Osteoporosis and Rheumatology Clinic, Kobe, Japan.;Post-Marketing Medical Research Group, Medical Department, EA Pharma Co., Ltd., Tokyo, Japan.;Post-Marketing Medical Research Group, Medical Department, EA Pharma Co., Ltd., Tokyo, Japan.;Clinical Development Department, Data Science Group, EA Pharma Co., Ltd., Tokyo, Japan.;Clinical Planning Department, Medical HQs, Eisai Co., Ltd., Tokyo, Japan.;Clinical Planning Department, Medical HQs, Eisai Co., Ltd., Tokyo, Japan.",
"authors": "Soen|Satoshi|S|;Arai|Yuki|Y|;Matsuda|Saori|S|;Emori|Kento|K|;Ikezaki|Toshimi|T|;Osawa|Mitsuharu|M|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.afos.2020.11.002",
"fulltext": "\n==== Front\nOsteoporos Sarcopenia\nOsteoporos Sarcopenia\nOsteoporosis and Sarcopenia\n2405-5255 2405-5263 Korean Society of Osteoporosis \n\nS2405-5255(20)30102-3\n10.1016/j.afos.2020.11.002\nOriginal Article\nA 3-year postmarketing study on the safety and effectiveness of once-monthly risedronate in Japanese patients with osteoporosis\nSoen Satoshi [email protected]∗ Arai Yuki b Matsuda Saori b Emori Kento c Ikezaki Toshimi d Osawa Mitsuharu d a Soen Orthopaedics, Osteoporosis and Rheumatology Clinic, Kobe, Japan\nb Post-Marketing Medical Research Group, Medical Department, EA Pharma Co., Ltd., Tokyo, Japan\nc Clinical Development Department, Data Science Group, EA Pharma Co., Ltd., Tokyo, Japan\nd Clinical Planning Department, Medical HQs, Eisai Co., Ltd., Tokyo, Japan\n∗ Corresponding author. Soen Orthopaedics, Osteoporosis and Rheumatology Clinic, 2-14-10 Okamoto, Higashinada-ku, Kobe, Hyogo, 658-0072, Japan. [email protected]\n19 11 2020 \n12 2020 \n19 11 2020 \n6 4 191 198\n6 8 2020 14 10 2020 6 11 2020 © 2020 The Korean Society of Osteoporosis. Publishing services by Elsevier B.V.2020The Korean Society of OsteoporosisThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objectives\nThis postmarketing study aims to evaluate the safety and effectiveness of oral administration of risedronate at 75 mg once monthly for 36 months in patients with osteoporosis in Japan.\n\nMethods\nParticipants were ambulatory outpatients with osteoporosis who were ≥ 50 years old and had prevalent vertebral fractures. Outcomes were the incidence rate of adverse drug reaction (ADR), cumulative incidence of vertebral, nonvertebral, and hip fractures, the percent changes of lumbar spinal L2–4 bone mineral density (BMD), and low back pain. In addition, medication compliance was examined.\n\nResults\nSafety, vertebral fractures, and other outcomes were analyzed in 542, 328, and 535 patients, respectively. In the safety analysis set, 88.38% of the patients were women and the mean age was 75.9 years. The monthly medication compliance rate ranged from 83.24% to 95.38%. The incidence rate of ADRs, including 4 severe ADRs, was 10.52% (n = 57). The common ADRs were gastrointestinal disorders, musculoskeletal, and connective tissue disorders. No osteonecrosis of the jaw was reported. The cumulative incidences (95% CI) of vertebral, nonvertebral, and hip fractures at 36 months were 12.58% (8.61–18.18), 6.59% (4.31–10.01), and 1.58% (0.64–3.88), respectively. The L2–4 BMD increased by 10.59% compared with baseline value (P < 0.01), and the proportion of patients with low back pain decreased to 30.77%, at 36 months.\n\nConclusions\nAdministering 75 mg of risedronate once a month remains a favorable compliance rate and may be useful for the treatment of patients, even the elderly, with osteoporosis in daily practice.\n\nKeywords\nOnce-monthly risedronatePostmarketing surveyOsteoporosisMedication complianceVertebral fractureLow back pain\n==== Body\n1 Introduction\nOsteoporosis is not merely a bone aging phenomenon but a disease that requires prevention and treatment [1]. In Japan, the number of patients with osteoporosis in 2005 was approximately 13 million [2], which has been increasing annually because of the rapid aging of the population. Therefore, osteoporosis treatment for these patients is important. The primary symptom of a vertebral fracture developing in patients with osteoporosis is lower back or back pain during body movement, resulting in a decrease in activities of daily living. Consequently, bones and muscles weaken, inducing new fractures and pain and further lowering the quality of life (QOL). Considering that mortality increases with the number of vertebral fractures, accumulation of vertebral fractures is regarded as a life-threatening factor [3].\n\nRisedronate is classified as a third-generation bisphosphonate based on its structure with a pyridinyl group in the side chain; it suppresses bone turnover by strongly inhibiting bone resorption [4]. Since the first international launch of risedronate in 1998, it has been used long for patients with osteoporosis in various countries, including Japan. Risedronate has 3 formulations, namely, 2.5-mg once-daily formulation, 17.5-mg once-weekly formulation, and 75-mg once-monthly formulation in Japan. These formulations improve the bone density, bone metabolism markers, and QOL of patients with osteoporosis. With regard to bone fractures, a 96-week clinical trial in Japan reported that its 2.5-mg once-daily formulation of risedronate had a noninferior efficacy in new bone fractures compared with the formulation of etidronate [5]. In a previous study on Japanese patients with osteoporosis, the incidence of hip fractures on the unaffected side at 36 months was significantly lower in the risedronate group than in the control group (calcium, vitamin D3, vitamin K2, and calcitonin preparation or no treatment) [6]. Two overseas large-scale clinical studies also reported that 5-mg once-daily formulation of risedronate decreased the cumulative incidence of new vertebral fractures by 41% [7] and reduced the risk of new vertebral fractures by 49% [8] over 3 years in comparison with a placebo. The manufacturing and marketing of the 75-mg once-monthly formulation of risedronate was approved in Japan in December 2012. In terms of bone mineral density (BMD) and cumulative incidence of vertebral fracture at the end of a 1-year study, this formulation had a comparable efficacy compared with the 2.5-mg once-daily formulation of risedronate [9]. Hence, the fracture-preventing effect of risedronate was confirmed, and the 3 formulations of this drug were found to have similar efficacies. However, the overall compliance rate of daily bisphosphonate was reported to decrease to nearly half 1 year after the initial dose in daily practice in Japan [10] and overseas [11]. Moreover, patient compliance to the treatment regimen is extremely important among individuals with osteoporosis [[12], [13], [14], [15]]. Therefore, the efficacy of long-term treatment with once-monthly risedronate in actual practice remains unclear.\n\nWe have completed a 3-year nationwide postmarketing study to investigate its safety and effectiveness, including vertebral fracture risk assessment, in the actual clinical practice. Here, we report the results of the study.\n\n2 Methods\n2.1 Study design and subjects\nThis prospective, longitudinal, 3-year observational study focuses on the effectiveness and safety of 75-mg once-monthly formulation of risedronate in patients with osteoporosis registered through the central registration across Japan. The registration period was from May 2013 to October 2014, and this study was finished in April 2018. This study was performed in accordance with the Japanese Good Postmarketing Study Practice ordinance provided by the Ministry of Health, Labour, and Welfare of the Japanese government. In accordance with these regulations, the need for informed consent from patients was waived. This study was registered in the JAPIC clinical trials registry (JapicCTI-142479).\n\nEligible subjects were ambulatory outpatients with osteoporosis according to the Diagnostic Criteria for Primary Osteoporosis of the Japanese Society for Bone and Mineral Research [16]. The subjects had 1–4 prevalent baseline (within 3 months prior to the first prescription) fractures in the fourth thoracic spine–fourth lumbar spine (T4–L4) detected radiographically and were aged ≥ 50 years (women had to be in their postmenopausal stage). All subjects were orally administered with 75 mg of risedronate once every month (Actonel® tablet; EA Pharma Co., Ltd., Tokyo, Japan; or Benet® tablet; Takeda Pharmaceutical Company Limited, Osaka, Japan) and observed for 3 years. Patients who had already been treated with such risedronate formulation (75 mg once in a month) at the time of registration, those registered > 15 days after the first prescription date or outside the registration period, or those who had no information on adverse event status were excluded from analysis. During the observation period, the incidence of vertebral fractures was evaluated by spinal radiography at baseline and every 6 months up to 36 months. We also assessed the lumbar spine L2–4 BMD and bone metabolism markers such as serum tartrate-resistant acid phosphatase 5b (TRACP-5b) and type I procollagen-N-propeptide (P1NP), and urinary type I collagen cross-linked N-telopeptide (u-NTX), at baseline and at 3, 6, 12, 18, 24, 30, and 36 months. BMD was measured by dual-energy X-ray absorptiometry. We collected data on baseline characteristics such as sex, age, weight, diagnosis, complications, risk factors for bone fractures, and other current osteoporosis drug use.