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"abstract": "Antibodies against the 65-kDa isoform of the intracellular enzyme, glutamate decarboxylase (GAD65), have been found in patients with limbic encephalitis and drug-resistant autoimmune epilepsy. We report a 22-year-old female who presented with new-onset seizures and neuropsychiatric symptoms. Video-EEG captured unique, independent bitemporal-onset focal seizures with impaired awareness and ictal asystole. An autoimmune epilepsy panel revealed elevated GAD65 antibodies in the serum (225 nmol/l) and CSF (2.78 nmol/l), while [18F]-fluoro-deoxy-glucose positron emission tomography showed bitemporal hypometabolism (left > right). The patient was diagnosed with GAD65 antibody-associated autoimmune epilepsy. Our observation adds to the spectrum of neurocardiac syndromes associated with autoimmune epilepsy.",
"affiliations": "Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.;Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.",
"authors": "D'Souza|Caitlin E|CE|;Feyissa|Anteneh M|AM|",
"chemical_list": "D001323:Autoantibodies; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2018.0971",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "20(3)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "GAD65; asystole; autoimmune epilepsy; focal epilepsy; limbic encephalitis; neurocardiac syndromes",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D001323:Autoantibodies; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D005968:Glutamate Decarboxylase; D006801:Humans; D020363:Limbic Encephalitis; D055815:Young Adult",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "204-208",
"pmc": null,
"pmid": "29905150",
"pubdate": "2018-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "GAD65 antibody-associated autoimmune epilepsy with unique independent bitemporal-onset ictal asystole.",
"title_normalized": "gad65 antibody associated autoimmune epilepsy with unique independent bitemporal onset ictal asystole"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US20844",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
... |
{
"abstract": "An 82-year-old man with a history of end-stage renal disease presented with progressively worsening confusion and somnolence for the past 4-5 days. The patient was diagnosed with herpes zoster by his primary care physician 5 days ago and was started on a course of valacyclovir 1 g three times a day (dose not adjusted for renal impairment).A lumbar puncture was performed and cerebrospinal fluid (CSF) studies revealed 37 white blood cells (WBCs)/hpf (100% monocytes), protein 64 mg/dL and glucose 52 mg/dL. He was started on ceftriaxone, ampicillin and acyclovir. MRI of the brain was done and was unremarkable. Acyclovir-induced encephalopathy was high on differential, but his CSF findings were concerning for viral encephalitis. Nonetheless, all antimicrobials were discontinued and he was scheduled for a 5-hour dialysis session. The very next day, he showed immense improvement and eventually recovered completely. CSF PCR tests for both herpes simplex virus and varicella zoster virus came back negative.",
"affiliations": "Internal Medicine, Western Michigan University School of Medicine, Kalamazoo, Michigan, USA.;Internal Medicine, Western Michigan University School of Medicine, Kalamazoo, Michigan, USA.",
"authors": "Thind|Guramrinder Singh|GS|;Roach|Richard|R|",
"chemical_list": "D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220372",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Drugs: infectious diseases; Infection (neurology); Unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000212:Acyclovir; D000369:Aged, 80 and over; D000998:Antiviral Agents; D006562:Herpes Zoster; D006801:Humans; D008297:Male; D020258:Neurotoxicity Syndromes; D000077483:Valacyclovir; D014633:Valine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28536235",
"pubdate": "2017-05-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10225250;16540518;23284850;24777077;24942005;2538278;27418364;6305245;7973922;8245883",
"title": "A case of acyclovir neurotoxicity presenting with atypical cerebrospinal fluid findings.",
"title_normalized": "a case of acyclovir neurotoxicity presenting with atypical cerebrospinal fluid findings"
} | [
{
"companynumb": "US-CIPLA LTD.-2017US12297",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drugadditiona... |
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"abstract": "Loperamide is a widely available oral μ-opioid receptor agonist, and loperamide abuse is increasing by those seeking intoxication. Loperamide has potent QTc-prolonging properties, placing patients at risk for ventricular arrhythmias and sudden cardiac death.\nA 23-year-old woman was found to be in pulseless ventricular fibrillation with a QTc of 554 ms and received multiple defibrillations and IV lidocaine. Her toxicology studies were negative. She subsequently experienced multiple episodes of torsades de pointes and was found to be in cardiogenic shock with a left ventricular ejection fraction of 5%. Following multiple defibrillations, an Impella® mechanical circulatory support device was placed, and she was given IV magnesium and IV lidocaine. After mechanical circulatory support was withdrawn, she experienced major bleeding and was found to have a deep vein thrombosis, bilateral radial artery thrombosis, and multiple pulmonary embolisms in the setting of heparin-induced thrombocytopenia. After stabilizing, she admitted to taking 80 tablets of loperamide 2 mg in pursuit of euphoria.\nLoperamide is an increasingly popular agent of abuse. Loperamide-associated ventricular arrhythmias are rare with normal doses but more common with high doses, chronic ingestion, or interacting medications. Loperamide cardiotoxicity may be prolonged due to a long half-life and accumulation. Loperamide abuse may be under-recognized, leading to delays in treatment. Intravenous fluids, magnesium supplementation, chronotropes, transcutaneous or transvenous pacing, and defibrillation may be helpful in mitigating loperamide-associated polymorphic ventricular tachycardia. Clinicians should monitor for drug interactions in patients taking loperamide and screen for electrocardiographic abnormalities in those taking chronic or high-dose loperamide.",
"affiliations": "Department of Pharmacy, University of North Carolina Medical Center, 101 Manning Drive, CB 7600, Chapel Hill, NC 27514, USA.;UK Healthcare, 1000 S. Limestone, Room H110, Lexington, KY 40536, USA.;Department of Pharmacy, University of North Carolina Medical Center, 101 Manning Drive, CB 7600, Chapel Hill, NC 27514, USA.;Division of Cardiology, Department of Medicine, University of North Carolina, Burnett-Womack Building, 160 Dental Circle, CB# 7075, Chapel Hill, NC 27599, USA.;Division of Cardiology, Department of Medicine, University of North Carolina, Burnett-Womack Building, 160 Dental Circle, CB# 7075, Chapel Hill, NC 27599, USA.",
"authors": "Cicci|Jonathan D|JD|0000-0003-1688-2960;Jagielski|Sarah M|SM|0000-0001-8334-579X;Clarke|Megan M|MM|;Rayson|Robert A|RA|0000-0002-3505-416X;Cavender|Matthew A|MA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytz150",
"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 10.1093/ehjcr/ytz150ytz150Case ReportsLoperamide overdose causing torsades de pointes and requiring Impella temporary mechanical support: a case report http://orcid.org/0000-0003-1688-2960Cicci Jonathan D 1http://orcid.org/0000-0001-8334-579XJagielski Sarah M 2Clarke Megan M 1http://orcid.org/0000-0002-3505-416XRayson Robert A 3Cavender Matthew A 3Dinov Borislav Handling EditorMusella Francesca EditorKanakakis John EditorAziz Amir EditorGreen Peregrine Editor1 \nDepartment of Pharmacy, University of North Carolina Medical Center, 101 Manning Drive, CB 7600, Chapel Hill, NC 27514, USA2 \nUK Healthcare, 1000 S. Limestone, Room H110, Lexington, KY 40536, USA3 \nDivision of Cardiology, Department of Medicine, University of North Carolina, Burnett-Womack Building, 160 Dental Circle, CB# 7075, Chapel Hill, NC 27599, USA Corresponding author. Tel: +1 984 974 0229, Fax: +1 984 974 7163, Email: jcicci@unch.unc.edu12 2019 27 9 2019 27 9 2019 3 4 1 6 22 3 2019 23 4 2019 11 9 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.2019 This 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 journals.permissions@oup.comAbstract\nBackground\nLoperamide is a widely available oral μ-opioid receptor agonist, and loperamide abuse is increasing by those seeking intoxication. Loperamide has potent QTc-prolonging properties, placing patients at risk for ventricular arrhythmias and sudden cardiac death.\n\nCase summary\nA 23-year-old woman was found to be in pulseless ventricular fibrillation with a QTc of 554 ms and received multiple defibrillations and IV lidocaine. Her toxicology studies were negative. She subsequently experienced multiple episodes of torsades de pointes and was found to be in cardiogenic shock with a left ventricular ejection fraction of 5%. Following multiple defibrillations, an Impella® mechanical circulatory support device was placed, and she was given IV magnesium and IV lidocaine. After mechanical circulatory support was withdrawn, she experienced major bleeding and was found to have a deep vein thrombosis, bilateral radial artery thrombosis, and multiple pulmonary embolisms in the setting of heparin-induced thrombocytopenia. After stabilizing, she admitted to taking 80 tablets of loperamide 2 mg in pursuit of euphoria.\n\nDiscussion\nLoperamide is an increasingly popular agent of abuse. Loperamide-associated ventricular arrhythmias are rare with normal doses but more common with high doses, chronic ingestion, or interacting medications. Loperamide cardiotoxicity may be prolonged due to a long half-life and accumulation. Loperamide abuse may be under-recognized, leading to delays in treatment. Intravenous fluids, magnesium supplementation, chronotropes, transcutaneous or transvenous pacing, and defibrillation may be helpful in mitigating loperamide-associated polymorphic ventricular tachycardia. Clinicians should monitor for drug interactions in patients taking loperamide and screen for electrocardiographic abnormalities in those taking chronic or high-dose loperamide.\n\nLoperamideVentricular arrhythmiaTorsades de pointesQTc prolongationOverdoseCase report\n==== Body\nLearning points\n\nLoperamide is an increasingly popular agent of abuse and can cause life-threatening ventricular arrhythmias with high doses or interacting medications.\n\nLoperamide-associated ventricular arrhythmias are often under-recognized.\n\nLoperamide cardiotoxicity may be prolonged due to a long half-life and accumulation.\n\n\n\n\n\n\n\nIntroduction\nLoperamide is a µ-opioid receptor agonist that is 50 times more potent than morphine. Because loperamide is a P-glycoprotein substrate, efflux pumps in enterocytes and the central nervous system lead to low bioavailability and poor penetration through the blood–brain barrier. As a result, loperamide does not cause analgesia, euphoria, or respiratory depression at usual doses (≤16 mg in 24 h) and was historically viewed as ‘free of abuse potential’.1–7 Since the 1980s, loperamide has been classified as an over-the-counter product, and few incidents of intentional abuse have been reported to poison control centres through 2007.1,4,8\n\nBetween 2009 and 2015, the number of calls to poison control centres regarding intentional loperamide ingestions more than doubled, and Google searches for ‘loperamide high’ and ‘loperamide withdrawal’ steadily increased since 2011.1 Other analyses of online drug abuse forums note increased discussion of loperamide’s euphoric effects and potential for managing opiate withdrawal.7,9,10 About 18% of loperamide-related misuse/abuse cases from poison control centres involve cardiotoxicity, including tachycardia, bradycardia, ventricular arrhythmias, and cardiac arrest.1 Other investigations have observed increased loperamide-related activity through both the FDA Adverse Event Reporting System and poison control centres.4,5,9 Online drug abuse forums have endorsed using ‘boosters’ [including black pepper (piperine), cimetidine, and quinine] to increase bioavailability and augment loperamide’s euphoric effects.1\n\nWe describe a case report of a 23-year-old woman presenting with loperamide overdose and cardiac arrest requiring mechanical circulatory support.\n\nTimeline\nInitial presentation\t\n\nA 23-year-old woman was found with pulseless cardiac arrest and received bystander cardiopulmonary resuscitation (CPR).\n\nRhythm identified as pulseless ventricular fibrillation arrest. Received two defibrillations and intravenous lidocaine by emergency responders.\n\nQTc was 554 ms with a cove-like ST-elevation pattern upon hospital arrival and toxicology studies were negative.\n\n\n\t\nNext several days\t\n\nShe was intubated and targeted temperature management (TTM) was initiated to preserve neurological function; dobutamine was initiated after an echocardiogram revealed left ventricular ejection fraction (LVEF) 10–15%, consistent with a stress-induced cardiomyopathy.\n\nAfter completion of 24 h of TTM, she was extubated. She was then found to be in torsades de pointes (TdP) with QTc of 613 ms, requiring three electrical cardioversions.\n\nShe developed cardiogenic shock (blood pressure 84/43 mmHg, heart rate 109 b.p.m.), likely due to electrical instability from recurrent pulseless TdP. A bedside echocardiogram revealed worsening left ventricular hypokinesis with an LVEF of 5–10%, likely related to worsening stress-induced cardiomyopathy.\n\nAn Impella® 2.5 mechanical circulatory support device was placed percutaneously due to haemodynamic instability at the transferring centre.\n\n\n\t\nTransfer to tertiary academic medical centre\t\n\nTdP was managed with IV magnesium boluses and increased lidocaine infusion.\n\nImpella® device removed as she became haemodynamically stable.\n\nTwo spontaneous haemorrhages occurred at the right femoral arteriotomy site and led to decreased haemoglobin (nadir of 4.1 g/dL).\n\nShe was found to have a large subcapsular liver haematoma, right common iliac vein deep vein thrombosis, bilateral radial artery thrombosis, and multiple small pulmonary embolisms.\n\nArgatroban was initiated for heparin-induced thrombocytopenia with thrombosis, and patient was transitioned to dabigatran for discharge.\n\nShe admitted to ingesting 80 tablets of loperamide 2 mg (160 mg total) in pursuit of intoxication.\n\n\n\t\nCase presentation\nA 23-year-old woman with no known past medical history was found in pulseless ventricular fibrillation arrest and received cardiopulmonary resuscitation (CPR), two defibrillations, and intravenous lidocaine by emergency responders. Upon hospital arrival, her QTc was 554 ms with a cove-like ST-elevation pattern (Figure1). Toxicology studies were negative.\n\n\nFigure 1 Initial electrocardiogram demonstrating prolonged QTc and cove-like pattern of ST-segments in precordial leads.\n\nThe patient underwent targeted temperature management (TTM) to preserve neurologic function. An echocardiogram revealed a left ventricular ejection fraction (LVEF) of 10–15% with diffuse hypokinesis and a hypercontractile apex, most consistent with a stress-induced cardiomyopathy, and she was initiated on dobutamine. After completion of TTM and extubation, she experienced recurrent torsades de pointes (TdP) (QTc 613 ms) requiring three electrical cardioversions (Figure 2).\n\n\nFigure 2 Electrocardiogram upon arrival demonstrating prolonged QTc.\n\nFollowing these cardioversions, she developed worsening hypotension and was determined by the transferring facility to be in cardiogenic shock [blood pressure (BP) 84/34 mmHg, heart rate 109 b.p.m.]. Cardiogenic shock was felt to be secondary to recurrent, pulseless, electrical instability from TdP. A bedside echocardiogram demonstrated worsening left ventricular hypokinesis with an LVEF of 5–10%, likely related to worsening stress-induced cardiomyopathy. She was intolerant of increased inotropes due to recurrent arrhythmias, which persisted despite lidocaine administration. Amiodarone was avoided given concerns of further QTc-prolongation.\n\nGiven the clinical impression of cardiogenic shock and recurrent pulseless arrhythmias, the transferring facility placed an Impella® 2.5 mechanical circulatory support device via the right femoral artery. She was then transferred to University of North Carolina Medical Center (UNCMC) for further management. In transfer, new information obtained by interviewing the patient’s significant other indicated she had acutely ingested high doses of loperamide, in addition to previous chronic loperamide ingestion.\n\nUpon arrival to UNCMC, persistent episodes of TdP were managed with intravenous magnesium boluses and increased lidocaine infusion rates. Overdrive pacing with a temporary pacemaker was considered at this time, but her rhythm subsequently stabilized. Her QTc shortened over the subsequent days, and her BP normalized as she remained free of arrhythmias. Her mechanical circulatory support and lidocaine infusion were subsequently weaned.\n\nFollowing removal of the Impella®, she experienced two spontaneous haemorrhages at the right femoral arteriotomy site. The second episode was managed by balloon tamponade. After apparent haemostasis and angiographic resolution of her bleed, she developed worsening hypotension. Her haemoglobin acutely decreased to a nadir of 4.1 g/dL. A computed tomography scan demonstrated a large subcapsular liver haematoma and a right common iliac vein deep vein thrombosis (DVT). She was subsequently noted to have bilateral radial artery thrombosis. Argatrobran was started due to concern for heparin-induced thrombocytopenia with thrombosis (HITT). Her platelet factor 4 antibody was positive, and a ventilation/perfusion scan found multiple small pulmonary embolisms (PEs).\n\nHer oxygen requirement and thrombocytopenia improved with argatroban. After extubation, she admitted to taking up to 80 tablets of loperamide 2 mg (160 mg total) at a time in pursuit of intoxication. She had been practicing this behaviour for years after discovering it on the Internet and was unaware of potential complications. She was discharged on dabigatran for multiple PEs and DVT in the context of HITT.\n\nIn follow-up, the patient appeared well and had normalization of laboratory values, electrocardiogram, and LVEF (Figure3).\n\n\nFigure 3 Subsequent electrocardiogram in office follow-up demonstrating normalization of QTc.\n\nDiscussion\nLoperamide has been identified as a likely inhibitor of both the human ether-a-go-go-related gene (hERG) potassium channel Kv11.1 and the cardiac sodium channel Nav1.5.3,11 The hERG potassium channel underlies the delayed rectifier potassium current (IKr), and is the most common potassium channel associated with drug-induced QT-prolongation.12 Loperamide shares several structural similarities with and demonstrates comparable hERG-channel-affinity to terfenadine and cisapride, medications with established QTc-prolonging risks.3,11 Loperamide’s inhibition of the Nav1.5 channel may potentiate QRS widening, a side effect not shared with terfenadine or cisapride.3 Loperamide also inhibits L-type Ca2+ channels, which may further increase action potential duration.6,13\n\nLoperamide’s toxicity may be enhanced by interacting medications (Table1).14 Since loperamide is primarily metabolized by CYP2C8 and CYP3A4 and is a P-glycoprotein substrate, medications inhibiting these proteins may result in clinically significant loperamide interactions; clinically significant medication interactions involving CYP 2B6 and CYP 2D6 have not been reported.2,4,6,14,15\n\nTable 1 Loperamide medication interactions that may increase loperamide toxicity\n\nMedication\tProposed mechanism of interaction14,15\t\nCimetidine\tCYP3A4 inhibition\t\nClarithromycin\tCYP3A4 inhibition; P-glycoprotein inhibition\t\nErythromycin\tCYP3A4 inhibition; P-glycoprotein inhibition\t\nGemfibrozil\tCYP2C8 inhibition\t\nItraconazole\tCYP3A4 inhibition; P-glycoprotein inhibition\t\nKetoconazole\tCYP3A4 inhibition; CYP2C8 inhibition; P-glycoprotein inhibition\t\nQuinidine\tCYP3A4 inhibition; P-glycoprotein inhibition\t\nQuinine\tCYP2C8 inhibition; P-glycoprotein inhibition\t\nRanitidine\tCYP3A4 inhibition\t\nRitonavir\tP-glycoprotein inhibition\t\n\nNote: This is not a complete list of all loperamide medication interactions; other medications may interact with loperamide through similar mechanisms.\n\nCYP, cytochrome P450.\n\nManagement of loperamide-associated polymorphic ventricular tachycardia (VT) remains largely supportive. Loperamide and interacting medications should be immediately discontinued when toxicity is suspected. Intravenous fluids, magnesium, chronotropes, transcutaneous or transvenous pacing, and defibrillation may be helpful in mitigating polymorphic VT. Minimal data exist for using antiarrhythmic medications to manage loperamide-induced arrhythmias or using naloxone for loperamide-induced respiratory depression.4,14 Activated charcoal is not expected to be helpful in cases of chronic or acute loperamide use.16 Due to high protein binding, haemodialysis is unlikely to remove excess loperamide from circulation. Mechanical circulatory support may be considered for refractory cardiogenic shock, haemodynamic compromise, or recurrent cardiac arrest. Importantly, routine opiate screens do not include loperamide and loperamide-specific testing may not be available at all institutions.14 Additionally, large doses may lead to higher levels and a significantly prolonged half-life.17\n\nThis case is unique because it was complicated by recurring polymorphic VT and refractory cardiogenic shock. Mechanical support was considered warranted because the patient’s shock could not be successfully managed with inotropes. This strategy highlighted a lack of awareness of recognizing and managing loperamide intoxication, and the patient experienced multiple complications, including arteriotomy site bleeding and HITT. An alternative strategy could have been overdrive pacing with a transvenous pacemaker to suppress polymorphic VT.18 This may have allowed up-titration of vasoactive agents to manage hypotension while minimizing recurrent arrhythmias.\n\nAs awareness of opioid abuse has steadily increased in recent years, relatively little awareness exists regarding loperamide’s fatal arrhythmogenic potential. Reported cases of loperamide-associated mortality have increased sharply between 2014 and 2016, concurrent with the promotion of loperamide’s euphoric effects and symptom-withdrawal management by online forums.4 In January 2016, the FDA released a safety announcement outlining loperamide’s proarrhythmic effects, including cardiac arrest and death, and stated that loperamide should be considered as a possible cause of unexplained cardiac events.14 In January 2018, the FDA subsequently announced plans to reduce over-the-counter loperamide package size to minimize abuse potential.19 However, both loperamide and cimetidine, a common booster, are available over the counter without restriction. Given the ongoing opioid crisis, further efforts to minimize abuse potential should be considered. Clinicians should monitor for potential drug–drug interactions in all patients taking loperamide and should screen for electrocardiographic abnormalities in patients taking chronic and/or high-dose loperamide. Because of relatively low bioavailability in patients receiving standard doses without concomitant interacting medications, loperamide may be used cautiously in patients with pre-existing QTc abnormalities if clinically necessary.\n\nLead author biography\nJonathan D. Cicci graduated from the Ernest Mario School of Pharmacy at Rutgers University in 2011. He completed his PGY1 pharmacy practice residency and PGY2 cardiology specialty residency at the University of North Carolina Medical Center in 2012 and 2013. Since 2013, he has worked at the University of North Carolina Medical Center as a cardiology clinical specialist on the Cardiac Intensive Care Unit and General Cardiology services and as an Assistant Professor at the University of North Carolina Eshelman School of Pharmacy.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared.\n\nSupplementary Material\nytz150_Supplementary_Slide_Set Click here for additional data file.\n==== Refs\nReferences\n1 \nBorron SW , Watts SH , Tull J , Baeza S , Diebold S , Barrow A. \nIntentional misuse and abuse of loperamide: a new look at a drug with “low abuse potential” . J Emerg Med 2017 ;53 :73 –84 .28501383 \n2 \nVandenbossche J , Huisman M , Xu Y , Sanderson-Bongiovanni D , Soons P. \nLoperamide and P-glycoprotein inhibition: assessment of the clinical relevance . J Pharm Pharmacol 2010 ;62 :401 –412 .20604828 \n3 \nKang J , Compton DR , Vaz RJ , Rampe D. \nProarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic . Naunyn Schmiedebergs Arch Pharmacol 2016 ;389 :1133 –1137 .27530870 \n4 \nMiller H , Panahi L , Tapia D , Tran A , Bowman JD. \nLoperamide misuse and abuse . J Am Pharm Assoc (2003) 2017 ;57 :S45 –S50 .28189538 \n5 \nSwank KA , Wu E , Kortepeter C , McAninch J , Levin RL. \nAdverse event detection using the FDA post-marketing drug safety surveillance system: cardiotoxicity associated with loperamide abuse and misuse . J Am Pharm Assoc (2003) 2017 ;57 :S63 –S67 .28073687 \n6 \nBaker DE. \nLoperamide: a pharmacological review . Rev Gastroenterol Disord 2007 ;7(Suppl 3) :S11 –S18 .18192961 \n7 \nDierksen J , Gonsoulin M , Walterscheid JP. \nPoor man’s methadone: a case report of loperamide toxicity . Am J Forensic Med Pathol 2015 ;36 :268 –270 .26355852 \n8 U.S. Department of Justice. Lists of: scheduling actions controlled substances regulated chemicals. https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf (30 January 2018).\n9 \nLasoff DR , Koh CH , Corbett B , Minns AB , Cantrell FL. \nLoperamide trends in abuse and misuse over 13 years: 2002-2015 . Pharmacotherapy 2017 ;37 :249 –253 .27995643 \n10 \nDaniulaityte R , Carlson R , Falck R , Cameron D , Perera S , Chen L , Sheth A. \n“I just wanted to tell you that loperamide WILL WORK”: a web-based study of extra-medical use of loperamide . Drug Alcohol Depend 2013 ;130 :241 –244 .23201175 \n11 \nEkins S , Balakin KV , Savchuk N , Ivanenkov Y. \nInsights for human ether-a-go-go-related gene potassium channel inhibition using recursive partitioning and Kohonen and Sammon mapping techniques . J Med Chem 2006 ;49 :5059 –5071 .16913696 \n12 \nRoden DM. \nPredicting drug-induced QT prolongation and torsades de pointes . J Physiol 2016 ;594 :2459 –2468 .26660066 \n13 \nEnakpene EO , Riaz IB , Shirazi FM , Raz Y , Indik JH. \nThe long QT teaser: loperamide abuse . Am J Med 2015 ;128 :1083 –1086 .26052029 \n14 U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse. 2016 \nhttps://www.fda.gov/Drugs/DrugSafety/ucm504617.htm (30 January 2018).\n15 Lexicomp Online®, Lexi-Drugs® Hudson, OH: Lexi-Comp, Inc.; 2017 .\n16 \nLitovitz T , Clancy C , Korberly B , Temple AR , Mann KV. \nSurveillance of loperamide ingestions: an analysis of 216 poison center reports . J Toxicol Clin Toxicol 1997 ;35 :11 –19 .9022646 \n17 \nEggleston W , Nacca N , Marraffa JM. \nLoperamide toxicokinetics: serum concentrations in the overdose setting . Clin Toxicol (Phila) 2015 ;53 :495 –496 .25817442 \n18 \nOverbey AN , Austin A , Seidensticker DF , Lin AH. \nOverdrive pacing in a patient with incessant torsades de pointes . BMJ Case Rep 2013 ;2013 \npii : bcr2013200146 . doi: 10.1136/bcr-2013-200146. \n19 U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA limits packaging for anti-diarrhea medicine Loperamide (Imodium) to encourage safe use. 2018 \nhttps://www.fda.gov/Drugs/DrugSafety/ucm594232.htm (30 January 2018).\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "3(4)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Loperamide; Overdose; QTc prolongation; Torsades de pointes; Ventricular arrhythmia",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "31911979",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "28501383;26660066;27995643;9022646;16913696;18192961;25817442;26052029;26355852;28189538;24121811;28073687;23201175;20604828;27530870",
"title": "Loperamide overdose causing torsades de pointes and requiring Impella temporary mechanical support: a case report.",
"title_normalized": "loperamide overdose causing torsades de pointes and requiring impella temporary mechanical support a case report"
} | [
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"companynumb": "US-MYLANLABS-2020M1026661",
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"activesubstance": {
"activesubstancename": "MAGNESIUM"
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"drugadditional": "3",
... |
{
"abstract": "Valproate is one of the most used anti-epileptic drugs. Its common side effects are nausea, vomiting, weight gain, hair loss, tremor, changes in behavior, slowed thinking and impaired liver function. Blood dyscrasias are also relatively frequent and a few studies reported changes in serum immunoglobulin concentrations with valproate treatment. We describe a case of panhypogammaglobulinemia with transient pancytopenia due to valproate. Pancytopenia was recovered after discontinuation of valproate but panhypogammaglobulinemia has been persisting. Intravenous immunoglobulin is being administrated monthly. Previous reports describe that other sodium channel blockers, such as phenytoin and carbamazepine, have been associated with hypogammaglobulinemia. This report also suggests that immunodeficiencies can be caused by valproate.",
"affiliations": null,
"authors": "Eom|Tae-Hoon|TH|;Lee|Hyun-Seung|HS|;Jang|Pil-Sang|PS|;Kim|Young-Hoon|YH|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-012-1153-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "34(6)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": null,
"medline_ta": "Neurol Sci",
"mesh_terms": "D000361:Agammaglobulinemia; D000927:Anticonvulsants; D005260:Female; D006801:Humans; D007223:Infant; D010198:Pancytopenia; D013226:Status Epilepticus; D014635:Valproic Acid",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "1003-4",
"pmc": null,
"pmid": "22797722",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "15007150;12653849;15710303;22251925;2730260",
"title": "Valproate-induced panhypogammaglobulinemia.",
"title_normalized": "valproate induced panhypogammaglobulinemia"
} | [
{
"companynumb": "KR-UNICHEM LABORATORIES LIMITED-UCM201701-000016",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nSolid pseudopapillary neoplasms of the pancreas (SPN) are rare tumors. For patients with unresectable liver metastases of SPN, no standard treatment has been defined so far. Here we report a case of a 40-year-old woman with SPN and metastases confirmed to the liver, and disease progression in the liver after primary tumor resection and chemotherapy with gemcitabine and cisplatin.\n\n\nMETHODS\nChemosaturation with percutaneous hepatic perfusions is a minimally invasive, repeatable regional therapy which delivers chemotherapy directly to the liver while limiting systemic toxicity. As an individual treatment approach, the patient was treated with chemosaturation with percutaneous hepatic perfusions of melphalan.\n\n\nRESULTS\nThe procedure was performed twice within 8 weeks after which the liver metastases showed a marked reduction in size and vascularization (partial response). Grade 3 leukopenia after the second procedure was managed effectively with granulocyte colony-stimulating factor. No other toxicities were observed. Ten months after initiating treatment, the patient had a good performance status and remained stable.\n\n\nCONCLUSIONS\nFor SPN with unresectable liver metastases and progression despite systemic treatment, repeat chemosaturation with high-dose melphalan may also offer an effective regional treatment option.",
"affiliations": "National Center for Tumor Diseases, University of Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. Electronic address: Helene.Hofmann@med.uni-heidelberg.de.;Department of Anesthesiology, University Clinic of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.;Department of Surgery, University Clinic of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.;Department of Radiology, University Clinic of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.;Department of Pathology, University Clinic of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.;Department of Surgery, University Clinic of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.;National Center for Tumor Diseases, University of Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.;Department of Radiology, University Clinic of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.;National Center for Tumor Diseases, University of Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany; Marienhospital Wesel, Medical Department II, Pastor-Janssen-Strasse 8-38, 46483 Wesel, Germany.",
"authors": "Hofmann|Helene|H|;von Haken|Rebecca|R|;Werner|Jens|J|;Kortes|Nikolas|N|;Bergmann|Frank|F|;Schemmer|Peter|P|;Jäger|Dirk|D|;Radeleff|Boris|B|;Schulze-Bergkamen|Henning|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin; D008558:Melphalan",
"country": "Switzerland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1424-3903",
"issue": "14(6)",
"journal": "Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]",
"keywords": "Frantz tumor; Hepatic perfusions; Melphalan; Metastases; Pancreas; Pseudopapillary neoplasms",
"medline_ta": "Pancreatology",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D002291:Carcinoma, Papillary; D002945:Cisplatin; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008558:Melphalan; D010190:Pancreatic Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "100966936",
"other_id": null,
"pages": "546-9",
"pmc": null,
"pmid": "25280592",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unresectable isolated hepatic metastases from solid pseudopapillary neoplasm of the pancreas: a case report of chemosaturation with high-dose melphalan.",
"title_normalized": "unresectable isolated hepatic metastases from solid pseudopapillary neoplasm of the pancreas a case report of chemosaturation with high dose melphalan"
} | [
{
"companynumb": "DE-CIPLA LTD.-2015DE03464",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Patients affected by autoimmune diseases (rheumatoid arthritis, psoriasis, dermatomyositis) who are treated with methotrexate (MTX) sometimes develop lymphoproliferative disorders (LPDs). In approximately 40% of reported cases, the affected sites have been extranodal, and have included the gastrointestinal tract, skin, lung, kidney, and soft tissues. However, MTX-associated LPD (MTX-LPD) is extremely rare in the oral cavity. Here we report a 69-year-old Japanese woman with rheumatoid arthritis (RA) who developed MTX-LPD resembling Hodgkin's disease--so-called \"Hodgkin-like lesion\"--in the left upper jaw. Histopathologically, large atypical lymphoid cells including Hodgkin or Reed-Sternberg-like cells were found to have infiltrated into granulation tissue in the ulcerative oral mucosa. Immunohistochemistry showed that the large atypical cells were positive for CD20, CD30 and Epstein-Barr virus (EBV)-latent infection membrane protein-1 (LMP-1) and negative for CD15. EBV was detected by in situ hybridization (ISH) with EBV-encoded small RNA (EBER), and polymerase chain reaction (PCR) for LMP-1 and EBNA-2 in material taken from the formalin-fixed, paraffin-embedded specimen. To our knowledge, this is the first reported case of MTX-related EBV-associated LPD (MTX-EBVLPD), \"Hodgkin-like lesion\", of the oral cavity in a patient with RA.",
"affiliations": "Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan. k-kikuchi@dent.meikai.ac.jp",
"authors": "Kikuchi|Kentaro|K|;Miyazaki|Yuji|Y|;Tanaka|Akio|A|;Shigematu|Hisao|H|;Kojima|Masaru|M|;Sakashita|Hideaki|H|;Kusama|Kaoru|K|",
"chemical_list": "D018501:Antirheumatic Agents; D012367:RNA, Viral; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1007/s12105-010-0202-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-055X",
"issue": "4(4)",
"journal": "Head and neck pathology",
"keywords": null,
"medline_ta": "Head Neck Pathol",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D008727:Methotrexate; D009055:Mouth; D012367:RNA, Viral",
"nlm_unique_id": "101304010",
"other_id": null,
"pages": "305-11",
"pmc": null,
"pmid": "20676828",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11054684;15086409;6327772;15053043;18670155;19075188;10664623;8656264;8235288;19589162;18571037;17469100;10847469;12010788;9306970;20154586;10071343;16859835;3207388;8827036",
"title": "Methotrexate-related Epstein-Barr Virus (EBV)-associated lymphoproliferative disorder--so-called \"Hodgkin-like lesion\"--of the oral cavity in a patient with rheumatoid arthritis.",
"title_normalized": "methotrexate related epstein barr virus ebv associated lymphoproliferative disorder so called hodgkin like lesion of the oral cavity in a patient with rheumatoid arthritis"
} | [
{
"companynumb": "JP-PFIZER INC-2017000017",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "Hyponatremia is a most common disorder of electrolytes encountered in everyday clinical practice. Although many cases are mild and relatively asymptomatic, hyponatremia is nonetheless important clinically because of the potential for substantial morbidity and mortality. Despite the knowledge of hyponatremia since the mid-20th century, this common disorder remains incompletely understood in many basic areas because of its causation by multiple etiologies with differing pathophysiological mechanisms. Up to this time, the optimal treatment strategies have not been well defined. The authors present 3 typical hypotonic hyponatremic patients for colleages in clinical practice for studying, for establishing a common conception for the managing of hyponatremia. Orv Hetil. 2019; 160(8): 314-319.",
"affiliations": "II. Belgyógyászati Klinika és Kardiológiai Központ, Szegedi Tudományegyetem, Általános Orvostudományi Kar Szeged, Semmelweis u. 8., 6725.;I. Belgyógyászati Klinika, Szegedi Tudományegyetem, Általános Orvostudományi Kar Szeged.;Pszichiátriai Klinika, Szegedi Tudományegyetem, Általános Orvostudományi Kar Szeged.;I. Belgyógyászati Klinika, Szegedi Tudományegyetem, Általános Orvostudományi Kar Szeged.;II. Belgyógyászati Klinika és Kardiológiai Központ, Szegedi Tudományegyetem, Általános Orvostudományi Kar Szeged, Semmelweis u. 8., 6725.",
"authors": "Vígh|József|J|;Ábrahám|György|G|;Kálmán|János|J|;Zöllei|Magdolna|M|;Forster|Tamás|T|",
"chemical_list": null,
"country": "Hungary",
"delete": false,
"doi": "10.1556/650.2019.31318",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-6002",
"issue": "160(8)",
"journal": "Orvosi hetilap",
"keywords": "agyödéma; brain oedema; encephalopathia; encephalopathy; hyponatraemia; hyponatremia; osmotic demyelinating syndrome; ozmotikus demyelinisatiós szindróma",
"medline_ta": "Orv Hetil",
"mesh_terms": "D001929:Brain Edema; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D014882:Water-Electrolyte Balance",
"nlm_unique_id": "0376412",
"other_id": null,
"pages": "314-319",
"pmc": null,
"pmid": "30773034",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The clinical importance of hyponatremia.",
"title_normalized": "the clinical importance of hyponatremia"
} | [
{
"companynumb": "HU-ACCORD-116200",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "POTASSIUM"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "A Medical Acute Care Unit (MACU) was established at Chris Hani Baragwanath Academic Hospital (CHBAH) to provide comprehensive medical specialist care to the patients presenting with acute medical emergencies. Improved healthcare delivery systems at the MACU may result in shorter hospital stays, better outcomes, and less mortality.\nThe study's objective was to describe the demographics, diagnoses, disease patterns, and outcomes, including patient's mortality, admitted to the MACU at CHBAH.\nRecords of 200 patients admitted, between March 2015 to August 2015, to the MACU at CHBAH were reviewed. Patient demographics, diagnosis at admission, duration of stay, and outcomes were documented. Patients transferred to the medical ward, the Intensive Care Unit (ICU), or discharge. The leading causes of mortality were documented.\nOf the 200 patients, 59% were females. The patients' mean age was 46 (17.2) years, and the mean duration of stay at the MACU was 1.45 (1.25) days. Non-communicable diseases accounted for 76% of admissions. The most frequently diagnosed conditions included: diabetic ketoacidosis acidosis (DKA) and hyperosmolar non-ketotic (HONK) (17.5%), non-accidental self-poisoning (16%), hypertensive emergencies (9.5%), decompensated cardiac failure (8%) and ischemic heart disease (7%). Infectious diseases comprised 14% of the diagnoses, of which cases of pneumonia were the most common (5%). Most patients (77.5%) were transferred to medical wards, 12% to ICU, while 10% demised at the MACU. The leading causes of death included sepsis (25%), DKA/HONK (20%), non-accidental self-poisoning (10%), and cardiac failure (10%).\nNon-communicable diseases, particularly diabetic emergencies, were the leading causes of admission to the MACU at CHBAH. During the study period, high rates of case improvement, patient discharge, shorter hospital stay, and less mortality were observed. The leading cause of mortality was sepsis related.",