\n\n2.2 Outcomes\nThe clinical outcomes were incidence of adverse drug reactions (ADRs); the cumulative incidences (ie, incidence proportion) of vertebral, nonvertebral (including hip), and hip fractures; changes in L2–4 BMD and bone metabolism markers; and the proportion of patients with low back pain. Medication compliance rate was also assessed. Meanwhile, the data of patients who dropped out was evaluated up to the day of dropout.\n\nWith regard to safety, we assessed for any presence of ADRs, which we defined as any adverse event for which a causal relationship with risedronate could not be ruled out. Adverse events were coded according to the Medical Dictionary for Regulatory Activities terminology (Japanese, version 21.0).\n\nWe defined a vertebral fracture as any new fractures or worsening of a prevalent fracture confirmed on spinal radiography according to the justification criteria for vertebral fractures [17]. A new vertebral fracture occurred if the ratio of the central vertebral height (C) to the anterior vertebral height (A) or C to posterior vertebral height (P) was less than 0.8, the ratio of A to P was less than 0.75, or if A, C, and P all decreased at least 20% from the height of the upper or lower vertebral body. A prevalent vertebral fracture worsened if C/A, C/P, or A/P decreased by 20% or more from the baseline. For the standardization of the evaluations, a summary protocol indicating how to evaluate vertebral fractures was distributed to each institution, and radiographic assessments were performed by attending physicians in accordance with the protocol.\n\nIn terms of nonvertebral and hip fractures, we radiographically evaluated patients with suspected fractures and confirmed its diagnosis. Percent changes from baseline in L2–4 BMD and bone metabolism markers were calculated at each evaluation timepoint.\n\nTo determine the presence of low back pain and the medication compliance rate during the observation period, we interviewed the patients and asked whether they had low back pain and took risedronate on the scheduled days. We defined the compliance rate as the proportion of the behavior of taking the drug on the scheduled day as per the prescription.\n\n2.3 Statistical analysis\nA sample size of 500 patients was determined for the evaluation of the cumulative incidence of vertebral fractures, assuming a dropout rate of 50% because the dropout of the past clinical study on 2.5 mg of risedronate for 2 years resulted in 26.7%. Safety was assessed using a safety analysis set on patients who took 1 or more doses of the drug and was registered as per protocol. Furthermore, an efficacy analysis set included patients whose any efficacy data were available, whereas a vertebral fracture analysis set included patients who had 1 to 4 baseline vertebral fractures.\n\nThe incidence proportion of vertebral fractures was estimated using the Kaplan–Meier method, and a two-sided 95% confidence interval was calculated. In this analysis, patients who did not visit or switch to other drugs were considered discontinued and were treated as censored at the time of the last visit. Patients were also censored at the time of the first vertebral fracture. Likewise, in terms of nonvertebral and hip fracture analyses, patients with confirmed fractures were censored at the time of the first fracture. Percent changes from baseline in L2–4 BMD and bone metabolism markers were assessed with a paired t-test. These data were analyzed by SAS 9.2 (SAS Institute Inc., Cary, NC, USA). A value of P < 0.05 indicates statistical significance.\n\n3 Results\n3.1 Subject baseline characteristics\nA total of 579 patients were registered at 148 sites, and 572 case reports were collected. We excluded 30 patients because of no treatment with the study drug (15 patients), no report on safety data (1 patient), or registration violation (15 patients) such as registration > 15 days after the first prescription date. Ultimately, 542 patients were included in the safety analysis set. Furthermore, 535 patients were included in the efficacy analysis, and 328 of them who had 1 to 4 confirmed baseline vertebral fractures based on the evaluable radiographic data before the start of treatment were included in the vertebral fracture analysis set (Supplemental Fig. 1).\n\nTable 1 summarizes the baseline characteristics of the safety analysis set and the vertebral fracture analysis set. In the safety analysis set, 88.38% of patients were women, the mean age was 75.9 years, and the mean body mass index was 22.81 kg/m2. Primary osteoporosis was present in 88.75% of patients. The common risk factors for fractures were history of steroid use (6.46%) and drinking habit (4.98%). The mean duration of disease was 1.5 years. Osteoporosis drugs were concomitantly used by 46.13% patients, especially active vitamin D3 preparations 39.30%. The vertebral fracture analysis set had similar baseline characteristics.Table 1 Baseline characteristics.\n\nTable 1Variable\tSafety analysis set (n = 542)\tVertebral fracture analysis set (n = 328)\t\nCharacteristic\tNumber of patients\tPercentage or mean ± SD\tNumber of patients\tPercentage or mean ± SD\t\nSex\t\t\t\t\t\n\tFemale\t479\t88.38%\t288\t87.80%\t\n\tMale\t63\t11.62%\t40\t12.20%\t\nAge, yr\t541\t75.9 ± 8.0\t328\t75.6 ± 8.3\t\n\t< 65\t50\t9.23%\t33\t10.06%\t\n\t65– < 75\t172\t31.73%\t113\t34.45%\t\n\t≥ 75\t319\t58.86%\t182\t55.49%\t\n\tUnknowna\t1\t0.18%\t0\t0.00%\t\nWeight, kg\t348\t50.37 ± 11.79\t224\t50.49 ± 11.30\t\nHeight, cm\t304\t148.65 ± 7.88\t203\t149.05 ± 7.12\t\nBody mass index, kg/m2\t277\t22.81 ± 4.81\t184\t22.80 ± 4.18\t\nDiagnosis\t\t\t\t\t\n\tPrimary\t481\t88.75%\t295\t89.94%\t\n\tSecondary\t28\t5.17%\t17\t5.18%\t\n\tUnknown\t33\t6.09%\t16\t4.88%\t\nRisk factors for fracture\t\t\t\t\t\n\tParent fractured hip\t5\t0.92%\t5\t1.52%\t\n\tHistory of steroid use\t35\t6.46%\t23\t7.01%\t\n\tDrinking habit\t27\t4.98%\t21\t6.40%\t\n\tCurrent smoker\t22\t4.06%\t13\t3.96%\t\nDuration of disease, yr\t462\t1.5 ± 2.8\t274\t1.5 ± 3.0\t\nComplications\t453\t83.58%\t273\t83.23%\t\nMedical history\t111\t20.48%\t76\t23.17%\t\nPrior use of osteoporosis drugs\t201\t37.08%\t128\t39.02%\t\n Risedronate\t15\t2.77%\t10\t3.05%\t\n Bisphosphonate other than risedronate\t16\t2.95%\t10\t3.05%\t\n Calcium preparation\t16\t2.95%\t12\t3.66%\t\n Active vitamin D3\t143\t26.38%\t87\t26.52%\t\n Parathyroid hormone\t2\t0.37%\t1\t0.30%\t\nConcomitant use of drugs\t452\t83.39%\t277\t84.45%\t\n Osteoporosis drugs\t250\t46.13%\t160\t48.78%\t\n Calcium preparation\t24\t4.43%\t19\t5.79%\t\n Active vitamin D3\t213\t39.30%\t131\t39.94%\t\n Parathyroid hormone\t2\t0.37%\t2\t0.61%\t\n Anti-inflammatory analgesics\t233\t42.99%\t134\t40.85%\t\n Cardiovascular medicine\t154\t28.41%\t111\t33.84%\t\n Central nervous system medicine\t90\t16.61%\t56\t17.07%\t\n Antidiabetic drugs\t25\t4.61%\t21\t6.40%\t\n Digestive medicine\t204\t37.64%\t131\t39.94%\t\n Others\t203\t37.45%\t127\t38.72%\t\n Steroid\t33\t6.09%\t25\t7.62%\t\nPhysiotherapy\t178\t32.84%\t118\t35.98%\t\nValues are presented as mean ± standard deviation or number (%).\n\nSD, standard deviation.\n\na The first prescription date to define the age was missing.\n\n\n\n3.2 Medication compliance\nConsidering that 1 patient of the safety analysis set had no record of the first administration date of the drug, the 541 remaining patients were analyzed. During the observation period, the proportion of patients who took risedronate on the scheduled day (compliance rate) was 83.24%–95.38% at each month (Fig. 1). The median of dosing interval was 30.0–31.0 days [quartile (Q) 1, 28.0–30.0 days and Q3, 31.0 days]. On the other hand, a very small proportion of patients who did not take risedronate was observed at each month.Fig. 1 Change in compliance status of patients to treatment with 75-mg once-monthly formulation of risedronate for 36 months. ∗One patient from the safety analysis set was excluded from analysis because of lack of the first administration date.