"affiliations": "Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.;Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.;Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.",
"authors": "Khan|Uzma|U|;Menezes|Colin N|CN|;Govind|Nimmisha|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.afjem.2020.11.006",
"fulltext": "\n==== Front\nAfr J Emerg Med\nAfr J Emerg Med\nAfrican Journal of Emergency Medicine\n2211-419X 2211-4203 African Federation for Emergency Medicine \n\nS2211-419X(20)30141-5\n10.1016/j.afjem.2020.11.006\nOriginal Article\nPatterns and outcomes of admissions to the medical acute care unit of a tertiary teaching hospital in South Africa\nKhan Uzma uzmak5267@gmail.com⁎ Menezes Colin N. Govind Nimmisha Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa\nDepartment of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa\n⁎ Corresponding author. uzmak5267@gmail.com\n08 12 2020 \n3 2021 \n08 12 2020 \n11 1 26 30\n2 5 2020 17 11 2020 22 11 2020 © 2018 Published by Elsevier Ltd. CC BY-NC-ND 4.0.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nA Medical Acute Care Unit (MACU) was established at Chris Hani Baragwanath Academic Hospital (CHBAH) to provide comprehensive medical specialist care to the patients presenting with acute medical emergencies. Improved healthcare delivery systems at the MACU may result in shorter hospital stays, better outcomes, and less mortality.\n\nObjectives\nThe study's objective was to describe the demographics, diagnoses, disease patterns, and outcomes, including patient's mortality, admitted to the MACU at CHBAH.\n\nMethods\nRecords of 200 patients admitted, between March 2015 to August 2015, to the MACU at CHBAH were reviewed. Patient demographics, diagnosis at admission, duration of stay, and outcomes were documented. Patients transferred to the medical ward, the Intensive Care Unit (ICU), or discharge. The leading causes of mortality were documented.\n\nResults\nOf the 200 patients, 59% were females. The patients' mean age was 46 (17.2) years, and the mean duration of stay at the MACU was 1.45 (1.25) days. Non-communicable diseases accounted for 76% of admissions. The most frequently diagnosed conditions included: diabetic ketoacidosis acidosis (DKA) and hyperosmolar non-ketotic (HONK) (17.5%), non-accidental self-poisoning (16%), hypertensive emergencies (9.5%), decompensated cardiac failure (8%) and ischemic heart disease (7%). Infectious diseases comprised 14% of the diagnoses, of which cases of pneumonia were the most common (5%). Most patients (77.5%) were transferred to medical wards, 12% to ICU, while 10% demised at the MACU. The leading causes of death included sepsis (25%), DKA/HONK (20%), non-accidental self-poisoning (10%), and cardiac failure (10%).\n\nConclusion\nNon-communicable diseases, particularly diabetic emergencies, were the leading causes of admission to the MACU at CHBAH. During the study period, high rates of case improvement, patient discharge, shorter hospital stay, and less mortality were observed. The leading cause of mortality was sepsis related.\n\nKeywords\nEmergencyMedicalAcuteCare unit\n==== Body\nAfrican relevance\n• This study was conducted in the largest hospital in Africa, the Chris Hani Baragwanath Academic Hospital.\n\n• Most patients in this study were resident in the surrounding urban township, Soweto.\n\n• This cross-sectional study highlights the acute medical conditions that patients have and their outcomes\n\n\n\nIntroduction\nAs a result, hospitals looked for structural reforms to improve the quality of care. The admission process of the Emergency centre (EC) for acutely ill medical patients to Internal Medicine needed to be improved [7]. This led to the introduction of a Medical Acute Care Unit (MACU), and “Acute Medicine” emerged as a branch of Internal Medicine in the developed world [7]. Acute Medicine is a subspecialty of Internal Medicine focused on the immediate and early specialist management of acute medical patients presenting to hospitals as emergencies [7]. The MACU is a dedicated ward where this takes place [8].\n\nThis model of health care has been widely implemented in the United Kingdom (U.K.) [7], Australia [9], and New Zealand [10], resulting in reports of good outcomes in terms of patients care and service delivery [11,12]. Currently, Acute Medicine is not a formally recognised specialty of Internal Medicine in South Africa. The MACU health care model is a new concept that we have adapted at Chris Hani Baragwanath Academic Hospital (CHBAH), a tertiary institution located in Soweto, South Africa (S.A.).\n\nSince the MACU was established at the CHBAH, there have not been studies regarding disease and mortality patterns. It is essential to understand acute medical admissions causes to develop or amend preventive and therapeutic protocols for specific diseases. This information is also essential for health care planners as it identifies areas of priority for ongoing service development.\n\nObjectives\nThis study aims to describe the pattern of diseases and outcomes, including mortality, in acutely ill medical patients admitted to the MACU at the CHBAH.\n\nMethods\nStudy setting\nChris Hani Baragwanath Academic Hospital is a tertiary referral hospital in Soweto, South Africa. It provides medical care to an indigent population of 3.6 million in all specialties. The Department of Internal Medicine has 500 beds. It is the hospital's busiest department with admits 36,000 admissions annually, with an average of 100 patients per day. Patients are referred from the EC, secondary hospitals, and clinics. Patients are assessed first by EC doctors and then referred to the medical registrar allocated to the MACU. The MACU is a 16-bed facility located close to the EC and radiology. It is a specifically equipped ward where haemodynamic monitoring and specific therapeutic services, excluding mechanical ventilation, can be provided. It is staffed by general medical registrars, nurses, and allied health professionals and supervised by a specialist physician. Patients with acute reversible illnesses with predicted favourable outcomes are accepted to the MACU. The general medicine specialist on duty for the day regularly reviews the patients and initiates the post-admission rounds at the MACU. The resuscitation and subsequent observations to monitor response to the therapy given are ensured. Any predicted adverse outcomes are documented and acted upon immediately. Once the acute illness is resolved, patients can be discharged home or transferred to the medical wards. Patients requiring mechanical ventilation or invasive haemodynamic monitoring are referred to the Intensive Care Unit or coronary care unit depending on the acute illness.\n\nStudy population\nWe included a convenient sample of 200 patients 18 years and older, with any form of medical emergency admitted to the MACU between March 2015 to August 2015. This period is not limited to one season.\n\nStudy design\nA retrospective review of the admission register of the MACU was performed. Demographic data, including gender and age, initial diagnosis, and outcomes, were recorded. In addition to the MACU register, patients' hospital files containing clinical details, duration of stay, and mortality were reviewed.\n\nThe initial diagnosis was assigned to systemic subgroups according to the organ system affected: cardiovascular, respiratory, renal, neurology, endocrine, non-accidental poisoning, and others. The initial diagnosis was further subdivided into specific diagnostic categories to assess the pattern of diseases.\n\nThe outcome was defined as the patient's discharge endpoint, i.e., directly home, transfer to the medical wards, ICU/ High Care, or death. The leading causes of mortality were documented.\n\nStatistical analysis\nThe statistical package, STATA®, version 12, was used for the data analysis. For descriptive data, means with standard deviations and medians with inter-quartile ranges were used. Demographic characteristics were expressed as frequencies and percentages. Analytical data were expressed using the Chi-square test. Variables having a two-tailed p < 0.05 were considered significant.\n\nEthics permission\nThe study was approved by the Human Research Ethics Committee of the University of the Witwatersrand (certificate no: M159953).\n\nResults\nIn the study cohort, there was a predominance of females, and the mean age of the patients was 46 (17.2) years. Patients in the 46–60 age group were the most frequently admitted, constituting a third of all admissions (Table 1).Table 1 Demographics of patients admitted to the MACU at Chris Hani Baragwanath Academic Hospital, South Africa (n = 200).\n\nTable 1Characteristic\tn (%)\t\nGender\t\nMale\t82.0 (41)\t\nFemale\t118 (59)\t\n\n\n\t\nAge groups in years\t\n18–30\t41 (20.5)\t\n31–45\t52 (26.0)\t\n46–60\t65 (32.5)\t\n61–75\t34 (17.0)\t\n>75\t8.0 (4.0)\t\n\n\n\t\nEthnicity\t\nAfrican\t182 (91)\t\nAsian\t8.0 (4.0)\t\nWhite\t6.0 (3.0)\t\nMixed ancestry\t4.0 (2.0)\t\n\n\nThe central organ systems affected in the study group included: cardiac (24.5%), endocrine (19.5%), and non-accidental self-poisoning (18.5%) (Table 2).Table 2 Reasons for admission by organ system affected, mean age and gender distribution of the study population at MACU, Chris Hani Baragwanath Academic Hospital, South Africa (n = 200).\n\nTable 2Affected organ system\tMean age in years\tMale\tFemale\tn (%)\t\nCardiac\t50(1.21)\t22\t27\t49 (24.5%)\t\nEndocrine\t48(1.11)\t23\t16\t39 (19.5%)\t\nNon-accidental self-poisoning\t28(1.21)\t13\t24\t37(18.5%)\t\nOthers\t46(1.41)\t11\t20\t31(15.5%)\t\nRespiratory\t43(1.31)\t7.0\t15\t22 (11.0%)\t\nNeurology\t60(1.41)\t7.0\t8.0\t15 (7.5%)\t\nRenal\t55(1.21)\t2.0\t5.0\t7.0 (3.5%)\t\n\n\nNon-accidental self-poisoning occurred more commonly in younger patients with a mean age of 28(1.21) years. Non-accidental self-poisoning and respiratory system disorders affected mainly females in the study population.\n\nThe most common diagnoses of the patients on admission to the MACU included diabetic ketoacidosis/hyperosmolar non-ketotic (17.5%), non-accidental self-poisoning with organophosphate and other agents (16%), hypertensive emergencies (9.5%), decompensated cardiac failure (8%), and ischemic heart disease (7%). Infectious diseases (14%) such as pneumonia, malaria, gastroenteritis, tuberculosis, and meningitis were noted. (Table 3).Table 3 Frequency of the Diagnoses of patients admitted to the MACU at Chris Hani Baragwanath Academic Hospital, South Africa (n = 200).\n\nTable 3Diagnosis\tFrequency n (%)\t\nDiabetic ketoacidosis/Hyperosmolar non-ketotic\t35 (17.5)\t\nHypertensive emergency\t19 (9.5)\t\nNon-accidental self-poisoning with organophosphates\t17 (8.5)\t\nDecompensated cardiac failure\t16 (8.0)\t\nNon-accidental self-poisoning with other toxic agents\t15 (7.5)\t\nMyocardial infarction\t14 (7.0)\t\nCerebrovascular accident\t13 (6.5)\t\nPneumonia\t10 (5.0)\t\nExacerbation of asthma\t6.0 (3.0)\t\nExacerbation of Chronic obstructive pulmonary disease\t6.0 (3.0)\t\nGastroenteritis\t6.0 (3.0)\t\nMalaria\t6.0 (3.0)\t\nNon-accidental self-poisoning with paracetamol\t5.0 (2.5)\t\nSeptic shock\t5.0 (2.5)\t\nPulmonary embolism\t4.0 (2.0)\t\nDisseminated Tuberculosis\t4.0 (2.0)\t\nAcute renal failure\t4.0 (2.0)\t\nChronic renal failure\t3.0 (1.5)\t\nMeningitis\t2.0 (1.0)\t\nEpilepsy\t2.0 (1.0)\t\nHypoglycaemia\t2.0 (1.0)\t\nThyroid storm\t2.0 (1.0)\t\nAlcohol intoxication\t1.0 (0.5)\t\nSystemic lupus erythematosus\t1.0 (0.5)\t\nPyelonephritis\t1.0 (0.5)\t\nThrombotic thrombocytopenic purpura\t1.0 (0.5)\t\n\n\nThe duration of stay of the study population at the MACU was short, with 22.5% of patients stayed for less than one day (Fig. 1).Fig. 1 Duration of stay of patients at MACU, Chris Hani Baragwanath Academic Hospital, South Africa (n = 200).\n\nPE = Pulmonary Embolus, HONK = Hyperosmolar non-ketotic.\n\nFig. 1\n\nThe mean duration of stay at the MACU was 1.45(1.25) days, which differed in the different age groups. It was longer, 1.90 (1.44) days in the younger patients 18–30 years old. The shortest mean duration of stay, 1.00 (1.69), was noted in older patients >75 years old. However, this difference in duration of stay was not significant (p-value 0.07). The duration of stay did not differ significantly among males versus females. There was no significant relationship between duration of stay and the organ system affected or diagnosis.\n\nThe outcomes of admissions to the MACU were favourable in most patients (77.5%), showed recovery, and transfer to the general medical wards. A few patients (12%) required invasive haemodynamic monitoring and were subsequently transferred to the ICU, and (1%) were discharged home. A proportion of 10% of the patients admitted to the MACU, demised.\n\nOf 20 patients who demised in MACU, the leading causes of death were sepsis-related (25%), diabetic ketoacidosis/hyperosmolar non-ketotic (20%), non-accidental self-poisoning with organophosphates and other toxic agents (15%), cardiac failure (10%), and hypertension (5%) (Fig. 2).Fig. 2 Causes of death of study patients who demised in MACU presented as percentages (n−20).\n\nFig. 2\n\nDiscussion\nTo the best of our knowledge, this was the first study describing the patterns of diseases in acute medical admissions to the MACU in S.A.\n\nIn this study, most patients were females (59%), in keeping with demographics seen in MACUs from the developed world. [13,14] The predominant age group of all the patients admitted at the MACU was 40–60 years (32.5%), also reported elsewhere [13,14]. Most of the patients in this sample were of African ethnicity (91%).\n\nIn the present study, 76% of admissions at the MACU were due to non-communicable diseases such as diabetic ketoacidosis/ hyperosmolar non-ketotic, hypertensive emergency, non-accidental self-poisoning, cardiac failure, ischemic heart disease, and cerebrovascular accident. The most commonly encountered disorders were within the scope of cardiology, endocrinology, non-accidental self-poisoning, and neurology, which is like data reported by other medical acute units in the developed world [7,13,14,15] (Table 4).Table 4 Patterns of diseases at the MACU, Chris Hani Baragwanath Academic Hospital, South Africa, and other international units.\n\nTable 4South Africa\nPresent study\tUnited Kingdom\n[7]\tUnited Kingdom\n[13]\tUnited Kingdom\n[14]\tIreland\n[15]\t\nDKA/HONK\tNonspecific chest pain\tCellulitis\tChest pain\tHeart failure\t\nSelf-poisoning\tPneumonia\tPsychiatric\tFalls\tAtrial fibrillation\t\nHypertensive emergency\tUrinary tract infection\tEndocrine\tPneumonia\tDiabetes\t\nCardiac failure\tCOPD\tCVA\tCOPD\tHyponatremia\t\nIschemic heart disease\tAcute bronchitis\tAlcohol excess\tGastrointestinal bleeding\tCOPD\t\nCVA\tCardiac dysrhythmias\tSelf-poisoning\tDiarrhoea and vomiting\tAnaemia\t\nPneumonia\tCoronary artery disease\tCollapse\tUrinary tract infection\tAltered mental status\t\nExacerbation of asthma\tSkin and soft tissue infection\tHeadache/Migraine\tCVA\tPneumonia\t\nExacerbation of COPD\tEpilepsy\tUrinary tract infection\tSelf-poisoning\tNeoplasia\t\nMalaria\tCerebrovascular disease\tGastritis\tCVA\tAcute myocardial infarction\t\nCHBAH-Chris Hani Baragwanath Academic Hospital CVA = Cerebrovascular accident, COPD = Chronic obstructive airway disease, DKA = Diabetic ketoacidosis, HONK=Hyperosmolar non-ketotic, MACU = Medical Acute Care Unit.\n\n\n\nThere is a shortage of data on the pattern of diseases at the MACUs in a developing country like S.A.; therefore, a local comparison was not possible. However, the findings of the current study could be explained by several reasons: there is a rising prevalence of the non-communicable diseases of urbanisation that were previously unknown in rural S.A. [16], such as diabetes [17] and cardiovascular diseases. [18] Chris Hani Baragwanath Academic Hospital serves Soweto's population, where risk factors for these diseases [19], such as obesity and smoking [20,21,22], are highly prevalent predisposing the individuals towards non-communicable diseases. Communicable diseases like HIV/AIDS and tuberculosis were the causes of epidemics in S.A. [23]. However, the reduced frequency of these disorders observed in this study might reflect effective case management with specific therapies. Widespread use of highly active antiretroviral therapy (HAART) in S.A. since 2005/6 resulted in increased survival of patients with HIV/AIDS with an accompanying rise in non-communicable disease co-morbidities in this subgroup [24]. Interestingly, metabolic syndrome, altered glucose metabolism, dyslipidaemia, and lipodystrophy are seen frequently in patients with HIV/AIDS [26,26]. The use of some antiretroviral drugs in these patients, such as zidovudine, didanosine, and protease inhibitors, can predispose them to an increased risk of diabetes [27]. However, data from the present study did not include information on the HIV status of patients. Also, patients with advanced HIV/AIDS or disseminated tuberculosis with poor prognosis may not meet the criteria for admission in the MACU and are admitted directly to the medical wards at CHBAH. For the same reasons, infectious diseases such as pneumonia, gastroenteritis, malaria, and meningitis were found in small numbers (12%), possibly because they also admitted directly to the internal medicine wards.\n\nNon-accidental self-poisoning was noted as a frequent reason for admission and mortality in the present study, especially in young African females, as previously reported in S.A. [28]. Most of these cases were individuals who attempted suicide [29]. The types of toxic agents used include organophosphates, paracetamol, cocaine, and other substances [30]. This could be explained based on the high prevalence of psychosocial stresses, such as untreated mental illness [31], substance abuse [32], family circumstances, and poverty [33].\n\nDuring the study period, outcomes of admissions to the MACU were favourable in most cases. Most patients improved and were discharged to the medical wards (77.5%). The improved quality of care in the MACU healthcare model may partly explain this result.\n\nThe duration of stay at the MACU was short, 1.45 (1.2) days. Similarly, a small duration of stay was reported elsewhere [13,14]. It is possible that most uncomplicated non-communicable diseases and acute communicable diseases may be treated within a shorter time period. The short duration of stay might have a positive benefit on local government health finances.\n\nThe mortality rate was lower in the MACU than the general medical wards at 10% and 13%, respectively. The differences in mortality reflect more intensive care in MACU and a different spectrum of illnesses in MACU as compared to the general medical wards. The most frequently reported causes of death (sepsis, DKA, self-poisoning, cardiac failure, and hypertension) may also be attributed to the high prevalence of these disorders and the increased percentage of older individuals in the present research. The high mortality associated with diabetes also raises concerns about whether suboptimal care is offered to diabetics at a community health clinic level [34,35] or whether these patients may delay in presenting to healthcare facilities.\n\nSepsis remains a problem in the South African context [36]. High mortality due to sepsis in this study may indicate loopholes in the management and failure to institute the time-sensitive resuscitation process, which is vital to the control of sepsis.\n\nOur results on mortality patterns were like reported elsewhere in the developed world [15]. However, due to the lack of data from MACUs in South Africa, our results do not have local comparisons.\n\nThe current study has several limitations. One of them is poor record-keeping, as is described in retrospective record reviews. We tried to overcome this through a precise search and retrieval of the data available. We excluded patients with incomplete data. There is a possibility of diagnostic errors due to a lack of diagnostic standards available for the study. Unfortunately, the percentage of patients that were discharged home after being discharged from MACU is not known. A further weakness is that only patients admitted to the MACU were included in the study, and the data does not consider acute medical patients that required direct admission to the general ward or ICU. Nonetheless, the data represents disease patterns, not the actual number of patients with acute conditions.\n\nFurthermore, this study was conducted over a short duration. The conduction of similar studies over a more extended period would offer more robust evidence for these findings. Considering the study's limitations, the community's actual disease pattern may not be accurately reflected. However, this study provides a valuable foundation for further studies on acute admission patterns at Chris Hani Baragwanath Academic Hospital despite these limitations.\n\nConclusion\nNon-communicable diseases, particularly diabetic emergencies, were the leading causes of admission to the MACU at CHBAH. During the study period, outcomes of admissions to the MACU were favourable in most cases. High rates of case improvement, patient discharge, shorter hospital stay, and less mortality were observed. The leading causes of mortality were sepsis-related, diabetes, and non-accidental self-poisoning.\n\nDissemination of results\nThe results of this study were presented at the academic meeting at the Chris Hani Baragwanath Academic Hospital.\n\nAuthor's contribution\nAuthors contributed as follow to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; and drafting the work or revising it critically for important intellectual content: UK contributed 40%; CM 30%; and NG 30%. All authors approved the version to be published and agreed to be accountable for all aspects of the work.\n\nDeclaration of competing interest\nThe authors declared no conflicts of interest.\n==== Refs\nReferences\n7 Subbe C.P. Bottle R.A. Bell D. Acute medicine: triage, timing, and teaching in the context of medical emergency admissions Eur J Intern Med 22 4 2011 339 343 10.1016/j.ejim.2011.05.015 21767749 \n8 Bell D. Skene H. Jones M. Vaughan L. A guide to the acute medical unit Br J Hosp Med 69 Sup7 2008 M107 M109 10.12968/hmed.2008.69.Sup7.30432 \n9 McNeill G.B.S. Brand C. Clark K. Optimizing care for acute medical patients: the Australasian medical assessment unit survey Intern Med J 41 1 A 2011 19 26 10.1111/j.1445-5994.2010.02359.x 21040322 \n10 Providence C. Gommans J. Burns A. Managing acute medical admissions: a survey of acute medical services and medical assessment and planning units in New Zealand Intern Med J 42 1 2012 51 56 10.1111/j.1445-5994.2010.02331.x 20681959 \n11 Rooney T. Moloney E.D. Bennett K. O’Riordan D. Silke B. Impact of an acute medical admission unit on hospital mortality: a 5-year prospective study QJM 101 6 2008 457 465 10.1093/qjmed/hcn025 18319292 \n12 Byrne D. Silke B. Acute medical units: review of the evidence Eur J Intern Med 22 4 2011 344 347 10.1016/j.ejim.2011.05.016 21767750 \n13 Downing H. Scott C. Kelly C. Evaluation of a dedicated short-stay unit for acute medical admissions Clin Med (Lond) 8 1 2008 18 20 18335661 \n14 James N.J. Hussain R. Moonie A. Richardson D. Waring W.S. Patterns of admissions in an acute medical unit: priorities for service development and education Acute Med 11 2 2012 74 80 22685697 \n15 Kellett J. Deane B. The diagnoses and co-morbidity encountered in the hospital practice of acute internal medicine Eur J Intern Med 18 6 2007 467 473 17822658 \n16 Mayosi B.M. Flisher A.J. Lalloo U.G. The burden of non-communicable diseases in South Africa Lancet 374 2009 934 947 10.1016/S0140-6736(09)61087-4 19709736 \n17 Bradshaw D. Norman R. Pieterse D. Levitt N.S. Estimating the burden of disease attributable to diabetes in South Africa in 2000 S Afr Med J 97 8 Pt 2 2007 700 706 17952227 \n18 Opie L.H. Mayosi B.M. Cardiovascular disease in sub-Saharan Africa Circulation 112 23 2005 3536 3540 10.1161/circulationaha.105.597765 16330692 \n19 Tibazarwa K. Ntyintyane L. Sliwa K. A time bomb of cardiovascular risk factors in South Africa: results from the heart of Soweto study “heart awareness days.” Int J Cardiol 132 2 2009 233 239 10.1016/j.ijcard.2007.11.067 18237791 \n20 Stein L. Urban M.I. Weber M. Effects of tobacco smoking on cancer and cardiovascular disease in urban black south Africans Br J Cancer 98 9 2008 1586 1592 10.1038/sj.bjc.6604303 18362941 \n21 Vorster H.H. The emergence of cardiovascular disease during the urbanization of Africans Public Health Nutr 5 1A 2002 239 243 12027290 \n22 Kruger H.S. Puoane T. Senekal M. van der Merwe M.T. Obesity in South Africa: challenges for government and health professionals Public Health Nutr 8 5 2005 491 500 16153330 \n23 Karim S.S. Churchyard G.J. Karim Q.A. Lawn S.D. HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response Lancet 374 9693 2009 921 933 10.1016/S0140-6736(09)60916-8 19709731 \n24 Oni T. Youngblood E. Boulle A. Patterns of HIV, T.B., and non-communicable disease multi-morbidity in peri-urban South Africa- a cross-sectional study BMC Infect Dis 2015 15 20 10.1186/s12879-015-0750-1 Jan 17 25583097 \n26 Samaras K. The burden of diabetes and hyperlipidemia in treated HIV infection and approaches for cardiometabolic care Curr HIV/AIDS Rep 9 3 2012 206 217 10.1007/s11904-012-0124-x 22752405 \n27 Samaras K. Prevalence and pathogenesis of diabetes mellitus in HIV-1 infection treated with combined antiretroviral therapy J Acquir Immune Defic Syndr 50 5 2009 499 505 10.1097/qai.0b013e31819c291b 19223782 \n28 Joubert P.H. Poisoning admissions of black south Africans J Toxicol Clin Toxicol 28 1 1990 85 94 2381025 \n29 Burrows S. Laflamme L. Suicide mortality in South Africa Soc Psychiat Epidemiol 41 2 2006 108 114 10.1007/s00127-005-0004-4 \n30. Eddleston M. Patterns and problems of deliberate self-poisoning in the developing world QJM 93 11 2000 715 731 11077028 \n31 Khasakhala L. Sorsdahl K.R. Harder V.S. Lifetime mental disorders and suicidal behaviour in South Africa Afr J Psychiatry 14 2 2011 134 139 \n32 Wild L.G. Flisher A.J. Bhana A. Lombard C. Substance abuse, suicidality, and self-esteem in south African adolescents J Drug Educ 34 1 2004 1 17 10.2190/07C2-P41F-4U2P-JH0Q 15468744 \n33 Aliber M. Chronic poverty in South Africa: incidence, causes, and policies World Dev 31 3 2003 473 490 \n34 Kramer M.K. McWilliams J.R. Chen H.-Y. Siminerio L.M. A community-based diabetes prevention program: evaluation of the group lifestyle balance program delivered by diabetes educators Diabetes Educ 37 5 2011 659 668 10.1177/0145721711411930 21918204 \n35 Coleman R. Gill G. Wilkinson D. Non-communicable disease management in resource-poor settings: a primary care model from rural South Africa Bull World Health Organ 76 6 1998 633 640 10191559 \n36 Ferrer R. Martin-Loeches I. Phillips G. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program Crit Care Med 42 8 2014 1749 1755 24717459\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-419X",
"issue": "11(1)",
"journal": "African journal of emergency medicine : Revue africaine de la medecine d'urgence",
"keywords": "Acute; Care unit; Emergency; Medical",
"medline_ta": "Afr J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101572277",
"other_id": null,
"pages": "26-30",
"pmc": null,
"pmid": "33318914",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": "18237791;21918204;16330692;25595711;16153330;22752405;24717459;21767750;12027290;19709736;21687912;22685697;18319292;18833973;21767749;16362168;10191559;11077028;17822658;19709731;15468744;18362941;19223782;18335661;21040322;17952227;2381025;20681959",
"title": "Patterns and outcomes of admissions to the medical acute care unit of a tertiary teaching hospital in South Africa.",
"title_normalized": "patterns and outcomes of admissions to the medical acute care unit of a tertiary teaching hospital in south africa"
} | [
{
"companynumb": "ZA-JNJFOC-20210460055",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nSince its registration in 2004, the calcimimetic agent cinacalcet has been established as an alternative treatment for secondary hyperparathyroidism (SHPT). Working by allosteric activation of the calcium-sensing receptor, cinacalcet can lower parathyroid hormone (PTH) and calcium (Ca) in patients with SHPT. The influence of calcimimetics on the perioperative course has been unclear so far.\n\n\nMETHODS\nWe retrospectively analyzed the data of patients with primary operation for SHPT between 2004 and 2011, comparing the perioperative course of patients with and without preoperative cinacalcet treatment.\n\n\nRESULTS\nFifty-six patients had cinacalcet therapy, and 54 patients had no calcimimetic medication prior to surgery. Gender, age, hemodialysis, and medical treatment were similar in both groups. Also, PTH levels were similar preoperatively and postoperatively (preoperative, 1,249 ± 676 vs. 1,196 ± 601 pg/ml; postoperative, 86 ± 220 vs. 62 ± 91 pg/ml). Patients with cinacalcet preoperatively had significant lower Ca levels preoperatively (2.49 ± 0.25 vs. 2.61 ± 0.24 mmol/l) and postoperatively (1.75 ± 0.37 vs. 1.86 ± 0.35 mmol/l) and had a higher rate of oral Ca substitution postoperatively (93 vs. 74 %). The risk for postoperative persistent disease was slightly higher in these patients compared to those without preoperative cinacalcet therapy (5 vs. 0 %, not significant).\n\n\nCONCLUSIONS\nIn our experience, cinacalcet did not alter the perioperative course in SHPT patients.",
"affiliations": "Department of Visceral and Endocrine Surgery, Lukaskrankenhaus Neuss, Preussenstr. 84, 41464 Neuss, Germany. dwirowski@lukasneuss.de",
"authors": "Wirowski|Denis|D|;Goretzki|Peter E|PE|;Schwarz|Katharina|K|;Lammers|Bernhard J|BJ|",
"chemical_list": "D057966:Calcimimetic Agents; D009281:Naphthalenes; D010281:Parathyroid Hormone; D002118:Calcium; D000069449:Cinacalcet",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00423-012-1005-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1435-2443",
"issue": "398(1)",
"journal": "Langenbeck's archives of surgery",
"keywords": null,
"medline_ta": "Langenbecks Arch Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D057966:Calcimimetic Agents; D002118:Calcium; D000069449:Cinacalcet; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D006996:Hypocalcemia; D016030:Kidney Transplantation; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes; D010281:Parathyroid Hormone; D016105:Parathyroidectomy; D011183:Postoperative Complications; D011300:Preoperative Care; D012189:Retrospective Studies; D013965:Thyroidectomy",
"nlm_unique_id": "9808285",
"other_id": null,
"pages": "131-8",
"pmc": null,
"pmid": "23007384",
"pubdate": "2013-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "21150219;19765255;16030053;20585352;14520607;21361849;15658670;21118366;19193912;18345956;19040330;21181622;19333685;19765253;19955824;17054287;21442382;20683565;17981190;21888861;19774959;22036941;21134538;18036025;18328354;16164656;21327525;22075073;19644521;19032523;16221104;19369690;20228675;17533023;18064514;15071126",
"title": "Cinacalcet effects on the perioperative course of patients with secondary hyperparathyroidism.",
"title_normalized": "cinacalcet effects on the perioperative course of patients with secondary hyperparathyroidism"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2019151263",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CINACALCET HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "OBJECTIVE\nIn light of current FDA guidelines on opioid use in children, we sought to determine the risk of post-tonsillectomy hemorrhage (PTH) in children who received ibuprofen with acetaminophen versus those who received narcotic with acetaminophen for postoperative pain control.\n\n\nMETHODS\nThis was an IRB-approved retrospective chart review of patients at a tertiary-care pediatric center. The medical records of 449 children who received acetaminophen and ibuprofen following intracapsular tonsillectomy with or without adenoidectomy were reviewed (NSAID group) and compared with medical records of 1731 children who underwent intracapsular tonsillectomy and received acetaminophen with codeine or hydrocodone with acetaminophen postoperatively (narcotic group). Main outcome measure was the incidence of PTH requiring return to the operating room. Secondary outcome measures included incidence of primary PTH, secondary PTH, and postoperative evaluation in the emergency department or readmission for pain and/or dehydration.\n\n\nRESULTS\nIncidence of PTH requiring return to the operating room was higher in the NSAID group (1.6%) compared with the narcotic group (0.5%), P=0.01. Incidence of primary PTH was significantly higher in the NSAID group (2%) versus the narcotic group (0.12%), P<0.0001. Incidence of secondary PTH was 3.8% in the NSAID group and 1.1% in the narcotic group (P<0.0001).\n\n\nCONCLUSIONS\nUse of ibuprofen after intracapsular tonsillectomy in children is associated with statistically significant increase in PTH requiring return to the operating room, as well as an increase in overall rates of both primary and secondary PTH. Ibuprofen provides pain control that is at least equivalent to narcotic and is not associated with respiratory depression. Further study of ibuprofen use in the post-tonsillectomy patient is warranted.",
"affiliations": "Thomas Jefferson University Hospital, 1020 Walnut St, Philadelphia, PA 19107, United States. Electronic address: Jill.Dsouza@jefferson.edu.;Thomas Jefferson University Hospital, 1020 Walnut St, Philadelphia, PA 19107, United States; Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803, United States. Electronic address: Richard.schmidt@nemours.org.;Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803, United States. Electronic address: Li.Xie@nemours.org.;Temple University, 3401 North Broad St, Philadelphia, PA 19140, United States. Electronic address: Julie.Adelman@tuhs.temple.edu.;Thomas Jefferson University Hospital, 1020 Walnut St, Philadelphia, PA 19107, United States; Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803, United States. Electronic address: heather.nardone@nemours.org.",
"authors": "D'Souza|Jill N|JN|;Schmidt|Richard J|RJ|;Xie|Li|L|;Adelman|Julie P|JP|;Nardone|Heather C|HC|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; D003061:Codeine; D007052:Ibuprofen",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5876",
"issue": "79(9)",
"journal": "International journal of pediatric otorhinolaryngology",
"keywords": "Ibuprofen; Intracapsular; Post-tonsillectomy hemorrhage; Tonsillectomy",
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D000082:Acetaminophen; D000233:Adenoidectomy; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002648:Child; D002675:Child, Preschool; D003061:Codeine; D003681:Dehydration; D004359:Drug Therapy, Combination; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007052:Ibuprofen; D015994:Incidence; D008297:Male; D010149:Pain, Postoperative; D010359:Patient Readmission; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D012307:Risk Factors; D014068:Tonsillectomy",
"nlm_unique_id": "8003603",
"other_id": null,
"pages": "1472-6",
"pmc": null,
"pmid": "26164211",
"pubdate": "2015-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Postoperative nonsteroidal anti-inflammatory drugs and risk of bleeding in pediatric intracapsular tonsillectomy.",
"title_normalized": "postoperative nonsteroidal anti inflammatory drugs and risk of bleeding in pediatric intracapsular tonsillectomy"
} | [
{
"companynumb": "US-JNJFOC-20160300587",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Juvenile parkinsonism can be caused by recessive mutations in several genes. Among these, homozygous or compound heterozygous mutations in the F-box only protein 7 gene (FBXO7) cause juvenile parkinsonism with variable degrees of pyramidal disturbances (PARK15). So far, only five families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported with this form. Here, we describe a new Turkish family with homozygous FBXO7 mutation (c.1492C > T, p.Arg498*). Three out of nine siblings born from consanguineous parents suffered from juvenile-onset progressive parkinsonism. Mental retardation was also documented in two of them. Of note, pyramidal signs were absent. The response to dopaminergic medications was present, but limited by dyskinesias and psychiatric side effects. Further genetic analysis of this Turkish family and the Italian PARK15 family reported previously revealed that the c.1492C > T mutation is present on two different haplotypes in the Italian family, and one of these haplotypes is shared in homozygous state in the Turkish patients. These findings contribute to the ongoing delineation of the genetic and clinical spectrum of PARK15.",
"affiliations": "Department of Neurology, Hacettepe University, Ankara, Turkey.;Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.;Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.;Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.;Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum - Università di Bologna, and IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy.;Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. Electronic address: v.bonifati@erasmusmc.nl.;Department of Neurology, Hacettepe University, Ankara, Turkey. Electronic address: elibol@hacettepe.edu.tr.",
"authors": "Yalcin-Cakmakli|Gul|G|;Olgiati|Simone|S|;Quadri|Marialuisa|M|;Breedveld|Guido J|GJ|;Cortelli|Pietro|P|;Bonifati|Vincenzo|V|;Elibol|Bulent|B|",
"chemical_list": "D044783:F-Box Proteins; C489149:FBXO7 protein, human",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1353-8020",
"issue": "20(11)",
"journal": "Parkinsonism & related disorders",
"keywords": "FBXO7; Gene; Juvenile; Mutation; Parkinsonism; Turkey",
"medline_ta": "Parkinsonism Relat Disord",
"mesh_terms": "D000293:Adolescent; D044783:F-Box Proteins; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D020734:Parkinsonian Disorders; D010375:Pedigree; D014421:Turkey; D055815:Young Adult",
"nlm_unique_id": "9513583",
"other_id": null,
"pages": "1248-52",
"pmc": null,
"pmid": "25085748",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism.",
"title_normalized": "a new turkish family with homozygous fbxo7 truncating mutation and juvenile atypical parkinsonism"
} | [
{
"companynumb": "PHHY2015TR086184",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
"druga... |
{
"abstract": "To expand the limited longterm data on sirolimus treatment in patients with lupus nephritis (LN). Our pilot short-term data suggested efficacy of sirolimus treatment in these patients.\n\n\n\nWe retrospectively reviewed 16 class III/IV/V patients with LN who have received prednisolone (PSL) and sirolimus either as initial or maintenance treatment.\n\n\n\nSixteen patients received sirolimus treatment (9 because of intolerance to standard immunosuppressants and 7 because of a history of malignancy) for 45.3 ± 36.5 months. In 5 patients, sirolimus and PSL were given as induction for active nephritis, and they showed improvements in proteinuria (2.8 ± 1.9 g/day at baseline, 0.1 ± 0.1 g/day after 36 mos, p = 0.011), anti-dsDNA (107.7 ± 91.9 IU/ml and 37.0 ± 55.4 IU/ml, respectively, p = 0.178), and C3 (54.8 ± 26.1 mg/dl and 86.3 ± 18.6 mg/dl, respectively, p = 0.081). Eleven patients received sirolimus and low-dose PSL as longterm maintenance, and they showed continued improvement in C3 (90.4 ± 18.1 mg/dl and 117.7 ± 25.1 mg/dl at commencement and after 36 mos, respectively, p = 0.025), stable renal function (estimated glomerular filtration rate 58.6 ± 25.8 ml/min and 63.0 ± 29.6 ml/min, respectively, p = 0.239), and proteinuria (0.8 ± 0.7 g/day and 0.7 ± 0.7 g/day respectively, p = 0.252). Renal flare occurred in 1 patient, and another patient who had stage 4 chronic kidney disease when sirolimus was started developed endstage renal failure after 27 months. Sirolimus was discontinued in 5 patients, in 4 cases related to drug side effects. Deterioration of dyslipidemia occurred in 4 patients, but was adequately controlled with statin therapy.\n\n\n\nThe preliminary evidence suggests that sirolimus may serve as an alternative treatment for patients with LN who do not tolerate standard treatment or who had a history of malignancy, and it has an acceptable longterm safety profile.",
"affiliations": "From the Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.;From the Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.;From the Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.;From the Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.;From the Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.;From the Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.;From the Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong. dtmchan@hku.hk.",
"authors": "Yap|Desmond Y H|DYH|0000-0001-8179-8293;Tang|Colin|C|;Chan|Gary C W|GCW|;Kwan|Lorraine P Y|LPY|;Ma|Maggie K M|MKM|;Mok|Maggie M Y|MMY|;Chan|Tak Mao|TM|",
"chemical_list": "D007166:Immunosuppressive Agents; D011239:Prednisolone; D020123:Sirolimus",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.180507",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "45(12)",
"journal": "The Journal of rheumatology",
"keywords": "LONGTERM TREATMENT; LUPUS NEPHRITIS; MALIGNANCY; SIROLIMUS",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D012189:Retrospective Studies; D020123:Sirolimus; D016896:Treatment Outcome",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "1663-1670",
"pmc": null,
"pmid": "30275264",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Longterm Data on Sirolimus Treatment in Patients with Lupus Nephritis.",
"title_normalized": "longterm data on sirolimus treatment in patients with lupus nephritis"
} | [
{
"companynumb": "HK-PFIZER INC-2018404623",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Venous thromboembolism (VTE) prophylaxis has become routine for patients undergoing most operations, but it remains controversial for breast operations due to a perceived low risk of VTE. There is limited evidence to support routine or extended VTE prophylaxis in breast surgery. We investigated the benefits and risks of the Caprini risk stratification tool and corresponding prevention program, including extended prophylaxis for high-risk groups, in patients undergoing operations for benign and malignant breast lesions.\n\n\n\nUsing Boston Medical Center data, we reviewed records of patients who underwent lumpectomy or total mastectomy (with or without axillary surgery and/or reconstruction), between 2011 and 2018, to collect information about operation, Caprini score, administration of prophylaxis, and postoperative VTE or bleeding events. Descriptive statistics were performed.\n\n\n\nSeven hundred fifty patients underwent 881 operations; 48.9% were at low or moderate risk of VTE, 43.8% were at high risk, and 7.3% were at highest risk. There were no VTE events in the low- and moderate-risk groups, 5 (1.3%) in the high-risk, and 1 (1.6%) in the highest-risk group. One patient was diagnosed with VTE during hospitalization. None of the 5 patients who developed VTE after discharge was prescribed the recommended extended chemoprophylaxis. There were 19 bleeding events that did not require reoperation; 3 patients returned to the operating room. There was no correlation of bleeding with receipt of extended chemoprophylaxis.\n\n\n\nThe Caprini protocol can identify high-risk breast surgery patients who may benefit from extended VTE chemoprophylaxis, as well as low-risk patients who require no chemoprophylaxis. Furthermore, administration of extended chemoprophylaxis was not associated with an increased risk of bleeding.",
"affiliations": "Department of Surgery, Boston Medical Center, Boston, MA.;Boston University School of Medicine, Boston, MA.;Department of Surgery, Boston Medical Center, Boston, MA; Boston University School of Medicine, Boston, MA.;Miami Cancer Institute, Baptist Health South Florida, Miami, FL.;Department of Surgery, Boston Medical Center, Boston, MA; Boston University School of Medicine, Boston, MA.;Department of Surgery, Boston Medical Center, Boston, MA; Boston University School of Medicine, Boston, MA.;Department of Medicine, Boston Medical Center, Boston, MA; Boston University School of Medicine, Boston, MA.;Department of Surgery, Boston Medical Center, Boston, MA; Boston University School of Medicine, Boston, MA.;Department of Surgery, Boston Medical Center, Boston, MA; Boston University School of Medicine, Boston, MA. Electronic address: michael.cassidy@bmc.org.",
"authors": "Kim|Na Eun|NE|;Conway-Pearson|Liam|L|;Kavanah|Maureen|M|;Mendez|Jane|J|;Sachs|Teviah F|TF|;Drake|F Thurston|FT|;Ko|Naomi Y|NY|;McAneny|David|D|;Cassidy|Michael R|MR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jamcollsurg.2019.11.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1072-7515",
"issue": "230(6)",
"journal": "Journal of the American College of Surgeons",
"keywords": null,
"medline_ta": "J Am Coll Surg",
"mesh_terms": "D000328:Adult; D000368:Aged; D001943:Breast Neoplasms; D018890:Chemoprevention; D005260:Female; D006801:Humans; D008408:Mastectomy; D008875:Middle Aged; D061646:Operative Time; D011183:Postoperative Complications; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D054556:Venous Thromboembolism",
"nlm_unique_id": "9431305",
"other_id": null,
"pages": "947-955",
"pmc": null,
"pmid": "31809861",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Standardized Risk Assessment and Risk-Stratified Venous Thromboembolism Prophylaxis for Patients Undergoing Breast Operation.",
"title_normalized": "standardized risk assessment and risk stratified venous thromboembolism prophylaxis for patients undergoing breast operation"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/21/0134222",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FONDAPARINUX SODIUM"
},
"drugadditional"... |
{
"abstract": "Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied.\n\n\n\nTo analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy.\n\n\n\nProspective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time.\n\n\n\nOf the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity.\n\n\n\nIn the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.",
"affiliations": "Faculdade de Saúde e Ecologia Humana, Vespasiano, MG - Brazil.;Rede Materdei de Saúde, Belo Horizonte, MG - Brazil.;University of Oslo, Oslo - Noruega.;Rede Materdei de Saúde, Belo Horizonte, MG - Brazil.;Rede Materdei de Saúde, Belo Horizonte, MG - Brazil.;Universidade Federal do Paraná, Curitiba, PR - Brazil.;University of Oslo, Oslo - Noruega.",
"authors": "de Barros|Márcio Vinícius Lins|MVL|0000-0002-6213-3226;Macedo|Ariane Vieira Scarlatelli|AVS|;Sarvari|Sebastian Imre|SI|;Faleiros|Monica Hermont|MH|;Felipe|Patricia Tavares|PT|;Silva|Jose Luiz Padilha|JLP|;Edvardsen|Thor|T|",
"chemical_list": "D018943:Anthracyclines; D000970:Antineoplastic Agents; D004317:Doxorubicin; D000068878:Trastuzumab",
"country": "Brazil",
"delete": false,
"doi": "10.5935/abc.20180220",
"fulltext": "\n==== Front\nArq Bras CardiolArq. Bras. CardiolabcArquivos Brasileiros de Cardiologia0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBC 10.5935/abc.20180220Original ArticleLeft Ventricular Regional Wall Motion Abnormality is a Strong\nPredictor of Cardiotoxicity in Breast Cancer Patients Undergoing\nChemotherapy de Barros Márcio Vinícius Lins 12Macedo Ariane Vieira Scarlatelli 2Sarvari Sebastian Imre 3Faleiros Monica Hermont 2Felipe Patricia Tavares 2Silva Jose Luiz Padilha 4Edvardsen Thor 3\n1 Faculdade de Saúde e Ecologia Humana, Vespasiano, MG -\nBrazil\n2 Rede Materdei de Saúde, Belo Horizonte, MG - Brazil\n3 University of Oslo, Oslo - Noruega\n4 Universidade Federal do Paraná, Curitiba, PR - BrazilMailing Address: Márcio Vinícius Lins de\nBarros, Rua Paracatu, 1451 Apt 500. Postal Code 30180-091, Santo\nAgostinho, Belo Horizonte, MG - Brazil. E-mail:\nmvbarros@cardiol.br,\nmarciovlbarros@gmail.com1 2019 1 2019 112 1 50 56 30 3 2018 05 7 2018 23 7 2018 This is an Open Access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is\nproperly cited.Background\nChemotherapeutic agents of anthracyclines class and humanized monoclonal\nantibodies are effective treatments for breast cancer, however, they present\na potential risk of cardiotoxicity. Several predictors have been recognized\nas predictors in the development of cardiac toxicity, and the evaluation of\nleft ventricular segmental wall motion abnormalities (LVSWMA) has not been\nstudied.\n\nObjective\nTo analyze prospectively the role of LVSWMA among echocardiographic\nparameters in the prediction of development of cardiotoxicity in breast\ncancer patients undergoing treatment with chemotherapy.\n\nMethods\nProspective cohort of patients diagnosed with breast cancer and in\nchemotherapy treatment with potential cardiotoxicity medications including\ndoxorubicin and trastuzumab. Transthoracic echocardiograms including speckle\ntracking strain echocardiography were performed at standard times before,\nduring and after the treatment to assess the presence (or lack thereof) of\ncardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left\nventricular ejection fraction, on at least one echocardiogram. Multivariate\nlogistic regression models were used to verify the predictors related to the\noccurrence of cardiotoxicity over time.\n\nResults\nOf the 112 patients selected (mean age 51,3 ± 12,9 years), 18\nparticipants (16.1%) had cardiotoxicity. In the multivariate analysis using\nthe logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03;\n37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p\n< 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%:\n1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity.\n\nConclusion\nIn the present study, we showed that LVWMA, in addition to global\nlongitudinal strains, were strong predictors of cardiotoxicity and could be\nuseful in the risk stratification of these patients.\n\nVentricular Dysfunction, LeftDrug TherapyCardiotoxicityBreast NeoplasmsAnthracyclinesTrastuzumab\n==== Body\nIntroduction\nThe introduction of new chemotherapeutic agents, and the use of advanced and precise\nradiotherapy techniques in the last decades have dramatically improved breast cancer\nsurvival.1 Chemotherapeutic\ndrugs of the anthracycline class, and the humanized monoclonal antibodies, such as\ntrastuzumab, are widely used and highly effective agents for breast cancer\ntreatment.2 Unfortunately,\nanthracyclines can induce cardiotoxic effects, and the severity of these adverse\neffects is compounded by concomitant use of trastuzumab.3\n\nChemotherapy may induce numerous cardiovascular complications, including\nhypertension, congestive heart failure, thromboembolic diseases, ischemic heart\ndisease, QT prolongation, and bradycardia.3 When used in combination, anthracyclines and trastuzumab may\nresult in heart failure in up to 27% of patients.4 Among cancer survivors, a third will die of cardiovascular\ndisease. Thus, the need for optimal cardiac care in the cancer population has become\nevident. Early detection of cardiac dysfunction may allow implementation of\ncardioprotective strategies before potentially irreversible myocardial damage has\noccured.5\n\nThe definition of cancer therapy-related cardiac dysfunction (CTRCD) is based on a\nserial decline in left ventricular (LV) ejection fraction (EF). Two-dimensional\nechocardiography (2DE) is increasingly used for monitoring cardiac function during\ncancer treatment due to its widespread availability and safety. Echocardiography\nallows assessment of systolic and diastolic function, pulmonary pressures, valvular\nfunction, right ventricular function, and the pericardium.6\n\nReduction in LV EF likely occurs late in the natural history of CTRCD patients as\nreduction in LV EF may not be overt until a substantial amount of myocardial reserve\nhas been exhausted, therefore more sensitive screening modalities for LV dysfunction\nare needed. Despite the recognition of several echocardiographic parameters\nassociated with CTRCD, including novel echocardiography-derived parameters of\nmyocardial mechanics, such as strain and strain rate, currently there is no\nconsensus in the medical practice to fully predict which patients are prone to\ndevelop cardiotoxicity.6-8\nPrevious studies have demonstrated the presence of regional myocardial dysfunction\nin patients with CTRCD,9-11\nhowever its role as a risk predictor has not been established. The purpose of this\nstudy is to verify the association between the occurrence of LV segmental wall\nmotion abnormality and the development of cardiotoxicity in patients with breast\ncancer undergoing chemotherapy.\n\nMethods\nStudy population\nThis study is part of a prospective cohort study of patients with breast cancer\nrecruited from the Mater Dei Hospital in the city of Belo Horizonte - MG from\nJanuary 2010 through December 2016. Inclusion criteria were, age above 18 years,\nhistologically confirmed breast cancer diagnosis, treatment with doxorubicin\nand/or trastuzumab, and who underwent echocardiography, according to the rules\nof the hospital protocol. Exclusion criteria were patients with previous\ndiagnosis of ventricular dysfunction including regional wall motion abnormality,\nsignificant valve disease, congenital heart disease, arrhythmias, chronic\ncoronary artery disease and left bundle branch block by electrocardiography.\nTreatment regimens were at the discretion of the oncologist and consisted of the\nuse of the following drugs alone or in combination: 1) doxorubicin and\ncyclophosphamide; 2) paclitaxel; 3) trastuzumab. The dosages of the medications\nwere prescribed according to guidelines.12\n\n\nClinical (e.g., hypertension, dyslipidemia, diabetes) laboratorial (e.g., sodium,\npotassium, calcium, magnesium, hemoglobin, creatinine and BNP) and transthoracic\nechocardiograms were collected at baseline and standardized time intervals for\neach treatment regimen, 6 months after treatment completion and annually\nthereafter.\n\nEchocardiography\nAll patients were referred to a transthoracic echocardiogram, including\nlongitudinal strain assessment with two-dimensional speckle-tracking\nechocardiography (2D STE). The echocardiographic studies and analyses were\nperformed by an experienced cardiologist (M.V.L.B.). The following\nechocardiographic parameters were assessed: LV end-systolic and end-diastolic\ndiameters and left atrial diameter. LV ejection fraction was assessed using\nSimpson's biplane method. Visual assessment of regional myocardial function was\nassessed on the basis of the observed wall thickening and endocardial motion of\nthe myocardial segment, as described previously.13 Abnormal septal motion was characterized as a\natypical movement of the interventricular septum during cardiac cycle with a\ntwo-dimensional echocardiography-guided M-mode approach. Diastolic function was\nassessed and classified using published criteria.14 LV diastolic dysfunction was stratified into\nfour grades as normal, impaired relaxation, pseudo normal filling or\nrestrictive.\n\nLongitudinal strain by 2D STE was obtained from apical four-chamber, two-\nchamber, and long-axis views. Three cardiac cycles from each view were recorded\nfor offline analyses with a frame rate > 50 frames/sec. Peak negative\nlongitudinal strain was assessed in 16 LV segments, defined as the peak negative\nvalue during the entire cardiac cycle, hence including post systolic shortening,\nand was averaged to global longitudinal strain (GLS). CTRCD was defined as a\ndecrease in LVEF of > 10 percentage points, to a value < 53% at repeated\ncardiac imaging studies during follow-up after chemotherapy.15\n\n\nThe echocardiographic studies were performed at standardized intervals according\nto the treatment regimen. 1) Patients treated with anthracyclines without\ntrastuzumab underwent an echocardiographic study at baseline, at completion of\nchemotherapy, and every six months after completed treatment. 2) Patients\ntreated with anthracyclines and trastuzumab underwent an echocardiographic study\nat baseline, after completion of the anthracycline treatment regimen, every 3\nmonths during trastuzumab therapy, and every six months after completed\ntreatment. 3) Patients treated with trastuzumab without anthracyclines underwent\nan echocardiographic study at baseline, every 3 months during trastuzumab\ntherapy, and every six months after completed treatment.\n\nEchocardiographic assessment was completed in patients with at least three\nechocardiographic studies performed during the research period.\n\nStatistical Analysis\nTo describe the qualitative variables, the absolute and relative frequencies were\nused, while to describe the quantitative variables, measures of central\ntendency, dispersion and position were used.\n\nIn order to identify the factors that influenced the occurrence of cardiotoxicity\nover time, the Generalized Estimation Equations (GEE) approach was used. An\nexchangeable correlation structure was assumed for the repeated observations of\nthe same individual. Univariable and multivariable models with a logit link\nfunction were considered. There was no occurrence of cardiotoxicity at the first\nmeasurement occasion and therefore we also included the baseline values of the\ntime-dependent predictors. Missing values were excluded from the analyses.\nVariables that were statistically significant at the 0.20 level were included in\nthe multivariable model. For this final model, a level of significance of 0.05\nwas adopted. Reproducibility of visual assessment of abnormal regional\nmyocardial function was evaluated by the kappa statistics.\n\nROC curves were built and the discrimination ability of the model was assessed by\nthe area under the ROC curve. All statistical analysis was performed using R\nStatistical Software 3.4.1 and the R packages gee, pROC and PredictABEL.\n\nEthical considerations\nThe study complies with the Declaration of Helsinki and was approved by the\nResearch and Ethical Council of the Mater Dei Hospital.\n\nResults\nStudied population\nA total of 112 patients were included. Mean follow-up time was 491 days. The\ncharacteristics of the population studied are summarized in Table 1. Most of the patients in the cohort\nwere female (98.2%). Mean age was 51.3 ± 12.9 years.\n\nTable 1 Clinical and laboratorial characteristics of 112 patients undergoing\nchemotherapy\n\nVariable\tn\t\nAge (mean ± SD)\t51,4 ± 11,1\t\nFemale (n/%)\t111 (99,1%)\t\nBMI (kg/m2)\t26,1 ± 5,8\t\nMastectomy (n/%)\t111 (99,1%)\t\nMedian follow-up time (months)\t16\t\nRadiotherapy (n/%)\t74 (66)\t\nChemotherapy (n/%)\t \t\nAC-T\t90 (80)\t\nAnti HER2\t29 (26)\t\nOthers\t20 (18)\t\nHormone Therapy (n/%)\t72 (64)\t\nCardiovascular risk factors (n/%)\t \t\nHypertension\t39 (35)\t\nDiabetes\t8 (7)\t\nHyperlipidemia\t21 (19)\t\nSmoking\t25 (22)\t\nBMI: body mass index; AC-T: Doxorubicin/cyclophosphamide - Taxol\n(Paclitaxel).\n\nOf the 112 patients followed up, 18 (16.1%) presented CTRCD.\n\nThe characteristics of the patients with abnormal LV segmental wall motion are\nsummarized in table 2. LV segmental wall\nmotion abnormality was found in 16 (14%) patients, most commonly at the time of\nthe second echocardiographic study (43%). LV segmental wall motion analyses by\nvisual assessment showed abnormalities most frequently in the interventricular\nseptum (78.5% - Figure 1), the inferior\n(14.3%), and the inferolateral (7.1%) walls. During the follow-up, no patient\npresented left bundle branch block by electrocardiography study.\n\nTable 2 Characteristics in patients with segmental wall motion abnormality during\nchemotherapy\n\nPatient\tAge\tTreatment*\tAbnormal contraction\tEchocardiographic follow-up\tRisk factors\tCTRCD\tFollow-up\t\n2\t49\t1,2,\tInfero-septal Hypokinesis\t5\tno\tyes\tDeath\t\n5\t40\t1,2\tAbnormal Septal motion\t2\tno\tyes\tNYHA I\t\n12\t68\t1,2\tÍnfero-lateral Hypokinesis\t5\tno\tyes\tNYHA I\t\n21\t30\t1,2\tAbnormal Septal motion\t3\tdyslipidemia\tno\t \t\n27\t43\t1,2\tAbnormal Septal motion\t2\tno\tno\t \t\n52\t73\t1,\tinferior Hypokinesis\t4\tDiabetes, Hypertension\tyes\tNYHA I\t\n63\t53\t1\tSeptal Hypokinesis\t2\tno\tno\t \t\n67\t77\t1,2\tAbnormal Septal motion\t4\thypertension\tyes\tNYHA II\t\n72\t44\t1,2\tAbnormal Septal motion\t2\tno\tno\t \t\n84\t59\t1,2\tInferior Hypokinesis\t4\tno\tno\t \t\n88\t34\t1\tAbnormal Septal motion\t3\tno\tno\t \t\n92\t39\t1\tAbnormal Septal motion\t3\tno\tyes\tdeath\t\n100\t41\t1\tInfero-septal Hypokinesis\t2\tno\tno\t \t\n110\t62\t1\tSeptal hypokinesis\t2\tno\tyes\tNYHA !\t\n* 1: anthracycline; 2: transtuzumab; CTRCD: cancer therapy-related\ncardiac dysfunction.\n\n\nFigure 1 Two-dimensional echocardiography-guided M-mode showing abnormal\nmotion of interventricular septum (arrow) during chemotherapy\ntreatment. LV: left ventricle; RV: right ventricle.\n\n\n\n\nAmong the variables studied, it was observed at multivariable analysis that GLS\nmeasurements as well as LV systolic dimensions and the presence of LV regional\nwall motion abnormalities at the baseline study could predict development of\ncardiotoxicity (Tables 3 and 4). The analysis of ROC curve of the final\nmodel (Figure 2) showed an area under the\ncurve (AUC) of 0.93 (0.88 - 0.98). When we exclude the presence of wall motion\nabnormality in the model, the AUC was 0.84 (0.72-0.96) showing additive\npredictive power of this variable (p = 0.047). Intraobserver variability and\ninterobserver variability for wall motion assessment were 0.89 and 0.81,\nrespectively.\n\nTable 3 Univariate analyses of predictors related of cardiotoxicity\n\nVariable\tO.R.\t95% CI\tp\t\nAge\t1.03\t[0.99; 1,07]\t0.151\t\nLVDD\t1.22\t[0.99; 1.50]\t0.061\t\nLVSD\t1.69\t[1.35; 2.12]\t0.000\t\nDiastolic dysfunction\t3.55\t[1.34; 9.44]\t0.011\t\nRegional wall motion abnormality\t8,91\t[2.75; 28.82]\t0.000\t\nLA\t0.95\t[0.78; 1.16]\t0.624\t\nGLS\t1.96\t[1.25; 3.09]\t0.022\t\nPASP\t1.86\t[0.32; 10.99]\t0.491\t\nBNP\t1.24\t[00.91; 1.70]\t0.306\t\nTroponin\t3.36\t[0.49; 23.14]\t0.219\t\nCreatinine\t0.04\t[0.00; 2.20]\t0.113\t\nHemoglobin\t0.90\t[0.60; 1.35]\t0.608\t\nSodium\t1.01\t[0.98; 1.03]\t0.623\t\nPotassium\t1.33\t[0.51; 3.51]\t0.559\t\nCalcium\t1.06\t[0.81; 1.39]\t0.657\t\nMagnesium\t6.20\t[0.67; 57.73]\t0.204\t\nHypertension\t0.79\t[0.26; 2.39]\t0.673\t\nDyslipidemia\t0.41\t[0.07; 2.21]\t0.298\t\nDiabetes\t1.15\t[0.15; 8.83]\t0.894\t\nLVDD: left ventricular diastolic dimension; LVSD: left ventricular\nsystolic dimension; GLS: global longitudinal strain; LA: left atrium\ndimension; PASP: pulmonary artery systolic pressure; BNP: brain\nnatriuretic peptidium.\n\nTable 4 Multivariate analysis of predictors related of cardiotoxicity\n\nVariable\tO.R.\t95% CI\tp\t\nLVSD\t1.34\t[1.01; 1.79]\t0.044\t\nRegional wall motion abnormality\t6.25\t[1.03; 37.95]\t0.046\t\nGLS\t1,48\t[1,02; 2.12]\t0.036\t\nLVSD: left ventricular systolic dimension; GLS: global longitudinal\nstrain.\n\n\nFigure 2 Roc curve of the multivariate model with and without evaluation of\nsegmental abnormal contractility.\n\n\n\n\nDiscussion\nIn this prospective, longitudinal cohort study, we showed that the presence of\nregional wall motion disturbance and decreased GLS are strong predictors of\nCTRCD.\n\nEarlier histopathological studies performed from endomyocardial biopsies have\ndemonstrated an initially focal and dispersed involvement of myocytes, surrounded by\nnormal cells in patients treated with anthracyclines.16 As the toxicity evolves, the frequency of these\nalterations increases, leading to significant myocardial damage and later on to\ndiffuse myocardial fibrosis. Thus, segmental contractile dysfunction may precede the\nintense and diffuse involvement of the heart seen in CTRCD. In this context,\ninterventricular septum dyssynchrony, as well as segmental hypokinesia may be\npresent due to tissue edema and/or focal cellular damage.17\n\nIndeed, Piotrowsk et al.9\ndemonstrated that in 60.9% of patients with LV systolic dysfunction regional wall\nmotion abnormalities were observed in the first echocardiography that revealed a\nsignificant drop of LVEF. In the majority of these cases (64%), regional hypokinesis\ninvolved the interventricular septum.9 Previous studies using tissue Doppler and 2D strain have also\nshown regional contractile alterations in patients treated with\nchemotherapy.10,11\nBoyd et al.18 demonstrated that in\nthe group with subclinical LV dysfunction (> 11% reduction in GLS compared to\nbefore therapy) 58% of regional segments had a reduction in strain by > 11%,\ncompared to 29% of regional segments in the group without subclinical LV dysfunction\n(p < 0.001).18\n\nIt is well known that reduction of longitudinal strain is an early predictive factor\nof cardiotoxicity induced by treatment with anthracyclines and trastuzumab, as\nconfirmed by our results. Negishi et al. showed that GLS was an independent\npredictor of subsequent reductions in EF, with a discrimination improvement by\nadding GLS of -18.6% to traditional parameters by echocardiography in patients at\nrisk for trastuzumab-induced cardiotoxicity.19 In another study, Sawaya el al.20 showed that in patients with breast cancer treated\nwith chemotherapy, GLS measured at the completion of anthracycline therapy was\nuseful in the prediction of subsequent cardiotoxicity.20\n\nIt was shown in a systematic review that an early reduction of 10% to 15% in GLS was\na useful parameter for the prediction of cardiotoxicity.21 A small cohort study was associated with\nsubclinical LV dysfunction as early as 1 week after treatment, showing a significant\ndecrease in GLS and annular systolic velocity of the lateral LV wall 7 days after by\ntrastuzumab treatment.22 Fei et\nal.23 found, in a cohort\nof 95 patients treated with anthracycline and trastuzumab, and followed for a mean\ntime of 17 months, 20% with cardiotoxicity, demonstrating a significant association\nbetween GLS reduction and LVEF decline.23\n\nThe presence of diastolic dysfunction was not an independent predictor of CTRCD in\nour study. The use of diastolic dysfunction as a surrogate marker for predicting\ntrastuzmab-induced cardiotoxicity is controversial. Earlier studies have shown that\ndiastolic impairment of the LV occurs before deterioration in LV EF in\nanthracycline24,25\nand transtuzumab26,27 induced cardiotoxicity. Development of diastolic dysfunction\nhas been reported in up to 57% of patients after treatment with anthracyclines or\nanthracyclines plus trastuzumab.28\nCochet et al.28 Serrano et\nal.29 evaluated\nMUGA-derived diastolic parameters and found that impaired LV diastolic function\nbefore treatment was an independent predictor of trastuzumab-mediated\ncardiotoxicity. Boyd at al.18\nshowed in a cohort involving 140 patients followed for seven days that LV diastolic\ndysfunction grade significantly increased from 46% to 57% (p < 0.001) after\ntreatment with anthracyclines. Importantly, diastolic dysfunction was more prevalent\nin the subgroup with a significant reduction in GLS, demonstrating the close\nassociation between systolic and diastolic dysfunction.18 A study using MUGA-derived diastolic function\nparameters investigated whether impairment of systolic function was preceded by\ndiastolic dysfunction in a group of 77 female breast cancer patients undergoing\ntrastuzumab therapy. The results of this study showed a nearly even number of\npatients with diastolic dysfunction preceding systolic dysfunction (54%), as\ncompared to the number of patients with the opposite order (42%).30 Discrepancy among those studies is\nprobably related to the different designs and interpretation of the results.\n\nLimitations\nAll patients were recruited from one center and the study consisted of a limited\nnumber of patients. The study was limited by a short duration of patient\nfollow-up, and therefore any possible long term impact of the early\nechocardiography abnormalities are uncertain. Long term follow up is therefore\nnecessary to determine the significance of these early observations. The\nproposed treatment was individually defined, including the use of\ncardio-protective drugs, which may have influenced our results.\n\nConclusion\nIn this prospective cohort of 112 patients undergoing treatment with chemotherapy for\nbreast cancer, we found segmental wall motion abnormality to be a strong predictor\nof cardiotoxicity. Therefore, assessment of segmental wall motion might be a useful\ntool in the evaluation of patients at risk of developing CTRCT, resulting in early\ndetection of myocardial dysfunction and potential reduction in morbidity and\nmortality in these patients.\n\nSources of Funding\n\nThere were no external funding sources for this study.\n\nStudy Association\n\nThis study is not associated with any thesis or dissertation work.\n\nEthics approval and consent to participate\n\nThis study was approved by the Ethics Committee of the Faculdade de Saúde\ne Ecologia Humana (FASEH) under the protocol number CAAE 55029916.6.0000.5101.\nAll the procedures in this study were in accordance with the 1975 Helsinki\nDeclaration, updated in 2013. Informed consent was obtained from all\nparticipants included in the study.\n\nAuthor contributions\n\nConception and design of the research and critical revision of the manuscript for\nintellectual contente: Barros MVL, Macedo AVS, Sarvari SI, Faleiros MH, Felipe\nPT, Silva JLP, Edvardsen T; acquisition of data: Barros MVL, Faleiros MH, Felipe\nPT; analysis and interpretation of the data: Barros MVL, Macedo AVS, Sarvari SI,\nSilva JLP; statistical analysis: Silva JLP; writing of the manuscript: Barros\nMVL, Macedo AVS, Sarvari SI, Felipe PT, Edvardsen T.\n\nPotential Conflict of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n==== Refs\nReferences\n1 DeSantis CE Ma J Goding Sauer A Newman LA Jemal A Breast cancer statistics, 2017, racial disparity in mortality by\nstate CA Cancer J Clin 2017 67 6 439 448 28972651 \n2 Hari KN Benjamin F Abigail MK Theodore P David H Akinyemi B Noninvasive measures of ventricular-arterial coupling and\ncircumferential strain predict cancer therapeutics-related cardiac\ndysfunction JACC Cardiovasc Imaging 2016 9 10 1131 1141 27085442 \n3 Yeh ET Bickford CL Cardiovascular complications of cancer therapy: incidence,\npathogenesis, diagnosis, and management J Am Coll Cardiol 2009 53 24 2231 2247 19520246 \n4 Slamon DJ Leyland-Jones B Shak S Fuchs H Paton V Bajamonde A Use of chemotherapy plus a monoclonal antibody against HER2 for\nmetastatic breast cancer that overexpresses HER2 N Engl J Med 2001 344 11 783 792 11248153 \n5 Yeh ET Chang H Oncocardiology - past, present, and future: A\nreview JAMA Cardiol 2016 1 9 1066 1072 27541948 \n6 López-Fernández T Thavendiranathan P Emerging cardiac imaging modalities for the early detection of\ncardiotoxicity due to anticancer therapies Rev Esp Cardiol 2017 70 6 487 495 28189542 \n7 Meattini I Curigliano G Terziani F Becherini C Airoldi M Allegrini G SAFE trial: an ongoing randomized clinical study to assess the\nrole of cardiotoxicity prevention in breast cancer patients treated with\nanthracyclines with or without Trastuzumab Med Oncol 2017 34 5 75 75 28364270 \n8 Reinbolt RE Patel R Pan X Timmers CD Pilarski R Shapiro CL Risk factors for anthracycline-associated\ncardiotoxicity Support Care Cancer 2016 24 5 2173 2180 26563179 \n9 Piotrowski G Gawor R Stasiak A Gawor Z Potemski P Banach M Cardiac complications associated with trastuzumab in the setting\nof adjuvant chemotherapy for breast cancer overexpressing human epidermal\ngrowth factor receptor type 2 - a prospective study Arch Med Sci 2012 8 2 227 235 22661994 \n10 Kapusta L Thijssen J Groot-Loonen J Antonius T Mulder J Daniëls O Tissue Doppler imaging in detection of myocardial dysfunction in\nsurvivors of childhood cancer treated with anthracyclines Ultrasound Med Biol 2000 26 7 1099 1108 11053744 \n11 Kapusta L Groot-Loonen J Thijssen J de Graaf R Daniëls O Regional cardiac wall motion abnormalities during and shortly\nafter anthracyclines therapy Med Pediatr Oncol 2003 41 5 426 435 14515381 \n12 Onitilo AA Engel JM Stankowski RV Cardiovascular toxicity associate with adjuvant Trastuzumab\ntherapy: prevalence, patient characteristics, and risk\nfactors Ther Adv Drug Saf 2014 5 4 154 166 25083270 \n13 Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Recommendations for cardiac chamber quantification by\nechocardiography in adults: an update from the American Society of\nEchocardiography and the European Association of Cardiovascular\nImaging J Am Soc Echocardiogr 2015 28 1 1 39.e14 25559473 \n14 Nagueh SF Smiseth OA Appleton CP Byrd 3rd BF Dokainish H Edvardsen T Recommendations for the evaluation of left ventricular diastolic\nfunction by echocardiography: an update from the american society of\nechocardiography and the european association of cardiovascular\nimaging J Am Soc Echocardiogr 2016 29 4 277 314 27037982 \n15 Plana JC Galderisi M Barac A Ewer MS Ky B Scherrer-Crosbie M Expert consensus for multimodality imaging evaluation of adult\npatients during and after cancer therapy: a report from the American Society\nof Echocardiography and the European Association of Cardiovascular\nImaging J Am Soc Echocardiogr 2014 27 9 911 939 25172399 \n16 Singal P Deally C Weinberg L Subcellular effects of adriamycin in the heart: A concise\nreview J Mol Cell Cardiol 1987 19 8 817 828 3320376 \n17 De Beer E Bottone A Voest E Doxorubicin and mechanical performance of cardiac trabeculae\nafter acute and chronic treatment: a review Eur J Pharmacol 2001 415 1 1 11 11245845 \n18 Boyd A Stoodley P Richards D Hui R Harnett P Vo K Anthracyclines induce early changes in left ventricular systolic\nand diastolic function: A single centre study PLoS ONE 2017 12 4 e0175544 28407011 \n19 Negishi K Negishi T Hare JL Haluska BA Plana JC Marwick TH Independent and incremental value of deformation indices for\nprediction of trastuzumab-induced cardiotoxicity J Am Soc Echocardiogr 2013 26 5 493 498 23562088 \n20 Sawaya H Sebag IA Plana JC Januzzi JL Ky B Tan TC Assessment of echocardiography and biomarkers for the extended\nprediction of cardiotoxicity in patients treated with anthracyclines,\ntaxanes, and trastuzumab Circ Cardiovasc Imaging 2012 5 5 596 603 22744937 \n21 Thavendiranathan P Poulin F Lim K Plana J Woo A Marwick T Use of myocardial strain imaging by echocardiography for the\nearly detection of cardiotoxicity in patients during and after cancer\nchemotherapy J Am Coll Cardiol 2014 63 25 Pt A 2751 2768 24703918 \n22 Emren SV Tuluce SY Levent F Tuluce K Kalkan T Alacacioglu A Evaluation of Trastuzumab-induced early cardiac dysfunction using\ntwo dimensional Strain Echocardiography Med Ultrason 2015 17 4 496 502 26649345 \n23 Fei HW Ali MT Tan TC Cheng KH Salama L Hua L Left ventricular global longitudinal strain in HER-2 + breast\ncancer patients treated with anthracyclines and trastuzumab who develop\ncardiotoxicity is associated with subsequent recovery of left ventricular\nejection fraction Echocardiography 2016 33 4 519 526 26992012 \n24 Lee BH Goodenday LS Muswick GJ Yasnoff WA Leighton RF Skeel RT Alterations in left ventricular diastolic function with\ndoxorubicin therapy J Am Coll Cardiol 1987 9 1 184 188 3794095 \n25 Marchandise B Schroeder E Bosly A Doyen C Weynants P Kremer R Early detection of doxorubicin cardiotoxicity: Interest of\nDoppler echocardiographic analysis of left ventricular filling\ndynamics Am Heart J 1989 118 1 92 98 2741800 \n26 Lange SA Ebner B Wess A Kogel M Gajda M Hitschold T Echocardiography signs of early cardiac impairment in patients\nwith breast cancer and trastuzumab therapy Clin Res Cardiol 2012 101 6 415 426 22249492 \n27 Cao L Cai G Chang C Miao AY Yu XL Yang ZZ Diastolic dysfunction occurs early in her2-positive breast cancer\npatients treated concurrently with radiation therapy and\ntrastuzumab Oncologist 2015 20 6 605 614 25933931 \n28 Cochet A Quilichini G Dygai-Cochet I Touzery C Toubeau M Berriolo- Riedinger A Baseline diastolic dysfunction as a predictive factor of\ntrastuzumab- mediated cardiotoxicity after adjuvant anthracycline therapy in\nbreast cancer Breast Cancer Res Treat 2011 130 3 845 854 21918836 \n29 Serrano JM Gonzalez I Del Castillo S Muniz J Morales LJ Moreno F Diastolic dysfunction following anthracycline-based chemotherapy\nin breast cancer patients: Incidence and predictors Oncologist 2015 20 8 864 872 26185196 \n30 Reuvekamp EJ Bulten BF Nieuwenhuis AA Meekes MRA de Haan AFJ Tol J Does diastolic dysfunction precede systolic dysfunction in\ntrastuzumab-induced cardiotoxicity: Assessment with multigated radionuclide\nangiography (MUGA) J Nucl Cardiol 2016 23 4 824 832 26048264\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0066-782X",
"issue": "112(1)",
"journal": "Arquivos brasileiros de cardiologia",
"keywords": null,
"medline_ta": "Arq Bras Cardiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018943:Anthracyclines; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D066126:Cardiotoxicity; D004317:Doxorubicin; D004452:Echocardiography; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D013318:Stroke Volume; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left",
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"pages": "50-56",
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"pubdate": "2019-01",
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"title": "Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy.",
"title_normalized": "left ventricular regional wall motion abnormality is a strong predictor of cardiotoxicity in breast cancer patients undergoing chemotherapy"
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"abstract": "Condylomata acuminata (CA) caused by human papillomavirus, often involves the external genitalia, perianal skin, and other moist mucous membranes. Urethral involvement is uncommon and little recognized, and usually limited to the distal 3 cm of the meatus. It is difficult to treat CA involving the urethra because of the anatomical location, risk of complications and recurrence. One effective method for the treatment of CA located at the urinary meatus is 5-aminolevulinic acid photodynamic therapy (ALA-PDT). However, experience of using this method for the treatment of whole urethral CA is still very limited. Herein, we treated a whole urethral CA successfully with photodynamic and holmium laser therapies. The case of a 25-year-old patient who underwent kidney transplant effected by intraurethral CA is presented and discussed. Catheter implantation and (or) immunosuppression treatment increases the risk of urethral condyloma acuminatum. The ALA-PDT is a safe, straightforward, effective, and well-tolerated treatment procedure for intraurethral CA. ALA-PDT combined with holmium laser treatment can successfully treat kidney transplant patients with intraurethral CA.",
"affiliations": "Department of Dermatology and Venereology, The First Affiliated Hospital of USTC.;Department of Urological Surgery, The First Affiliated Hospital of USTC, Hefei, Anhui, China.;Department of Urological Surgery, The First Affiliated Hospital of USTC, Hefei, Anhui, China.;Department of Dermatology and Venereology, The First Affiliated Hospital of USTC.;Department of Dermatology and Venereology, The First Affiliated Hospital of USTC.;Department of Dermatology and Venereology, The First Affiliated Hospital of USTC,. Electronic address: jiangfxing@126.com.;Department of Dermatology and Venereology, The First Affiliated Hospital of USTC.",
"authors": "Chang|Ruixue|R|;Xu|Congyun|C|;Liu|Yixun|Y|;Liu|Jinli|J|;Liu|Wei|W|;Jiang|Faxing|F|;Zhang|Siping|S|",
"chemical_list": null,
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"doi": "10.1016/j.pdpdt.2021.102496",
"fulltext": null,
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"issn_linking": "1572-1000",
"issue": "36()",
"journal": "Photodiagnosis and photodynamic therapy",
"keywords": "5-aminolevulinic acid photodynamic therapy; Condylomata acuminata; Human papillomavirus",
"medline_ta": "Photodiagnosis Photodyn Ther",
"mesh_terms": null,
"nlm_unique_id": "101226123",
"other_id": null,
"pages": "102496",
"pmc": null,
"pmid": "34428575",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "5-aminolevulinic acid photodynamic therapy and holmium laser treatment for intraurethral condylomata acuminata in a renal transplant patient.",
"title_normalized": "5 aminolevulinic acid photodynamic therapy and holmium laser treatment for intraurethral condylomata acuminata in a renal transplant patient"