\n\nFig. 1\n\n3.3 Safety\nAmong the 542 patients, 57 (10.52%) had 81 ADRs (Table 2). Common ADRs (≥ 3) were gastrointestinal disorders such as nausea, abdominal pain upper, diarrhea, abdominal discomfort, and dyspepsia; musculoskeletal and connective tissue disorders such as back pain and arthralgia; pyrexia; and spinal compression fracture. However, no thigh pain or osteonecrosis of the jaw was reported.Table 2 Adverse drug reactions.\n\nTable 2\t\tn\t(%)\t\t\t\nNumber of all the patients\t542\t\t\t\t\nNumber of patients with ADRs\t57\t(10.52)\t\t\t\nNumber of incidence of ADRs\t81\t\t\t\t\nNumber of patients with serious ADRs\n\t4\t(0.74)\t\t\t\nNumber of incidence of serious ADRs\t4\t\t\t\t\n\t\tCommon ADRs\tSerious ADRs\t\n\t\tn\t(%)\tn\t(%)\t\nGastrointestinal disorders\t\t\t\t\t\n\tNausea\t7\t(1.29)\t\t\t\n\tAbdominal pain upper\t5\t(0.92)\t\t\t\n\tDiarrhea\t4\t(0.74)\t\t\t\n\tAbdominal discomfort\t3\t(0.55)\t\t\t\n\tDyspepsia\t3\t(0.55)\t\t\t\n\tTooth ache\t\t\t1\t(0.18)\t\nMusculoskeletal and connective tissue disorders\t\t\t\t\t\n\tArthralgia\t3\t(0.55)\t\t\t\n\tBack pain\t5\t(0.92)\t\t\t\n\tOsteonecrosis\t\t\t1\t(0.18)\t\nGeneral disorders and administration site conditions\t\t\t\t\t\n\tPyrexia\t3\t(0.55)\t\t\t\nInjury, poisoning and procedural complications\t\t\t\t\t\n\tSpinal compression fracture\t4\t(0.74)\t\t\t\n\tFemur fracture\t\t\t1\t(0.18)\t\nSurgical and medical procedures\t\t\t\t\t\n\tHospitalization\t\t\t1\t(0.18)\t\nValues are presented as number (%).\n\nADRs, adverse drug reactions.\n\nCommon ADRs (≥ 3) and serious ADRs are presented.\n\n\n\nFour patients (0.74%) had serious ADRs, which included toothache, osteonecrosis, femur fracture, and hospitalization (one each). The toothache occurred in a 68-year-old woman approximately 11 months after the treatment with the drug (12 doses). A causal relationship between the event and the drug could not be assessed because she did not visit the hospital thereafter. The osteonecrosis occurred at the medial condyle of the left femur of a 73-year-old man administered with the drug for approximately 2 years and 3 months. He recovered after discontinuation of the drug. A femur fracture occurred at the neck of femur in an 83-year-old woman approximately 9 months after the treatment with the drug. However, factors other than the drug may also be related to the events because she had a proximal femur with a low mineral density prior to the start of treatment, suffered from comorbid diseases such as diabetes and osteoarthritis, and sustained a fall before the event. Furthermore, hospitalization was reported in an 83-year-old woman who was, however, admitted to another department with unknown reason.\n\n3.4 Bone fracture\nIn the vertebral fracture analysis set of 328 patients, 196 (59.76%) had one basal fracture, 86 (26.22%) had two, 31 (9.45%) had three, and 15 (4.57%) had four. The mean (SD) number of vertebral fractures at the baseline was 1.6 (0.8).\n\nFour patients in the vertebral fracture analysis set had no radiographic data at the same site at the baseline; consequently, the remaining patients (n = 324) were assessed (Fig. 2A). A total of 29 fractures were reported. The cumulative incidence of vertebral fractures was 7.35% (95% CI: 4.85–11.06) at 12 months, 8.82% (95% CI: 5.97–12.93) at 24 months, and 12.58% (95% CI: 8.61–18.18) at 36 months.Fig. 2 Cumulative incidence of vertebral (A), nonvertebral (B), and hip fractures (C).\n\n+, censored; NAR, number at risk.\n\nFig. 2\n\nIn total, 535 patients were assessed and 22 nonvertebral fractures (including 5 hip fractures) and 5 hip fractures were recorded within 36 months. The cumulative incidences of nonvertebral and hip fractures were 6.59% (95% CI: 4.31–10.01) and 1.58% (95% CI: 0.64–3.88), respectively (Fig. 2B and C).\n\n3.5 BMD and bone turnover markers\nAt the baseline, the mean (SD) value of L2–4 BMD in the efficacy analysis set was 0.8149 (0.1668) g/cm2, which gradually and significantly increased at any evaluation timepoint (Fig. 3A). At the baseline, the mean (SD) values of TRACP-5b, P1NP, and u-NTX were 442.19 (180.25) mU/dL, 56.594 (20.611) μg/L, and 70.41 (83.44) nmol BCE/mmol Cr, respectively. The values of these markers subsequently decreased during the observation period (Fig. 3B, C, and D).Fig. 3 Time-course changes in L2–4 BMD (A), serum TRACP-5b (B), serum P1NP (C), and urinary NTX (D).\n\nMean ± SD. ∗P < 0.0001. L2–4 BMD, bone mineral density of the lumbar spine L2–4; LO, last observation; P1NP, type I procollagen-N-propeptide; TRACP-5b, tartrate-resistant acid phosphatase 5b; u-NTX, urinary type I collagen cross-linked N-telopeptide.\n\nFig. 3\n\n3.6 Low back pain\nIn the efficacy analysis set, 376 patients reported the presence or absence of low back pain at baseline. Among them, 285 complained of low back pain, 83 had no pain, and 8 were unclear. The proportion of patients with low back pain decreased gradually to 30.77% at 36 months (Fig. 4). In contrast, the proportion of patients without pain reached 51.50% at 6 months and increased to approximately 70% at 36 months.Fig. 4 Time course of the proportion of patients with low back pain.\n\nBL, baseline; M, month; LO, last observation.\n\nFig. 4\n\n4 Discussion\nIn this 3-year postmarketing survey among the patients with osteoporosis with prevalent vertebral fractures, half of the patients were aged ≥ 75 years, and most of the patients had complications, indicating that 75-mg once-monthly formulation of risedronate was prescribed to older patients in actual practice. The current study comprised of 63 (11.62%) male patients. The number of male patients included in this study was higher than that included in a phase 3 study [9]. However, the number was still extremely small. Hence, an analysis based on sex could not be performed. The compliance rate for this 75-mg formulation (once-monthly) of risedronate was high in actual clinical practice. Its safety profile was similar to that of the formulation of risedronate used in a previous study [9]. The effectiveness on the bone was demonstrated with an increase in BMD and decrease in bone turnover markers. The incidence proportion of vertebral fractures was 12.58% at 36 months, and the proportion of patients with low back pain gradually decreased to the end of the study.\n\nThe monthly compliance rate for 3 years ranged from 83.24% to 95.38%. Approximately 10% of the patients took risedronate on another day than scheduled. The possible causes of this event were forgetting to take medicines on the scheduled days and altered body conditions associated with age. However, only a small proportion of the patients in this study had not taken the drug. An excellent compliance rate has also been observed in the post-marketing studies for the once-daily and once-weekly formulations of risedronate [6,18]. On the other hand, in studies that investigated the adherence and persistence, half of the patients on once-daily formulation of bisphosphonates dropped out [10]. It has been reported that the once-weekly formulation improves the persistence rate when compared with the once-daily formulation [19], and that the once-monthly formulation is even better [20,21]. The persistence rate of monthly bisphosphonate was reported to be approximately 70% in Japanese patients [21]. Similarly, 70% of the patients in the present study continued the treatment for 1 year. A study reported that the main reason for selecting the monthly formulation and not the weekly formulation is the ease of following a treatment regimen for a longer time [22], thus indicating patient preference [23]. This observation should be related to the high compliance rate and persistence rate of the monthly formulation of risedronate. Hence, the compliance rate was favorable and the drug-taking rate was high, indicating that the clinical safety and efficacy profile of risedronate in this study may be compared with those in other clinical studies performed on patients with high adherence to the therapy.\n\nDuring a 3-year follow-up period, the incidence rate of ADRs associated with once-monthly risedronate was 10.52%, and it was lower than that of a 1-year phase 3 study of this formulation [24]. The types of ADRs in this study were similar to those of previous studies and surveys [9,18]. Four (0.74%) patients presented with serious ADRs, and none of the patients experienced osteonecrosis of the jaw. However, since long-term treatment with bisphosphonate preparations are commonly prescribed, attention must be paid to severe adverse events, including osteonecrosis of the jaw [[25], [26], [27], [28]].