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"abstract": "Heparin-induced thrombocytopenia (HIT) is an immune adverse reaction to heparin that is associated with life-threatening thrombotic complications. More rarely, HIT may begin after stopping of heparin or after flushes of heparin (autoimmune HIT). Fondaparinux has been proposed as a candidate treatment for HIT, but there are few data on its use in autoimmune HIT. An 86-year-old man with a history of diabetes mellitus, arterial hypertension, and hypercholesterolemia was admitted to our hospital for carotid endarterectomy. During surgery, only one heparin dose of 5,000 U was used. Platelet count started to decrease on the 11th day after surgery. Since the patient was not receiving heparin treatment/prophylaxis, HIT was not suspected. On day 19, platelet count was 61 × 10 3 /μL, and the patient was investigated for a diagnosis of HIT. Immunoglobulin (Ig)-G-specific enzyme-linked immunosorbent assay (ELISA) was positive and HIT was confirmed by a platelet aggregation test; fondaparinux 5 mg once a day was started. During fondaparinux treatment, platelet count did not increase and a lower leg deep vein thrombosis occurred. Fondaparinux was stopped and rivaroxaban 15 mg twice a day was started. Platelet count returned to base line after 10 days from fondaparinux withdrawal. There was no thrombotic event or bleeding complication during rivaroxaban treatment. Anecdotal evidence suggests risk of failure of fondaparinux treatment for autoimmune HIT and supports the use of rivaroxaban for treatment of HIT, justifying larger studies.",
"affiliations": "Cardiovascular Department, Angiology and Blood Coagulation Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy.;Cardiovascular Department, Angiology and Blood Coagulation Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy.",
"authors": "Sartori|Michelangelo|M|;Cosmi|Benilde|B|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0040-1713175",
"fulltext": "\n==== Front\nTH Open\nTH Open\n10.1055/s-00033990\nTH Open: Companion Journal to Thrombosis and Haemostasis\n2567-3459 2512-9465 Georg Thieme Verlag KG Stuttgart · New York \n\n10.1055/s-0040-1713175\n200013\nCase Report\nFailure of Fondaparinux in Autoimmune Heparin-Induced Thrombocytopenia\nSartori Michelangelo 1 Cosmi Benilde 1 1 Cardiovascular Department, Angiology and Blood Coagulation Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy\nAddress for correspondence Michelangelo Sartori, MD, PhD U.O. di Angiologia e Malattie della Coagulazione, Azienda Ospedaliera di Bologna, Policlinico Sant'Orsola MalpighiPad. 2, Via Albertoni, 15, 40138 BolognaItalymichelangelo.sartori@aosp.bo.it\n10 2020 \n20 10 2020 \n4 4 e305 e308\n19 3 2020 11 5 2020 \nThe Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (\nhttps://creativecommons.org/licenses/by/4.0/\n).\n2020The Author(s).This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is properly cited.\nHeparin-induced thrombocytopenia (HIT) is an immune adverse reaction to heparin that is associated with life-threatening thrombotic complications. More rarely, HIT may begin after stopping of heparin or after flushes of heparin (autoimmune HIT). Fondaparinux has been proposed as a candidate treatment for HIT, but there are few data on its use in autoimmune HIT. An 86-year-old man with a history of diabetes mellitus, arterial hypertension, and hypercholesterolemia was admitted to our hospital for carotid endarterectomy. During surgery, only one heparin dose of 5,000 U was used. Platelet count started to decrease on the 11th day after surgery. Since the patient was not receiving heparin treatment/prophylaxis, HIT was not suspected. On day 19, platelet count was 61 × 10\n3\n/μL, and the patient was investigated for a diagnosis of HIT. Immunoglobulin (Ig)-G-specific enzyme-linked immunosorbent assay (ELISA) was positive and HIT was confirmed by a platelet aggregation test; fondaparinux 5 mg once a day was started. During fondaparinux treatment, platelet count did not increase and a lower leg deep vein thrombosis occurred. Fondaparinux was stopped and rivaroxaban 15 mg twice a day was started. Platelet count returned to base line after 10 days from fondaparinux withdrawal. There was no thrombotic event or bleeding complication during rivaroxaban treatment. Anecdotal evidence suggests risk of failure of fondaparinux treatment for autoimmune HIT and supports the use of rivaroxaban for treatment of HIT, justifying larger studies.\n\n\nKeywords\nheparin-induced thrombocytopeniarivaroxabandeep vein thrombosisfondaparinuxFunding\nNone.\n==== Body\nIntroduction\n\nHeparin-induced thrombocytopenia (HIT) is a prothrombotic condition that is associated with increased in vivo thrombin generation that needs to be treated with nonheparin anticoagulants.\n1\nIn the majority of cases (typical-onset HIT), after a mean of 4 to 6 days of heparin exposure, immunoglobulin (Ig)-G antibodies against platelet factor 4 (PF4) bound to heparin develop. This is followed by the onset of the platelet count fall, and finally by thrombosis.\n2\nMore rarely, HIT may follow the exposure to heparin “flushes” or after stopping heparin. Such condition has been described and classified as “autoimmune HIT.”\n3\nOften, autoimmune HIT patients have severe thrombocytopenia that may last for several weeks, and this is not a contraindication to anticoagulant therapy.\n3\nPatients with autoimmune HIT require nonheparin anticoagulants, high therapeutic levels of anticoagulation are needed to control such hypercoagulable state.\n3\nRecent guidelines recommend the use of danaparoid, argatroban, fondaparinux, or a direct oral anticoagulant for HIT treatment.\n4\nFondaparinux is commonly used in every day clinical practice for clinically suspected and confirmed acute HIT. In a German registry, no thrombotic complication occurred in HIT patients treated with fondaparinux,\n5\nwhereas some case reports have shown failure of fondaparinux anticoagulation for HIT with evidence of in vivo cross-reactivity HIT antibodies.\n6\n7\nRecently, rivaroxaban, an oral direct factor Xa inhibitor, has been proposed as a candidate for treatment of HIT because it seems to have a better safety profile than the aforementioned agents and it is administered orally by fixed dosing.\n8\nAs suggested by several case series, the administration of rivaroxaban may be adequate for thrombosis treatment and normalization of platelet count in patients with HIT\n9\nand with autoimmune HIT.\n3\n6\nHere, we report a case of autoimmune HIT, in which a new thrombosis occurred during fondaparinux treatment, whereas rivaroxaban was not associated with thrombotic events or bleeding complications.\n\n\nCase Description\n\nAn 86-year-old man (weight: 74 kg) with a history of diabetes mellitus, arterial hypertension, hypercholesterolemia was admitted to our hospital for carotid endarterectomy. He was on therapy with ramipril 5 mg once a day, aspirin 100 mg once a day, amlodipine 10 mg once a day, omeprazole 20 mg once a day, and simvastatin 40 mg once a day. His medical history included a previous ischemic stroke and the presence of an infrarenal abdominal aortic aneurysm (diameter: 4.2 mm) and a 70% stenosis of left internal carotid. During carotid endarterectomy a bolus of unfractionated heparin (UFH), dose of 5,000 U, was used. Aspirin was continued during and after surgery. No prophylactic low molecular weight heparin was administered after surgery. As shown in the figure, in the morning before surgery his platelet count was 143 × 10\n3\n/μL (day 0: D0), platelet count decreased to 115 × 10\n3\n/μL on D3. On D5, platelet count increased, and reached 138 × 10\n3\n/μL on D7. Platelet count was not repeated till D11 when a decrease was observed (110 × 10\n3\n/μL). Since the patient was not receiving heparin treatment/prophylaxis, HIT was not initially suspected. On D16, platelet count was 91 × 10\n3\n/μL, the pretest clinical score (4 T’s) for the diagnosis of HIT\n10\nwas 4, but HIT was still not suspected. On D18, the platelet count declined further to 61 × 10\n3\n/μL and the patient was therefore investigated for a diagnosis of delayed onset and persisting (autoimmune) HIT. A whole leg ultrasound did not show any deep vein thrombosis (DVT), 4T's score was 5 and, on D19, HIT was diagnosed on the basis of the presence of HIT antibodies. An IgG-specific ELISA (PF4-enhanced IgG, Immucor GTI Diagnostics, Inc.) was strongly positive (OD = 2.359). The presence of HIT was confirmed by a platelet aggregation test. Platelet aggregation was performed using a four channel Chrono-Log platelet aggregometer (model 540, Chrono-Log Corp., Havertown, Pennsylvania, United States): 10 μL of UFH (1 and 100 IU/mL final concentration) was added to the cuvette and the aggregation response was monitored for 20 minutes.\n11\nThe presence of HIT was confirmed if the aggregation was >20% with 1 IU/mL UFH and completely inhibited or <20% with 100 IU/mL UFH. The patient's serum induced rapid activation of platelets from two donors in the presence of 1 IU/mL UFH, as well as in the absence of UFH, that was inhibited with 100 IU/mL UFH. He had renal insufficiency: serum creatinine was 1.2 mg/dL (estimated creatinine clearance with Cockcroft–Gault formula was 46 mL/min), and fondaparinux treatment was started. Given the absence of thrombosis and the presence of chronic kidney disease stage III, the dose of 5 mg once a day was used, aspirin was stopped. Since there was no clinical sign of venous/arterial thrombosis, the patient was discharged from the Hospital on D23. A close follow-up by our outpatient clinic was performed. During fondaparinux treatment, platelet count slightly decreased: being 46 × 10\n3\n/μL on D24 and D25, and 43 × 10\n3\n/μL on D27. On D27, he complained of calf pain and swelling, a whole leg ultrasound revealed a thrombosis confined to the internal gastrocnemius vein and to the soleal vein in the symptomatic leg, that is, isolated distal DVT. Fondaparinux was stopped and rivaroxaban 15 mg twice a day was started. As shown in\nFig. 1\n, the platelet count returned to baseline by 10 days following fondaparinux withdrawal. After 20 days since fondaparinux withdrawal, the patient was asymptomatic and the whole leg ultrasound showed recanalization of the calf DVT, rivaroxaban dosage was reduced to 20 mg once a day, the gel immunoassay was still positive for PF4-heparin complexes. After 3 months, rivaroxaban was stopped, whole-leg ultrasound did not show any distal DVT or any proximal DVT and the gel immunoassay gave a negative result. In summary, the patient completed a total of 3 months of rivaroxaban therapy with no recurrent thrombotic or bleeding complications. During follow-up (1 year), no arterial, neither venous thrombosis occurred.\n\n\nFig. 1 \nTrend in platelet counts after carotid endarterectomy (D0: day 0). On D0 a bolus of heparin dose of 5,000 U was used, 27 days afterwards (D27) a thrombosis confined to the internal gastrocnemius vein and to the soleal vein occurred (deep vein thrombosis). Fondaparinux: fondaparinux 5 mg once a day, Rivaroxaban: rivaroxaban 15 mg twice a day.\n\n\nDiscussion\nOur experience suggests that fondaparinux should be used with caution in autoimmune HIT and, consistent with previous reports, rivaroxaban may be safely used to prevent new thrombosis in this hypercoagulable condition.\n\n\nA recent German multicentre observational study showed no thrombotic complication in patient treated with fondaparinux\n5\nsupporting the use of fondaparinux in the everyday clinical practice for the treatment of suspected and confirmed HIT.\n12\nSeveral limitation of the aforementioned study should be acknowledged: the study was retrospective, HIT was not confirmed in several patients, and the choice of the anticoagulant agent was left to the decision of the physician in charge. On the contrary, a retrospective study in English patients\n13\nfound a 16% thromboembolic rate in patients treated with fondaparinux for HIT. Here, we report a case of autoimmune HIT refractory to fondaparinux. Patients with autoimmune HIT seem to be at higher thrombotic risk than patients with HIT and often require a higher and stable therapeutic levels of anticoagulation. Since the presence of chronic kidney disease and since no thrombosis was found, fondaparinux at a dose of 5 mg was used. It should be noted that the dose suggested for acute thromboembolism therapy is higher than the dose we used (5 vs. 7.5 mg), and this may explain the failure of fondaparinux in the present case. Moreover, it has been shown that fondaparinux may, although infrequently, cross-react with antiheparin PF4 antibodies, and at least theoretically provoke or exacerbate HIT. We did not measure fondaparinux cross reactivity with HIT antibodies, thus we can only speculate the cause of fondaparinux failure in the present case. It has to be noticed that, despite platelet started to decrease 11 days after surgery, HIT was suspected only after 16 days and anticoagulant treatment was started after 19 days. This delay may have lead to higher thrombotic burden and favored the occurrence of a new thrombosis.\n\n\n\nThe efficacy of rivaroxaban, an oral, direct factor Xa inhibitor, in the treatment of venous thromboembolism has been clearly established.\n14\nRivaroxaban does not show any interaction with PF4 or anti-PF4/heparin,\n15\nand there is growing evidence that rivaroxaban can be an alternative anticoagulant agent in HIT, so far more than 100 patients with HIT have been treated with such agent with low thromboembolic and bleeding complications.\n9\nDuring the past 4 years, we have already used rivaroxaban in other two cases of HIT, one has already been described,\n16\nanother was an HIT associated with DVT after orthopaedic surgery. We used rivaroxaban for HIT because it has been shown to be efficacious as single agent in the acute phase of DVT without a short initial parenteral anticoagulant treatment and it allowed us to treat the patient at home. We did not observed thromboembolic complications during rivaroxaban treatment in these three patients. It has to be noted that all the three patients whom we treated with rivaroxaban had HIT associated with thrombosis limited to the vein of lower leg. In our opinion, these patients may be a lower risk than patients with HIT associated with pulmonary embolism or arterial thrombosis.\n\n\n\nAutoimmune HIT is caused by platelet-activating anti-PF4/polyanion antibodies that are able to activate platelets in the absence of heparin.\n3\nAutoimmune HIT encompasses several clinical conditions, including delayed-onset HIT, spontaneous HIT syndrome (HIT without proximate heparin exposure), flush heparin HIT (HIT induced by exposure to heparin flushes), fondaparinux-associated HIT (HIT triggered by exposure to fondaparinux), and is associated with persistent thrombocytopenia and often with disseminated intravascular coagulation.\n3\nThis condition requires treated with consistently therapeutic levels of anticoagulation. Our patient clearly had a diagnosis of autoimmune HIT based on the clinical picture of delayed onset and persisting thrombocytopenia following a single-intraoperative UFH exposure, as well as the laboratory demonstration of patient's serum-induced platelet aggregation that occurred even in the absence of heparin but which was inhibited by high concentrations of heparin.\n\n\n\nRivaroxaban is one of the treatment options recommended for treating the hypercoagulability state associated with autoimmune HIT.\n3\nIndeed, at least seven cases of autoimmune HIT\n6\n9\n17\n18\n19\nhave been successfully treated with rivaroxaban. In contrast, several reports\n6\n7\n17\nhave highlighted unsuccessful outcomes when fondaparinux was used as the first therapeutic agent for autoimmune HIT. There are at least two explanations why rivaroxaban, given 15 mg twice a day, may be superior to fondaparinux in treating autoimmune HIT. First, twice-daily dosing of rivaroxaban versus once-daily fondaparinux dosing may better achieve persistent levels of therapeutic anticoagulation, and control of severe HIT-associated hypercoagulability. Second, autoimmune HIT may be a high-risk situation for fondaparinux cross-reactivity, a problem not seen with rivaroxaban.\n\n\nLimitations and Conclusion\n\nSome limitations of our report should be acknowledged. First, we were not able to determine whether fondaparinux cross-reactivity was a potential explanation for treatment failure in our patient with autoimmune HIT. Second, we cannot exclude the possibility that the explanation for fondaparinux failure was the dose administered (5 mg), which was lower than the usual dose (7.5 mg) recommended for treatment of acute HIT-associated thromboembolism. However, it should be noted that the Food and Drug Administration (FDA) recommends that fondaparinux be used with caution in patients with creatinine clearance of 30 to 50 mL/min, and our patient had additional considerations (advanced age and concomitant antiplatelet medications).\n20\nThus, the 5mg dose we gave seemed appropriate for initial treatment in our 86-year-old male patient with chronic renal disease. Despite the additional limitation of a single case report, our observations are consistent with emerging clinical experience and supports the intriguing hypothesis that rivaroxaban may be a superior option over fondaparinux for treating autoimmune HIT.\n\n\nConflict of Interest None declared.\n\nNote\nInformed consent was obtained from the patient for the purpose of publication.\n==== Refs\nReferences\n1 Cosmi B Current management of heparin-induced thrombocytopenia\nExpert Rev Hematol 2015 8 06 837 849\n26368591 \n2 Greinacher A Heparin-induced thrombocytopenia\nJ Thromb Haemost 2009 7 019 12\n19630757 \n3 Greinacher A Selleng K Warkentin T E Autoimmune heparin-induced thrombocytopenia\nJ Thromb Haemost 2017 15 11 2099 2114\n28846826 \n4 Cuker A Arepally G M Chong B H American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia\nBlood Adv 2018 2 22 3360 3392\n30482768 \n5 Schindewolf M Steindl J Beyer-Westendorf J Use of fondaparinux off- label or approved anticoagulants for management of heparin- induced thrombocytopenia\nJ Am Coll Cardiol 2017 70 21 2636 2648\n29169470 \n6 Poudel D R Ghimire S Dhital R Forman D A Warkentin T E Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review\nPlatelets 2017 28 06 614 620\n28856946 \n7 Tvito A Bakchoul T Rowe J M Greinacher A Ganzel C Severe and persistent heparin-induced thrombocytopenia despite fondaparinux treatment\nAm J Hematol 2015 90 07 675 678\n25683147 \n8 Linkins L A Warkentin T E Pai M Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study\nJ Thromb Haemost 2016 14 06 1206 1210\n27061271 \n9 Warkentin T E Pai M Linkins L A Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review\nBlood 2017 130 09 1104 1113\n28646118 \n10 Lo G K Juhl D Warkentin T E Sigouin C S Eichler P Greinacher A Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings\nJ Thromb Haemost 2006 4 04 759 765\n16634744 \n11 Legnani C Cini M Pili C Boggian O Frascaro M Palareti G Evaluation of a new automated panel of assays for the detection of anti-PF4/heparin antibodies in patients suspected of having heparin-induced thrombocytopenia\nThromb Haemost 2010 104 02 402 409\n20539902 \n12 Schindewolf M Steindl J Beyer-Westendorf J Frequent off-label use of fondaparinux in patients with suspected acute heparin-induced thrombocytopenia (HIT)--findings from the GerHIT multi-centre registry study\nThromb Res 2014 134 01 29 35\n24703295 \n13 Kang M Alahmadi M Sawh S Kovacs M J Lazo-Langner A Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study\nBlood 2015 125 06 924 929\n25515959 \n14 Cohen A T Bauersachs R Rivaroxaban and the EINSTEIN clinical trial programme\nBlood Coagul Fibrinolysis 2019 30 03 85 95\n30920394 \n15 Krauel K Hackbarth C Fürll B Greinacher A Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies\nBlood 2012 119 05 1248 1255\n22049520 \n16 Sartori M Favaretto E Cini M Legnani C Cosmi B Rivaroxaban in the treatment of heparin-induced thrombocytopenia\nJ Thromb Thrombolysis 2015 40 03 392 394\n25804370 \n17 Manji F Warkentin T E Sheppard J I Lee A Fondaparinux cross-reactivity in heparin-induced thrombocytopenia successfully treated with high-dose intravenous immunoglobulin and rivaroxaban\nPlatelets 2020 31 01 124 127\n31397594 \n18 Bakchoul T Borst O Riessen R Autoimmune heparin-induced thrombocytopenia after transcatheter aortic valve implantation: successful treatment with adjunct high-dose intravenous immunoglobulin\nTH Open 2019 3 02 e200 e202\n31263800 \n19 Mian H Warkentin T E Sheppard J I Autoimmune HIT due to apheresis catheter heparin flushes for stem cell harvesting before autotransplantation for myeloma\nBlood 2017 130 14 1679 1682\n28830891 \n20 ARIXTRA. Accessed 28 April 2020 at:https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021345s010lbl.pdf\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2512-9465",
"issue": "4(4)",
"journal": "TH open : companion journal to thrombosis and haemostasis",
"keywords": "deep vein thrombosis; fondaparinux; heparin-induced thrombocytopenia; rivaroxaban",
"medline_ta": "TH Open",
"mesh_terms": null,
"nlm_unique_id": "101715740",
"other_id": null,
"pages": "e305-e308",
"pmc": null,
"pmid": "33103050",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "16634744;30482768;29169470;25515959;19630757;28646118;26368591;28830891;22049520;25683147;31263800;20539902;27061271;25804370;28846826;31397594;24703295;30920394;28856946",
"title": "Failure of Fondaparinux in Autoimmune Heparin-Induced Thrombocytopenia.",
"title_normalized": "failure of fondaparinux in autoimmune heparin induced thrombocytopenia"
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"companynumb": "IT-MYLANLABS-2020M1096289",
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"occurcountry": "IT",
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"activesubstancename": "ASPIRIN"
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{
"abstract": "The safety and efficacy of immune checkpoint inhibitors in solid organ transplant recipients (SOTR) are unclear, as SOTR are usually excluded from clinical investigations due to their high risk for irreversible allograft rejection. We observed a kidney transplant patient with metastatic cutaneous squamous cell carcinoma who experienced complete response under anti-tumour therapy using cemiplimab and prevention of transplant rejection by fixed dose everolimus.",
"affiliations": "Department of Dermatology, Christian Hospital Unna, Unna, Germany.;Department of Dermatology, Christian Hospital Unna, Unna, Germany.;Skin Cancer Center, Department of Dermatology, Ruhr-University Bochum, Bochum, Germany.;Department of Dermatology, Christian Hospital Unna, Unna, Germany.",
"authors": "Gambichler|T|T|https://orcid.org/0000-0001-7862-3695;Hessam|S|S|;Lüttringhaus|T|T|;Boms|S|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ced.15018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": null,
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": null,
"nlm_unique_id": "7606847",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34767651",
"pubdate": "2021-11-12",
"publication_types": "D016422:Letter",
"references": null,
"title": "Prompt response of advanced cutaneous squamous cell carcinoma to cemiplimab in a kidney transplant patient receiving treatment with everolimus.",
"title_normalized": "prompt response of advanced cutaneous squamous cell carcinoma to cemiplimab in a kidney transplant patient receiving treatment with everolimus"
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"occurcountry": "DE",
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"activesubstancename": "TACROLIMUS"
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"abstract": "Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres.\n\n\n\nTo assess efficacy of all-oral HCV therapy in advanced liver disease.\n\n\n\nBetween December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed.\n\n\n\nGenotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively.\n\n\n\nAll-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.",
"affiliations": "Philadelphia, PA, USA.;New Haven, CT, USA.;San Diego, CA, USA.;Saint Louis, MO, USA.;Houston, TX, USA.;Gainesville, FL, USA.;Aurora, CO, USA.;Indianapolis, IN, USA.;New York, NY, USA.;Baltimore, MD, USA.;Chapel Hill, NC, USA.;Ann Arbor, MI, USA.;La Jolla, CA, USA.;Chapel Hill, NC, USA.;San Francisco, CA, USA.;Gainesville, FL, USA.;Chapel Hill, NC, USA.;Hannover, Germany.",
"authors": "Reddy|K R|KR|;Lim|J K|JK|;Kuo|A|A|;Di Bisceglie|A M|AM|;Galati|J S|JS|;Morelli|G|G|;Everson|G T|GT|;Kwo|P Y|PY|;Brown|R S|RS|;Sulkowski|M S|MS|;Akuschevich|L|L|;Lok|A S|AS|;Pockros|P J|PJ|;Vainorius|M|M|;Terrault|N A|NA|;Nelson|D R|DR|;Fried|M W|MW|;Manns|M P|MP|;|||",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1111/apt.13823",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "45(1)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents; D016208:Databases, Factual; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D038622:Internationality; D008103:Liver Cirrhosis; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "115-126",
"pmc": null,
"pmid": "27790729",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.",
"title_normalized": "all oral direct acting antiviral therapy in hcv advanced liver disease is effective in real world practice observations through hcv target database"
} | [
{
"companynumb": "US-GILEAD-2017-0293874",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nTo investigate oxaliplatin-induced severe anaphylactic reactions (SAR) in metastatic colorectal cancer in a retrospective case series analysis and to conduct a systemic literature review.\n\n\nMETHODS\nDuring a 6-year period from 2006 to 2011 at Kaohsiung Veterans General Hospital, a total of 412 patients exposed to oxaliplatin-related chemotherapy were retrospectively reviewed. Relevant English-language studies regarding life-threatening SAR following oxaliplatin were also reviewed in MEDLINE® and PubMed® search.\n\n\nRESULTS\nEight patients (1.9%, 8 of 412 cases) were identified. Seven patients were successful resuscitated without any sequelae and one patient expired. We changed the chemotherapy regimen in five patients and rechallenged oxaliplatin use in patient 3. Twenty-three relevant English-language studies with 66 patients were reported. Patients received a median of 10 cycles of oxaliplatin (range, 2 to 29). Most common symptoms were respiratory distress (60%), fever (55%), and hypotension (54%). Three fatal events were reported (4.5%). Eleven patients (16%) of the 66 cases were rechallenged by oxaliplatin.\n\n\nCONCLUSIONS\nSAR must be considered in patients receiving oxaliplatin-related chemotherapy, especially in heavily pretreated patients. Further studies on the mechanism, predictors, preventive methods and management of oxaliplatin-related SAR are recommended.",
"affiliations": "Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veteran General Hospital, Kaohsiung 81346, Taiwan, China.",
"authors": "Wang|Jui-Ho|JH|;King|Tai-Ming|TM|;Chang|Min-Chi|MC|;Hsu|Chao-Wen|CW|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v18.i38.5427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "18(38)",
"journal": "World journal of gastroenterology",
"keywords": "Anaphylactic; Colorectal cancer; Metastasis; Oxaliplatin",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000707:Anaphylaxis; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012189:Retrospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5427-33",
"pmc": null,
"pmid": "23082060",
"pubdate": "2012-10-14",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016454:Review",
"references": "10416017;14692042;10566767;21524570;16154353;11085200;9647612;15539924;16282245;20346128;19031966;12888815;18845186;19352593;15864887;12210395;12712487;21448307;20826449;11859992;9135491;11822769;16493620;20210930;11249043;20205880;15831089;20092386;15175436;14551506;19822513;11484969;18607839;17909865;16865410;9849497;10623704;16907658;20437874",
"title": "Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: case series analysis.",
"title_normalized": "oxaliplatin induced severe anaphylactic reactions in metastatic colorectal cancer case series analysis"
} | [
{
"companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-339458",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
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"abstract": "Immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment for human immunodeficiency virus (HIV) infection has a wide variety of causes. Delayed diagnosis and treatment of IRIS is fatal. We report a case of a 21-year-old man with HIV infection and Pneumocystis jirovecii pneumonia. The patient presented with fever and dyspnea with deterioration of pulmonary infiltrations 5 days after starting antiretroviral treatment. We reached the diagnosis of IRIS based on radial endobronchial ultrasound (EBUS)-guided lung biopsy. In conclusion, radial EBUS-guided lung biopsy via bronchoscopy is a valuable and minimally invasive technique for the rapid diagnosis of IRIS-associated Pneumocystis jirovecii pneumonia.",
"affiliations": "Department of Infectious Disease, First Hospital of China Medical University, Shenyang, China.;Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, China.;Department of Infectious Disease, First Hospital of China Medical University, Shenyang, China.;Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, Shenyang, China.;Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, China.;Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, China.",
"authors": "Wen|Ying|Y|;Wang|Meng-Chan|MC|;Zhou|Ying|Y|;Lin|Xu-Yong|XY|;Hou|Gang|G|https://orcid.org/0000-0003-3438-1764;Yin|Yan|Y|",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/0300060520946544",
"fulltext": "\n==== Front\nJ Int Med Res\nJ. Int. Med. Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520946544\n10.1177_0300060520946544\nCase Report\nImmune reconstitution inflammatory syndrome associated with Pneumocystis pneumonia in a patient with AIDS\nWen Ying 1 Wang Meng-chan 2 Zhou Ying 1 Lin Xu-yong 3 https://orcid.org/0000-0003-3438-1764Hou Gang 2* Yin Yan 2* \n1 Department of Infectious Disease, First Hospital of China Medical University, Shenyang, China\n\n2 Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, China\n\n3 Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, Shenyang, China\n* These authors contributed equally to this work.\n\nYan Yin, Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, No. 155 Nanjing Street, Shenyang, Liaoning 110001, China. Email: yinyan1b@126.com\n27 8 2020 \n8 2020 \n48 8 03000605209465443 2 2020 10 7 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment for human immunodeficiency virus (HIV) infection has a wide variety of causes. Delayed diagnosis and treatment of IRIS is fatal. We report a case of a 21-year-old man with HIV infection and Pneumocystis jirovecii pneumonia. The patient presented with fever and dyspnea with deterioration of pulmonary infiltrations 5 days after starting antiretroviral treatment. We reached the diagnosis of IRIS based on radial endobronchial ultrasound (EBUS)-guided lung biopsy. In conclusion, radial EBUS-guided lung biopsy via bronchoscopy is a valuable and minimally invasive technique for the rapid diagnosis of IRIS-associated Pneumocystis jirovecii pneumonia.\n\nHuman immunodeficiency virusimmune reconstitution inflammatory syndromeendobronchial ultrasoundtransbronchial lung biopsyPneumocystis jirovecii pneumoniahighly active antiretroviral therapytypesetterts2\n==== Body\nIntroduction\nPatients with acquired immunodeficiency syndrome (AIDS) suffer from opportunistic infections (OIs). When such patients start highly active antiretroviral therapy (HAART), they may experience a paradoxical worsening or recurrence of OIs, termed “immune reconstitution inflammatory syndrome” (IRIS).1 IRIS is associated with considerable morbidity and mortality.2 Thus, rapid definite diagnosis and targeted treatment of IRIS are urgently needed. Sampling with bronchoscopy is an important method of obtaining a definite diagnosis. Here, we report a case of IRIS-associated Pneumocystis jirovecii pneumonia (PJP)3 in a patient with AIDS that was confirmed by bronchoscopy and radial endobronchial ultrasound (EBUS)-guided lung biopsy. The patient recovered rapidly after treatment with trimethoprim/sulfamethoxazole (TMP/SMX) and methylprednisolone.\n\nCase report\nA 21-year-old man was referred to our hospital with a 20-day history of dyspnea and productive cough. He started empirical antibiotic treatment but the symptoms were not relieved. On admission, his vital signs were normal: temperature 36.5°C; respiration rate 15 breaths/minute; pulse 70 beats/minute; and blood pressure 105/60 mmHg. Breath sounds in the bilateral lungs were rough without rales. Chest computed tomography (CT) on the day of admission showed ground-glass opacities in the bilateral lungs (Figure 1a). Blood gas analysis showed type I respiratory failure [pH 7.41; arterial partial pressure of CO2 (PaCO2) 34 mmHg; and arterial partial pressure of O2 (PaO2) 52 mmHg], and a combination human immunodeficiency virus (HIV) antigen/antibody test was positive. The CD4+ T cell count was 81 cells/μL. The lactate dehydrogenase (LDH) level was 471 U/L, and C-reactive protein (CRP) level was 8.40 mg/L. Renal and liver function were normal. The patient was diagnosed with “possible PJP,” and treatment with TMP/SMX (TMP 15 mg and SMX 75 mg)/kg orally daily and levofloxacin 500 mg intravenously daily was initiated. After 8 days of treatment, the patient recovered. He was discharged from our hospital with a plan to complete a 21-day course of TMP/SMX and a 1-week course of levofloxacin.\n\nFigure 1. Chest CT findings. (a) Chest CT at first admission showed characteristic GGOs in the bilateral lungs. (b) A repeated CT performed after 21 days of TMP/SMX treatment demonstrated that the GGO in bilateral lungs were obviously resolved. (c) Chest CT at second admission showed deterioration of pulmonary infiltration mostly in the right lung. (d) Follow-up CT after 28 days of methylprednisolone and TMP/SMX treatment showed resolution of the GGOs and consolidation. CT, computed tomography; GGOs, ground-glass opacities; TMP/SMX, trimethoprim/sulfamethoxazole.\n\nAfter 3 weeks of treatment of PJP with TMP/SMX, the chest CT showed obvious resolution (Figure 1b), so the dosage of TMP/SMX was reduced to a prophylactic dose, and antiretroviral treatment with efavirenz, tenofovir ester, and lamivudine was initiated. Five days later, the patient presented with a high fever lasting 3 days, with 39.6°C as the highest temperature. He also suffered from chills and nausea, accompanied by productive cough and dyspnea. At presentation, the patient was afebrile (36.7°C) with an oxygen saturation level of 87.2% on room air, a respiration rate of 20 breaths/minute, a heart rate of 116 beats/minute, and blood pressure of 105/70 mmHg. Thoracic auscultation revealed a “Velcro sound” in the bilateral lower lobes. Blood tests revealed type I respiratory failure (pH 7.423; PaCO2 27.9 mmHg; and PaO2 54.7 mmHg), elevated white blood cell count (14.51 × 109/L), CRP level (90.50 mg/L), and LDH level (554 U/L); and a CD4+ count of 189 cells/µL. A chest CT demonstrated bilateral diffuse patches with the air bronchogram sign (Figure 1c), revealing that the pulmonary infiltrations had worsened compared with the previous chest CT. Empirical antibiotic therapy was started with meropenem, levofloxacin, caspofungin, oseltamivir phosphate, and clarithromycin. However, the patient did not respond to treatment. To obtain a definite diagnosis and select a targeted treatment, we performed bronchoscopy with EBUS-guided lung biopsy (Figure 2). The EBUS image revealed heterogeneous internal echoes and an irregular margin of the lesion within the lumen of right bronchus 6 (RB6), with almost no vessels or bronchi within the lesion (Figure 2c and d). We obtained six biopsies with forceps for histopathological examination. We also performed bronchoalveolar lavage to identify potential pathogens. Hematoxylin and eosin staining showed consolidation of the lung tissue, proliferated fibrous tissue with inflammatory cell infiltration, and a local pink-stained substance (Figure 3a). Histopathologic evaluation of the tissue showed the presence of pneumonitis. One diagnostic criterion for IRIS is progressive pneumonitis or the development of organizing pneumonia after treatment for pulmonary Mycobacterium tuberculosis or PJP.1,4 PJP was subsequently confirmed with a positive result following Gomori’s methanamine silver nitrate staining for P. jirovecii in the biopsied specimens (Figure 3b) and detection of P. jirovecii DNA in the bronchoalveolar lavage fluid. We diagnosed the patient with IRIS-associated PJP. Then, antibiotic treatment for PJP was initiated, with methylprednisolone 40 mg orally daily and TMP/SMX (TMP 20 mg and SMX 100 mg)/kg orally daily. After 7 days of therapy, the patient’s condition was significantly improved, and a chest CT revealed recovery of the infiltrations (Figure 1d).\n\nFigure 2. Manifestations on bronchoscopy and EBUS images. (a, b) Bronchoscopy revealed increased secretions from different bronchi. (c, d) The EBUS image revealed heterogeneous internal echoes and an irregular margin of the lesion within the lumen of RB6, with almost no vessels or bronchi within the lesion. EBUS, radial endobronchial ultrasound; RB6, right bronchus 6.\n\nFigure 3. Histopathology of the transbronchial lung biopsy. (a) Hematoxylin and eosin staining showed frothy eosinophilic exudates and obvious consolidation of lung tissue with inflammatory cell infiltration. (b) Gomori’s methanamine silver nitrate staining showing a cluster of Pneumocystis cysts.\n\nThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent for the patient’s information and images to be published was provided by the patient.\n\nDiscussion\nCurrent HAART regimens suppress HIV replication and provide significant immune reconstitution.2 However, for patients with AIDS who develop OIs and then initiate HAART, an intense inflammatory reaction to foreign antigens may occur due to the recovery of T cell-mediated immunity.1 As a result, a rapid onset of pulmonary inflammation and respiratory distress is followed by immune recovery, which is called IRIS.5\n\nIRIS comprises two distinct syndromes: paradoxical IRIS and unmasking IRIS.6 The clinical presentation of IRIS is nonspecific and mainly consists of fever and the deterioration of primary OIs; therefore, similar clinical conditions and treatment failures must be ruled out before diagnosing IRIS.4 In adults, IRIS has most frequently been observed in persons with nontuberculous mycobacteria, PJP, and cryptococcal infections.2\nP. jirovecii is an opportunistic fungal respiratory pathogen that causes life-threatening pneumonia in patients suffering from defects in cell-mediated immunity, including those with AIDS.7 Despite major advances in health care, PJP remains a leading cause of death among HIV-infected patients and a significant cause of AIDS-related mortality and morbidity.8 Notably, IRIS should be considered when relapse is associated with a short time between the diagnosis of an OI and the initiation of HAART.1 The history, worsening clinical manifestations, and chest CT all indicated that our patient might have IRIS.1 However, progression of the initial infection and development of a new OI should be ruled out before diagnosing IRIS. Thus, histopathologic or cytologic evaluation of tissue, fluid, bronchoalveolar lavage fluid, or induced sputum samples is required to reach a definitive diagnosis.1,9\n\nEBUS-guided lung biopsy is performed by introducing a guide sheath-covered mini-probe into the target bronchus and then withdrawing the mini-probe after lesion detection, leaving the guide sheath in situ as a working channel for obtaining lesion samples.10 It can increase the ability to diagnose peripheral pulmonary lesions endoscopically,11 even lesions that are predominantly ground-glass opacities,12 with a diagnostic yield of 58% for benign peripheral disease.13 In our case, we performed bronchoscopy and radial EBUS-guided lung biopsy to obtain a definite diagnosis.\n\nFor the treatment of patients who develop IRIS soon after initiation of HAART, HAART should be continued and OI-related treatment should be initiated.2 A short course of corticosteroids is recommended for acute respiratory failure.\n\nConclusion\nPatients with AIDS who develop OIs and then initiate HAART may experience IRIS, which is characterized by a paradoxical worsening or recurrence of OI symptoms. Radial EBUS-guided lung biopsy via bronchoscopy is a valuable and less invasive technique for the rapid diagnosis of IRIS-associated PJP.\n\nAuthors’ contributions\nHG and YY made substantial contributions to the conception or design of the work. All authors contributed to the acquisition of data for the work. WY and YY helped collect the data. YY and W-MC wrote the manuscript. HG, YY and WY interpreted the data. HG performed the bronchoscopy. All authors revised the paper critically for important intellectual content. All authors gave final approval of the version to be published. All authors agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThe work was supported by the science and technology foundation of Shenyang (China) of Ying Wen (18-014-4-30) in the First Affiliated Hospital of China Medical University.\n\nORCID iD\nGang Hou https://orcid.org/0000-0003-3438-1764\n==== Refs\nReferences\n1 Achenbach CJ Harrington RD Dhanireddy S , et al\nParadoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection.\n\nClin Infect Dis \n2012 ; \n54 : 424 –433\n. DOI: 10.1093/cid/cir802.22095568 \n2 Mofenson LM Brady MT Danner SP , et al\nGuidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics\n. MMWR Recomm Rep \n2009 ; \n58 : 1 –166\n.\n3 Da Cunha Colombo ER Mora DJ Silva-Vergara ML. \nImmune reconstitution inflammatory syndrome (IRIS) associated with Cryptococcus neoformans infection in AIDS patients.\n\nMycoses \n2011 ; \n54 : e178 –e182\n. DOI: 10.1111/j.1439-0507.2010.01870.x.20337940 \n4 Manzardo C Guardo AC Letang E , et al\nOpportunistic infections and immune reconstitution inflammatory syndrome in HIV-1-infected adults in the combined antiretroviral therapy era: a comprehensive review.\n\nExpert Rev Anti Infect Ther \n2015 ; \n13 : 751 –767\n. DOI: 10.1586/14787210.2015.1029917.25860288 \n5 Bhagwat SP Wright TW Gigliotti F. \nAnti-CD3 antibody decreases inflammation and improves outcome in a murine model of Pneumocystis pneumonia.\n\nJ Immunol \n2010 ; \n184 : 497 –502\n. DOI: 10.4049/jimmunol.0901864.19949093 \n6 Curic K Poljak M Ihan A , et al\nVery recent HIV infection accompanied by Pneumocystis jirovecii pneumonia and Mycobacterium avium complex immune reconstitution inflammatory syndrome: a case report\n. Acta Dermatovenerol Alp Pannonica Adriat \n2016 ; \n25 : 57 –58\n.27695869 \n7 Wang J Gigliotti F Bhagwat SP , et al\nImmune modulation with sulfasalazine attenuates immunopathogenesis but enhances macrophage-mediated fungal clearance during Pneumocystis pneumonia.\n\nPLoS Pathog \n2010 ; \n6 : e1001058 . DOI: 10.1371/journal.ppat.1001058.20808846 \n8 Zhang ZQ Wang J Hoy Z , et al\nNeither classical nor alternative macrophage activation is required for Pneumocystis clearance during immune reconstitution inflammatory syndrome.\n\nInfect Immun \n2015 ; \n83 : 4594 –4603\n. DOI: 10.1128/IAI.00763-15.26371121 \n9 Kaplan JE Benson C Holmes KK , et al\nGuidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America\n. MMWR Recomm Rep \n2009 ; \n58 :1 –207\n; quiz CE1-4.\n10 Ikezawa Y Shinagawa N Sukoh N , et al\nUsefulness of endobronchial ultrasonography with a guide sheath and virtual bronchoscopic navigation for ground-glass opacity lesions\n. Ann Thorac Surg \n2017 ; \n103 : 470 –475\n. DOI: 10.1016/j.athoracsur.2016.09.001.27825686 \n11 Kurimoto N Miyazawa T Okimasa S , et al\nEndobronchial ultrasonography using a guide sheath increases the ability to diagnose peripheral pulmonary lesions endoscopically\n. Chest \n2004 ; \n126 : 959 –965\n. DOI: 10.1378/chest.126.3.959.15364779 \n12 Ikezawa Y Sukoh N Shinagawa N , et al\nEndobronchial ultrasonography with a guide sheath for pure or mixed ground-glass opacity lesions\n. Respiration \n2014 ; \n88 : 137 –143\n. DOI: 10.1159/000362885.24993187 \n13 Shinagawa N Nakano K Asahina H , et al\nEndobronchial ultrasonography with a guide sheath in the diagnosis of benign peripheral diseases.\n\nAnn Thorac Surg \n2012 ; \n93 : 951 –957\n. DOI: 10.1016/j.athoracsur.2011.11.073.22305056\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "48(8)",
"journal": "The Journal of international medical research",
"keywords": "Human immunodeficiency virus; Pneumocystis jirovecii pneumonia; endobronchial ultrasound; highly active antiretroviral therapy; immune reconstitution inflammatory syndrome; transbronchial lung biopsy",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D001999:Bronchoscopy; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D011020:Pneumonia, Pneumocystis; D055815:Young Adult",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "300060520946544",
"pmc": null,
"pmid": "32851886",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19949093;19357635;27695869;19730409;20337940;22305056;24993187;25860288;22095568;26371121;20808846;15364779;27825686",
"title": "Immune reconstitution inflammatory syndrome associated with Pneumocystis pneumonia in a patient with AIDS.",
"title_normalized": "immune reconstitution inflammatory syndrome associated with pneumocystis pneumonia in a patient with aids"
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"companynumb": "CN-GILEAD-2020-0500441",
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"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
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"abstract": "OBJECTIVE\nCurrent guidelines favor the use of chelating agents (d-penicillamine, trientine) in first line therapy of symptomatic Wilson disease patients. Development of chelator induced immunological adverse events are a concern especially under d-penicillamine therapy. This study assessed the prevalence of co-existing or therapy-related immune-mediated diseases in Wilson disease patients, and evaluated the role of antinuclear antibodies in therapy monitoring.\n\n\nMETHODS\nWe retrospectively analyzed 235 Wilson disease patients. Medical regimens were classified and analyzed in relation to adverse events and antinuclear antibody courses.\n\n\nRESULTS\nCoexisting immune-mediated diseases were evident in 19/235 (8.1%) patients, of which 13/235 (5.5%) had pre-existing autoimmune diseases. Six patients (2.6%) developed an autoimmune disease under therapy, all of them under long-term d-penicillamine treatment. Data relating to antinuclear antibody courses during treatment and adverse events were available for patients treated with d-penicillamine (n = 91), trientine (n = 58), and zinc salts (n = 58). No significant increase in antinuclear antibody titers in patients treated with d-penicillamine (16/91; 17.6%), trientine (12/58; 20.7%), and zinc (7/58; 12.1%) were found.\n\n\nCONCLUSIONS\nUnder long-term d-penicillamine therapy a minority of patients developed immune-mediated disease. Elevations in antinuclear antibodies were found frequently, but no correlations were evident between increases in antinuclear antibodies and the development of immune-mediated diseases or medical regimes. Thus, the value of antinuclear antibodies for monitoring adverse events under chelator therapy seems to be limited.",
"affiliations": "Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.;Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.;Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.;Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.;Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.;Department of Gastroenterology, University Hospital Vienna, Vienna, Austria.;Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany.;Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120, Heidelberg, Germany. karl-heinz_weiss@med.uni-heidelberg.de.",
"authors": "Seessle|Jessica|J|;Gotthardt|Daniel Nils|DN|;Schäfer|Mark|M|;Gohdes|Annina|A|;Pfeiffenberger|Jan|J|;Ferenci|Peter|P|;Stremmel|Wolfgang|W|;Weiss|Karl Heinz|KH|",
"chemical_list": "D000974:Antibodies, Antinuclear; D002614:Chelating Agents; D010396:Penicillamine; D015032:Zinc; D014266:Trientine",
"country": "United States",
"delete": false,
"doi": "10.1007/s10545-015-9866-0",
"fulltext": null,
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"issn_linking": "0141-8955",
"issue": "39(1)",
"journal": "Journal of inherited metabolic disease",
"keywords": null,
"medline_ta": "J Inherit Metab Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000974:Antibodies, Antinuclear; D001327:Autoimmune Diseases; D002614:Chelating Agents; D002648:Child; D003430:Cross-Sectional Studies; D016903:Drug Monitoring; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006527:Hepatolenticular Degeneration; D006801:Humans; D008297:Male; D010396:Penicillamine; D012189:Retrospective Studies; D014266:Trientine; D055815:Young Adult; D015032:Zinc",
"nlm_unique_id": "7910918",
"other_id": null,
"pages": "125-30",
"pmc": null,
"pmid": "26067812",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": "9512879;7034252;24016388;16233999;11484692;4100034;16918691;4467179;22988469;12955875;3579660;17368141;12428861;23542331;18506894;14723607;21185835;24754532;16709660;978218;25496901;9324014;25291347;22340672",
"title": "Concomitant immune-related events in Wilson disease: implications for monitoring chelator therapy.",
"title_normalized": "concomitant immune related events in wilson disease implications for monitoring chelator therapy"
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"abstract": "Fluvoxamine is a selective serotonin reuptake inhibitor, with a half-life of about 30 hours, that is commonly prescribed in the treatment of depression and obsessive and compulsive disorders. Though its more favorable adverse effect profile in comparison to tricyclic antidepressants, overdosages could lead to severe central nervous system depression. We hereby report the case of a 48-year-old woman with psychiatric disorders, who died in the Protected Community where she lived. An autopsy, during which multiorgan congestion and aspiration of gastric content were found, was performed 9 days after the death. Femoral and cardiac blood, urine and bile were collected for toxicological analysis. GC-MS, LC-MS-MS and LC-HRMS screenings were performed on blood samples. The analysis allowed to identify the following drugs: fluvoxamine, clotiapine, 7-aminoclonazepam, propranolol, gabapentin and haloperidol. Quantification of the detected drugs in blood was performed by means of a validated LC-MS-MS analytical procedure, and the following results were achieved: fluvoxamine (2.20 mg/L), gabapentin (41.00 mg/L), 7-aminoclonazepam (0.24 mg/L), clotiapine (0.07 mg/L), haloperidol (<0.01 mg/L) and propranolol (0.24 mg/L). Fluvoxamine concentration in blood exceeded ~10 times the upper limit of therapeutic blood levels (0.23 mg/L). Contributory causes of death, such as due to multiple drug use, however, cannot be excluded. The distribution of fluvoxamine in all biological fluids was evaluated and a postmortem redistribution effect was observed (C/P blood ratio: 1.86). Fluvoxamine acid metabolite was identified in urine, bile and in cardiac blood, through an LC-QTOF analytical procedure.",
"affiliations": "Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini, 12, 27100 Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini, 12, 27100 Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini, 12, 27100 Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini, 12, 27100 Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini, 12, 27100 Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini, 12, 27100 Pavia, Italy.;Department of Public Health, Experimental and Forensic Medicine, University of Pavia, via Forlanini, 12, 27100 Pavia, Italy.",
"authors": "Vignali|Claudia|C|;Moretti|Matteo|M|;Quaiotti|Jessica|J|;Freni|Francesca|F|;Tajana|Luca|L|;Osculati|Antonio Marco Maria|AMM|;Morini|Luca|L|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D016666:Fluvoxamine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkaa084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "45(4)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D001646:Bile; D002853:Chromatography, Liquid; D005260:Female; D016666:Fluvoxamine; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008875:Middle Aged; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "7705085",
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"pages": "e1-e5",
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"pmid": "32672818",
"pubdate": "2021-04-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Distribution of Fluvoxamine and Identification of the Main Metabolite in a Fatal Intoxication.",
"title_normalized": "distribution of fluvoxamine and identification of the main metabolite in a fatal intoxication"
} | [
{
"companynumb": "IT-TEVA-2020-IT-1817949",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUVOXAMINE"
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... |
{
"abstract": "A 61-year-old woman underwent surgical resection of rectal cancer(SI, N3, Stage IIIb)and received 12 courses of adjuvant mFOLFOX6 chemotherapy. Six months after completion of adjuvant chemotherapy, she was found to have pulmonary metastases, and was treated with FOLFIRI plus bevacizumab. After 6 courses of chemotherapy, the pulmonary nodules showed central cavitation without any change in size. After 6 additional courses of chemotherapy, pulmonary lesions increased in and had consolidated. She was treated with regorafenib as second-line chemotherapy for recurrent disease. After 6 courses of regorafenib, the pulmonary nodules became cavitated. According to the RECIST criteria, the tumor response was stable disease. However, the morphology was significantly changed and tumor growth had been controlled for a long time. Assessment of tumor response depends not onlyon size according to the RECIST criteria, but also on the morphologic response when we assess tumor response to molecular targeted drugs.",
"affiliations": "Dept. of Surgery, Jichi Medical University.",
"authors": "Taniguchi|Masatake|M|;Mori|Misuzu|M|;Sata|Naohiro|N|;Fujii|Hirofumi|H|",
"chemical_list": "D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0385-0684",
"issue": "43(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008875:Middle Aged; D010671:Phenylurea Compounds; D011725:Pyridines; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "757-9",
"pmc": null,
"pmid": "27306815",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Patient with Cavitated Pulmonary Metastases Treated with Regorafenib.",
"title_normalized": "a patient with cavitated pulmonary metastases treated with regorafenib"
} | [
{
"companynumb": "JP-BAYER-2016-137186",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "REGORAFENIB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nOropharyngeal squamous cell carcinoma (SCC) is known for its propensity for aggressive local progression and regional lymphatic spread. Distant metastases are relatively uncommon and the likelihood of hematogenous dissemination is primarily related to the extent and location of cervical lymph node metastases. Common sites of distant metastasis include the liver and lung.\n\n\nMETHODS\nWe report an unusual case of base of tongue SCC with infiltrative bone marrow carcinomatosis presenting months after definitive chemoradiation despite locoregional control.\n\n\nRESULTS\nOur patient exhibited an unusual pattern of distant dissemination after definitive chemoradiation had resulted in locoregional control.\n\n\nCONCLUSIONS\nPatients who present with bone marrow failure after definitive treatment with apparent disease control should be monitored for bone marrow infiltration by the tumor and, if such infiltration is present, should be evaluated for palliative chemotherapy. Unfortunately, the prognosis for such patients is poor. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2449-E2453, 2016.",
"affiliations": "Department of Radiation Oncology, University of Florida, Gainesville, Florida.;Division of Hematology and Oncology, University of Florida, Gainesville, Florida.;Department of Pathology, University of Florida, Gainesville, Florida.;Department of Radiology, University of Florida, Gainesville, Florida.;Department of Radiation Oncology, University of Florida, Gainesville, Florida.",
"authors": "Christopherson|Kaitlin|K|;Reisman|David N|DN|;Fredenburg|Kristianna|K|;DeJesus|Reordan|R|;Mendenhall|William M|WM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hed.24155",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "38(7)",
"journal": "Head & neck",
"keywords": "base of tongue; carcinomatosis; case report; definitive chemoradiation; squamous cell carcinoma",
"medline_ta": "Head Neck",
"mesh_terms": null,
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E2449-E2453",
"pmc": null,
"pmid": "26040510",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Base of tongue squamous cell carcinoma with infiltrative bone marrow carcinomatosis after definitive chemoradiation: A case report.",
"title_normalized": "base of tongue squamous cell carcinoma with infiltrative bone marrow carcinomatosis after definitive chemoradiation a case report"
} | [
{
"companynumb": "US-CORDEN PHARMA LATINA S.P.A.-US-2016COR000207",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugad... |
{
"abstract": "OBJECTIVE\nA case of a patient who received ceftaroline fosamil as salvage therapy for a methicillin-resistant Staphylococcus aureus (MRSA) epidural abscess is reported.\n\n\nCONCLUSIONS\nA 48-year-old white woman arrived at the emergency department (ED) with an altered mental status. She had been to the ED two days prior with complaints of sudden-onset and worsening neck pain. She had a history of compacted disks in her neck secondary to a motor vehicle accident that occurred three years prior but that did not require surgical intervention. Computed tomography and magnetic resonance imaging scans confirmed an epidural abscess with wound cultures growing MRSA. The admitting physician indicated that the patient was severely septic. Acyclovir, ceftriaxone, and vancomycin were initiated for empirical treatment due to suspected meningitis. Paired blood cultures also continued to grow MRSA in four of four bottles collected four days after admission. This indicated that antimicrobial therapy was not successfully eradicating the MRSA found in the blood and the patient's clinical status was deteriorating. Ceftaroline was used as salvage therapy, resulting in rapid clearance of MRSA from the blood and the patient becoming afebrile in 24 hours. Blood culture tests on hospital day 11-one day after ceftaroline initiation-were clear of MRSA. The patient was discharged to a long-term-care facility and ordered ceftaroline fosamil 600 mg i.v. every 12 hours for four weeks.\n\n\nCONCLUSIONS\nA MRSA epidural abscess in a 48-year-old woman was successfully treated with ceftaroline fosamil 600 mg every 12 hours as salvage therapy.",
"affiliations": "John Bucheit, Pharm.D., is Pharmacy Practice Resident, Pharmacy Department; Rebeccah Collins, Pharm.D., is Residency Director, Antimicrobial Stewardship; and Prajwol Joshi, M.D., is Infectious Disease Physician, Infectious Disease, Memorial Regional Medical Center, Mechanicsville, VA.",
"authors": "Bucheit|John|J|;Collins|Rebeccah|R|;Joshi|Prajwol|P|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C515501:ceftaroline fosamil",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp130246",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "71(2)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004359:Drug Therapy, Combination; D004632:Emergency Medical Services; D020802:Epidural Abscess; D005260:Female; D006801:Humans; D007796:Laminectomy; D008134:Long-Term Care; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D019547:Neck Pain; D016879:Salvage Therapy; D013203:Staphylococcal Infections; D013921:Thrombocytopenia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "110-3",
"pmc": null,
"pmid": "24375602",
"pubdate": "2014-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methicillin-resistant Staphylococcus aureus epidural abscess treated with ceftaroline fosamil salvage therapy.",
"title_normalized": "methicillin resistant staphylococcus aureus epidural abscess treated with ceftaroline fosamil salvage therapy"
} | [
{
"companynumb": "US-BAXTER-2014BAX055010",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Acute fibrinous and organizing pneumonia (AFOP) is a rare histologic interstitial pneumonia pattern recently described in the literature with fewer than 120 cases published. AFOP is often difficult to diagnose and may be mistaken for other pulmonary disorders such as interstitial pneumonias or pneumonitides. Patients often present with vague symptoms of cough, dyspnea, hemoptysis, fatigue, and occasionally respiratory failure. Radiological findings show diffuse patchy opacities and ground glass appearance of the lungs. On histologic examination, intra-alveolar fibrin balls are observed. We discuss a case of a man who presented with hemoptysis and dyspnea and whose open lung biopsy revealed AFOP. We will describe the presentation, diagnosis, and post-discharge course, and review the current literature. There are only 4 cases which have reported the patients' course of disease after 1 year, the longest being 2 years. To our knowledge, this is the only case of AFOP in the literature that describes the course of a patient more than 2 years after the diagnosis of AFOP, and is the most comprehensive review of the current literature.",
"affiliations": "Department of Anesthesiology and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA; Department of Anesthesiology, University of Massachusetts Medical School, 55 North Lake Avenue, Worcester, MA, 01655, USA. Electronic address: catherine.kuza@gmail.com.;Department of Anesthesiology, University of Massachusetts Medical School, 55 North Lake Avenue, Worcester, MA, 01655, USA.;Department of Medicine (Pulmonary/Critical Care Medicine), University of Massachusetts Medical School, 55 North Lake Avenue, Worcester, MA, 01655, USA.;Department of Anesthesiology, University of Massachusetts Medical School, 55 North Lake Avenue, Worcester, MA, 01655, USA.",
"authors": "Kuza|Catherine|C|;Matheos|Theofilos|T|;Kathman|Deirdre|D|;Heard|Stephen O|SO|",
"chemical_list": "D000974:Antibodies, Antinuclear; D007166:Immunosuppressive Agents; C009753:fiberglass; D001194:Asbestos",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-9441",
"issue": "31(1)",
"journal": "Journal of critical care",
"keywords": "Acute fibrinous and organizing pneumonia; Interstitial lung diseases",
"medline_ta": "J Crit Care",
"mesh_terms": "D000974:Antibodies, Antinuclear; D001194:Asbestos; D003240:Connective Tissue Diseases; D005898:Glass; D006801:Humans; D007166:Immunosuppressive Agents; D008168:Lung; D017563:Lung Diseases, Interstitial; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D010102:Oxygen Inhalation Therapy; D014057:Tomography, X-Ray Computed; D014850:Waiting Lists",
"nlm_unique_id": "8610642",
"other_id": null,
"pages": "255-61",
"pmc": null,
"pmid": "26578116",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17117329;23614642;11937645;20920123;10379213;25890084;18069424;16954940;22348347;22957292;12204055;15272286;25120840;19946550;23683442;25891742;23337545;15689928;19350842;17885309;25742910;19666216;25551348;21775026;21633758;20946526;20700558;25221891;24103205;24660769;20194812;21211407;19712502;19543497;25600847;16282908;26029580;25817128;23208573;17545929;23793436",
"title": "Life after acute fibrinous and organizing pneumonia: a case report of a patient 30 months after diagnosis and review of the literature.",
"title_normalized": "life after acute fibrinous and organizing pneumonia a case report of a patient 30 months after diagnosis and review of the literature"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-004104",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditi... |
{
"abstract": "Immunotherapy provided with checkpoint inhibitors such as the programmed cell death-1 (PD-1) receptor or its ligand-1 (PD-L1) protein has been shown to be effective for treating several types of cancer, and was recently approved for use in treating malignant melanoma, advanced non-small cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell carcinoma, liver cancer, and additional forms of cancer. However, there is little evidence concerning its effectiveness in treating thymic squamous cell carcinoma (TSCC). Here, we report two cases of refractory TSCC that were treated with PD-1 single/combination therapy in a clinical setting. The patients exhibited variable responses to therapy without any serious adverse events. In summary, our findings show that immunotherapy provided with an immuno-checkpoint inhibitor in combination with chemotherapy/anti-angiogenesis therapy can improve the treatment response of patients with refractory TSCC. Anti-PD-1 single/combination therapy may be used as a strategy for treating advanced refractory TC.",
"affiliations": "Department of Chinese Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.;State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.;Department of Chinese Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.",
"authors": "Jin|Wei|W|0000-0002-3236-9254;Duan|Jian-Chun|JC|;Wang|Zhi-Jie|ZJ|;Lin|Lin|L|;Bai|Hua|H|;Wang|Jie|J|;Feng|Li|L|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CMAR.S274830",
"fulltext": "\n==== Front\nCancer Manag Res\nCancer Manag Res\ncmar\ncancmanres\nCancer Management and Research\n1179-1322 Dove \n\n274830\n10.2147/CMAR.S274830\nCase Series\nThe Effect and Safety of Anti-PD-1 Single/Combination Therapy in Refractory Thymic Carcinoma: A Case-Series Study\nJin et alJin et alhttp://orcid.org/0000-0002-3236-9254Jin Wei 1* Duan Jian-Chun 2* Wang Zhi-Jie 2 Lin Lin 2 Bai Hua 2 Wang Jie 2 Feng Li 1 1 Department of Chinese Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing\n100021, People’s Republic of China\n2 State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing\n100021, People’s Republic of China\nCorrespondence: Jie Wang State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing100021, People’s Republic of ChinaTel +86 139-1070-4669 Email zlhuxi@163.comLi Feng Department of Chinese Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing100021, People’s Republic of ChinaTel +86 186-1814-7576 Email fengli663@126.com* These authors contributed equally to this work\n\n\n06 11 2020 \n2020 \n12 11351 11358\n30 7 2020 15 10 2020 © 2020 Jin et al.2020Jin et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nImmunotherapy provided with checkpoint inhibitors such as the programmed cell death-1 (PD-1) receptor or its ligand-1 (PD-L1) protein has been shown to be effective for treating several types of cancer, and was recently approved for use in treating malignant melanoma, advanced non-small cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell carcinoma, liver cancer, and additional forms of cancer. However, there is little evidence concerning its effectiveness in treating thymic squamous cell carcinoma (TSCC). Here, we report two cases of refractory TSCC that were treated with PD-1 single/combination therapy in a clinical setting. The patients exhibited variable responses to therapy without any serious adverse events. In summary, our findings show that immunotherapy provided with an immuno-checkpoint inhibitor in combination with chemotherapy/anti-angiogenesis therapy can improve the treatment response of patients with refractory TSCC. Anti-PD-1 single/combination therapy may be used as a strategy for treating advanced refractory TC.\n\nKeywords\nthymic carcinomaanti-PD-1single/combination therapyno financial fundingAll authors declare that no financial funding was received.\n==== Body\nIntroduction\nThymic carcinoma (TC) is a rare mediastinal malignant tumor derived from thymic epithelial cells, and accounts for 5~36% of all thymic epithelial tumors (TETs).1–3 Histological examinations have shown that the majority of TCs are either squamous carcinomas or undifferentiated carcinomas. A retrospective study by the Chinese Alliance for Research in Thymomas (ChART) showed that the most frequent histologic subtype of TCs was squamous cell carcinoma.4 A study has shown that the 5-year survival rate of patients with TC is only 30%.5 Surgical resection is the primary method used to manage early-stage TC when a complete resection is possible. However, the postoperative recurrence rate of TC is high,6,7 and the prognosis of TC patients is poor. As most cases of TC are diagnosed at an advanced stage, chemotherapy is usually administered to slow the progress of the tumor. The efficacy of conventional chemotherapy in patients with advanced-stage or relapsing tumors is poor,8 there are few published findings regarding the efficacy of second-line chemotherapy in patients with previously treated or advanced TC.\n\nThe evolution of immune-checkpoint inhibitors (ICIs) has revolutionized the field of immunotherapy. Cancer cells are known to activate different immune checkpoints, and several ICIs including pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab have recently shown promising results for suppressing cancer growth and progression.\n\nICIs that target PD-1/PD-L1 have been shown to be beneficial in treating multiple types of solid tumors, and to increase the overall response rate (ORR) with a low rate of immune-related adverse events. Investigations into methods for obtaining long-term immune responses and increasing patient survival times by using ICIs has become an increasingly popular area of research. Several anti-PD-1/PDL-1 drugs have recently been approved by the Food and Drug Administration for use in treating malignant melanoma, NSCLC, and other types of solid tumors. Under normal physiologic conditions, PD-1 expressed on activated T-cells is known to protect the host against autoimmunity by inhibiting effector T-cell activity and stimulating the activity of immunosuppressive regulatory T cells (Tregs).9 Expression of the PD-ligand (PD-L1) is specifically upregulated in the presence of a tumor, and that upregulation further promotes tumor invasion and growth by suppressing the T-cell response.\n\nThe thymus is a complex immune organ known to play a critical role in creating and building a T-cell repertoire. Previous studies have demonstrated PD-L1 expression in the thymus, and several studies reported the frequency of PD-L1 expression in thymomas (23%-68%) and TCs (70%-75%).10,11 A study that analyzed PD-1 and PD-L1 and their levels of mRNA expression in 68 samples of formalin-fixed paraffin-embedded thymic epithelial neoplasm tissue (63 thymomas and 5 thymic carcinomas) suggest possible involvement of the PD-1 and PD-L1 pathway in TETs’ progression.12 Although still controversial, given the immunological significance of PD-1/PD-L1 within the thymus and the recent emergence of PD-L1 as an important predictive biomarker for the effectiveness of cancer immunotherapies,13,14 anti-PD-1/PD-L1 therapies could play an important role in the management of advanced TC. It is also possible that combination treatment with conventional cytotoxic agents plus immunotherapy agents could increase the efficacy of both types of agents.15 However, the low prevalence of TC significantly limits the ability of investigators to generate epidemiological evidence regarding the efficacy of anti-PD-1/PD-L1 therapies used for advanced-stage TC. The low number of available patients could also be responsible for the current lack of consensus on how to best treat advanced-stage TC patients in clinical practice.\n\nHere, we describe two cases of advanced-stage recurrent TSCC treated with PD-1 inhibitor single/combination therapy and provide an assessment of the efficacy and safety of the treatment.\n\nCase Presentations\nCase 1\nA 40-year-old male presented at the hospital and was subsequently diagnosed with squamous cell carcinoma of the thymus (Masaoka stage IV) in November 2004 (Figure 1). The patient was administered preoperative and postoperative chemotherapy with cyclophosphamide, epirubicin, and cisplatin. Because of repeated local recurrence, the patient received gamma knife treatment in 2006, and again in 2014. Shortly afterwards, the patient presented with an inoperable relapse and was administered concurrent radiochemotherapy with docetaxel and oxaliplatin. In 2015, second-line treatment with albumin paclitaxel was initiated; however, the disease continued to progress, and third-line treatment with gemcitabine plus bevacizumab was initiated. A second axillary lymph node biopsy was performed, which revealed the same histological type as the primary lesion. Immunohistochemistry (IHC) showed that the biopsy tissue was PD-1 and PD-L1 positive. In June 2016 (Figure 2A), ICI therapy was initiated consisting of 40 cycles of nivolumab. That treatment continued until May 2018 (Figure 2B) and resulted in SD with a progression-free survival (PFS) time of 38 months. In August 2019, the patient received one cycle of pembrolizumab plus vinorelbine due to re-emergence of the disease. Chest imaging revealed a right hilar lymph node lesion that showed a 10% increase in size. This finding was followed by re-initiation of treatment with 3 cycles of nivolumab in combination with nab-paclitaxel, which resulted in a partial response. Unfortunately, the treatment had to be discontinued due to complaints of chest tightness and asthma. The disease then rapidly progressed, with the right hilar lymph node lesion showing 50% enlargement. Since December 2019, the patient has been receiving oral anlotinib therapy. With the exception of itchy skin on the limbs (CTCAE grade 1), no serious adverse events were observed during these single/combination treatments.Figure 1 Histopathology from case 1. (A) ×40. (B) ×200.\n\nFigure 2 CT images from case 1. (A) Chest CT revealing postoperative changes of thymic carcinoma, scattered fibrous foci of the left lung, left pleural hypertrophy with a small amount of pleural effusion. Soft tissue shadows are observed around the posterior mediastinal thoracic aorta. (B) PET-CT revealing the left mediastinal pleura and bilateral costal pleura were irregularly thickened, and some of them were accompanied by increased metabolism. Left pleural effusion and atelectasis of the lower left lung. Right hilar enlarged lymph nodes with increased metabolism were considered for metastasis.\n\n\n\nCase 2\nIn 2017, a 52-year-old male presented at the hospital with complaints of progressive chest pain. Chest imaging revealed an anterior mediastinum mass with enlarged lymph nodes and a left pleura metastasis. A small needle biopsy of the anterior mediastinal mass revealed poorly differentiated squamous cell carcinoma of the thymus (Figure 3). Immunohistochemistry showed that 70% of the cells were positive for PD-L1. The patient was administered first-line treatment with paclitaxel liposomes plus carboplatin; however, the disease continued to progress. Next, immunotherapy was initiated with pembrolizumab as second-line treatment, and the patient showed progressive disease after 2 cycles of immunotherapy. Subsequently, the treatment was modified to include combination therapy with albumin paclitaxel as a third-line treatment, which led to significant disease remission after 2 cycles. Upon examination, the patient showed only slight progress after the 3rd cycle (Figure 4A), and was switched to treatment with pembrolizumab plus anlotinib, which subsequently resulted in progressive disease. This was followed by the introduction of palliative radiotherapy, and concurrent administration of targeted therapy with anlotinib. Combination therapy with anlotinib plus pembrolizumab was continued for 16 cycles as a part of a sequential regimen, resulting in the maintenance of stable disease until December 2019 (Figure 4B), when an enlarged pleural tubercle and new bone metastases were observed (Figure 4C). As a consequence of these findings, the third-line chemotherapy was judged to be ineffective, and the patient was switched to one cycle of combination therapy with pembrolizumab plus gemcitabine. To our surprise, the patient exhibited a partial response (Figure 4D). Furthermore, during the entire course of pembrolizumab immunotherapy and immunocombination therapy with albumin paclitaxel/anlotinib, the patient experienced only grade 1 nausea without any additional immunotherapy-related side effects. However, the patient did experience a grade 3 skin reaction that manifested as rashes on the trunk and limbs, accompanied by itching during treatment with pembrolizumab plus gemcitabine combination therapy. Later, a marked improvement in the skin reaction was observed after initiation of hormone therapy. In summary, the duration of anti-PD-1 single therapy and immunotherapy in combination with chemotherapy/antiangiogenic therapy lasted for a total of 23 months.Figure 3 Histopathology from case 2. (A) ×40. (B) ×200. (C) CD5. (D) CD117. (E) P40. (F) P63.\n\nFigure 4 CT images from case 2. (A) Chest enhancement CT revealing the maximum cross-section of the anterior mediastinal mass is 2.1×1.1cm in size (red arrow). (B) Chest enhancement CT revealing an irregular, ill-defined mass of the anterior mediastinal, difficult to accurately measure (red arrow). (C) Chest enhancement CT revealing the pleural effusion appears on the left side (red arrow). (D) The left pleural effusion was absorbed and soft tissue mass near the left posterior mediastinum smaller than before (red arrow).\n\n\n\nDiscussion\nTCs are malignant mediastinal neoplasms derived from thymic epithelial cells and have a poor prognosis. Due to the rarity of these tumors, treatment decisions are often based on findings from underpowered prospective clinical studies. Moreover, TCs are more aggressive, less responsive to chemotherapy, and have an increased likelihood of producing distant metastases when compared with other types of tumors. TSCCs are known to respond poorly to chemotherapy, with objective positive rates ranging from 22% to 36%.16,17 To date, the response of TSCCs to radiotherapy is also controversial. In addition, there is no standard second-line treatment for patients with recurrent TC. These factors emphasize the need for prognostic biomarkers and new alternative strategies for treating TC. Recently, ICIs have ushered in a new era in cancer treatment, provoking us to evaluate the prospects for using ICIs in treatment of TCs.\n\nPD-L1 expression is the most studied biomarker for judging the efficacy of a PD-1/PD-L1 inhibitor. The efficacy of pembrolizumab was recently evaluated in a single-arm Phase II study that enrolled 40 patients with recurrent TC that had progressed after at least one cycle of chemotherapy. Only 3% of those patients achieved a complete response, 20% achieved a partial response, and 53% achieved stable disease.18 Another phase II trial enrolled 26 patients with refractory or recurrent TET. In that study, 19.2% of the patients showed a partial response, 53.8% of patients achieved stable disease, and the median PFS time was 6.1 months.19 A recent case study showed that 100% of squamous cell carcinoma specimens obtained from a Japanese patient treated with pembrolizumab expressed PD-L1. The patient’s tumor was successfully treated, as verified by its significant regression without any accompanying serious adverse side effects. These studies suggest that inhibition of the PD-1/PD-L1 axis by anti-PD-1 or anti-PD-L1 antibodies might be a strategy for treating TC.20\n\nBoth patients (case #1 and case #2) in our case-series tested positive for PD-L1 expression. Our immunohistochemical analysis of one of the patients (case #2) showed a high level of PD-L1 expression (up to 70%), and that patient received pembrolizumab as second-line therapy. However, the patient showed disease progression after only 2 cycles of treatment, suggesting a lack of efficacy. Our results are in sharp contrast with those of a previous study that reported a positive association between a high level of PD-L1 expression (>50% of cells) and a favorable prognosis.\n\nFurthermore, in a small study that evaluated the efficacy of nivolumab in four patients with TC, 3 patients showed a partial response and the remaining patient achieved stable disease; those results suggest the potential benefits of using these inhibitors to treat TCs in real-world clinical setting.21 In our case study, one patient (case #1) who received nivolumab as monotherapy achieved stable disease and a PFS time of 38 months, which was consistent with previous reports of a durable response to immunotherapy lasting longer than one year.22,23 Due to the low incidence of TC, we were unable verify the correlation between PD-1 expression and the efficacy of TC treatment; further emphasizing the need for a larger sample size.