\n\nIn terms of efficacy, an increase in L2–4 BMD and decrease in bone metabolism markers were observed during the study period. These changes at 12 months, observed in this study, were comparable with those in a phase 3 study of this formulation [9] and a postmarketing study of once-weekly formulation for 3 years [18]. Therefore, the efficacy of 75-mg once-monthly formulation was confirmed in patients with osteoporosis who presented with prevalent vertebral fractures.\n\nPrevention of bone fracture is the most important outcome of the treatment of osteoporosis. The cumulative incidence of new vertebral fractures or exacerbations of prevalent vertebral fractures was 8.82% and 12.58% at months 24 and 36, respectively. A Japanese randomized double-blind study conducted in a similar, but slightly younger population, that is, patients with osteoporosis with 1–4 vertebral fractures, using the 2.5-mg once-daily formulation of risedronate obtained a cumulative incidence of 12.3% at approximately 24 months (week 96) [5]. A postmarketing survey of the 17.5-mg once-weekly formulation of risedronate demonstrated that the cumulative incidences at weeks 96 and 156 were 18.25% and 24.92%, respectively [18]. The cumulative incidence of hip fractures at 36 months was 1.58%. A previous study investigated the incidence of recurrent hip fracture among elderly Japanese women. The results showed that the cumulative incidence of this type of fracture at 36 months was lower in women taking the 2.5-mg once-daily formulation of risedronate (4.3%) than in controls (13.1%) [6]. Thus, the values in this study were similar to or lower than those in the previous study. However, a simple comparison of the bone fracture incidence rate cannot be conducted due to differences in target population and assessment methods.\n\nChronic low back pain associated with vertebral fractures is a common and serious consequence of osteoporosis that limits body function and negatively affects one’s QOL [29]. In the present study, approximately 80% of the patients had low back pain at baseline among those who had records about pain. The proportion of patients with such pain decreased gradually over the observation period; approximately 70% of patients no longer had low back pain at 36 months. Similar results were reported by previous studies using other anti-osteoporotic drugs [[30], [31], [32]]. The 2.5-mg once-daily formulation [33] and 17.5-mg once-weekly formulation [34] of risedronate demonstrated improvement in QOL using EQ-5D [35] in patients with osteoporosis. In general, osteoporosis pain is directly caused by a spinal compression fracture. Ohtori et al. reported that bone resorption due to osteoporosis may cause low back pain in menopausal women with osteoporosis despite the absence of vertebral fractures, and that the pain was lowered after treatment with bisphosphonate (risedronate) with reducing NTX levels [36]. Based on the results, they proposed another mechanism for pain, which involved neuropeptides such as substance P produced through osteoclast-generated tumor necrosis factor-α. Risedronate would have reduced pain by suppressing osteoclast activation. The mitigation of low back pain by the administration of 75 mg of risedronate may contribute to the improvement of patients’ QOL.\n\nHowever, this study has some limitations. This was an open-label surveillance with both investigators and the participants being aware of receiving risedronate, thereby possibly affecting the evaluation of safety and efficacy of the drugs being studied. This study is not a placebo-controlled randomized study; hence, the exact extent of risedronate contributing to the prevention of bone fractures in patients with osteoporosis remains unclear.\n\n5 Conclusions\nThis postmarketing survey revealed that administering 75 mg of risedronate once in a month remained a favorable compliance rate and may be useful for the treatment of patients, even the elderly, with osteoporosis in daily practice.\n\nCRediT author statement\nSatoshi Soen: Supervision, Writing - original draft. Yuki Arai: Investigation, Data curation, Writing - original draft, Project administration. Saori Matsuda: Investigation, Data curation, Writing - original draft, Project administration. Kento Emori: Formal analysis, Writing - original draft. Toshimi Ikezaki: Investigation, Writing - original draft. Mitsuharu Osawa: Investigation, Writing - original draft.\n\nConflicts of interest\nSatoshi Soen received a honorarium as a medical professional from EA Pharma Co., Ltd. for this study. Yuki Arai, Saori Matsuda, and Kento Emori are employees of EA Pharma Co., Ltd. Toshimi Ikezaki and Mitsuharu Osawa are employees of Eisai Co., Ltd.\n\nAppendix A Supplementary data\nThe following is the supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgments\nThis work was supported by 10.13039/100014421EA Pharma Co., Ltd., 10.13039/100008373Takeda Pharmaceutical Company Limited, and 10.13039/501100003769Eisai Co., Ltd., which were involved in the study design, implementation, data collection, and data analysis.\n\nThe authors would like to express our deepest gratitude to the physicians who provided valuable data and for their cooperation in conducting this study. We also thank EPS Corporation (formerly AC Medical Inc.) for analyzing all data and WysiWyg Co., Ltd. for helping the manuscript preparation. ORCID Satoshi Soen: 0000-0002-0955-2747. Yuki Arai: 0000-0002-3574-7783. Saori Matsuda: 0000-0002-9804-7020. Kento Emori: 0000-0001-5877-7937. Toshimi Ikezaki: 0000-0002-2817-3347. Mitsuharu Osawa: 0000-0002-9572-2422.\n\nPeer review under responsibility of The Korean Society of Osteoporosis.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.afos.2020.11.002.\n==== Refs\nReferences\n1 Orimo H. Nakamura T. Hosoi T. Iki M. Uenishi K. Endo N. Japanese 2011 guidelines for prevention and treatment of osteoporosis-executive summary Arch Osteoporos 7 2012 3 20 23203733 \n2 Yoshimura N. Nakamura K. Epidemiology of locomotive organ disorders and symptoms: an estimation using the population-based cohorts in Japan Clin Rev Bone Miner Metabol 14 2016 68 73 \n3 Ensrud K.E. Thompson D.E. Cauley J.A. Nevitt M.C. 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Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO) Curr Med Res Opin 21 2005 1895 1903 16368038 \n23 Silverman S.L. Schousboe J.T. Gold D.T. Oral bisphosphonate compliance and persistence: a matter of choice? Osteoporos Int 22 2011 21 26 20458571 \n24 Review report: Actonel Tablets 75 mg/Benet Tablets 75 mg Japan: pharmaceuticals and medical devices agency [Japanese] [Internet] [cited 2020 12 October]. Available from: https://www.pmda.go.jp/drugs/2012/P201200168/11189000_22400AMX01500_A100_2.pdf \n25 Yoneda T. Hagino H. Sugimoto T. Ohta H. Takahashi S. Soen S. Bisphosphonate-related osteonecrosis of the jaw: position paper from the allied task force committee of Japanese society for bone and mineral Research, Japan osteoporosis society, Japanese society of periodontology, Japanese society for oral and maxillofacial radiology, and Japanese society of oral and maxillofacial surgeons J Bone Miner Metabol 28 2010 365 383 \n26 Urade M. Tanaka N. Furusawa K. Shimada J. Shibata T. Kirita T. Nationwide survey for bisphosphonate-related osteonecrosis of the jaws in Japan J Oral Maxillofac Surg 69 2011 e364 e371 21782307 \n27 Shibahara T. Morikawa T. Yago K. Kishimoto H. Imai Y. Kurita K. National survey on bisphosphonate-related osteonecrosis of the jaws in Japan J Oral Maxillofac Surg 76 2018 2105 2112 29746838 \n28 Iba K. Takada J. Sonoda T. Yamashita T. Effect of continuous long-term treatment for 10 years with bisphosphonate on Japanese osteoporosis patients J Bone Miner Metabol 38 2020 240 247 \n29 Silverman S.L. Piziak V.K. Chen P. Misurski D.A. Wagman R.B. Relationship of health related quality of life to prevalent and new or worsening back pain in postmenopausal women with osteoporosis J Rheumatol 32 2005 2405 2409 16331772 \n30 Iwamoto J. Makita K. Sato Y. Takeda T. Matsumoto H. Alendronate is more effective than elcatonin in improving pain and quality of life in postmenopausal women with osteoporosis Osteoporos Int 22 2011 2735 2742 21104227 \n31 Hadji P. Zanchetta J.R. Russo L. Recknor C.P. Saag K.G. McKiernan F.E. The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures Osteoporos Int 23 2012 2141 2150 22159672 \n32 Hongo M. Miyakoshi N. Kasukawa Y. Ishikawa Y. Shimada Y. Additive effect of elcatonin to risedronate for chronic back pain and quality of life in postmenopausal women with osteoporosis: a randomized controlled trial J Bone Miner Metabol 33 2015 432 439 \n33 Nakamura T. Umemura T. Kamisaki T. Nishikawa M. Uchida S. QOL-change and examination of factors by treatment of risedronate 2.5mg for patients with osteoporosis [Japanese] Osteoporosis Jpn 20 2012 551 563 \n34 Nakamura T. Osawa M. Itoh M. Yamaguchi H. Iinuma N. Hayakawa Y. The effect of risedronate (17.5 mg/week) treatment on quality of life in Japanese women with osteoporosis: a prospective observational study J Bone Miner Metabol 30 2012 715 721 \n35 Tsuchiya A. Ikeda S. Ikegami N. Nishimura S. Sakai I. Fukuda T. Estimating an EQ-5D population value set: the case of Japan Health Econ 11 2002 341 353 12007165 \n36 Ohtori S. Akazawa T. Murata Y. Kinoshita T. Yamashita M. Nakagawa K. Risedronate decreases bone resorption and improves low back pain in postmenopausal osteoporosis patients without vertebral fractures J Clin Neurosci 17 2010 209 213 20044258\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2405-5255",