\n\nIt is believed that immunotherapy might be even more beneficial when administered in combination with other therapies such as chemotherapy, radiotherapy, and antiangiogenic therapy. These potentially synergistic combination therapies may cause an anti-tumor immune response by releasing antigens that promote tumor cell apoptosis, and thereby restore active immunity.24,25 Consistent with literature reports, both patients with progressive disease in our study who were administered nivolumab/pembrolizumab in combination with albumin paclitaxel achieved a partial response. Furthermore, one of those patients was further treated with pembrolizumab in combination with the traditional chemotherapy drug gemcitabine, and continued to show a partial response. Knowledge regarding chemotherapy for TC has mainly been based on retrospective series with small patient samples. A retrospective analysis reported that gemcitabine achieved moderate outcomes concerning in 4(36.4%) of 11 patients with refractory TC who had previously been treated mainly with platinum-based chemotherapy, suggesting gemcitabine as a possible important drug for treating TC.26 Another study evaluated the efficacy of second-line chemotherapy in patients with previously treated advanced TC. When gemcitabine was used as the second-line chemotherapeutic agent, the response rate was 28.6%.8 However, gemcitabine was only used as a second-line treatment for TC in the above studies, and there is no standard treatment after multiple lines of chemotherapy have been used. Because of its rarity, there are no randomized studies on the effects of chemotherapy in treatment of TC, and additional evidence is required to prove the efficacy of gemcitabine when used as a single agent in treatment of TC. Our study suggests the potential clinical benefits of receiving different combinations of an ICI plus other forms of therapy. A previous retrospective study showed that elevated levels of PD-L1 and PD-1 expression after chemotherapy are markers that support the use of anti-PD-1/L1 drugs for treating TM and TC, as well as the continued use of those agents after chemotherapy.27 Our results are also consistent with that study, as they suggest the benefit of providing ICI therapy after conventional chemotherapy.\n\nWe observed a favorable response in one patient (case #2) who was administered pembrolizumab in combination with the antiangiogenic drug, anlotinib, as that patient achieved 15 months of PFS. Tumor growth requires the generation of new blood vessels (i.e. neovascularization) to maintain a continuous supply of oxygen and nutrients. While angiogenesis is critical for the growth of primary tumors, it also has a complex relationship with the immune system.28 Tumor cells evade immune surveillance by immunologically suppressing their microenvironment. VEGF produced by tumors not only plays an essential role in tumor vascularization but also inhibits the immune system by identifying and destroying immune cells that attack tumor cells.29 VEGF signaling specifically modulates immunoregulation by inhibiting the activity of T cells to reduce an antitumor response. Several Phase 2 trials have reported the activity and safety of multi-targeted kinase inhibitors, mainly targeting VEGR, as second-line treatment for thymic carcinoma. The activity of sunitinib malate, a multitargeted kinase inhibitor targeting the VEGFR, was tested in 23 patients with thymic carcinoma and 16 patients with thymoma in a phase 2 trial, in which 6 (26%) of the 23 patients with thymic carcinoma achieved a partial response.30 Another multicenter, phase 2 trial assessed the activity and safety of lenvatinib as a second-line treatment in advanced or metastatic thymic carcinoma. Those findings showed that 16 (38%) of 42 patients had a partial response.31 These results suggest that sunitinib and lenvatinib could become treatment options for patients with previously treated advanced or metastatic thymic carcinoma. However, the above trials all have the limitation of a small sample size, and their results need to be confirmed in larger trials. Anlotinib is a novel TKI that was independently developed in China. Anlotinib can bind to VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, fibroblast growth factor receptor (FGFR), c-Kit, Ret, and other targets. Several clinical trials have demonstrated that anlotinib has good efficacy and safety when used in the treatment of non-small cell lung cancer, soft tissue sarcoma, small cell lung cancer, medullary thyroid carcinoma, renal carcinoma and colorectal cancer. Because of the rarity of thymic carcinoma, no clinical trials have investigated the safety and efficacy of anlotinib in treatment of TC. However, such findings support the use of antiangiogenic agents in treatment of advanced thymic malignancies. Previous success stories regarding the effectiveness of anlotinib therapy motivated us to treat two of our patients with that drug. The results were encouraging, as one of the patients reaped the benefits of immunotherapy provided in combination with anlotinib, further confirming the stimulatory effect of anti-angiogenesis drugs on the immune system.32 The use of anlotinib in combination with traditional chemotherapy, targeted therapy, and immunotherapy needs further exploration. It is hoped that immune-based combination therapy will become more widely used to treat various types of tumors in the future, and thus benefit more patients.\n\nIn conclusion, our study showed that different individuals can respond differently to immunotherapy. Although we observed a suboptimal response rate, the responses we did observe when using immunomonotherapy or an immuno-checkpoint inhibitor in combination with chemotherapy/anti-angiogenesis therapy was beneficial, and those treatments were accompanied by an acceptable level of toxicity. Our study further emphasizes the need for investigating the role that combination therapies consisting of an ICI plus chemotherapy/antiangiogenic drugs can play in treating refractory TC. Despite the limitations of our study, results for the 2 cases described here suggest that immune-based combination therapy may be used as a treatment option for patients with advanced refractory TC, a population for which no standard treatments are available. However, our results must be viewed with caution and reveal the need for conducting large-scale prospective studies that explore the role of immunotherapy in TSCC. Furthermore, prognostic biomarkers could play an essential role in realizing the possible synergistic antitumor effects that ICIs might exert when used as part of combination therapy for TC. Whether PD-L1 can be used as a potential biomarker for TC, still needs to be verified in studies with large sample sizes.\n\nAcknowledgment\nSource of the work: Cases from the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.\n\nEthics and Consent\nAll procedures involving human subjects were performed in accordance with ethical standards of the institutional and/or national research committee, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This was a retrospective study, and written informed consent has been provided by the patients to have the case details and any accompanying images published. The study does not require institutional approval to publish the case details. The patients’ data had been de-identified prior to analysis. The study was based on data obtained from anonymized patients to protect the confidentiality and privacy of the patients.\n\nDisclosure\nAll authors declare having no conflicts of interest.\n==== Refs\nReferences\n1. Wick \nMR , Weiland \nLH , Scheithauer \nBW , et al. Primary thymic carcinomas\n. Am J Surg Pathol . 1982 ;6 (7 ):613 –630\n. doi:10.1097/00000478-198210000-00003 6295194 \n2. Suster \nS , Rosai \nJ . Thymic carcinoma. A clinicopathologic study of 60 cases\n. Cancer . 1991 ;67 (4 ):1025 –1032\n.1991250 \n3. Hsu \nCP , Chen \nCY , Chen \nCL , et al. Thymic carcinoma. Ten years’ experience in twenty patients\n. J Thorac Cardiovasc Surg . 1994 ;107 (2 ):615 –620\n. doi:10.1016/S0022-5223(94)70112-1 8302083 \n4. Fu \nH , Gu \nZ , Fang \nW , et al. Long-term survival after surgical treatment of thymic carcinoma: a retrospective analysis from the Chinese alliance for research of thymoma database\n. Ann Surg Oncol . 2016 ;23 (2 ):619 –625\n. doi:10.1245/s10434-015-4825-4 26474558 \n5. Weksler \nB , Dhupar \nR , Parikh \nV , et al. Thymic carcinoma: a multivariate analysis of factors predictive of survival in 290 patients\n. Ann Thorac Surg . 2013 ;95 (1 ):299 –303\n. doi:10.1016/j.athoracsur.2012.09.006 23141529 \n6. Kondo \nK , Monden \nY . Therapy for thymic epithelial tumors: a clinical study of 1320 patients from Japan\n. Ann Thorac Surg . 2003 ;76 (3 ):878 –884\n. doi:10.1016/s0003-4975(03)00555-1 12963221 \n7. Tseng \nY-L . Thymic carcinoma: a rare cancer requiring special attention\n. Formos J Surg . 2011 ;44 (4 ):136 –140\n. doi:10.1016/j.fjs.2011.08.007 \n8. Tateishi \nK , Ryo \nK , Shukuya \nT , et al. Clinical outcomes of second-line chemotherapy in patients with previously treated advanced thymic carcinoma: a retrospective analysis of 191 patients from the NEJ023 study\n. Oncologist . 2020 ;25 (4 ):e668 –e674\n. doi:10.1634/theoncologist.2019-0593 \n9. Freeman \nGJ , Long \nAJ , Iwai \nY , et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation\n. J Exp Med . 2000 ;192 (7 ):1027 –1034\n. doi:10.1084/jem.192.7.1027 11015443 \n10. Padda \nSK , Riess \nJW , Schwartz \nEJ , et al. Diffuse high intensity PD-L1 staining in thymic epithelial tumors\n. J Thorac Oncol . 2015 ;10 (3 ):500 –508\n. doi:10.1097/JTO.0000000000000429 25402569 \n11. Katsuya \nY , Fujita \nY , Horinouchi \nH , et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma\n. Lung Cancer . 2015 ;88 (2 ):154 –159\n. doi:10.1016/j.lungcan.2015.03.003 25799277 \n12. Rossana \nB , Gaia \nG , Alessandro \nB , et al. Prognostic relevance of programmed cell death protein 1/programmed death-ligand 1 pathway in thymic malignancies with combined immunohistochemical and biomolecular approach\n. Expert Opin Ther Targets . 2020 :1 –7\n. doi:10.1080/14728222.2020.1790529 .\n13. Patel \nSP , Kurzrock \nR . PD-L1 expression as a predictive biomarker in cancer immunotherapy\n. Mol Cancer Ther . 2015 ;14 (4 ):847 –856\n. doi:10.1158/1535-7163.MCT-14-0983 25695955 \n14. Song \nY , Li \nZ , Xue \nW , et al. Predictive biomarkers for PD-1 and PD-L1 immune checkpoint blockade therapy\n. Immunotherapy . 2019 ;11 (6 ):515 –529\n. doi:10.2217/imt-2018-0173 30860441 \n15. Gadgeel \nS , Rodríguez-Abreu \nD , Speranza \nG , et al. Updated analysis From KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer\n. J Clin Oncol . 2020 ;38 (14 ):1505 –1517\n. doi:10.1200/JCO.19.03136 32150489 \n16. Lemma Girum \nL , Lee \nJ-W , Aisner Seena \nC , et al. Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma\n. J Clin Oncol . 2011 ;29 (15 ):2060 –2065\n. doi:10.1200/JCO.2010.32.9607 21502559 \n17. Hirai \nF , Yamanaka \nT , Taguchi \nK , et al. A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L\n. Ann Oncol . 2015 ;26 (2 ):363 –368\n. doi:10.1093/annonc/mdu541 25403584 \n18. Giaccone \nG , Kim \nC , Thompson \nJ , et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study\n. Lancet Oncol . 2018 ;19 (3 ):347 –355\n. doi:10.1016/S1470-2045(18)30062-7 29395863 \n19. Cho \nJ , Kim \nHS , Ku \nBM , et al. Pembrolizumab for patients with refractory or relapsed thymic epithelial tumor: an open-label phase II trial\n. J Clin Oncol . 2019 ;37 (24 ):2162 –2170\n. doi:10.1200/JCO.2017.77.3184 29906252 \n20. Isshiki \nT , Isobe \nK , Tochigi \nN , et al. Successful use of pembrolizumab to treat refractory thymic carcinoma with high PD-L1 expression\n. Case Rep Oncol . 2018 ;11 (3 ):688 –692\n. doi:10.1159/000493187 30483099 \n21. Uchida \nN , Fujita \nK , Okamura \nM , et al. The clinical benefits of immune checkpoint inhibitor for thymic carcinomas~experience of single public hospital in Japan\n. Respir Med Case Rep . 2019 ;26 :39 –41\n. doi:10.1016/j.rmcr.2018.11.007 30505679 \n22. Brahmer Julie \nR , Drake Charles \nG , Wollner \nI , et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates\n. J Clin Oncol . 2010 ;28 (19 ):3167 –3175\n. doi:10.1200/JCO.2009.26.7609 20516446 \n23. Topalian \nSL , Stephen Hodi \nF , Brahmer \nJR , et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer\n. N Engl J Med . 2012 ;366 (26 ):2443 –2454\n. doi:10.1056/NEJMoa1200690 22658127 \n24. Sara \nP , Angel \nM-VM , Niki \nK , et al. Integrating the molecular background of targeted therapy and immunotherapy in lung cancer: a way to explore the impact of mutational landscape on tumor immunogenicity\n. Transl Lung Cancer Res . 2015 ;4 (6 ):721 –727\n. doi:10.3978/j.issn.2218-6751.2015.10.11 26798581 \n25. Tan \nW-L , Jain \nA , Takano \nA , et al. Novel therapeutic targets on the horizon for lung cancer\n. Lancet Oncol . 2016 ;17 (8 ):e347 –e362\n. doi:10.1016/S1470-2045(16)30123-1 27511159 \n26. Okuma \nY , Hosomi \nY , Watanabe \nK , et al. Gemcitabine in patients previously treated with platinum-containing chemotherapy for refractory thymic carcinoma: radiographic assessment using the RECIST criteria and the ITMIG recommendations\n. Int J Clin Oncol . 2016 ;21 (3 ):531 –538\n. doi:10.1007/s10147-015-0926-0 26646221 \n27. Katsuya \nY , Horinouchi \nH , Asao \nT , et al. Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: impact on treatment efficacy and alteration in expression after chemotherapy\n. Lung Cancer . 2016 ;99 :4 –10\n. doi:10.1016/j.lungcan.2016.05.007 27565906 \n28. Nakamura \nK , Smyth Mark \nJ . Targeting cancer-related inflammation in the era of immunotherapy\n. Immunol Cell Biol . 2017 ;95 (4 ):325 –332\n. doi:10.1038/icb.2016.126 27999432 \n29. Ohm \nJE , Carbone \nDP . VEGF as a mediator of tumor-associated immunodeficiency\n. Immunol Res . 2001 ;23 (2–3 ):263 –272\n. doi:10.1385/IR:23:2-3:263 11444391 \n30. Thomas \nA , Rajan \nA , Berman \nA , et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial\n. Lancet Oncol . 2015 ;16 (2 ):177 –186\n. doi:10.1016/S1470-2045(14)71181-7 25592632 \n31. Sato \nJ , Satouchi \nM , Itoh \nS , et al. Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial\n. Lancet Oncol . 2020 ;21 (6 ):843 –850\n. doi:10.1016/S1470-2045(20)30162-5 32502444 \n32. Ken \nG . Promising early results for immunotherapy-antiangiogenesis combination\n. J Natl Cancer Inst . 2014 ;106 (11 ). doi:10.1093/jnci/dju392\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "12()",
"journal": "Cancer management and research",
"keywords": "anti-PD-1; single/combination therapy; thymic carcinoma",
"medline_ta": "Cancer Manag Res",
"mesh_terms": null,
"nlm_unique_id": "101512700",
"other_id": null,
"pages": "11351-11358",
"pmc": null,
"pmid": "33192094",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "The Effect and Safety of Anti-PD-1 Single/Combination Therapy in Refractory Thymic Carcinoma: A Case-Series Study.",
"title_normalized": "the effect and safety of anti pd 1 single combination therapy in refractory thymic carcinoma a case series study"
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"abstract": "Leukaemia cutis is a relatively rare manifestation in chronic lymphocytic leukaemia, characterized by a diverse morphology of skin lesions. We report two patients who developed zosteriform skin symptoms; however, the histological analysis revealed leukaemia infiltration as the cause of their symptoms. Contrary to previous reports, varicella zoster virus DNA was detectable in the lesions. These findings suggest that varicella zoster virus plays an active role in the development of zosteriform leukaemia cutis.",
"affiliations": "Department of Dermatology, Venereology and Oncodermatology, University of Pecs, Pecs, Hungary.;Department of Dermatology, Venereology and Oncodermatology, University of Pecs, Pecs, Hungary.;Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary.;Department of Dermatology, Venereology and Oncodermatology, University of Pecs, Pecs, Hungary.;Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary.;Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary.;Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary.;Department of Dermatology, Venereology and Oncodermatology, University of Pecs, Pecs, Hungary.;Department of Dermatology, Venereology and Oncodermatology, University of Pecs, Pecs, Hungary.",
"authors": "Szlávicz|E|E|;Kálmán|E|E|;Gyömörei|C|C|;Kovács|L A|LA|;Ócsai|H|H|;Varga|E|E|;Oláh|J|J|;Gyulai|R|R|;Lengyel|Z|Z|",
"chemical_list": "D004279:DNA, Viral",
"country": "England",
"delete": false,
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"issue": "44(5)",
"journal": "Clinical and experimental dermatology",
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"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000368:Aged; D004279:DNA, Viral; D005260:Female; D014645:Herpesvirus 3, Human; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D017254:Leukemic Infiltration; D008297:Male; D008875:Middle Aged; D012867:Skin",
"nlm_unique_id": "7606847",
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"title": "Presence of varicella zoster virus in zosteriform leukaemia cutis.",
"title_normalized": "presence of varicella zoster virus in zosteriform leukaemia cutis"
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"companynumb": "HU-CELLTRION INC.-2019HU022951",
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"abstract": "Rathke's cleft cysts are known to cause hormone-related abnormalities. However, the natural history of this disorder is obscure, so it is rarely associated with acute adrenal insufficiency. We herein describe a case of Rathke's cleft cyst associated with acute adrenal insufficiency in a 27-year-old man. The patient experienced severe headaches due to acute adrenal insufficiency without changes in the size of the cyst. Glucocorticoid administration improved these symptoms, and the cyst spontaneously shrank before operation. This case led us to conclude that Rathke's cleft cysts should be considered in the differential diagnosis of patients who present with adrenal insufficiency, and that the cysts can be reduced by glucocorticoids.",
"affiliations": "Department of Endocrinology and Diabetes, Hachinohe City Hospital, Japan.",
"authors": "Hirayama|Yoji|Y|;Kudo|Takanori|T|;Kasai|Nobuhiko|N|",
"chemical_list": "D005938:Glucocorticoids",
"country": "Japan",
"delete": false,
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"mesh_terms": "D000208:Acute Disease; D000309:Adrenal Insufficiency; D000328:Adult; D020863:Central Nervous System Cysts; D003937:Diagnosis, Differential; D005938:Glucocorticoids; D006261:Headache; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D016896:Treatment Outcome",
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"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Adrenal Insufficiency Associated with Rathke's Cleft Cyst.",
"title_normalized": "acute adrenal insufficiency associated with rathke s cleft cyst"
} | [
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"companynumb": "JP-ACTAVIS-2016-07446",
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"abstract": "Ochrobactrum anthropi is an emerging opportunist pathogen in immunocompromised patients. We report a case of septicaemia due to O. anthropi in an elderly male patient with coronary artery disease with severe left ventricular dysfunction admitted in the Intensive coronary care unit. Following intraaortic balloon pump (IABP) insertion, the patient developed a haematoma at the local site, which led to septicaemia. In spite of intensive treatment, the condition of the patient continued to deteriorate and he died on the seventh day. This infection with the microbiological characteristics useful for identification of the organism is described.",
"affiliations": "Department of Microbiology, Government Medical College, Amritsar, India. ushar_ora@yahoo.co.in",
"authors": "Arora|U|U|;Kaur|S|S|;Devi|P|P|",
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"issue": "26(1)",
"journal": "Indian journal of medical microbiology",
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"mesh_terms": "D003324:Coronary Artery Disease; D017809:Fatal Outcome; D016905:Gram-Negative Bacterial Infections; D006406:Hematoma; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D008297:Male; D008875:Middle Aged; D020621:Ochrobactrum anthropi; D018805:Sepsis",
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"references": null,
"title": "Ochrobactrum anthropi septicaemia.",
"title_normalized": "ochrobactrum anthropi septicaemia"
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"companynumb": "IN-PFIZER INC-2020513127",
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... |
{
"abstract": "Recent publications describe pigmentary changes in the retina associated with the use of pentosan polysulfate sodium, the only FDA-approved oral agent for relief of bladder pain or discomfort associated with interstitial cystitis.\n\n\n\nTo evaluate this association, we reviewed data from the FDA Adverse Event Reporting System and published case reports and observational studies.\n\n\n\nThe totality of clinical and epidemiology evidence does not resolve the question of causation between pentosan use and retinal pigmentary changes; however, several elements support a potential association.\n\n\n\nHere, we provide our perspective on the available evidence the agency weighed when retinal pigmentary changes were added to pentosan labeling. It is important for urogynecologists prescribing pentosan to be aware of this potential association and be vigilant about assessing eye health in pentosan users.",
"affiliations": "Division of Pharmacovigilance, Office of Surveillance and Epidemiology, FDA, Silver Spring, MD, USA. Allison.lardieri@fda.hhs.gov.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, FDA, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, FDA, Silver Spring, MD, USA.;Division of Pharmacovigilance, Office of Surveillance and Epidemiology, FDA, Silver Spring, MD, USA.;Division of Epidemiology, Office of Surveillance and Epidemiology, FDA, Silver Spring, MD, USA.;Division of Urology, Obstetrics, and Gynecology, Office of New Drugs, FDA, Silver Spring, MD, USA.;Division of Urology, Obstetrics, and Gynecology, Office of New Drugs, FDA, Silver Spring, MD, USA.;Division of Ophthalmology, Office of New Drugs, FDA, Silver Spring, MD, USA.;Division of Epidemiology, Office of Surveillance and Epidemiology, FDA, Silver Spring, MD, USA.",
"authors": "Lardieri|Allison|A|0000-0002-8341-545X;Konkel|Karen|K|;McCulley|Lynda|L|;Jones|S Christopher|SC|;Moeny|David|D|;Nguyen|Christine|C|;Sewell|Catherine|C|;Chambers|Wiley|W|;Ajao|Adebola|A|",
"chemical_list": "D010426:Pentosan Sulfuric Polyester",
"country": "England",
"delete": false,
"doi": "10.1007/s00192-021-04970-0",
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"issue": "32(11)",
"journal": "International urogynecology journal",
"keywords": "Bladder pain syndrome; Drug safety; Interstitial cystitis; Pentosan polysulfate; Retinal pigmentary changes",
"medline_ta": "Int Urogynecol J",
"mesh_terms": "D018856:Cystitis, Interstitial; D006801:Humans; D017699:Pelvic Pain; D010426:Pentosan Sulfuric Polyester; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "101567041",
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"pages": "2891-2897",
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"pmid": "34505923",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "29801663;31229012;31486843;31671200;31570285;32043016;31757495;31004677;32085877;32305545;12913705;1693797;7688432;31694837",
"title": "Pentosan associated retinal pigmentary changes: FDA's perspective on an emerging postmarketing safety finding.",
"title_normalized": "pentosan associated retinal pigmentary changes fda s perspective on an emerging postmarketing safety finding"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-03659",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditiona... |
{
"abstract": "Adipsic diabetes insipidus (ADI) is a rare disorder. It can occur after transcranial surgery for craniopharyngeoma, suprasellar pituitary adenoma and anterior communicating artery aneurysm but also with head injury, toluene exposure and developmental disorders. It is often associated with significant hypothalamic dysfunction and complications like obesity, sleep apnea, thermoregulatory disorders, seizures and venous thromboembolism (VTE). Morbidity and mortality data have been reported as single case reports with only one large series suggesting increased risk for VTE in patients with ADI. Here we report a mini-series of four patients with ADI and VTE. Post-surgery immobilization, obesity, infection, with prolonged hospitalization, hemoconcentration and changes in coagulation which might be induced by inadequate hormone treatment in the postoperative period (high doses of glucocorticoids, sex steroids and DDAVP replacement) may all contribute to the pathogenesis of VTE. Thromboprophylactic treatment after pituitary surgery and during episodes of hypernatremia is therefore warranted.",
"affiliations": "Clinic of Endocrinology, Medical Faculty, Belgrade University, Clinical Center of Serbia, Belgrade, Serbia.;Clinic of Hematology; Medical Faculty, Belgrade University, Clinical Center of Serbia, Belgrade, Serbia.;Clinic of Endocrinology, Medical Faculty, Belgrade University, Clinical Center of Serbia, Belgrade, Serbia.;Clinic of Endocrinology, Medical Faculty, Belgrade University, Clinical Center of Serbia, Belgrade, Serbia.;Clinic of Endocrinology, Clinical Center of Serbia; Belgrade, Serbia.;Clinic of Endocrinology, Medical Faculty, Belgrade University, Clinical Center of Serbia, Belgrade, Serbia.;Clinic of Endocrinology, Medical Faculty, Belgrade University, Clinical Center of Serbia, Belgrade, Serbia.",
"authors": "Miljic|Dragana|D|;Miljic|Predrag|P|;Doknic|Mirjana|M|;Pekic|Sandra|S|;Stojanovic|Marko|M|;Petakov|Milan|M|;Popovic|Vera|V|",
"chemical_list": "D000925:Anticoagulants",
"country": "Switzerland",
"delete": false,
"doi": "10.14310/horm.2002.1496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1109-3099",
"issue": "13(3)",
"journal": "Hormones (Athens, Greece)",
"keywords": null,
"medline_ta": "Hormones (Athens)",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D001777:Blood Coagulation; D003919:Diabetes Insipidus; D005260:Female; D006801:Humans; D006955:Hypernatremia; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures; D010902:Pituitary Gland; D012307:Risk Factors; D016896:Treatment Outcome; D054556:Venous Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "101142469",
"other_id": null,
"pages": "420-3",
"pmc": null,
"pmid": "25079469",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Adipsic diabetes insipidus and venous thromboembolism (VTE): recommendations for addressing its hypercoagulability.",
"title_normalized": "adipsic diabetes insipidus and venous thromboembolism vte recommendations for addressing its hypercoagulability"
} | [
{
"companynumb": "RS-SA-2014SA115374",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.",
"affiliations": "Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA. Electronic address: elum@mednet.ucla.edu.;Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA.;Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA.;Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA.;Division of Nephrology, David Geffen School of Medicine at UCLA, Los Angeles, CA.",
"authors": "Lum|Erik L|EL|;Huang|Edmund|E|;Bunnapradist|Suphamai|S|;Pham|Thu|T|;Danovitch|Gabriel|G|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000961:Antilymphocyte Serum; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D013792:Thalidomide; D000077269:Lenalidomide; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2016.11.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "69(5)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Kidney allograft rejection; acute renal allograft rejection; case report; chemotherapy regimen; immunomodulatory chemotherapy agent; immunosuppression withdrawal; kidney transplant; lenalidomide; malignancy; multiple myeloma",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000961:Antilymphocyte Serum; D000069340:Deprescriptions; D005260:Female; D006084:Graft Rejection; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007668:Kidney; D016030:Kidney Transplantation; D000077269:Lenalidomide; D060046:Maintenance Chemotherapy; D009101:Multiple Myeloma; D009173:Mycophenolic Acid; D016891:Polycystic Kidney, Autosomal Dominant; D016559:Tacrolimus; D013792:Thalidomide",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "701-704",
"pmc": null,
"pmid": "28189378",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Kidney Allograft Rejection Precipitated by Lenalidomide Treatment for Multiple Myeloma.",
"title_normalized": "acute kidney allograft rejection precipitated by lenalidomide treatment for multiple myeloma"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP013201",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"dru... |
{
"abstract": "BACKGROUND\nIn a retrospective analysis of a prospective single center registry we compared the use of bivalirudin, unfractionated heparin (UFH) monotherapy, UFH + abciximab in 1240 consecutive patients with acute coronary syndrome (ACS) undergoing stent implantation.\n\n\nRESULTS\nBivalirudin was associated with tendentially reduced in-hospital minor or major bleeding rates compared to UFH monotherapy (5.9 % vs. 9.4 % adjusted odds ratio (OR) 0.82, 95 % confidence interval CI 0.45-1.51, p = 0.53) and compared to the pooled UFH group (5.9 % vs. 11.9 %, adjusted OR 0.62, 95 % CI 0.36-1.08, p = 0.09) but with significantly lower bleeding hazards compared to UFH + abciximab (5.9 % vs. 16 %, adjusted OR 0.41, 95 % CI 0.22-0.78, p < 0.01). After 3 years of follow-up, adjusted cardiovascular mortality rates were similar between all groups, particularly between bivalirudin vs. UFH monotherapy (hazard ratio HR 1.12, 95 % CI 0.58-2.16, p = 0.73) and vs. UFH + abciximab (HR 0.91, 95 % CI 0.40-2.10, p = 0.83). Acute or subacute stent thrombosis occurred at a rate of 0.8 % with no significant differences between the groups.\n\n\nCONCLUSIONS\nThis retrospective analysis in a real world situation of medium to high-risk ACS patients undergoing invasive revascularization confirmed the results of most large-scale randomized trials by demonstrating reduced bleeding rates in favor of bivalirudin vs. UFH + GPI but with no significant differences between treatment strategies for long-term all-cause and cardiovascular mortality.",
"affiliations": "3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria. miklos.rohla@meduniwien.ac.at.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.;Department of Cardiology, Medical University, Vienna, Austria.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.;Deutsches Herzzentrum, Technische Universität, Munich, Germany.;Columbia University Medical Center and the Cardiovascular Research Foundation, New York, USA.;3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160, Vienna, Austria.",
"authors": "Rohla|Miklos|M|http://orcid.org/0000-0002-8967-0806;Tentzeris|Ioannis|I|;Freynhofer|Matthias K|MK|;Farhan|Serdar|S|;Jarai|Rudolf|R|;Egger|Florian|F|;Weiss|Thomas W|TW|;Wojta|Johann|J|;Geppert|Alexander|A|;Kastrati|Adnan|A|;Stone|Gregg W|GW|;Huber|Kurt|K|",
"chemical_list": "D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C074619:bivalirudin",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-016-1078-6",
"fulltext": "\n==== Front\nWien Klin WochenschrWien. Klin. WochenschrWiener Klinische Wochenschrift0043-53251613-7671Springer Vienna Vienna 107810.1007/s00508-016-1078-6Original ArticleImpact of bivalirudin on mortality and bleeding complications in acute coronary syndrome patients undergoing invasive revascularization A real world experiencehttp://orcid.org/0000-0002-8967-0806Rohla Miklos MDmiklos.rohla@meduniwien.ac.at 1Tentzeris Ioannis MD1Freynhofer Matthias K. MD1Farhan Serdar MD1Jarai Rudolf MD1Egger Florian MD1Weiss Thomas W. MD PhD FESC15Wojta Johann PhD2Geppert Alexander MD1Kastrati Adnan MD FESC3Stone Gregg W. MD FACC FSCAI4Huber Kurt MD FESC FACC FAHA151 3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Montleartstraße 37, 1160 Vienna, Austria 2 Department of Cardiology, Medical University, Vienna, Austria 3 Deutsches Herzzentrum, Technische Universität, Munich, Germany 4 Columbia University Medical Center and the Cardiovascular Research Foundation, New York, USA 5 Medical School, Sigmund Freud University, Vienna, Austria 13 9 2016 13 9 2016 2016 128 23 906 915 18 6 2016 5 8 2016 © The Author(s) 2016\nOpen Access This 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.Summary\nBackground\nIn a retrospective analysis of a prospective single center registry we compared the use of bivalirudin, unfractionated heparin (UFH) monotherapy, UFH + abciximab in 1240 consecutive patients with acute coronary syndrome (ACS) undergoing stent implantation.\n\nResults\nBivalirudin was associated with tendentially reduced in-hospital minor or major bleeding rates compared to UFH monotherapy (5.9 % vs. 9.4 % adjusted odds ratio (OR) 0.82, 95 % confidence interval CI 0.45–1.51, p = 0.53) and compared to the pooled UFH group (5.9 % vs. 11.9 %, adjusted OR 0.62, 95 % CI 0.36–1.08, p = 0.09) but with significantly lower bleeding hazards compared to UFH + abciximab (5.9 % vs. 16 %, adjusted OR 0.41, 95 % CI 0.22–0.78, p < 0.01). After 3 years of follow-up, adjusted cardiovascular mortality rates were similar between all groups, particularly between bivalirudin vs. UFH monotherapy (hazard ratio HR 1.12, 95 % CI 0.58–2.16, p = 0.73) and vs. UFH + abciximab (HR 0.91, 95 % CI 0.40–2.10, p = 0.83). Acute or subacute stent thrombosis occurred at a rate of 0.8 % with no significant differences between the groups.\n\nConclusions\nThis retrospective analysis in a real world situation of medium to high-risk ACS patients undergoing invasive revascularization confirmed the results of most large-scale randomized trials by demonstrating reduced bleeding rates in favor of bivalirudin vs. UFH + GPI but with no significant differences between treatment strategies for long-term all-cause and cardiovascular mortality.\n\nKeywords\nBivalirudinAcute coronary syndromePercutaneous coronary interventionAnticoagulationHeparinAssociation for the Promotion of Research in Atherosclerosis, Thrombosis and Vascular BiologyLudwig Boltzmann Foundation for Cardiovascular Researchissue-copyright-statement© Springer-Verlag Wien 2016\n==== Body\nIntroduction\nInvasive revascularization with stent implantation is the standard of care for the majority of patients presenting with acute coronary syndrome (ACS) and improves clinical outcomes compared to a more conservative approach [1]. Recent studies have suggested that novel antithrombotic and antiplatelet strategies, namely fondaparinux [2], bivalirudin [3, 4], ticagrelor [5] and rivaroxaban in combination with dual antiplatelet therapy [6] may reduce mortality in ACS patients. In recent large-scale prospective randomized trials, the favorable pharmacological action of bivalirudin translated into lower 30-day major bleeding rates compared to unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) and also vs. UFH monotherapy but exhibited similar or even worse rates in ischemic events depending on study design, patient selection and concomitant therapy [4, 7–9]. While previous guidelines have led to an increased use of bivalirudin in the USA, bivalirudin is infrequently used in ACS patients undergoing percutaneous coronary interventions (PCI) in western Europe (approximately 10 % of patients) with the exception of some highly specialized centers. Of note, international trials have mainly compared bivalirudin (monotherapy) with UFH + GPI in ACS patients and real world observations vs. UFH monotherapy are scarce [3, 9–11]. Accordingly, we investigated the efficacy and safety of bivalirudin compared to heparin-based strategies in patients with ST-elevation or non-ST-elevation myocardial infarction (STEMI and NSTEMI, respectively) referred for acute angiography who subsequently received PCI and stent implantation.\n\nPatients and methods\nStudy population\nIn this post hoc analysis of a prospective registry, antithrombotic therapy (as used per the discretion of the interventional cardiologist), cardiovascular risk factors, comorbidities and coronary morphology were evaluated in 1240 consecutive patients with ACS who were referred for PCI with stent implantation between January 2004 and June 2012. We included STEMI patients presenting with ST-segment elevation of 1 mm or more in two or more contiguous leads, as well as NSTEMI patients with elevated troponin I, troponin T or creatine kinase MB levels (CK-MB) above the upper limit of normal and/or ST-segment depression of ≥1 mm. Patients lacking laboratory or electrocardiographic evidence suggestive of high-risk ACS were excluded from this analysis as were patients referred for rescue PCI after thrombolytic therapy, patient records with a missing cause of death (n = 4) or patients who were in cardiogenic shock at any time during index hospitalization. In contrast to current practice, PCI was performed by the femoral approach in the vast majority of patients included into the registry (93 %). The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee (EK 10-046-VK_NZ).\n\nStudy treatment\nAs the institutional standard of care, all patients received aspirin and clopidogrel as a 600 mg loading dose (LD) followed by 75 mg maintenance dose (MD), prasugrel (60 mg LD followed by 10 mg MD except in patients >75 years or <60 kg who received 5 mg MD) or ticagrelor (180 mg LD followed by 180 mg MD). Prasugrel was used in most STEMI patients and in high-risk NSTEMI patients starting in 2010. All STEMI patients were pretreated with UFH (60 IU/kg i.v. bolus but maximum 5000 U) by emergency physicians. All NSTEMI patients received anticoagulation with enoxaparin, UFH or fondaparinux until diagnostic coronary angiography. In the case of fondaparinux being given prior to catheterization, UFH was exclusively added in the catheterization laboratory as i.v. bolus of 85 IU/kg body weight. The NSTEMI patients who were pretreated with enoxaparin or UFH and STEMI patients either received UFH in the catheterization laboratory or bivalirudin, which was administered as bolus and infusion only until the end of the intervention due to practical reasons (both STEMI and NSTEMI: 0.75 mg/kg bolus, 1.75 mg/kg/h infusion). If extended bed rest after PCI was indicated, enoxaparin was administered at a thrombosis prophylactic dose until full mobilization. Abciximab was used in the presence of increased thrombus load in the infarct-related artery or as bail-out therapy in patients with slow or no-reflow in the recommended dosage (bolus +infusion for 12 h). Moreover, patients received optimal secondary prevention, i. e. statin therapy with a target low-density lipoprotein (LDL) of less than 70 mg/dl (1.8 mmol/l) but also other guideline-recommended treatment, such as beta blockers, angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers. All ACS patients received parenteral anticoagulation, aspirin and an approved P2Y12 inhibitor, as early as possible, usually in the emergency room of the department but in the majority before the catheter laboratory. Decisions regarding the choice of P2Y12 inhibitor, bail-out use of abciximab, access site, performance of thrombus aspiration, stent type and duration of dual antiplatelet therapy were left to the physician’s discretion.\n\nStudy outcome\nThe primary efficacy endpoint was cardiovascular mortality after 3 years of follow-up. As secondary efficacy endpoints we evaluated all-cause mortality after 3 years of follow-up as well as acute and subacute stent thrombosis. Mortality data for all patients were obtained from Statistics Austria, an independent and non-profit-making federal institution under public law that supports scientific services. Cases of death occurring in Austria are centrally recorded by Statistics Austria and data are made available for authorized institutions on request. Cause of death is reported by means of the International Statistical Classification of Disease and Related Health Problems (ICD-10). A cardiovascular death was adjudicated when an ICD-10 chapter I00-I99 diagnosis was reported as the cause of death. Acute and subacute stent thrombosis was evaluated and reported according to the definition proposed by the Academic Research Consortium [12]. The primary safety endpoint was a composite of in-hospital minor or major bleeding events based on the Thrombolysis in Myocardial Infarction (TIMI) classification. As tertiary endpoint we registered days from PCI to hospital discharge. This tertiary endpoint was compared between patients with and without bleeding complications and between the different antithrombotic strategies. For the detection of in-hospital bleeding, levels of hemoglobin and hematocrit were measured before and daily after PCI until hospital discharge. For categorization of periprocedural bleeding events, we calculated the difference in hemoglobin concentrations between the most recent hemoglobin value before PCI and the hemoglobin nadir post-PCI. In accordance with the TIMI bleeding classification [13] the following cut-off levels were used: minor bleeding was defined as a drop in hemoglobin from ≥3 to <5 g/dl or a ≥10 % decrease in hematocrit and major bleeding was defined as a drop in hemoglobin ≥5 g/dl or a ≥15 % decrease in hematocrit.