"issue": "6(4)",
"journal": "Osteoporosis and sarcopenia",
"keywords": "Low back pain; Medication compliance; Once-monthly risedronate; Osteoporosis; Postmarketing survey; Vertebral fracture",
"medline_ta": "Osteoporos Sarcopenia",
"mesh_terms": null,
"nlm_unique_id": "101666399",
"other_id": null,
"pages": "191-198",
"pmc": null,
"pmid": "33426308",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "11368289;16368038;10527181;26297076;24184313;21394496;31667583;17002926;20458571;11685647;22159672;19459025;18460036;16197664;23203733;20044258;29746838;14504697;21782307;16331772;17308956;25123562;17897451;12007165;22868656;15316868;17704995;27565972;10733048;23620095;27375371;21104227;20333419;10663363",
"title": "A 3-year postmarketing study on the safety and effectiveness of once-monthly risedronate in Japanese patients with osteoporosis.",
"title_normalized": "a 3 year postmarketing study on the safety and effectiveness of once monthly risedronate in japanese patients with osteoporosis"
}
|
[
{
"companynumb": "JP-TEVA-2021-JP-1885446",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISEDRONIC ACID"
},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Toothache",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SOEN S, ARAI Y, MATSUDA S, EMORI K, IKEZAKI T, OSAWA M. A 3?YEAR POSTMARKETING STUDY ON THE SAFETY AND EFFECTIVENESS OF ONCE?MONTHLY RISEDRONATE IN JAPANESE PATIENTS WITH OSTEOPOROSIS. OSTEOPOROS?SARCOPENIA 2020?6(4):191?198.",
"literaturereference_normalized": "a 3 year postmarketing study on the safety and effectiveness of once monthly risedronate in japanese patients with osteoporosis",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20210304",
"receivedate": "20210304",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20210420"
}
] |
{
"abstract": "BACKGROUND\nRenal transplantation is the optimal treatment for suitable patients with end-stage renal disease (ESRD). However, acute graft dysfunction occurs in 5%-35% of patients. This is commonly due to acute rejection, drug toxicity, ureteric obstruction, or infection. Atypical hemolytic uremic syndrome (aHUS), either recurrent or de novo, is uncommon after transplantation.\n\n\nMETHODS\nWe highlight three cases of acute transplant dysfunction in which transplant biopsy revealed HUS without associated clinical or hematologic clues to the etiology. Two cases had recurrent HUS and 1 had de novo HUS secondary to tacrolimus therapy. Screenings for ADAMTS-13 and gene mutations of complement regulatory proteins were negative. Thrombocytopenia and red blood cell fragments on blood film appeared some days later.\n\n\nMETHODS\nTreatment comprised a combination of plasma exchange with fresh-frozen plasma and switching immunosuppressive therapy, which led to the recovery of the above hematologic features but salvaged graft function in only 1 case.\n\n\nCONCLUSIONS\nClassical hematologic findings of HUS appeared late in these cases. HUS should be considered in cases of allograft dysfunction where there is no obvious cause, and biopsy should be performed. This enables early initiation of therapy to gain rapid recovery of hematologic parameters and potentially of transplant function.",
"affiliations": "Department of Renal Medicine, Hull and East Yorkshire Hospitals, NHS Trust, and Hull and York Medical School, Hull, East Yorkshire, United Kingdom.",
"authors": "Ali|M N|MN|;Ali|M N A|MN|;Syed|A|A|;Syed|A B|AB|;Bhandari|S|S|;Bhandari|S C|SC|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "45(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D005260:Female; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D016559:Tacrolimus",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3284-8",
"pmc": null,
"pmid": "24182801",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case series: hemolytic uremic syndrome--another cause of transplant dysfunction.",
"title_normalized": "case series hemolytic uremic syndrome another cause of transplant dysfunction"
}
|
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},
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Haemolytic uraemic syndrome",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
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},
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"literaturereference": "ALI MNA, SYED AB, BHANDARI SC. CASE SERIES: HEMOLYTIC UREMIC SYNDROME - ANOTHER CAUSE OF TRANSPLANT DYSFUNCTION. TRANSPLANT-PROC 2013; 45(9) 3284-3288",
"literaturereference_normalized": "case series hemolytic uremic syndrome another cause of transplant dysfunction",
"qualification": "3",
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},
"primarysourcecountry": "GB",
"receiptdate": "20141216",
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},
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},
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"transmissiondate": "20150529"
},
{
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{
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Haemolytic uraemic syndrome",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "ALI MNA, SYED AB, BHANDARI SC. CASE SERIES: HEMOLYTIC UREMIC SYNDROME - ANOTHER CAUSE OF TRANSPLANT DYSFUNCTION. TRANSPLANT-PROC 2013; 45(9) 3284-3288",
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"qualification": "3",
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},
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},
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}
] |
{
"abstract": "Synthetic cannabinoids (SC) have exploded on to the scene. With this rise in SC use, the number of complications and potential adverse effects are also well documented in the literature and is on the rise. The most frequently cited side effects are behavioral in nature and range for severe agitation to psychosis and delirium. We report a case of hyperthermia with severe rhabdomyolysis from SC use.",
"affiliations": "Department of Emergency Medicine, NYMC, Metropolitan Hospital Center, New York, NY.;Department of Internal Medicine, NYMC, Metropolitan Hospital Center, New York, NY.;Department of Emergency Medicine, NYMC, Metropolitan Hospital Center, New York, NY.;Department of Emergency Medicine, NYMC, Metropolitan Hospital Center, New York, NY.;Department of Emergency Medicine, NYMC, Metropolitan Hospital Center, New York, NY.;Department of Emergency Medicine, NYMC, Metropolitan Hospital Center, New York, NY.;Department of Emergency Medicine, NYMC, Metropolitan Hospital Center, New York, NY. Electronic address: [email protected].",
"authors": "Sweeney|Brett|B|;Talebi|Soheila|S|;Toro|David|D|;Gonzalez|Kristhiam|K|;Menoscal|Jean-Paul|JP|;Shaw|Ronald|R|;Hassen|Getaw Worku|GW|",
"chemical_list": "D002186:Cannabinoids; D013287:Illicit Drugs",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "34(1)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D002186:Cannabinoids; D005334:Fever; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D011605:Psychoses, Substance-Induced; D012206:Rhabdomyolysis",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "121.e1-2",
"pmc": null,
"pmid": "26143311",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyperthermia and severe rhabdomyolysis from synthetic cannabinoids.",
"title_normalized": "hyperthermia and severe rhabdomyolysis from synthetic cannabinoids"
}
|
[
{
"companynumb": "US-WATSON-2016-00331",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
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"activesubstance": {
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},
"drugadditional": null,
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"drugauthorizationnumb": "070981",
"drugbatchnumb": "UNCONFIRMED",
"drugcharacterization": "1",
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"drugdosagetext": "UNK",
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"medicinalproduct": "OLANZAPINE."
},
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"abstract": "BACKGROUND\nEntecavir-resistance mutations are commonly induced by entecavir treatment in chronic hepatitis B patients. However, entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations induced by sequential or combination treatment with lamivudine and adefovir dipivoxil have never been reported.\n\n\nRESULTS\nWe retrospectively reviewed 1200 patients who had been tested for anti-HBV drug resistance at Beijing Ditan Hospital of Capital Medical University, and five patients showing multidrug resistance to lamivudine and adefovir dipivoxil were enrolled. Stored serum samples were used for genetic analysis, which yielded a total of 135 clones. Entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations were identified in 60 % (3/5) entecavir-naïve patients who received sequential therapy with adefovir dipivoxil and lamivudine. Specifically, we found one rtM204I+rtL180 M+rtM250 V+rtA181 V clone among 23 clones from patient 1 (4.35 %), one rtM204 V+vrtL180 M +rtM250 V+rtA181 V clone among 24 clones from patient 2 (4.17 %), and 2 clones harboring rtM204 V+rtL180 M+rtM250 V+rtA181 V and rtM204 V+rtL180 M+rtI169 V+rtA181 V among 20 clones from patient 3 (10.0 %). The other 2 patients showed multidrug resistance after lamivudine/telbivudine and adefovir dipivoxil combination therapy, but no entecavir-resistance mutations were found in these two patients.\n\n\nCONCLUSIONS\nDe novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations can be induced by sequential therapy with adefovir dipivoxil and lamivudine in patients who never take entecavir. These results provide important information for sequential therapy with adefovir dipivoxil and lamivudine and the use of entecavir as a rescue therapy for these patients with multidrug resistance.",
"affiliations": "Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015, China.;Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015, China.;Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015, China.;Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015, China.;Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015, China.;Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015, China. [email protected].",
"authors": "Yang|Song|S|;Xing|Huichun|H|;Wang|Qi|Q|;Wang|Xiaomei|X|;Liu|Shunai|S|;Cheng|Jun|J|",
"chemical_list": "D000998:Antiviral Agents; D063065:Organophosphonates; D014764:Viral Proteins; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D000225:Adenine; C106812:adefovir dipivoxil",
"country": "England",
"delete": false,
"doi": "10.1186/s12941-016-0138-0",
"fulltext": "\n==== Front\nAnn Clin Microbiol AntimicrobAnn. Clin. Microbiol. AntimicrobAnnals of Clinical Microbiology and Antimicrobials1476-0711BioMed Central London 13810.1186/s12941-016-0138-0Short ReportDe novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations resulting from sequential therapy with adefovir dipivoxil, and lamivudine Yang Song [email protected] Xing Huichun [email protected] Wang Qi [email protected] Wang Xiaomei [email protected] Liu Shunai [email protected] Cheng Jun +86 10 8432 [email protected] Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015 China Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, 8 East Jingshun Street, Chaoyang District, Beijing, 100015 China 14 4 2016 14 4 2016 2016 15 245 11 2015 29 3 2016 © Yang et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEntecavir-resistance mutations are commonly induced by entecavir treatment in chronic hepatitis B patients. However, entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations induced by sequential or combination treatment with lamivudine and adefovir dipivoxil have never been reported.\n\nResults\nWe retrospectively reviewed 1200 patients who had been tested for anti-HBV drug resistance at Beijing Ditan Hospital of Capital Medical University, and five patients showing multidrug resistance to lamivudine and adefovir dipivoxil were enrolled. Stored serum samples were used for genetic analysis, which yielded a total of 135 clones. Entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations were identified in 60 % (3/5) entecavir-naïve patients who received sequential therapy with adefovir dipivoxil and lamivudine. Specifically, we found one rtM204I+rtL180 M+rtM250 V+rtA181 V clone among 23 clones from patient 1 (4.35 %), one rtM204 V+vrtL180 M +rtM250 V+rtA181 V clone among 24 clones from patient 2 (4.17 %), and 2 clones harboring rtM204 V+rtL180 M+rtM250 V+rtA181 V and rtM204 V+rtL180 M+rtI169 V+rtA181 V among 20 clones from patient 3 (10.0 %). The other 2 patients showed multidrug resistance after lamivudine/telbivudine and adefovir dipivoxil combination therapy, but no entecavir-resistance mutations were found in these two patients.\n\nConclusion\nDe novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations can be induced by sequential therapy with adefovir dipivoxil and lamivudine in patients who never take entecavir. These results provide important information for sequential therapy with adefovir dipivoxil and lamivudine and the use of entecavir as a rescue therapy for these patients with multidrug resistance.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12941-016-0138-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nHepatitis B virusMultidrug resistanceEntecavirAdefovir dipivoxilLamivudineBeijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding SupportZY201402Cheng Jun The Capital Health Research and Development of Special2011-2017-02Yang Song issue-copyright-statement© The Author(s) 2016\n==== Body\nFindings\nChronic hepatitis B virus (HBV) infection is estimated to affect approximately 120 million people in China, with an annual death toll of approximately 300,000, mostly resulting from HBV-related cirrhosis and hepatocellular carcinoma (HCC) [1]. Although antiviral therapy with nucleoside/nucleotide analogues (NAs) and interferons (IFNs) can be used to suppress HBV replication and prevent disease progression, the side effects of antiviral drugs should be monitored regularly [2, 3]. Five NAs are currently approved for anti-HBV treatment in China, including lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (LdT), entecavir (ETV), and tenofovir disoproxil fumarate (TDF). One major concern for NA therapies is the emergence of HBV resistance after prolonged treatment, especially for drugs with low resistance barriers (LAM, ADV, and LdT) [2, 3]. In some patients, mutations causing multidrug resistance (MDR) may occur after sequential monotherapy with low-resistance barrier NAs [3]. Yim et al. reported three cases of LAM+ADV-resistant patients after sequential therapy with LAM and ADV [4]. Liu et al. detected a ETV+ADV+LAM triple-resistant HBV strain in a LAM+ADV-resistant patient who had taken sequential ETV as a rescue therapy [5]. Additionally, Kim et al. reported six cases of ETV+ADV+LAM resistance that occurred after sequential therapy with LAM, ADV, and ETV [6].\n\nETV resistance mutations are commonly induced by ETV treatment. However, Yang et al. reported that LAM-resistant HBV also had reduced susceptibility to ETV (37- to 471-fold reduction) [7]. Additionally, Inoue et al. described a patient who received LAM+ADV and then developed de novo ETV resistance with rtM204 V+rtL180 M+rtT184 S mutations [8]. However, it is still not clear whether or not sequential or combination therapy with LAM and ADV induces ETV+ADV+LAM triple-resistance mutations. Furthermore, ETV+ADV is still used for rescue therapy in many LAM+ADV-resistant patients [9–11], especially in China where TDF is costly and not covered by the reimbursement system. Therefore, we retrospectively analyzed chronic hepatitis B (CHB) patients in Beijing Ditan Hospital of Capital Medical University in whom sequential or combination therapy with LAM+ADV was not successful. Genetic analyses of stored serum samples revealed ETV+ADV+LAM triple-resistance mutations in three ETV-naïve patients who received sequential therapy with ADV+LAM.\n\nThe initial study population consisted of 1200 CHB patients who underwent drug resistance testing by nested polymerase chain reaction (PCR)-based direct sequencing at the Beijing Ditan Hospital. Written consent was obtained from each patient. Demographic and clinical data were collected using a questionnaire. Serum samples were stored at −20 °C until further analysis. Patients exhibiting MDR to both LAM and ADV were selected for the study. Clinical data were confirmed by checking medical records in the hospital information system. This study was approved by ethics committee of Beijing Ditan Hospital.\n\nHBV DNA extraction was conducted using an AxyPrep Body Fluid Viral DNA/RNA Miniprep Kit (Corning Inc., Corning, NY). Nested PCR-direct sequencing was performed as previously described [12]. The PCR products were purified using a QIAquick PCR purification Kit (Qiagen, Valencia, CA, USA) according to the manufacturer’s instructions. Purified DNA was sequenced using an automated ABI 3730 DNA sequencer (Applied Biosystems, Foster City, CA, USA) at Beijing Augct Bioengineering Co., Ltd. DNA sequences were aligned using SeqMan and EditSeq software (DNASTAR Inc., Madison, WI). The HBV polymerase sequencing results were also used for HBV genotyping with the genotyping tool of the website of the National Center for Biotechnology Information [13]. PCR-amplified HBV DNA was cloned into the pGEM-T easy vector (Promega, Madison, WI) according to the manufacturer’s instructions. Clones (n = 20–38) were selected from each patient, and the sequences were analyzed using MegAlign software (DNASTAR Inc.).