\n\nClinical outcome data were compared between the pooled bivalirudin group (with or without GPI use) vs. UFH monotherapy, vs. UFH + abciximab and vs. the pooled UFH group. As the group of patients receiving bivalirudin + abciximab represented only 1.1 % of the whole cohort (14 patients), a separate analysis for this subgroup was not performed.\n\nStatistical methods\nDescriptive statistics were performed on baseline variables and stratified by the different treatment groups. Discrete characteristics are expressed as frequency counts and percentages and differences were determined by the χ2-test. Continuous characteristics are expressed as means and standard deviations or medians (where appropriate), with differences examined with the Kruskal-Wallis test throughout all groups or the Mann-Whitney test for the comparison of two treatment arms. The level of significance used for all tests was a two-sided p-value of 0.05.\n\nUnivariate analysis in the Cox proportional hazards and the logistic regression model was performed to estimate mortality and bleeding hazards between different antithrombotic treatments. A 1:1 matched propensity score for the abovementioned two-group comparisons was obtained in order to account for confounding variables. Covariates were chosen based on significant differences between groups (Table 1) and well-established risk factors, e.g. age, gender, body mass index (BMI), estimated glomerular filtration rate (eGFR), baseline hemoglobin, hypertension, hyperlipidemia, smoking, diabetes, clinical presentation (STEMI or NSTEMI), type of stent, number of diseased vessels, previous MI, previous invasive revascularization, peripheral artery disease, prior stroke or transient ischemic attack (TIA), heart failure, history of malignancies, atrial fibrillation, vascular access site, year of index hospitalization, statin treatment and antiplatelet substance. The corresponding propensity scores were then included in the Cox regression (mortality) and logistic regression (in-hospital bleeding) analyses for the two-group comparisons.Table 1 Baseline characteristics of patients stratified by antithrombotic treatment groups\n\n\tAll patients n = 1240\tPooled bivalirudin n = 287\tUFH monotherapy n = 596\tUHF + GPI n = 357\t\np-value*\t\n\nClinical characteristics\n\t\nGender\tMale\t66.80 %\t64.80 %\t63.30 %\t74.20 %\t0.002\t\n–\tFemale\t33.20 %\t35.20 %\t36.70 %\t25.80 %\t–\t\nClinical presentation\tNSTEMI\t48.60 %\t59.60 %\t54.90 %\t29.40 %\t<0.001\t\n–\tSTEMI\t51.40 %\t40.40 %\t45.10 %\t70.60 %\t–\t\nDrug-eluting Stent\tdrug eluting stent\t48.10 %\t67.90 %\t44.60 %\t38.10 %\t<0.001\t\nAccess site\tFemoral\t93.30 %\t90.90 %\t93.10 %\t95.50 %\t0.067\t\nAge (years, median)\t63\t63\t65\t59\t<0.001\t\nBMI (median kg/m2)\t27.17\t27.34\t27.02\t27.34\t0.119\t\neGFR (median ml/min)\t88.68\t91.61\t82.73\t96.52\t<0.001\t\nBaseline creatinine (median mg/dl)\t0.9\t0.9\t0.97\t0.9\t0.053\t\nSBP (median mm Hg)\t140\t140\t135\t140\t0.758\t\nCRP (median mg/l)\t4\t3.5\t4.7\t4\t0.155\t\nBaseline Hb (median g/dl)\t14.15\t14.1\t13.8\t14.5\t<0.001\t\nBaseline PLTs (median g/l)\t232\t230\t233\t231\t0.603\t\nPeak troponin (median ng/ml)b\n\t13.97\t9.55\t9.53\t26.62\t<0.001\t\nCK-MB (median U/l)\t119\t93\t99.5\t170\t<0.001\t\n\nCardiovascular risk factors\n\t\nHypertension\t77.50 %\t80.80 %\t78.00 %\t73.90 %\t0.105\t\nHyperlipidaemia\t81.40 %\t81.20 %\t80.40 %\t83.20 %\t0.553\t\nSmoking (current or prior)\t50.80 %\t54.00 %\t44.30 %\t59.10 %\t<0.001\t\nDiabetes\t26.00 %\t30.30 %\t27.30 %\t20.40 %\t0.011\t\n\nComorbidities\n\t\nPrevious MCI\t15.00 %\t14.60 %\t16.80 %\t12.30 %\t0.173\t\nPrevious PCI\t14.20 %\t16.40 %\t14.40 %\t12.00 %\t0.286\t\nPrevious CABG\t2.90 %\t3.50 %\t3.20 %\t2.00 %\t0.440\t\nPrior stroke or TIA\t6.40 %\t7.00 %\t8.10 %\t3.10 %\t0.009\t\nPAD\t5.90 %\t5.90 %\t7.00 %\t3.90 %\t0.140\t\nAtrial fibrillation\t6.50 %\t5.60 %\t8.70 %\t3.40 %\t0.004\t\nHistory for malignancies\t5.30 %\t5.60 %\t6.70 %\t2.80 %\t0.033\t\nHeart failure\t11.60 %\t11.10 %\t11.20 %\t12.60 %\t0.786\t\n\nDiseased vessels\n\t\n1-VD (one vessel disease)\t52.00 %\t50.20 %\t52.00 %\t53.50 %\t0.286\t\n2-VD (two vessel disease)\t30.60 %\t33.10 %\t31.90 %\t26.60 %\t–\t\n3-VD (three vessel disease)\t17.30 %\t16.70 %\t16.10 %\t19.90 %\t–\t\n\nMedication therapy\n\t\nARB\t13.10 %\t15.60 %\t11.40 %\t13.80 %\t0.217\t\nBeta blocker\t85.30 %\t86.10 %\t84.30 %\t86.40 %\t0.639\t\nStatins\t92.40 %\t96.50 %\t88.40 %\t95.80 %\t<0.001\t\nAcetylsalicylic acid\t99.20 %\t99.10 %\t98.80 %\t100 %\t0.191\t\n\nAntiplatelet substance\n\t\nClopidogrel\t76.10 %\t68.30 %\t80.00 %\t75.90 %\t<0.001\t\nPrasugrel\t13.90 %\t24.00 %\t9.40 %\t13.20 %\t–\t\nTicagrelor\t2.00 %\t4.20 %\t1.80 %\t0.60 %\t–\t\nOthera\n\t8.00 %\t3.50 %\t8.70 %\t10.40 %\t–\t\n\nUFH unfractionated heparin, GPI glycoprotein IIb/IIIa inhibitor, STEMI ST elevation myocardial infarction, NSTEMI Non-ST elevation myocardial infarction, BMI body mass index, eGFR estimated glomerular filtration rate, SBP systolic blood pressure, CRP baseline c‑reactive protein levels, Hb haemoglobin, HCT baseline haematocrit, PLT baseline platelet count, CK-MB creatine kinase myocardial band, MCI myocardial infarction, PCI percutaneous coronary intervention, CABG coronary artery bypass graft, TIA transient ischemic attack, PAD peripheral artery disease, ARB angiotensin receptor blocker, VD vessel disease\n\n*χ2-test/Kruska-Wallis test throughout three groups (pooled bivalirudin, UFH, UFH +GPI)\n\n\naOther refers to ticlopidin or inclusion in randomized trials with blinded treatment assignment\n\n\nbUpper limit of normal for troponin I was 0.045 ng/ml\n\n\n\n\nLikewise, the impact of bleeding and antithrombotic therapy on the duration of hospitalization was analyzed in a linear regression model. The Software Package for Social Sciences version 22 (SPSS, Chicago, IL) was used for all statistical calculations.\n\nResults\nStudy population\nRegistered baseline characteristics included cardiovascular risk factors, comorbidities, coronary morphology, medication at hospital discharge and laboratory findings (Table 1). From 1240 patients presenting with ACS and undergoing PCI plus stent implantation, 632 (51.4 %) patients presented with STEMI. Of the total cohort, 273 (22 %) received bivalirudin monotherapy in the catheterization laboratory, 14 (1.1 %) received bivalirudin + abciximab, 596 (48.1 %) received UFH alone and 357 (28.8 %) patients received UFH + abciximab. The NSTEMI patients more frequently received bivalirudin, while STEMI patients more frequently received UFH + abciximab (p < 0.01, Table 1). The utilization of the different antithrombotic strategies over time is presented in Fig. 3. There was a steep increase in bivalirudin use, starting from 2009 (p for trend <0.01).\n\nSimilarities as well as significant differences regarding baseline characteristics were detected between the study groups. While patients receiving UFH monotherapy, as compared to the pooled bivalirudin group were similar with respect to age, diabetes, hypertension, previous stroke, myocardial infarction or PCI, heart failure, coronary morphology and other characteristics (Table 1), these patients had lower levels of hemoglobin at admission (median 14.1 g/dl vs. 13.8 g/dl, p < 0.01) and lower levels of estimated glomerular filtration rate (eGFR, median 91.6 ml/min vs. 82.7 ml/min, p = 0.01). Patients receiving UFH + abciximab were younger (median age 63 years vs. 59 years, p < 0.01), had higher levels of baseline hemoglobin (median 14.1 mg/dl vs. 14.5 mg/dl, p < 0.01) and had a higher eGFR than patients of the pooled bivalirudin cohort (median eGFR 91.6 ml/min vs. 96.5 ml/min, p < 0.01). Risk factors and comorbidities, such as diabetes, hypertension, prior stroke, TIA or a history for malignant tumors were more prevalent in the pooled bivalirudin group, as opposed to UFH + abciximab. Discharge medications including ACE inhibitors, ARBs and beta blockers were similar between groups, while patients treated with UFH monotherapy received adequate statin therapy at hospital discharge less frequently than patients treated with bivalirudin or with UFH + abciximab (Table 1, p < 0.001). Moreover, bivalirudin treated patients received one of the novel P2Y12-receptor inhibitors twice as frequently compared to UFH-treated patients. In total, 88.9 % of patients with drug-eluting stent (DES) implantation received dual antiplatelet therapy for 12 months, while 8.7 % were treated for 6–9 months only. Therapy durations that were either shorter or longer were observed in 2.4 % of patients.\n\nMortality outcome\nPatients were followed for up to 3 years after the index hospitalization. In total, 113 (9.1 %) events occurred. Rates of all-cause death were 8.7 %, 10.2 % and 7.6 % in the pooled bivalirudin, UFH monotherapy and UFH + abciximab groups, respectively. Corresponding rates of cardiovascular death were 4.9 %, 6.4 % and 4.8 % after 3 years of follow-up, respectively. Univariate analysis revealed non-significant different rates of all-cause or cardiovascular death for bivalirudin vs. UFH monotherapy, vs. UFH + abciximab and the pooled UFH group as well as for UFH monotherapy vs. UFH + abciximab (Table 2).Table 2 Unadjusted and adjusted 3‑year outcomes and rates of stent thrombosis\n\n\nUnivariate outcomes\n\t\n–\t\nAll-cause death\n\t\nCV death\n\t\n\nHR\n\t\n95 % CI\n\t\np-value\n\t\nHR\n\t\n95 % CI\n\t\np-value\n\t\nPooled bivalirudin vs. UFH monotherapy\t0.84\t0.53; 1.34\t0.47\t0.76\t0.41; 1.40\t0.38\t\nPooled bivalirudin vs. UFH +GPI\t1.16\t0.67; 2.00\t0.59\t1.04\t0.51; 2.10\t0.92\t\nPooled bivalirudin vs. pooled UFH\t0.94\t0.60; 1.47\t0.79\t0.85\t0.47; 1.52\t0.57\t\nUFH vs. UFH +GPI\t1.34\t0.88; 2.20\t0.17\t1.36\t0.77; 2.41\t0.29\t\n\nAdjusted outcomes\n\t\n–\t\nAll-cause death\n\t\nCV death\n\t\n\nHR\n\t\n95 % CI\n\t\np-value\n\t\nHR\n\t\n95 % CI\n\t\np-value\n\t\nPooled bivalirudin vs. UFH monotherapy\t1.12\t0.68; 1.84\t0.66\t1.12\t0.58; 2.16\t0.73\t\nPooled bivalirudin vs. UFH +GPI\t0.9\t0.48; 1.71\t0.75\t0.91\t0.40; 2.10\t0.83\t\nPooled bivalirudin vs. pooled UFH\t1.09\t0.68; 1.76\t0.71\t1.08\t0.58; 2.01\t0.81\t\nUFH monotherapy vs. UFH +GPI\t0.76\t0.46; 1.25\t0.29\t0.75\t0.40; 1.41\t0.37\t\n\nStent thrombosis\n\t\n–\t\nAll\n\t\nDefinite\n\t\nProbable\n\t\nAcute\n\t\nSubacute\n\t\np = 0.748*\t\nPooled bivalirudin\t0.4 %\t0.4 %\t0 %\t0 %\t0.4 %\t–\t\nUFH monotherapy\t0.8 %\t0.5 %\t0.3 %\t0.3 %\t0.5 %\t–\t\nUFH +GPI\t1.1 %\t0.6 %\t0.6 %\t0.3 %\t0.8 %\t–\t\n\nUFH unfractionated heparin, GPI glycoprotein IIb/IIIa inhibitor, HR hazard ratio, CI confidence interval, CV cardiovascular\n\n*χ2-test, multivariate adjustment not performed\n\n\n\n\nAfter adjustment for confounders, similar mortality rates were observed for all comparisons. Univariate and multivariate analyses are presented in Table 2. Kaplan-Meier survival curves are shown in Fig. 1.Fig. 1 Kaplan-Meier plots for all-cause death (a) and cardiovascular death (b) after 3 years, stratified for antithrombotic treatment strategy. On propensity score adjusted Cox regression modelling, there were no significant differences between groups for both endpoints (Table 2)\n\n\n\n\nStent thrombosis\nAcute or subacute stent thrombosis occurred in 10 (0.8 %) patients. In the pooled bivalirudin group 1 (0.4 %) definite, subacute event occurred. In the UFH monotherapy group, three definite and two probable events occurred (0.8 %) of which two were acute and three subacute. In the UFH + abciximab group, we observed two definite and two probable stent thromboses (1.1 %) of which one event was acute. The differences between groups were not statistically significant (p = 0.748) (Table 2).\n\nBleeding outcome\nAs shown in Fig. 2 composite rates of in-hospital TIMI minor or major bleeding were 5.9 % for the pooled bivalirudin group, whereas these bleeding rates were 9.4 % for the UFH monotherapy, 16 % for the UFH + abciximab group and 11.9 % for the pooled UFH group.Fig. 2 Rates of in-hospital bleeding stratified by anticoagulant treatment groups. Combined minor or major bleeding events were significantly lower comparing pooled bivalirudin vs. UFH + abciximab (OR 0.41, 95 % CI 0.22–0.78, p = 0.01), whereas bleeding rates were similar between bivalirudin vs. UFH alone (OR 0.82, 95 % CI 0.45–1.51, p = 0.53)\n\n\n\n\nUnivariate and multivariate analyses in the logistic regression model are presented in Table 3.Table 3 Unadjusted and adjusted in-hospital minor or major bleeding rates\n\n\nUnivariate outcomes\n\t\n\t\nOR\n\t\n95 % CI\n\t\np-value\n\t\nPooled bivalirudin vs. UFH monotherapy\t0.61\t0.35; 1.06\t0.08\t\nPooled bivalirudin vs. UFH +GPI\t0.33\t0.19; 0.58\t<0.01\t\nPooled bivalirudin vs. pooled UFH\t0.47\t0.28; 0.79\t<0.01\t\nUFH monotherapy vs. UFH +GPI\t0.55\t0.37; 0.81\t<0.01\t\n\nAdjusted outcomes\n\t\n\t\nOR\n\t\n95 % CI\n\t\np-value\n\t\nPooled bivalirudin vs. UFH monotherapy\t0.82\t0.45; 1.51\t0.53\t\nPooled bivalirudin vs. UFH +GPI\t0.41\t0.22; 0.78\t0.01\t\nPooled bivalirudin vs. pooled UFH\t0.62\t0.36; 1.08\t0.09\t\nUFH monotherapy vs. UFH +GPI\t0.65\t0.43; 0.99\t0.047\t\n\nUFH unfractionated heparin, GPI glycoprotein IIb/IIIa inhibitor, OR odds ratio, CI confidence interval\n\n\n\n\nAfter adjustment for confounding baseline variables bivalirudin use was associated with significantly lower rates in the composite endpoint of TIMI minor or major bleeding as compared to UFH + abciximab (5.9 % vs. 16 %, OR 0.41, 95 % CI 0.22–0.78, p = 0.01). Adjusted rates of bleeding were non-significantly lower for pooled bivalirudin vs. UFH monotherapy (5.9 % vs. 9.4 %, OR 0.82, 95 % CI 0.45–1.51, p = 0.53), and were reduced by 35 % comparing UFH alone to UFH + abciximab (9.4 % vs. 16 %, OR 0.65, 95 % CI 0.43–0.99, p = 0.047). Comparing the pooled bivalirudin vs. the pooled UFH group, there was a non-significant trend towards reduced bleeding rates (5.9 % vs. 11.9 %, OR 0.62, 95 % 0.36–1.08, p = 0.09). The year of treatment was accounted for in all adjusted analyses and the utilization of anticoagulants over time is presented in Fig. 3.Fig. 3 Utilization of the different antithrombotic strategies over time. Timely linked to the publication of the HORIZONS-AMI trial, there was a significant increase in bivalirudin utilization, whereas strategies including abciximab were less frequently used thereafter\n\n\n\n\nDuration of hospitalization\nMedian days from PCI to hospital discharge are presented in Fig. 4. After adjustment for confounding baseline variables major and minor bleeding prolonged post-PCI hospital stay by 6.5 (95%CI 4.5–8.5, p < 0.01) and 3.2 (95 % CI 2.0–4.3, p < 0.01) days, respectively, as compared to patients without an in-hospital bleeding episode.Fig. 4 Median days from PCI to hospital discharge for the overall cohort and stratified by clinical presentation and bleeding severity. On adjustment for confounders, major and minor bleeding prolonged post-PCI hospital stay by 6.5 (95% CI 4.5–8.5, p < 0.01) and 3.2 (95 % CI 2.0–4.3, p < 0.01) days, respectively, compared to patients not experiencing a bleeding episode\n\n\n\n\nMedian days from PCI to hospital discharge were 5 (Interquartile range [IQR] 2;7), 5 (IQR 2; 7) and 7 (IQR 5; 8) in the pooled bivalirudin, UFH monotherapy and UFH + abciximab groups, respectively. After adjustment for confounders days from PCI to discharge were similar between the pooled bivalirudin and UFH monotherapy groups (−0.8, 95 % CI −1.7 to −0.06, p = 0.07) but reduced by 1.5 (95 % CI −2.2 to −0.7, p < 0.01) days compared to UFH + abciximab.\n\nDiscussion\nIn this retrospective analysis of a prospective registry, reflecting a real world situation, we were able to confirm the results of most randomized controlled trials in ACS patients undergoing invasive revascularization. Bivalirudin use was associated with a 59 % relative risk reduction in periprocedural combined TIMI minor or major bleeding rates compared to UFH +GPI, along with a reduced hospital stay after PCI. Bleeding rates were numerically but not statistically significantly lower comparing pooled bivalirudin vs. UFH alone or the pooled UFH group, whereas the rates of stent thrombosis, all-cause death and cardiovascular death were not statistically different between groups. Abciximab use increased significantly between 2006 and 2009 probably because of the recommendations issued by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on STEMI (2004) and NSTEMI (2007) as well as by the European Society of Cardiology (ESC) guidelines on the use of antiplatelet agents (2004) [14–16]. Moreover, timely linked to the publication of the HORIZONS-AMI trial in 2008, there was a significant increase in bivalirudin utilization, whereas strategies including abciximab were less recommended and also used thereafter [3]. This underlines the adherence to international guidelines at our center.\n\nMortality outcome\nSeveral earlier randomized trials conducted in the setting of moderate to high-risk NSTEMI (ACUITY and ISAR REACT 4) and STEMI (HORIZONS-AMI) revealed a positive net clinical benefit in favor of bivalirudin vs. UFH + GPI, primarily through the reduction of major bleeding events [3, 10, 11, 17]. The more recent EUROMAX trial investigated bivalirudin (with 12 % GPI use) vs. UFH (with 69 % GPI use) in a modern treatment setting for STEMI (50 % novel P2Y12 inhibitors) and also demonstrated a positive net clinical benefit in favor of bivalirudin. This benefit was mainly achieved through the reduction of major bleeding events, whereas cardiac death was not affected by the choice of the anticoagulant [7]. As the use of GPIs is usually low in a contemporary clinical setting, while radial access and novel P2Y12 receptor inhibitors are increasingly being used, the comparison vs. UFH monotherapy is particularly desirable [18]. The BRIGHT trial randomly assigned 2194 STEMI patients to bivalirudin with a 3‑h postprocedural infusion, UFH alone or UFH + tirofiban and reported no significant differences regarding major adverse cardiac or cerebral events at 30 days [8]. The recent MATRIX trial randomized 7213 ACS patients to either bivalirudin or UFH alone (only 0.2 % GPI use) and did not show a net improvement in adverse clinical events. Although cardiac death was reduced by 32 % (likely through reduction of major bleeding), this was counterbalanced by an excess in definite stent thrombosis [4]. In the single center HEAT-PPCI trial, also conducted in a modern setting (15 % GPI bail-out use, 90 % novel P2Y12 receptor inhibitors and over 80 % radial access) major adverse cardiovascular events were significantly increased by 52 % in the bivalirudin arm, with a fourfold risk of stent thrombosis and also an increase in bleeding hazards [9]. Meta-analyses provided conflicting results depending on the selection of these trials regarding reinfarction but showed no differences in mortality despite an increase in acute stent thrombosis in bivalirudin treated patients [19, 20]. In line with these findings we did not observe a mortality difference between groups, keeping in mind that statistical power was limited due to low sample size.\n\nStent thrombosis\nThe rate of stent thrombosis was in the range of previously published data, also considering that 51 % of patients received bare metal stents [21]. We did not observe significant differences between groups; however, event rates were too low for statistical adjustment for confounders. In this setting there was no excess in acute stent thrombosis in patients treated with bivalirudin, opposed to data from previous large-scale trials [4, 7, 9].\n\nBleeding outcomes\nOur data are similar to the findings from the HORIZONS-AMI, EUROMAX, ACUITY, ISAR-REACT 4, and REPLACE-2 trials regarding significantly reduced bleeding hazards for bivalirudin vs. UFH + GPI [3, 7, 10, 11, 22]. As expected, we also observed lower bleeding rates when UFH monotherapy was compared to UFH + abciximab. It has to be noted that from a clinical point of view, comparisons against UFH + GPI are less relevant as recent guidelines recommend to restrict GPI use to bail-out situations [18, 23].\n\nData from prospective, randomized trials comparing bivalirudin and UFH monotherapies with respect to bleeding rates pointed in the same direction in both stable and ACS patients: [4, 8, 24]. In the recent BRIGHT and MATRIX trials, bleeding rates were significantly lower in favor of bivalirudin vs. UFH alone even when bivalirudin was continued following the procedure [4, 8]. Interestingly, no differences in major bleeding could be observed in the HEAT-PPCI trial [9] conducted in a modern setting with respect to antiplatelet agents, access site and GPI use. A potential explanation could be the prominent use of new P2Y12 receptor inhibitors that are known to be associated with significantly higher spontaneous bleeding rates [5, 25]. This was further confirmed by a post hoc analysis of EUROMAX demonstrating similar clinical outcome but higher per protocol major bleeding rates in patients treated with prasugrel or ticagrelor as compared to clopidogrel [26]. Although in-hospital bleeding rates in ACS patients undergoing PCI might also depend on the vascular access site and the majority of femoral access in our study might have influenced bleeding rates, a recent analysis has shown benefits for bivalirudin over UFH monotherapy and over UFH +GPI for both access sites [7].\n\nHospital stay\nThe occurrence of TIMI minor and major bleeding had a substantial impact on post-PCI hospital stay in our analysis. As also described by others, major bleeding hazards accounted for an almost twofold prolongation of hospitalization in ACS patients [27]. Thus, preventing bleeding is important to preserve healthcare resource consumption, in addition to optimizing clinical outcomes.\n\nLimitations\nThe data from the present study were collected from a single center and in a non-randomized fashion as the treatment strategy was at the discretion of the treating interventional cardiologist; however, the 100 % follow-up rate strengthens the quality of data collection in this registry. Moreover, the number of patients in the bivalirudin arm was relatively low. This is mainly due to the fact that the majority of patients were included before publication of the recent NSTEMI and STEMI guidelines recommending bivalirudin monotherapy over UFH and UFH + GPI [28, 29]. Potential differences between treatment groups were existent but were accounted for in propensity score-adjusted models. Finally, additional safety and efficacy endpoints such as stroke, reinfarction, stent thrombosis, repeat revascularization, transfusion and thrombocytopenia, which may vary between the study regimens, are not available. Our findings might not apply to patients treated via a radial approach.\n\nConclusion\nThis real world experience in patients presenting with ACS and undergoing PCI and stent implantation indicates that bivalirudin is clinically similar to UFH monotherapy but superior to UFH + abciximab with respect to the reduction of bleeding events, which in turn was associated with a shorter hospital stay. The rate of stent thrombosis as well as long-term clinical outcomes in terms of all-cause and cardiovascular mortality were statistically similar between groups.\n\nOpen access funding provided by Medical University of Vienna.\n\nCompliance with ethical guidelines\nConflict of interest\nM. Rohla, I. Tentzeris, M.K. Freynhofer, S. Farhan, R. Jarai, F. Egger, J. Wojta, A. Geppert declare that they have no conflict of interests. T. W. Weiss received lecturing fees and advisory honoraria from AstraZeneca, Daiichi Sankyo and Sanofi-Aventis. A. Kastrati received lecturing fees and advisory honoraria from The Medicines Company. G. W. Stone received lecturing fees and advisory honoraria from The Medicines Company. Kurt Huber received lecturing fees and advisory honoraria from The Medicines Company, AstraZeneca, Eli Lilly, Daiichi Sankyo and Sanofi-Aventis.\n\nEthical standards\nAll studies described in this manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current revised form). Informed consent was obtained from all patients included in the study.\n==== Refs\nReferences\n1. Wijns W Kolh P Danchin N Di Mario C Falk V Folliguet T Guidelines on myocardial revascularization Eur Heart J 2010 31 20 2501 2555 10.1093/eurheartj/ehq277 20802248 \n2. 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Mega JL Braunwald E Wiviott SD Bassand JP Bhatt DL Bode C Rivaroxaban in patients with a recent acute coronary syndrome N Engl J Med 2012 366 1 9 19 10.1056/NEJMoa1112277 22077192 \n7. Steg PG van’t Hof A Hamm CW Clemmensen P Lapostolle F Coste P Bivalirudin started during emergency transport for primary PCI N Engl J Med 2013 369 23 2207 2217 10.1056/NEJMoa1311096 24171490 \n8. Han Y Guo J Zheng Y Zang H Su X Wang Y Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial JAMA 2015 313 13 1336 1346 10.1001/jama.2015.2323 25775052 \n9. Shahzad A Kemp I Mars C Wilson K Roome C Cooper R Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial Lancet 2014 384 9957 1849 1858 10.1016/S0140-6736(14)60924-7 25002178 \n10. Kastrati A Neumann FJ Schulz S Massberg S Byrne RA Ferenc M Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction N Engl J Med 2011 365 21 1980 1989 10.1056/NEJMoa1109596 22077909 \n11. Stone GW McLaurin BT Cox DA Bertrand ME Lincoff AM Moses JW Bivalirudin for patients with acute coronary syndromes N Engl J Med 2006 355 21 2203 2216 10.1056/NEJMoa062437 17124018 \n12. Cutlip DE Windecker S Mehran R Boam A Cohen DJ van Es GA Clinical end points in coronary stent trials: a case for standardized definitions Circulation 2007 115 17 2344 2351 10.1161/CIRCULATIONAHA.106.685313 17470709 \n13. Bovill EG Terrin ML Stump DC Berke AD Frederick M Collen D Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), phase II trial Ann Intern Med 1991 115 4 256 265 10.7326/0003-4819-115-4-256 1906692 \n14. Antman EM Anbe DT Armstrong PW Bates ER Green LA Hand M ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction) Circulation 2004 110 5 588 636 10.1161/01.CIR.0000134791.68010.FA 15289388 \n15. Anderson JL Adams CD Antman EM Bridges CR Califf RM Casey DE Jr. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine Circulation 2007 116 7 e148 e304 10.1161/CIRCULATIONAHA.107.181940 17679616 \n16. Patrono C Bachmann F Baigent C Bode C De Caterina R Charbonnier B Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology Eur Heart J 2004 25 2 166 181 10.1016/j.ehj.2003.10.013 14720534 \n17. Stone GW Witzenbichler B Guagliumi G Peruga JZ Brodie BR Dudek D Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3‑year results from a multicentre, randomised controlled trial Lancet 2011 377 9784 2193 2204 10.1016/S0140-6736(11)60764-2 21665265 \n18. Capodanno D De Caterina R Bivalirudin for acute coronary syndromes: premises, promises and doubts Thromb Haemost 2015 113 4 698 707 10.1160/TH14-09-0765 25519159 \n19. Capodanno D Gargiulo G Capranzano P Mehran R Tamburino C Stone GW Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI: an updated meta-analysis of 10,350 patients from five randomized clinical trials Eur Heart J Acute Cardiovasc Care 2015 5 3 253 262 10.1177/2048872615572599 25746943 \n20. Cavender MA Sabatine MS Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials Lancet 2014 384 9943 599 606 10.1016/S0140-6736(14)61216-2 25131979 \n21. Byrne RA Joner M Kastrati A Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014 Eur Heart J 2015 36 47 3320 3331 10.1093/eurheartj/ehv511 26417060 \n22. Lincoff AM Bittl JA Harrington RA Feit F Kleiman NS Jackman JD Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial JAMA 2003 289 7 853 863 10.1001/jama.289.7.853 12588269 \n23. Windecker S Kolh P Alfonso F Collet JP Cremer J Falk V 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Eur Heart J 2014 35 37 2541 2619 10.1093/eurheartj/ehu278 25173339 \n24. Kastrati A Neumann FJ Mehilli J Byrne RA Iijima R Buttner HJ Bivalirudin versus unfractionated heparin during percutaneous coronary intervention N Engl J Med 2008 359 7 688 696 10.1056/NEJMoa0802944 18703471 \n25. Wiviott SD Braunwald E McCabe CH Montalescot G Ruzyllo W Gottlieb S Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2007 357 20 2001 2015 10.1056/NEJMoa0706482 17982182 \n26. Huber K Hamm C Van’t Hof A Lapostolle F Coste P Thicoipe M Impact of P2Y12 inhibitor choice on 30-day outcomes after primary PCI: an analysis from the EUROMAX trial J Am Coll Cardiol 2014 63 12 A100 10.1016/S0735-1097(14)60100-5 \n27. Happe LE Rao SV Horblyuk R Franklin M Lunacsek OE Menditto L Consequences of major bleeding in hospitalized patients with non-ST segment elevation acute coronary syndromes receiving injectable anticoagulants Curr Med Res Opin 2009 25 2 413 420 10.1185/03007990802649133 19192986 \n28. Hamm CW Bassand JP Agewall S Bax J Boersma E Bueno H ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J 2011 32 23 2999 3054 10.1093/eurheartj/ehr236 21873419 \n29. Steg PG James SK Atar D Badano LP Lundqvist CB Borger MA ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC) Eur Heart J 2012 33 20 2569 2619 10.1093/eurheartj/ehs215 22922416\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0043-5325",
"issue": "128(23-24)",
"journal": "Wiener klinische Wochenschrift",
"keywords": "Acute coronary syndrome; Anticoagulation; Bivalirudin; Heparin; Percutaneous coronary intervention",
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000991:Antithrombins; D001317:Austria; D003131:Combined Modality Therapy; D005260:Female; D006629:Hirudins; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments; D062645:Percutaneous Coronary Intervention; D019106:Postoperative Hemorrhage; D015995:Prevalence; D011994:Recombinant Proteins; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "906-915",
"pmc": null,
"pmid": "27624328",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "25775052;17679616;22077192;15289388;25746943;25519159;24171490;26417060;21665265;14720534;21873419;20802248;19192986;25131979;12588269;22922416;22077909;18499566;20079528;17124018;25002178;1906692;19943881;18703471;25173339;17470709;17982182;26324049",
"title": "Impact of bivalirudin on mortality and bleeding complications in acute coronary syndrome patients undergoing invasive revascularization : A real world experience.",
"title_normalized": "impact of bivalirudin on mortality and bleeding complications in acute coronary syndrome patients undergoing invasive revascularization a real world experience"
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"companynumb": "AT-JNJFOC-20161225524",
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"activesubstancename": "HEPARIN SODIUM"
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... |
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"abstract": "The objective of this study was to describe the incidence of acute kidney injury (AKI) in children receiving intravenous acyclovir and determine risk factors that may be associated with it.\n\n\n\nThis was a retrospective cohort study, conducted by chart review.\n\n\n\nThe study was conducted across two paediatric hospitals.\n\n\n\nAll inpatients that received intravenous acyclovir in records from January 2015 to December 2015 were reviewed. Only patients with creatinine measurements taken before and after starting acyclovir were included in the study.\n\n\n\nThe main outcome measure was the development of AKI following intravenous acyclovir administration, with AKI defined according to change in serum creatinine.\n\n\n\n150 patients were included in the analysis. Patients' ages ranged from 2 days to 18.6 years. 27 children (18%) developed at least stage 1 AKI. Children receiving cancer treatment developed AKI more frequently than children with other diagnoses; 29.3% vs 10.9% (OR 3.4, 95% CI 1.5 to 8.2, p=0.008). The baseline estimated glomerular filtration rate (eGFR) was higher in those children who developed AKI. 34% of children had an eGFR >120 mL/min/1.73 m2 prior to acyclovir use. 31% of these children developed AKI compared with only 11% of those with a normal baseline eGFR (OR 3.6, 95 CI 1.3 to 10.1, p=0.02). Baseline eGFR was a significant predictor of AKI in a multivariable analysis that included cumulative dose and treatment duration (OR 1.02, p=0.013).\n\n\n\nAKI following intravenous acyclovir exposure is common in children. This study raises the possibility that glomerular hyperfiltration is a previously unrecognised risk factor for acyclovir-induced AKI.",
"affiliations": "Nephrology, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia blake.sandery@cw.bc.ca.;Prince of Wales Clinical School, UNSW Medicine, University of New South Wales, Sydney, New South Wales, Australia.;Nephrology, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia.",
"authors": "Sandery|Blake J|BJ|0000-0001-5264-9694;Erlich|Jonathan H|JH|;Kennedy|Sean E|SE|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1136/archdischild-2019-317990",
"fulltext": null,
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"issn_linking": "0003-9888",
"issue": "105(12)",
"journal": "Archives of disease in childhood",
"keywords": "general paediatrics; nephrology; therapeutics",
"medline_ta": "Arch Dis Child",
"mesh_terms": "D058186:Acute Kidney Injury; D000212:Acyclovir; D061605:Administration, Intravenous; D000293:Adolescent; D000998:Antiviral Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0372434",
"other_id": null,
"pages": "1215-1219",
"pmc": null,
"pmid": "32404442",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute kidney injury following intravenous acyclovir in children.",
"title_normalized": "acute kidney injury following intravenous acyclovir in children"
} | [
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"activesubstance": {
"activesubstancename": "ACYCLOVIR"
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{
"abstract": "Bruton's tyrosine kinase (BTK), encoded by the BTK gene, is a cytoplasmic protein critical in B cell development. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA), a primary immunodeficiency with characteristically low or absent B cells and antibodies. This report describes a five year-old boy who presented with otitis externa, arthritis, reduced immunoglobulins and no B cells. Flow cytometry showed undetectable monocyte BTK expression. Sequencing revealed a novel mutation at exon 13 of the BTK gene which created a de novo splice site with a proximal 5 nucleotide loss resulting in a truncated BTK protein. The patient still suffered from ear infection despite intravenous immunoglobulin replacement therapy. In this study, mosaicism was seen only in the mother's genomic DNA. These results suggest that a combination of flow cytometry and BTK gene analysis is important for XLA diagnosis and carrier screening.",
"affiliations": "Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia. Electronic address: chearct@imr.gov.my.;Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.;Paediatric Department, Hospital Sultanah Aminah, Johor Bahru, Malaysia.;Allergy and Immunology Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.",
"authors": "Chear|Chai Teng|CT|;Ripen|Adiratna Mat|AM|;Mohamed|Sharifah Adlena Syed|SA|;Dhaliwal|Jasbir Singh|JS|",
"chemical_list": "D022821:RNA Splice Sites; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0378-1119",
"issue": "560(2)",
"journal": "Gene",
"keywords": "Arthritis; BTK mutation; Splice site; X-linked agammaglobulinemia",
"medline_ta": "Gene",
"mesh_terms": "D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D040181:Genetic Diseases, X-Linked; D006801:Humans; D008297:Male; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases; D022821:RNA Splice Sites",
"nlm_unique_id": "7706761",
"other_id": null,
"pages": "245-8",
"pmc": null,
"pmid": "25680287",
"pubdate": "2015-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A novel BTK gene mutation creates a de-novo splice site in an X-linked agammaglobulinemia patient.",
"title_normalized": "a novel btk gene mutation creates a de novo splice site in an x linked agammaglobulinemia patient"
} | [
{
"companynumb": "MY-BAXTER-2015BAX014013",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": nu... |
{
"abstract": "Although there are encouraging reports showing the use of dexamethasone implant (Ozurdex) in uveitis in adults, the literature is scanty regarding its benefits and side effects in children. A 12-year-old boy presented with intermediate uveitis with disc oedema. He had 20/20 visual acuity and intraocular pressure (IOP) of 18 mm Hg in both eyes. He was treated with intravitreal Ozurdex in his left eye (LE) due to progressive worsening of uveitis and disc oedema. He developed increased IOP (31 mm Hg) that could not be controlled on maximal antiglaucoma medications and required the removal of the Ozurdex implant at 2.5 months. His IOP remained persistently high leading to increased cup disc ratio necessitating glaucoma filtration surgery (GFS). At 9 months of post-GFS follow-up, IOP was 12 mm Hg in LE without any medication. Though dexamethasone implant is being increasingly used in children with uveitis, its potential risk factors such as intractable glaucoma should be considered.",
"affiliations": "Advanced Eye Centre, Department of Ophthalmology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.",
"authors": "Kumari|Neha|N|;Parchand|Swapnil|S|;Kaushik|Sushmita|S|;Singh|Ramandeep|R|",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002648:Child; D020878:Device Removal; D003907:Dexamethasone; D004343:Drug Implants; D005901:Glaucoma; D005938:Glucocorticoids; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D014605:Uveitis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24311419",
"pubdate": "2013-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18645395;20714181;18349741;21757964;16552251;21220619;9400772;17923537;18779477;23122465;21960148",
"title": "Intractable glaucoma necessitating dexamethasone implant (Ozurdex) removal and glaucoma surgery in a child with uveitis.",
"title_normalized": "intractable glaucoma necessitating dexamethasone implant ozurdex removal and glaucoma surgery in a child with uveitis"
} | [
{
"companynumb": "PHHY2014IN008983",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HOMATROPINE HYDROBROMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nCoronary artery spasm (CAS) could cause serious lethal ventricular arrhythmias. While implantable cardioverter defibrillators (ICDs) have been recommend for secondary prevention of sudden cardiac death related to lethal ventricular arrhythmias. However, in resuscitated sudden cardiac death caused by CAS, the effect of ICD is still not well clear.\nA 60-year-old male presented with 2 episodes of syncope. Coronary angiography showed normal coronary arteries. Twenty-four hour Holter electrocardiograms revealed that there were repeatedly transient marked ST segment elevation in the all leads except avR lead, junctional rhythm, and subsequently nonsustained ventricular tachycardia.\nIschemic-induced lethal ventricular arrhythmias caused by CAS.\n\n\nMETHODS\nBoth calcium channel blocker (diltiazem, 180 mg twice daily) and nitrate (isosorbide dinitrate 40 mg twice daily) were initially administrated, and ICD was subsequently implanted as a secondary prevention.\n\n\nRESULTS\nIn the early stage of CAS, ICD therapy terminated the lethal ventricular arrhythmias. Conversely, after the administration of epinephrine, ICD therapy, even combined with external defibrillation, failed in resuscitating sudden cardiac death.\n\n\nCONCLUSIONS\nFor the sudden cardiac death related to lethal ventricular arrhythmias caused by CAS, ICD therapy is an efficient secondary prevention base on administrating coronary vasodilators. Furthermore, administration of epinephrine should be avoided during cardiorespiratory resuscitation of sudden cardiac death caused by CAS.",
"affiliations": "Department of Cardiology, Zhongshan Hospital of Sun Yat-sen University, Guangdong, China.",
"authors": "Sun|Jie|J|;Feng|Li|L|;Li|Fei|F|;Zhang|Yanchun|Y|;Dong|Jianting|J|",