\n\nFive HBV patients with MDR to both LAM/LdT and ADV were enrolled. The demographic and clinical characteristics of the patients, together with the direct sequencing results of the nested PCR products, are shown in Table 1. HBV genotyping showed that all 5 patients were infected with genotype C HBV.Table 1 Demographic and clinical characteristics of patients\n\nPatient\t1\t2\t3\t4\t5\t\nAge (years)\t61\t36\t55\t38\t40\t\nSex\tF\tM\tM\tM\tM\t\nRace\tAsian\tAsian\tAsian\tAsian\tAsian\t\nDiagnosis\tCHB\tCHB\tHBV-related cirrhosis, HCC\tCHB\tCHB\t\nHBV genotype\tC\tC\tC\tC\tC\t\nHBeAg/Anti-HBe\t−/+\t+/−\t+/−\t+/−\t+/−\t\nAntiviral treatment history (months)\tADV (36)\n↓a\n\nLAM (12)\tADV (36)\n↓\nLAM (12)\tADV (12)\n↓\nLAM (12)\tADV (12)\n↓\nLAM+ADV (8)\tLAM (36)\n↓\nLAM+ADV (8)\n↓\nLdT (6)\t\nResults of sequencing\trtM204 V+rtL180 M+rtA181 V\trtM204 V+rtL180 M+rtA181 V\trtM204 V+rtL180 M+rtA181 V\trtM204 I+rtA181 V/T\trtM204 V+rtL180 M+rtA181 V\t\n\nADV adefovir dipivoxil, LAM lamivudine, LdT telbivudine, PCR polymerase chain reaction, CHB chronic hepatitis B, HCC hepatocellular carcinoma, LAM + ADV LAM and ADV combination therapy\n\n\na↓ indicates followed by\n\n\n\nIn total, 135 clones were obtained from the five patients. All clones were submitted to NCBI GenBank, and the accession numbers are shown in Additional file 1: Table S1. The results of the clonal analysis are shown in Fig. 1. Patient 1 received ADV and LAM sequential therapy, and direct sequencing of the nested PCR product showed rtM204 V+rtL180 M+rtA181 V mutations upon secondary virological breakthrough, whereas rtM204 V+rtL180 M+rtA181 V strains accounted for 78.26 % (18/23) of the clones in the clonal analysis. In addition, 17.39 % (4/23) and 13.04 % (3/23) of the clones harbored the rtM204 I and rtA181 T mutations, respectively, which were not found by direct sequencing. Moreover, one clone (4.35 %) harbored rtM204 I+rtL180 M+rtM250 V+rtA181 V mutations, which resulted in resistance to LAM+ADV+ETV (Additional file 2: Figure S1); however, this patient had never received ETV therapy.Fig. 1 Genetic analysis of multidrug-resistant strains (135 clones) from patients receiving nucleoside/nucleotide analogue treatment. The expanded sections show de novo entecavir resistance mutations\n\n\n\nPatient 2 received ADV and LAM sequential therapy, and sequencing revealed rtM204 V+rtL180 M+rtA181 V mutations upon secondary virological breakthrough, whereas rtM204 V+rtL180 M+rtA181 V strains comprised 95.83 % (23/24) of the clones in the clonal analysis. Additionally, one clone (4.17 %) bore rtM204 V+rtL180 M+rtM250 V+rtA181 V mutations, which resulted in resistance to LAM+ADV+ETV (Additional file 3: Figure S2). This patient also never received ETV therapy.\n\nPatient 3 received ADV and LAM sequential therapy, and sequencing showed rtM204 V+rtL180 M+rtA181 V mutations upon secondary virological breakthrough, whereas 85.0 % (17/20) of the clones harbored rtM204 V+rtL180 M+rtA181 V mutations. In addition, one clone (5.0 %) bore rtM204 V+rtA181 T mutations. Moreover, two clones (10.0 %) bore ETV+LAM+ADV triple-resistance mutations (Additional file 4: Figure S3 and Additional file 5: Figure S4), even though this patient had also never received ETV therapy.\n\nPatient 4 received ADV+LAM for rescue therapy upon ADV resistance, and sequencing showed rtM204 I+rtA181 V+rtA181 T mutations upon secondary virological breakthrough. A high diversity of mutated strains was observed in the clonal analysis, with seven mutation patterns present in 30 clones. The rtN236 T mutation was not found by direct sequencing of PCR products, and no ETV-resistance mutations were detected in this patient.\n\nPatient 5 received ADV+LAM for rescue therapy upon LAM resistance, but was later switched to LdT monotherapy, which was requested by the patient because of concerns regarding creatinine elevation. Sequencing identified rtM204 V+rtL180 M+rtA181 V mutations upon secondary virological breakthrough. All clones harbored rtM204 V+rtL180 M+rtA181 V mutations, consistent with the sequencing results, and no de novo ETV resistance mutations were detected.\n\nThe possible overlapping S-gene mutations of all clones harboring the rtA181 T mutation were analyzed (Additional file 6: Table S2). In patient 1, 3 clones harboring the rtA181 T mutation had sW172*(stop codon) mutations in the overlapping S gene. Additionally, 1 clone and 15 clones harboring rtA181 T mutations in in patients 3 and 4, respectively, showed sW172* mutations.\n\nIn this study, we performed a genetic analysis with serum samples obtained from five patients with chronic HBV infection that exhibited MDR to LAM/LdT and ADV following sequential/combination therapy with LAM/LdT and ADV. Surprisingly, de novo ETV resistance mutations were present in all three patients who received sequential therapy with ADV+LAM. Inoue et al. previously performed a clonal analysis and reported that strains with ETV resistance harbored only ETV resistance mutations and no ADV resistance mutations. However, in the present study, all three patients had HBV strains with MDR for ETV+LAM+ADV, although these MDR clones comprised only a minor population of the quasispecies.\n\nThere are several reports of the use of ETV as a rescue therapy for patients with MDR to LAM+ADV. However, Heo et al. reported that ETV monotherapy is inferior as a rescue therapy in patients with MDR to LAM and ADV [14]. Additionally, Xu et al. reported the use of ETV+ADV for rescue therapy in 45 patients who failed to respond to treatment with multiple NAs, with 2/45 patients showing LAM+ADV resistance at baseline. However, after 24 months of treatment with ETV+ADV treatment, one patient still did not achieve a complete virological response (HBV DNA ≤500 copies/mL) (11). Moreover, Lim et al. reported that ETV + ADV could be used as a rescue therapy in patients with a suboptimal response to LAM+ADV; however, only 28.9 % (13/45) of the patients achieved virological responses (HBV DNA < 60 IU/mL) after 52 months of therapy [15]. Notably, this study also included two patients with de novo ETV resistance mutations at rtT184 A and rtM250 L after LAM+ADV treatment, but no further clonal analyses were conducted in these patients. According to these studies, de novo ETV-resistance mutations after sequential and/or combination therapy with LAM+ADV may play a role in the inferior efficacy of ETV rescue therapy in these patients.\n\nThe present study also indicates a need for more sensitive HBV drug resistance tests in clinical practice. Direct sequencing of PCR products is frequently used in clinical practice and trials to detect NA resistance [16, 17]; however, it can only identify mutations when they reach approximately 20 % of the total HBV quasispecies pool [18]. As shown in this study, direct sequencing of PCR products was unable to detect de novo ETV-resistant strains in patients 1, 2, and 3, as these strains comprised 4.35, 4.17, and 15.0 % of the total quasispecies, respectively. However, minor mutant strains can evolve to major strains under ETV selection pressure, and thus their early detection is important. More sensitive resistance tests have been reported to detect mutant strains comprising <5 % of the total HBV quasispecies, but they are either costly or inconvenient for widespread use in China [19, 20].\n\nThe study also calls attention to the use of less potent NAs in combination as a rescue therapy for NA resistance [2, 3]. Addition of LAM is a therapeutic option for ADV-resistant patients. In this study, patient 4 developed MDR to LAM+ADV while receiving LAM+ADV combination therapy to rescue ADV resistance. Other reports have described similar phenomena [8, 15]. Thus, thorough and rapid inhibition of HBV replication is critical for combination therapy; otherwise, combination therapy with LAM+ADV may increase the selection pressure of both drugs in patients with persistent viremia.\n\nIn this study, all MDR patients were infected with genotype C. we consider this is partly because genotype C is predominant in the northern part of China [1]. Several reports have indicated higher numbers of ADV or LAM resistance mutations in HBV genotype C compared with genotype B [21, 22]. However, the sample size was too small to establish a correlation between genotype C and MDR mutations.\n\nIt has been reported that the rtA181 T mutation in HBV may cause sW172* in the overlapping S gene in genotype D HBV infection [23]. In this study, all genotype C HBV clones harboring the rtA181 T mutation had sW172* mutations in the overlapping S-gene. Strains harboring the rtA181 T/sW172* mutation accounted for 13.04 % (3/23), 4.17 % (1/24), and 50.0 % (15/30) of the total clones in patients 1, 3, and 4, respectively. This also confirms that the HBV rtA181 T/sW172*mutation is usually detected in a mixed population with lower replication efficiency [24].\n\nIn conclusion, our results indicate that de novo LAM+ADV+ETV resistance mutations may be induced by sequential therapy with ADV+LAM in patients who never took ETV. These results provide important information for administration of sequential therapy with ADV and LAM and for the use of ETV for rescue therapy in patients with MDR to ADV+LAM.\n\nAdditional files\n\n10.1186/s12941-016-0138-0 GenBank accession numbers of 135 sequences from 5 chronic hepatitis B patients.\n\n\n10.1186/s12941-016-0138-0 Electropherogram of rtM204 V+rtL180 M+rtA181 V+rtM250 V clone in Patient 1 (GenBank accession number: KU736795).\n\n\n10.1186/s12941-016-0138-0 Electropherogram of rtM204 V+rtL180 M+rtA181 V+rtM250 V clone in Patient 2 (GenBank accession number: KU751680).\n\n\n10.1186/s12941-016-0138-0 Electropherogram of rtM204 V+rtL180 M+rtA181 V+rtI169 V clone in Patient 3 (GenBank accession number: KU751729).\n\n\n10.1186/s12941-016-0138-0 Electropherogram of rtM204 V+rtL180 M+rtA181 V+rtM250 V clone in Patient 3 (GenBank accession number: KU751733).\n\n\n10.1186/s12941-016-0138-0 Overlapping HBsAg mutations caused by HBV rtA181 T mutation.\n\n\n\nAbbreviations\nHBVhepatitis B virus\n\nMDRmultidrug resistance\n\nLAMlamivudine\n\nADVadefovir dipivoxil\n\nLdTtelbivudine\n\nETVentecavir\n\nTDFtenofovir disoproxil fumarate\n\nNAnucleoside/nucleotide analogue\n\nAuthors’ contributions\nCJ contributed to the study design, critical review of the manuscript, and approval of the final draft. YS contributed to data collection, lab testing, and drafting of the manuscript. WQ, WX, and LS contributed to data collection and lab testing. XH contributed to study design and critical review of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe study was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (No. ZY201402) and the Capital Health Research and Development of Special (No. 2011-2017-02).\n\nCompeting interests\nAll authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Cui Y Jia J Update on epidemiology of hepatitis B and C in China J Gastroenterol Hepatol 2013 28 Suppl 1 7 10 10.1111/jgh.12220 23855289 \n2. EASL clinical practice guidelines Management of chronic hepatitis B virus infection J Hepatol 2012 57 167 185 10.1016/j.jhep.2012.02.010 22436845 \n3. 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Lim YS Lee JY Lee D Shim JH Lee HC Lee YS Randomized trial of entecavir plus adefovir in patients with lamivudine-resistant chronic hepatitis B who show suboptimal response to lamivudine plus adefovir Antimicrob Agents Chemother 2012 56 2941 2947 10.1128/AAC.00338-12 22430972 \n16. Marcellin P Heathcote EJ Buti M Gane E de Man RA Krastev Z Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B N Engl J Med 2008 359 2442 2455 10.1056/NEJMoa0802878 19052126 \n17. Lai CL Shouval D Lok AS Chang TT Cheinquer H Goodman Z Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B N Engl J Med 2006 354 1011 1020 10.1056/NEJMoa051287 16525138 \n18. Lok AS Zoulim F Locarnini S Bartholomeusz A Ghany MG Pawlotsky JM Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management Hepatology 2007 46 254 265 10.1002/hep.21698 17596850 \n19. Niesters HG Zoulim F Pichoud C Buti M Shapiro F D’Heuvaert N Validation of the INNO-LiPA HBV DR assay (version 2) in monitoring hepatitis B virus-infected patients receiving nucleoside analog treatment Antimicrob Agents Chemother 2010 54 1283 1289 10.1128/AAC.00970-09 20065049 \n20. Kim HS Han KH Ahn SH Kim EO Chang HY Moon MS Evaluation of methods for monitoring drug resistance in chronic hepatitis B patients during lamivudine therapy based on mass spectrometry and reverse hybridization Antivir Ther 2005 10 441 449 15918335 \n21. Li W Warner N Sozzi V Yuen L Colledge D Li T Hepatitis B virus genotype C encoding resistance mutations that emerge during adefovir dipivoxil therapy: in vitro replication phenotype Hepatol Int 2013 7 443 450 10.1007/s12072-012-9411-2 26201776 \n22. Li X Wang L Zhong Y Wong VW Xu Z Liu Y Hepatitis B virus (HBV) subgenotypes C2 and B2 differ in lamivudine- and adefovir-resistance-associated mutational patterns in HBV-infected Chinese patients J Clin Microbiol 2010 48 4363 4369 10.1128/JCM.01518-10 20881176 \n23. Warner N Locarnini S The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound Hepatology 2008 48 88 98 10.1002/hep.22295 18537180 \n24. Ahn SH Park YK Park ES Kim JH Kim DH Lim KH The impact of the hepatitis B virus polymerase rtA181T mutation on replication and drug resistance is potentially affected by overlapping changes in surface gene J Virol 2014 88 6805 6818 10.1128/JVI.00635-14 24696492\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1476-0711",
"issue": "15()",
"journal": "Annals of clinical microbiology and antimicrobials",
"keywords": "Adefovir dipivoxil; Entecavir; Hepatitis B virus; Lamivudine; Multidrug resistance",
"medline_ta": "Ann Clin Microbiol Antimicrob",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D006147:Guanine; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates; D012189:Retrospective Studies; D014764:Viral Proteins",
"nlm_unique_id": "101152152",
"other_id": null,
"pages": "24",
"pmc": null,
"pmid": "27079793",
"pubdate": "2016-04-14",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23855289;17596850;23706010;22430972;24696492;19737565;23593607;18537180;16152756;20646776;20367795;22087161;23096938;20881176;22436845;20065049;16941700;21149926;15918335;26201776;16525138;19052126;15215470;25872678",
"title": "De novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations resulting from sequential therapy with adefovir dipivoxil, and lamivudine.",
"title_normalized": "de novo entecavir adefovir dipivoxil lamivudine triple resistance mutations resulting from sequential therapy with adefovir dipivoxil and lamivudine"
}
|
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] |
{
"abstract": "Medicaton used to treat tuberculosis is responsible for numerous side effects that have a major impact on patient's health, with a negative influence on the quality of life. Patients of all ages must be trained in order to recognize all the adverse effects and the undesirable reactions produced by antituberculosis medication. We report the case of a 24-year-old woman with generalized psoriasis and psoriatic arthropathy who was treated against tuberculosis. After 7 days of treatment with isoniazid, rifampicin, ethambutol and pyrazinamid she had severe allergic reaction with generalized pruritus and rash which were difficult to control with antiallergic treatment.\n\n\nCONCLUSIONS\nParticular to this case is the absence in patient's history of the allergic reactions to medication. The re-establishment of treatment of tuberculosis was done by clinical trials and the patient had responded to only three drugs: isoniazid, rifampicin and ofloxacin, so the patient received an individual treatment due to adverse reactions to tuberculosis medications.",
"affiliations": "Facultatea de Farmacie, Universităţii de Medicină şi Farmacie \"Grigore T. Popa\"--Iaşi.",
"authors": "Costin|Magda|M|;Tesloianu|A|A|;Mihăescu|T|T|;Butnaru|Elena|E|",
"chemical_list": "D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D015242:Ofloxacin; D007538:Isoniazid; D012293:Rifampin",
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0048-7848",
"issue": "116(2)",
"journal": "Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi",
"keywords": null,
"medline_ta": "Rev Med Chir Soc Med Nat Iasi",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D015535:Arthritis, Psoriatic; D003888:Desensitization, Immunologic; D003875:Drug Eruptions; D004977:Ethambutol; D005260:Female; D006801:Humans; D006967:Hypersensitivity; D007538:Isoniazid; D015242:Ofloxacin; D011565:Psoriasis; D011718:Pyrazinamide; D012293:Rifampin; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "0413735",
"other_id": null,
"pages": "487-9",
"pmc": null,
"pmid": "23077942",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Therapeutic approach in a case of allergic reaction to antituberculosis drugs -- a case report.",
"title_normalized": "therapeutic approach in a case of allergic reaction to antituberculosis drugs a case report"
}
|
[
{
"companynumb": "RO-LUPIN PHARMACEUTICALS INC.-2015-01044",
"fulfillexpeditecriteria": "2",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "090034",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TUBERCULOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "RIFAMPICIN"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OFLOXACIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TUBERCULOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OFLOXACIN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PYRAZINAMIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TUBERCULOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PYRAZINAMID"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TUBERCULOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ISONIAZID."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "078939",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TUBERCULOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ETHAMBUTOL"
}
],
"patientagegroup": null,
"patientonsetage": "24",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypersensitivity",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus generalised",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "COSTIN M, TESLOIANU A, MIHAESCU T, BUTNARU E. THERAPEUTIC APPROACH IN A CASE OF ALLERGIC REACTION TO ANTITUBERCULOSIS DRUGS - A CASE REPORT. REV MED CHIR SOC MED NAT IASI. 2012;116(2):.",
"literaturereference_normalized": "therapeutic approach in a case of allergic reaction to antituberculosis drugs a case report",
"qualification": "3",
"reportercountry": "RO"
},
"primarysourcecountry": "RO",
"receiptdate": "20150618",
"receivedate": "20150618",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 11198153,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
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