"chemical_list": "D002317:Cardiovascular Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000007251",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28658116MD-D-17-0285510.1097/MD.0000000000007251072513400Research ArticleClinical Case ReportAn interesting implantable cardioverter defibrillator treatment for lethal ventricular arrhythmias caused by coronary artery spasm A case reportSun Jie MDFeng Li PhDLi Fei PhDZhang Yanchun MDDong Jianting MD∗Bil. Jacek Department of Cardiology, Zhongshan Hospital of Sun Yat-sen University, Guangdong, China.∗ Correspondence: Jianting Dong, Department of Cardiology, Zhongshan Hospital of Sun Yat-sen University, Guangdong, China (e-mail: dongjianting@aliyun.com).6 2017 30 6 2017 96 26 e72517 5 2017 28 5 2017 31 5 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nCoronary artery spasm (CAS) could cause serious lethal ventricular arrhythmias. While implantable cardioverter defibrillators (ICDs) have been recommend for secondary prevention of sudden cardiac death related to lethal ventricular arrhythmias. However, in resuscitated sudden cardiac death caused by CAS, the effect of ICD is still not well clear.\n\nPatient Concerns:\nA 60-year-old male presented with 2 episodes of syncope. Coronary angiography showed normal coronary arteries. Twenty-four hour Holter electrocardiograms revealed that there were repeatedly transient marked ST segment elevation in the all leads except avR lead, junctional rhythm, and subsequently nonsustained ventricular tachycardia.\n\nDiagnoses:\nIschemic-induced lethal ventricular arrhythmias caused by CAS.\n\nInterventions:\nBoth calcium channel blocker (diltiazem, 180 mg twice daily) and nitrate (isosorbide dinitrate 40 mg twice daily) were initially administrated, and ICD was subsequently implanted as a secondary prevention.\n\nOutcomes:\nIn the early stage of CAS, ICD therapy terminated the lethal ventricular arrhythmias. Conversely, after the administration of epinephrine, ICD therapy, even combined with external defibrillation, failed in resuscitating sudden cardiac death.\n\nLessons:\nFor the sudden cardiac death related to lethal ventricular arrhythmias caused by CAS, ICD therapy is an efficient secondary prevention base on administrating coronary vasodilators. Furthermore, administration of epinephrine should be avoided during cardiorespiratory resuscitation of sudden cardiac death caused by CAS.\n\nKeywords\ncoronary artery spasmimplantable cardioverter defibrillatorlethal ventricular arrhythmiasOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCoronary artery spasm (CAS) could lead to sudden cardiac death due to serious lethal ventricular arrhythmias. Despite calcium antagonists have been demonstrated to be an effective treatment for CAS and has a potential role for preventing ventricular arrhythmia, the ventricular arrhythmia may recurrent at any time. Implantable cardioverter defibrillators (ICDs) have been recommend for secondary prevention of sudden cardiac death related to lethal ventricular arrhythmias. However, in resuscitated sudden cardiac death caused by CAS, the effect of ICD is still not well clear. In the present report, we showed a case of ICD treatment in a man who suffered from recurrent episodes of lethal ventricular arrhythmias induced by CAS.\n\n2 Case presentation\nWritten informed consent was obtained from patient's family, and institutional Ethics Committee of Zhongshan Hospital of Sun Yat-sen University approved this case report.\n\nA 60-year-old male was admitted with 2 episodes of syncope. At each time of syncope, several-minute retrosternal chest pain presented firstly, consciousness lost suddenly, and recovered normal quickly. Findings of physical examination, laboratory tests, 12-leads electrocardiograms (Fig. 1A), x-ray, echocardiography, magnetic resonance imaging of head, and electroencephalography were normal. Coronary angiography indicated normal coronary arteries. Twenty-four hour Holter electrocardiograms revealed that there were repeatedly transient marked ST segment elevation in the all leads except avR lead, junctional rhythm, and subsequently nonsustained ventricular tachycardia (Fig. 1B). Therefore, a definitive diagnosis with ischemic-induced lethal ventricular arrhythmias caused by CAS was established. Both calcium channel blocker (diltiazem, 180 mg twice daily) and nitrate (isosorbide dinitrate 40 mg twice daily) were initially administrated, and ICD was subsequently implanted as a secondary prevention.\n\nFigure 1 Electrocardiograms of different periods. (A) Twelve-lead electrocardiogram showed normal. (B) Twenty-four hour Holter electrocardiograms revealed transient marked ST segment elevation in all leads except avR lead, junctional rhythm, and subsequently nonsustained ventricular tachycardia. (C) Ventricular fibrillation could not been terminated by external defibrillation.\n\nAfter ICD implantation, the patient stayed in a persistent state of anxiety. On the sixth day after implantation, the patient present repeated chest pain with marked diffuse ST segment elevation, exhibited sustained ventricular tachycardia and ventricular fibrillation. The ICD accurately detected and successfully treated by multiple intracardiac shocks to restore sinus rhythm. However, after repeated heart attacks, the blood pressure could not been hold normal, even with administration of three vasopressors (dopamine, norepinephrine, and epinephrine). Suddenly, the patient's condition turned down sharply. Ventricular fibrillation could not been terminated by both electrical therapies of ICD and external defibrillation (Fig. 1C), and electromechanical dissociation finally appeared.\n\n3 Discussion\nPrevalences of CAS in patients with angina were wide differences among different countries. Several pathogenetic mechanisms, such as endothelial dysfunction, primary smooth muscle cells hyperreactivity, abnormal production of growth factors, and adventitial abnormalities, have been demonstrated to participate in CAS.[1] CAS could lead to transient myocardial ischemia and infarction and result in lethal ventricular arrhythmias.[2,3]\n\nLethal ventricular arrhythmias could be decreased by coronary vasodilators based on pathogenetic mechanisms of CAS.[2] Both calcium channel blockers and nitrates are the guideline medicine for relaxing vascular smooth muscle and preventing CAS.[3] However, CAS in some patients showed less response to these drugs so that lethal ventricular arrhythmias cannot be suppressed. For this intractable CAS, how to resuscitate patients from sudden cardiac death due to lethal ventricular arrhythmias became a particular critical issue.\n\nICD has been a proven effective device for terminating lethal ventricular arrhythmias. Furthermore, several case reports have demonstrated that ICDs were also useful for lethal ventricular arrhythmias caused by CAS.[4–6] However, there is still no large-scale clinical trial to support for it. On the contrary, Letsas et al[7] reported a multivessel spasm case with lethal ventricular arrhythmias and continuous ICD therapy was no efficacy for ventricular fibrillation. Therefore, in the field of lethal ventricular arrhythmias caused by CAS, the effect of ICD remained controversial.\n\nThe present case was quite different from those previous reported cases. He underwent 2 opposite responses to ICD therapy. In the early stage, ICD therapy terminated the lethal ventricular arrhythmias, even the electrocardiograms indicated multivessel CAS. The recurrence of CAS might be largely due to the persistent anxiety state of the patient. It showed that ICD was actually an effective device for secondary prevention of sudden cardiac death related to lethal ventricular arrhythmias. Conversely, in the end stage, ICD therapy, even combined with external defibrillation, failed in resuscitating sudden cardiac death. One reason might be the routine administration of norepinephrine and epinephrine which enhanced CAS and myocardial ischemia.[8,9] Zhang and coworkers[9] reported two cases of diffuse CAS aggravated by intravenous epinephrine and dopamine during cardiorespiratory resuscitation and immediately reversed by intracoronary injection of nitroglycerin. Another reason might be rupture of undiscovered vulnerable plaques caused by CAS that resulted in continued myocardial ischemia and myocardial infarction. Bil and coworkers[10] not only applied intravascular ultrasound to clearly reveal vulnerable plaques in a patient with CAS, but also intelligently used a bioresorbable vascular scaffold to fix the problem of plaque sealing.\n\n4 Conclusion\nFor the sudden cardiac death related to lethal ventricular arrhythmias caused by CAS, ICD therapy is an efficient secondary prevention base on administrating coronary vasodilators. Furthermore, administration of epinephrine should be avoided during cardiorespiratory resuscitation of sudden cardiac death caused by CAS.\n\nAbbreviations: CAS = coronary artery spasm, ICD = implantable cardioverter defibrillator.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Lanza GA Careri G Crea F \nMechanisms of coronary artery spasm . Circulation \n2011 ;124 :1774 –82 .22007100 \n[2] Chevalier P Dacosta A Defaye P \nArrhythmic cardiac arrest due to isolated coronary artery spasm: long-term outcome of seven resuscitated patients . J Am Coll Cardiol \n1998 ;31 :57 –61 .9426018 \n[3] JCS Joint Working Group . Guidelines for Diagnosis and Treatment of Patients With Vasospastic Angina (Coronary Spastic Angina) (JCS 2013) . Circ J \n2014 ;78 :2779 –801 .25273915 \n[4] Fuertes J Gallego P Peinado R \nImplantable cardioverter defibrillator as therapeutic option for sudden cardiac death secondary to severe coronary vasospasm . Int J Cardiol \n1998 ;63 :181 –3 .9510493 \n[5] Meisel SR Mazur A Chetboun I \nUsefulness of implantable cardioverter-defibrillators in refractory variant angina pectoris complicated by ventricular fibrillation in patients with angiographically normal coronary arteries . Am J Cardiol \n2002 ;89 :1114 –6 .11988204 \n[6] Matsue Y Suzuki M Nishizaki M \nClinical implications of an implantable cardioverter-defibrillator in patients with vasospastic angina and lethal ventricular arrhythmia . J Am Coll Cardiol \n2012 ;60 :908 –13 .22840527 \n[7] Letsas KP Filippatos GS Efremidis M \nSecondary prevention of sudden cardiac death in coronary artery spasm: is implantable cardioverter defibrillator always efficient? \nInt J Cardiol \n2007 ;117 :141 –3 .17046086 \n[8] Kiss G Corre O Gueret G \nManagement of cardiac arrest caused by coronary artery spasm: epinephrine/adrenaline versus nitrates . Heart Lung \n2009 ;38 :228 –32 .19486791 \n[9] Zhang ZP Su X Yang YC \nCardiac arrest with coronary artery spasm: does the use of epinephrine during cardiopulmonary arrest exacerbate the spasm? \nAm J Emerg Med \n2015 ;33 :479 e5 –6 .\n[10] Bil J Pawlowski T Gil RJ \nCoronary spasm revascularized with a bioresorbable vascular scaffold . Coron Artery Dis \n2015 ;26 :634 –6 .26267749\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "96(26)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D001145:Arrhythmias, Cardiac; D002317:Cardiovascular Agents; D003329:Coronary Vasospasm; D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e7251",
"pmc": null,
"pmid": "28658116",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19486791;25239694;9426018;22007100;25273915;26267749;11988204;17046086;22840527;9510493",
"title": "An interesting implantable cardioverter defibrillator treatment for lethal ventricular arrhythmias caused by coronary artery spasm: A case report.",
"title_normalized": "an interesting implantable cardioverter defibrillator treatment for lethal ventricular arrhythmias caused by coronary artery spasm a case report"
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"companynumb": "CN-MYLANLABS-2017M1054286",
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"abstract": "Studies on gastrointestinal stromal tumors (GISTs) in young patients are limited due to their rarity, and none have been conducted in Asian populations. GISTs from patients under the age of 30 were retrospectively reviewed and were analyzed for clinicopathologic features, immunohistochemistry for SDHB (succinate dehydrogenase subunit B), and mutations for exon 9, 11, 13, and 17 of KIT gene and exon 12, 14, and 18 of PDGFRA gene. We found two pediatric (<18 years old) and 20 young adult (18-30 years old) GIST cases. Pediatric GISTs occurred in two girls, both as solitary masses with epithelioid histology in the stomach. Both GISTs were wild type for KIT and PDGFRA genes, were negative for SDHB, and there was no recurrence during follow-up. Of the 20 GISTs in young adults, 12 (60%) were from extra-gastric locations (six duodenum, five jejunum, and one esophagus), and 16 (80%) showed a spindle cell morphology. Mutations of KIT or PDGFRA genes were identified in 14 (78%) of the 18 cases. One patient with multiple gastric GISTs with perigastric lymph node metastases at presentation developed multiple distant metastases and died of the disease 7.3 years after diagnosis. Of the 19 R0-resected young adult patients, one patient with small intestinal GIST harboring KIT exon 11 deletion mutation developed recurrence and showed partial responses for imatinib. In summary, compared with pediatric GIST cases, young adult GISTs are heterogeneous and share the characteristics of both pediatric and adult GISTs. When a mesenchymal tumor is clinically suspected in the small intestine of young adults, a GIST should be included in the differential diagnoses. Further mutation studies and extensive treatments are recommended for these cases.",
"affiliations": "Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Kang|Guhyun|G|;Park|Young Soo|YS|;Jung|Eun-Sun|ES|;Joo|Mee|M|;Kang|Mi Seon|MS|;Ahn|Soomin|S|;Kang|Gu Hyum|GH|;Kim|Kyoung-Mee|KM|",
"chemical_list": "C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha",
"country": "Denmark",
"delete": false,
"doi": "10.1111/apm.12085",
"fulltext": null,
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"issn_linking": "0903-4641",
"issue": "121(10)",
"journal": "APMIS : acta pathologica, microbiologica, et immunologica Scandinavica",
"keywords": "Gastrointestinal stromal tumor; pediatric; succinate dehydrogenase subunit B",
"medline_ta": "APMIS",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D044466:Asians; D001483:Base Sequence; D002648:Child; D005091:Exons; D005260:Female; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D012189:Retrospective Studies; D013385:Succinate Dehydrogenase",
"nlm_unique_id": "8803400",
"other_id": null,
"pages": "938-44",
"pmc": null,
"pmid": "23755839",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Gastrointestinal stromal tumors in children and young adults: a clinicopathologic and molecular genetic study of 22 Korean cases.",
"title_normalized": "gastrointestinal stromal tumors in children and young adults a clinicopathologic and molecular genetic study of 22 korean cases"
} | [
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"companynumb": "PHHY2013KR115023",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
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"activesubstancename": "SUNITINIB"
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"abstract": "BACKGROUND\nPsychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.\n\n\nOBJECTIVE\nDescription of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.\n\n\nMETHODS\nClinical case report and selective review of the literature with special consideration of existing systematic reviews.\n\n\nCONCLUSIONS\nThis case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.",
"affiliations": "Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Deutschland. david.zilles@med.uni-goettingen.de.;Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Deutschland.;Klinik für Anästhesiologie, Universitätsmedizin Göttingen, Göttingen, Deutschland.;Klinik für Anästhesiologie, Universitätsmedizin Göttingen, Göttingen, Deutschland.;Klinik für Kinderheilkunde und Jugendmedizin, Pädiatrische Kardiologie, Intensivmedizin und Pneumologie, Universitätsmedizin Göttingen, Göttingen, Deutschland.;Klinik für Gynäkologie und Geburtshilfe, Universitätsmedizin Göttingen, Göttingen, Deutschland.",
"authors": "Zilles-Wegner|David|D|;Trost|Sarah|S|;Walliser|Karoline|K|;Saager|Leif|L|;Horn|Sebastian|S|;Ernst|Mareike|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00115-020-00960-7",
"fulltext": "\n==== Front\nNervenarzt\nNervenarzt\nDer Nervenarzt\n0028-2804 1433-0407 Springer Medizin Heidelberg \n\n32681216\n960\n10.1007/s00115-020-00960-7\nÜbersichten\nElektrokonvulsionstherapie in der Schwangerschaft: Fallbericht und interdisziplinäre Behandlungsvorschläge\nElectroconvulsive therapy in pregnancy: case report and interdisciplinary treatment suggestions Zilles-Wegner David david.zilles@med.uni-goettingen.de 1 Trost Sarah 1 Walliser Karoline 2 Saager Leif 2 Horn Sebastian 3 Ernst Mareike 4 1 grid.411984.10000 0001 0482 5331Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Göttingen, Von-Siebold-Str. 5, 37075 Göttingen, Deutschland \n2 grid.411984.10000 0001 0482 5331Klinik für Anästhesiologie, Universitätsmedizin Göttingen, Göttingen, Deutschland \n3 grid.411984.10000 0001 0482 5331Klinik für Kinderheilkunde und Jugendmedizin, Pädiatrische Kardiologie, Intensivmedizin und Pneumologie, Universitätsmedizin Göttingen, Göttingen, Deutschland \n4 grid.411984.10000 0001 0482 5331Klinik für Gynäkologie und Geburtshilfe, Universitätsmedizin Göttingen, Göttingen, Deutschland \n17 7 2020 \n17 7 2020 \n2021 \n92 1 50 56\n© The Author(s) 2020Open Access. Dieser Artikel wird unter der Creative Commons Namensnennung 4.0 International Lizenz veröffentlicht, welche die Nutzung, Vervielfältigung, Bearbeitung, Verbreitung und Wiedergabe in jeglichem Medium und Format erlaubt, sofern Sie den/die ursprünglichen Autor(en) und die Quelle ordnungsgemäß nennen, einen Link zur Creative Commons Lizenz beifügen und angeben, ob Änderungen vorgenommen wurden.Die in diesem Artikel enthaltenen Bilder und sonstiges Drittmaterial unterliegen ebenfalls der genannten Creative Commons Lizenz, sofern sich aus der Abbildungslegende nichts anderes ergibt. Sofern das betreffende Material nicht unter der genannten Creative Commons Lizenz steht und die betreffende Handlung nicht nach gesetzlichen Vorschriften erlaubt ist, ist für die oben aufgeführten Weiterverwendungen des Materials die Einwilligung des jeweiligen Rechteinhabers einzuholen.Weitere Details zur Lizenz entnehmen Sie bitte der Lizenzinformation auf http://creativecommons.org/licenses/by/4.0/deed.de.Hintergrund\nPsychische Störungen in der Schwangerschaft sind häufig. Besonders bei schweren affektiven oder psychotischen Störungen mit Notwendigkeit eines raschen Ansprechens kann eine Elektrokonvulsionstherapie (EKT) indiziert sein. Dazu vorliegende Übersichtsartikel unterscheiden sich methodisch stark, was zu unterschiedlichen Schlussfolgerungen hinsichtlich der Anwendung der EKT bei Schwangerschaft führt.\n\nZiel der Arbeit\nDarstellung eines neuen klinischen Falls sowie interdisziplinärer Behandlungsvorschläge zur sicheren Anwendung der EKT bei Schwangerschaft.\n\nMethoden\nFallbericht und selektive Literaturübersicht unter besonderer Berücksichtigung der existierenden systematischen Reviews.\n\nErgebnisse und Diskussion\nDie aktuelle Kasuistik zeigt die potenziell hohe Wirksamkeit sowie die für Mutter und Fetus sichere Anwendung der EKT während der Schwangerschaft. Die in der Literatur beschriebenen unerwünschten Ereignisse entsprechen qualitativ weitgehend den Risiken bei schwerer psychischer Störung in der Schwangerschaft. Zur besseren Nutzen-Risiko-Abwägung wären größere Fall-Kontroll-Studien wünschenswert. Bei sorgfältiger Indikationsstellung, guter interdisziplinärer Abstimmung und Beachtung der Besonderheiten in der praktischen Durchführung ist die EKT auch in der Schwangerschaft eine sinnvolle Behandlungsoption.\n\nBackground\nPsychiatric disorders during pregnancy are common. Electroconvulsive therapy (ECT) can be indicated in severely affective or psychotic disorders with the necessity of a rapid response. Currently available review articles greatly differ in the methodology, leading to divergent conclusions concerning the use of ECT during pregnancy.\n\nObjective\nDescription of a new clinical case and interdisciplinary treatment suggestions for the safe application of ECT in pregnancy.\n\nMethods\nClinical case report and selective review of the literature with special consideration of existing systematic reviews.\n\nResults and conclusion\nThis case report shows the potentially high effectiveness and safe administration of ECT in pregnancy for both mother and fetus. The undesired adverse events associated with ECT described in the literature are largely qualitatively congruent with the risks of severe psychotic disorders in pregnancy per se. For a better risk-benefit analysis, larger case control studies would be desirable. Under the premise of a thorough evaluation of the indications, good interdisciplinary coordination and consideration of the specific practical requirements, ECT is a useful therapeutic option in pregnancy.\n\nSchlüsselwörter\nAnästhesieGeburtshilfeNeonatologieWirksamkeitSicherheitKeywords\nAnesthesiaObstetricsNeonatologyEffectivenessSafetyGeorg-August-Universität Göttingen (1018)Open Access funding provided by Projekt DEAL.\n\nissue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2021\n==== Body\nHintergrund\nSchwerwiegende psychische Erkrankungen in der Schwangerschaft stellen einen relevanten Risikofaktor für Geburtskomplikationen dar. Nach einer aktuellen Registerstudie sind schizophrene und affektive Psychosen während der Schwangerschaft mit einer Vielzahl von mütterlichen, fetalen und neonatalen Komplikationen verbunden [28]. Neben immanent psychiatrischen Aspekten wie Suizidalität mit ggf. erweitertem Suizid sowie einer gestörten Mutter-Kind-Bindung umfassen diese ein erhöhtes Risiko für Sectio, ante- und postpartale Blutungen, vorzeitige Plazentalösung, Frühgeburten, Totgeburten und fetale Auffälligkeiten wie Wachstumsrestriktion und chronischer fetaler Stress.\n\nDie Behandlung der psychischen Störung muss bei vorliegender Schwangerschaft in besonderem Maße Verträglichkeit und Sicherheit für Mutter und ungeborenes Kind gewährleisten. Zur Pharmakotherapie sind dazu Datenbanken wie etwa die des Pharmakovigilanz- und Beratungszentrums für Embryonaltoxikologie (www.embryotox.de) verfügbar, die auf Grundlage von Fallberichten und -serien spezifische Empfehlungen zu einzelnen Wirkstoffen geben.\n\nIn manchen Fällen akuter psychiatrischer Störungen in der Schwangerschaft ist eine Psychopharmakotherapie nicht möglich, nicht gewünscht oder aber nicht ausreichend wirksam, sodass bei gegebener Indikation basierend auf entsprechenden Leitlinienempfehlungen [5–7] eine Elektrokonvulsionstherapie (EKT) in Betracht gezogen werden kann. Nationale wie internationale Leitlinien berücksichtigen die EKT in ihren Empfehlungen bei schwangeren Patientinnen und entsprechendem Schweregrad der Erkrankung. Die NICE-Guideline „Antenatal and postnatal mental health“ etwa empfiehlt die EKT bei schwerer Depression, Manie, Mischzuständen oder Katatonie und zugleich bestehendem gesundheitlichem Risiko für Mutter oder Fetus [19]. Diese Empfehlungen basieren auf Fallsammlungen, die mangels der Möglichkeit randomisierter, kontrollierter Studien bei Schwangeren die bestmögliche Evidenz darstellen.\n\nDie Indikationsstellung zur EKT in der Schwangerschaft ist trotz der Leitlinienempfehlungen mit Unsicherheiten verbunden und erfolgt daher nur selten. 2008 wurden für Deutschland lediglich fünf Behandlungen bei Schwangeren beschrieben [16]. Dies mag auch damit zusammenhängen, dass bisherige Übersichtsarbeiten zu sehr unterschiedlichen Schlussfolgerungen hinsichtlich der Sicherheit der EKT bei Schwangeren gelangen [23]. Tab. 1 fasst die beschriebenen unerwünschten Ereignisse ohne Kausalitätsbeurteilung zusammen.Mutter\tFetus/Neugeborenes\t\nProlongierte Anfälle\tBradykardie/Arrhythmie\t\nUteruskontraktionen ohne Frühgeburt\tFrühgeburt\t\nAbdominelle Schmerzen\tAbort/Totgeburt\t\nVaginale Blutung\tKongenitale Anomalien\t\nPlazentalösung\tIntrauterine Wachstumsrestriktion\t\nHämaturie\tNeonatales Atemnotsyndrom\t\nPräeklampsie\tMentale Retardierung\t\nSectio\t\n\n\nIn einschlägigen Publikationen zur Therapie depressiver Störungen in der Schwangerschaft findet die EKT zum Teil keine Erwähnung [24]. In der deutschsprachigen Literatur fehlen konkrete Vorschläge zum praktischen Vorgehen [2], lediglich eine neuere internationale Publikation [26] beinhaltet Empfehlungen für das interdisziplinäre Management betroffener Patientinnen.\n\nZiel der aktuellen Arbeit ist es daher, basierend auf unserem konkreten Vorgehen im Einzelfall sowie den verfügbaren Literaturübersichten interdisziplinäre Vorschläge für die sichere Anwendung der EKT bei schwangeren Patientinnen zu erstellen.\n\nMethoden\nNeben der Darstellung des klinischen Falls werden Behandlungsvorschläge zum Vorgehen bei EKT in der Schwangerschaft aus den Fachdisziplinen Psychiatrie, Geburtshilfe, Anästhesiologie und Neonatologie gegeben. Diese haben nicht den Stellenwert von Leitlinienempfehlungen, sondern wurden im interdisziplinären Austausch aus der verfügbaren internationalen Literatur sowie den eigenen Erfahrungen im Sinne der guten klinischen Praxis abgeleitet.\n\nFallbericht\nPsychiatrie\nDie 18-jährige schwangere Patientin wurde mit einem schizomanischen Syndrom aufgenommen. Psychopathologisch bestand eine Wahnsymptomatik mit hoher Wahndynamik einschließlich einer Negierung der Schwangerschaft, formalgedanklich Ideenflucht und Gedankenabreißen, zum Teil Personenverkennungen und Ich-Störung im Sinne von Gedankeneingebungen. Der Affekt war teilweise aggressiv-gereizt, das Verhalten distanzlos, zum Teil bizarr, psychomotorisch agitiert mit reduziertem Schlafbedürfnis sowie Konzentrations- und Gedächtnisstörungen.\n\nEs wurde eine Medikation mit Quetiapin 700 mg/d sowie 30 mg/d Diazepam etabliert. Dennoch kam es zu aggressiven Erregungszuständen mit Gefährdung des ungeborenen Kindes, indem die Patientin sich auf den Bauch schlug, sich auf den Bauch warf oder diesen gegen Wände quetschte. Es erfolgte die Unterbringung nach Betreuungsrecht. Mehrfach waren Fixierungsmaßnahmen und intramuskuläre Medikation erforderlich.\n\nAufgrund der Notwendigkeit eines raschen Ansprechens sowie schwangerschaftsbedingt eingeschränkter Pharmakotherapie stellten wir die Indikation zur EKT. Patientin und gesetzlicher Betreuer willigten in die Behandlung ein. Ab der vollendeten 28. Schwangerschaftswoche (SSW) erfolgten neun EKT-Behandlungen (3/Woche, bitemporale Elektrodenplatzierung) in Anwesenheit von Gynäkologie/Geburtshilfe, Anästhesiologie und Neonatologie. Hierunter kam es zu einer raschen Besserung der Psychopathologie. Psychotische Symptome, psychomotorische Unruhe und aggressives Verhalten nahmen ab, Fixierungsmaßnahmen waren nicht mehr erforderlich. Ein einmalig prolongierter Anfall unter EKT wurde mittels Midazolam komplikationslos beendet. Parallel dazu kam es einmalig zu einer selbstlimitierenden fetalen Bradykardie (siehe unten). Die Patientin berichtete subjektiv über leichte Gedächtnisstörungen. Weitere unerwünschte Wirkungen traten nicht auf.\n\nDer Versuch einer pharmakologischen Erhaltungstherapie schlug fehl, da unter Quetiapin 1000 mg/d keine ausreichende Konzentration im therapeutischen Drug Monitoring erreicht wurde, am ehesten aufgrund schwangerschaftsassoziierter CYP3A4-Induktion [20, 27]. Parallel zur Umstellung auf Risperidon 7 mg/d erfolgten vier weitere EKT-Behandlungen, die letzte mit 33 SSW. Das schizomanische Syndrom war vollständig remittiert, entsprechend einem Wert von 1 auf der Clinical Global Impression Scale (CGI-I). Postpartal konnte die erreichte Stabilität unter Risperidon erhalten werden.\n\nAnästhesie\nDas regelhafte anästhesiologische Vorgehen für eine EKT außerhalb der Schwangerschaft beinhaltet eine intravenöse Narkoseinduktion. Das Narkotikum sollte einen raschen Wirkeintritt und eine kurze Wirkdauer besitzen und den induzierten Anfall möglichst gering beeinflussen. Zur Oxygenierung erfolgt nach Bewusstseinsverlust eine Beutel-Masken-Beatmung, seltener auch via Larynxmaske. Hierbei unterstützt eine moderate Hyperventilation eine angemessene Krampfaktivität. Eine endotracheale Intubation erfolgt in der Regel nicht, da der Eingriff an sich kein erhöhtes Aspirationsrisiko bedeutet. Vor Anfallsinduktion erfolgt eine Muskelrelaxation mittels eines kurz wirksamen Muskelrelaxans, in der Regel Succinylcholin [9].\n\nAb der 12. SSW besteht aufgrund einer verzögerten Magenentleerung ein erhöhtes Aspirationsrisiko. Zudem werden bereits in den ersten SSW die Schleimhäute vermehrt durchblutet mit Blutungs- und Ödemneigung der Schleimhäute im Bereich der oberen Atemwege und höherer Inzidenz für einen schwierigen Atemweg und erschwerter endotrachealer Intubation [22]. Weiterhin besteht bei Schwangeren eine niedrigere funktionelle Residualkapazität infolge des erhöhten intraabdominellen Drucks. Bei der Patientin wurde daher eine Nüchternheitszeit von sechs Stunden vor EKT streng eingehalten. Zur Pufferung des Magensafts erhielt sie zudem 30 ml 0,3-molares Natriumcitrat oral vor Narkoseeinleitung, zur Prophylaxe einer Hypersalivation Glycopyrroniumbromid i.v. (0,2 mg).\n\nDie Einleitung der Allgemeinanästhesie erfolgte im Zentral-OP in Notsectiobereitschaft [10]. Es erfolgte eine leichte Linkslagerung und Optimierung des intravasalen Volumenstatus vor Beginn der EKT. Zielparameter war ein arterieller Mitteldruck von mindestens 65 mm Hg. In Rückenlage besteht ab der 16.–20. SSW das Risiko eines Vena-cava-inferior-Kompressionssyndroms durch den graviden Uterus. Eine Kompression der Aorta abdominalis wiederum kann eine verminderte uterine Durchblutung mit möglicher fetaler Asphyxie bedingen. Die erwähnte Lagerung und Optimierung reduziert diese Risiken. Bei Bedarf wurde der Blutdruck durch Gabe von Akrinor® (ratiopharm GmbH, Ulm, Deutschland) gesteigert.\n\nNach Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %) erfolgte die Narkoseinduktion durch die i.v.-Gabe von Methohexital (initial 1 mg/kg Körpergewicht, im Verlauf benötigte die Patientin eine Dosissteigerung auf 1,6 mg/kg). Mit Erreichen einer ausreichenden Narkosetiefe folgte die i.v.-Gabe von Succinylcholin (1,5 mg/kg Körpergewicht). Neben der Schwangerschaft bestanden bei der Patientin keine Hinweise auf einen schwierigen Atemweg. Zugunsten einer kürzeren Narkosedauer und einer geringeren Invasivität bei absehbar regelmäßiger EKT mit vulnerablen Schleimhäuten entschieden wir uns trotz des Aspirationsrisikos gegen eine Atemwegssicherung mittels Endotrachealtubus. Nach Narkoseinduktion wurde eine druckkontrollierte Maskenbeatmung mit einem maximalen Beatmungsdruck von 15 mbar durchgeführt. Anders als bei nichtschwangeren Patienten wurde auf eine Normoventilation geachtet. Eine exzessive Hyperventilation kann durch Entstehung einer respiratorischen Alkalose und dadurch verminderte Sauerstoffabgabe vom maternalen an das fetale Blut zu einer fetalen Hypoxie führen [18, 26].\n\nBei einmalig prolongiertem Anfallsgeschehen wurde Midazolam i.v. (1,5 mg) verabreicht. Dies beeinträchtige das Aufwachverhalten der Patientin nicht. Ein erweitertes Atemwegsmanagement war nicht nötig.\n\nGynäkologie und Geburtshilfe\nEinen wichtigen Aspekt in der Betreuung der Patientin stellte die regelmäßige Vorstellung in der Schwangerensprechstunde dar, durch die es gelang, ein Vertrauensverhältnis zwischen Patientin und behandelnden Gynäkologen/-innen aufzubauen. Dadurch konnten gemäß den aktuellen Mutterschaftsrichtlinien die vorgeschriebenen Vorsorgeuntersuchungen durchgeführt und im Mutterpass dokumentiert werden.\n\nAufgrund der Assoziation sowohl psychischer Erkrankungen als auch der EKT mit fetalen und maternalen Komplikationen (fetale Herzrhythmusstörungen, vorzeitiger Blasensprung, Uteruskontraktionen mit Eröffnung der Zervix, Plazentalösung und Frühgeburt [4, 26]) erfolgte ein intensives CTG-Monitoring je eine Stunde vor, kontinuierlich während sowie nach jeder EKT. Zudem wurden zum Ausschluss eines vorzeitigen Blasensprungs sowie einer Plazentalösung eine vaginale Inspektion mit Bestimmung des pH-Werts beziehungsweise ein Amni-Check und eine Zervixlängenmessung nach jeder EKT durchgeführt. Diese Maßnahmen sind essentiell zum Erkennen einer drohenden Frühgeburt.\n\nZur Verhinderung eines Atemnotsyndroms im Fall einer Frühgeburt erfolgte vor der ersten EKT mit 28 SSW eine Lungenreifeinduktion (2 × 12 mg Betamethason i.m. im Abstand von 24 h; [3]). Bedingt durch das Risiko einer Frühgeburt sollten die Planung und Durchführung jeder EKT bei schwangeren Patientinnen interdisziplinär und unter Notsectiobereitschaft erfolgen [10].\n\nHinsichtlich der einmalig aufgetretenen fetalen Bradykardie handelte es sich gemäß der CTG-Bewertung nach FIGO um eine variable Dezeleration <3 min, die definitionsgemäß als suspekt einzustufen ist. Da sich im Anschluss wieder eine normale fetale Herzfrequenz mit regelrechtem Oszillationsmuster darstellte, bestand kein Handlungsbedarf (Abb. 1).\n\nGemeinsam mit der Patientin entschieden wir uns aufgrund maternaler Erschöpfung mit ausgeprägter Angst vor einem Spontanpartus für eine primäre Sectio mit 37 SSW. Allgemein stellt die EKT keine Kontraindikation für eine Spontangeburt dar.\n\nNeonatologie\nAnders als in klassischen Situationen der neonatologischen Beratungs- und Betreuungssituation konnte in diesem Fall kein adäquates pränatales „counseling“ der Mutter durchgeführt werden. Die durch die Grunderkrankung der Mutter eingeschränkte Kommunikationsmöglichkeit bei unzureichender Compliance bot keine Grundlage, über die etwaigen Risiken einer schwangerschaftsbegleitenden EKT für den Fetus bzw. das Neugeborene hinreichend aufzuklären. Daher erfolgte pränatal prioritär die Bereitstellung einer dem aktuellen Reifegrad des Fetus angepassten Erstversorgungsumgebung in den jeweiligen Operationseinheiten. Durch den Einsatz einer vollständig mobilen Erstversorgungseinheit als Inkubatormikroumgebung (Giraffe Omnibed-Shuttle® Einheit, Fa. GE) konnte auf die variable Gesundheitssituation der Mutter und den jeweiligen Therapieort der EKT kurzfristig eingegangen werden.\n\nBereits während der pränatalen Therapiephase ist zudem eine interdisziplinäre Planung der zu erwartenden Betreuungssituation des Neugeborenen durchzuführen. Ein Bindungsaufbau zwischen Mutter und Kind muss koordiniert und kann stufenweise und unter Wahrung der Sicherheit des Kindes auch im Setting einer Neugeborenen-IMC-Station etabliert werden.\n\nErgebnisse\nKlinischer Fall\nIm dargestellten Fall kam es unter EKT zu einer Remission des schizomanischen Syndroms inklusive des eigen- und fremdgefährdenden Verhaltens. Ein prolongierter Anfall der Patientin unter EKT konnte unkompliziert pharmakologisch beendet werden, eine einmalige kurzfristige fetale Bradykardie sistierte spontan, ansonsten traten keine relevanten unerwünschten Wirkungen auf. Das Kind wurde mittels geplanter Sectio mit 37 SSW gesund geboren und zeigte nach neonatologischer Untersuchung während des kurzfristigen stationären Aufenthalts keine organischen Auffälligkeiten und eine reife- und altersentsprechende Entwicklung.\n\nVorschläge zum interdisziplinären Management bei EKT in der Schwangerschaft\nBasierend auf den Erfahrungen der erfolgreichen Behandlung im oben dargestellten Fall sowie den zitierten systematischen Übersichtsarbeiten sollen nachfolgend tabellarisch Behandlungsvorschläge für die Durchführung der EKT in der Schwangerschaft formuliert werden (Tab. 2).Fachgebiet\tBehandlungsvorschlag\t\nPsychiatrie\tAufklärung über Diagnose, Behandlungsindikation, Therapieoptionen unter besonderer Berücksichtigung der Sicherheit für Mutter und Fetus. Abwägen der Chancen und Risiken der Therapie mit den nachteiligen Effekten der unbehandelten psychischen Störung\t\nDie Auswahl der Behandlungsparameter (Elektrodenposition, Stimulationsdosis, Pulsbreite etc.) unterscheidet sich bei Schwangeren nicht von den allgemeinen Prinzipien [8]\t\nInterdisziplinäre Durchführung mit Präsenz von Psychiatrie, Anästhesie, Gynäkologie/Geburtshilfe, Neonatologie\t\nGynäkologie/Geburtshilfe\tVor Beginn der EKT-Serienbehandlung\t\nAdäquate präpartale Versorgung:\n\n– Anlegen bzw. Vervollständigen des Mutterpasses\n\n– regelmäßige Vorstellung in Schwangerensprechstunde\n\n– frühzeitige Planung des Geburtsmodus zwischen Patientin, Geburtshilfe und Psychiatrie (Spontanpartus versus primäre Sectio; Spontanpartus bei guter Compliance möglich und primär angestrebt)\n\n\t\nQualifizierter Ultraschall mit Bestimmung von\n\n– fetalem Gewicht\n\n– Fruchtwassermenge\n\n– plazentarer Versorgung (Dopplersonographie)\n\n– Zervixlänge (Verkürzung und damit verbundenes Frühgeburtsrisiko)\n\n\t\nCTG zur Ermittlung des fetalen Zustands (Herzfrequenz und Kindsbewegungen) sowie maternaler Kontraktionen\t\nLungenreifeinduktion zwischen der 24+0. SSW und 34+0. SSW (2 × 12 mg Betamethason im Abstand von 24 h) zur Risikoreduktion eines „respiratory distress syndrome“\t\nWährend bzw. nach jeder EKT\t\nNotsectiobereitschaft\t\nCTG-Monitoring 1 h vor, kontinuierlich während und 1 h nach EKT\t\nVaginale Inspektion zum Ausschluss von Blutung bzw. Blasensprung (pH-Indikatorpapier bzw. Amni-Check)\t\nAnästhesiologie\tSorgfältige Anamnese\t\nHinweise auf eine erschwerte Atemwegssicherung (Mallampati-Klasse, Mundöffnung, Halswirbelsäulenbeweglichkeit, thyreomentale Distanz, bekannter schwieriger Atemweg in vorhergehenden Narkosen, Narkoseausweis vorhanden?)\t\nVor Beginn der EKT\t\nNüchternheitszeiten strikt einhalten\t\nGabe von Natriumcitrat per os\t\nFrühzeitiges Anlegen eines i.v.-Zugangs und Gabe von kristalloider Infusion\t\nGabe von Glycopyrroniumbromid i.v. vor Narkoseinduktion\t\nWährend EKT\t\nLeichte Linkslagerung\t\nSuffiziente Präoxygenierung (exspiratorische Sauerstoffkonzentration >75 %)\t\nNormoventilation via Beutel-Masken-Beatmung (Pinsp <20 mbar), Muskelrelaxation\t\nEngmaschige Blutdrucküberwachung, ggf. Gabe von Akrinor® (arterieller Mitteldruck >65 mm Hg)\t\nNach EKT\t\nNebenwirkungsmanagement:\n\n– Bei postinterventionellem Kopfschmerz Paracetamol als Mittel der Wahl. Alternativ Ibuprofen bis zur 28. Schwangerschaftswoche\n\n– Bei Übelkeit ist Meclozin Mittel der Wahl (über Auslandsapotheken erhältlich). Alternativ vorübergehend Dimenhydrinat (nicht im 3. Trimenon bei vorzeitiger Wehentätigkeit)\n\n\t\nNeonatologie\tSicherstellung der Verfügbarkeit einer Maximalversorgung in jeder SSW inkl. adäquater Personalausstattung\t\nNutzung einer mobilen Versorgungs- und Transporteinheit bei wechselnden Interventionsorten (integrierte Erstversorgungs- und Transporteinheit inkl. T‑Stück, Respirator und Gasversorgung)\t\nKenntnis über die während der EKT genutzten Anästhetika im Falle einer Sectio caesarea (Apnoerisiko des Neugeborenen)\t\nBenennung eines klinischen Teams (pflegerisch & ärztlich), welches die Interventionen möglichst kontinuierlich koordiniert/begleitet\t\n\n\nDiskussion\nUnser Fallbericht bestätigt, dass die EKT auch in der Schwangerschaft eine gut wirksame sowie für Mutter und Fetus sichere und verträgliche Therapieoption darstellen kann. Prinzipiell deckt sich diese Schlussfolgerung mit der verfügbaren Literatur. Sämtliche aktuellen deutschen Leitlinien für die Indikationen unipolare Depression, bipolare affektive Störung und Schizophrenie [5–7] benennen die EKT als therapeutische Option in der Schwangerschaft, jedoch mit der Einschränkung einer engen Indikationsstellung, sorgfältiger Nutzen-Risiko-Abwägung sowie Vorsichtsmaßnahmen („in Zentren der Maximalversorgung mit entsprechender Erfahrung in der Durchführung der EKT“ [7]). Diese Empfehlungen basieren auf vier systematischen Reviews [1, 15, 18, 21], die sich in ihrem methodischen Vorgehen relevant unterscheiden. Selbst zwei neuere und nahezu zeitgleich publizierte Arbeiten [15, 21] kommen aufgrund unterschiedlicher Einschlusskriterien und verschiedener Ansätze zur Bewertung von Komplikationen zu unterschiedlichen Risikoeinschätzungen [23]. Leiknes et al. [15] ließen in ihre Risikobewertung alle sog. „adverse events“ einfließen (d. h. alle unerwünschten Ereignisse unabhängig von einer möglichen Kausalität) und kommen zu einer sehr restriktiven Empfehlung der EKT bei Schwangerschaft im Sinne einer Ultima Ratio. Hingegen nahmen Pompili et al. [21] den Versuch einer Kausalitätsbeurteilung vor und fanden für viele Ereignisse keinen Zusammenhang mit der EKT. Entsprechend positiver fällt die Beurteilung der EKT aus als effektive therapeutische Option in der Schwangerschaft mit geringen Risiken.\n\nLetztlich sind die absoluten und relativen Risiken der EKT in der Schwangerschaft nicht exakt bezifferbar, da kontrollierte Studien, die mittels identisch schwer erkrankter Vergleichspopulationen die Effekte der psychiatrischen Störung von denen der Behandlung differenzieren könnten, fehlen. Eine ohne Kausalitätsprüfung vorgenommene Angabe der Häufigkeit unerwünschter Ereignisse bei EKT in der Schwangerschaft wird diese jedoch überschätzen, da die EKT-assoziierten „adverse events“ [23] qualitativ weitgehend deckungsgleich mit den Risiken einer schwerwiegenden psychischen Erkrankung in der Schwangerschaft [14, 28] sind (Tab. 1). Einigkeit sollte bestehen, dass durch die elektrische Stimulation keine teratogenen Effekte zu erwarten sind. Eine theoretische Arbeit zeigte zudem, dass die modellhaft berechneten Feldstärken im Bereich des fetalen Gehirns selbst bei maximalen Geräteeinstellungen unter den Grenzwerten für elektromagnetische Felder liegen [13].\n\nAus neonatologischer Sicht stellt am ehesten die Anästhesie ein potenzielles Risiko für den Fetus dar. Zur Anwendung im letzten Trimenon der Schwangerschaft liegt ein Warnhinweis der FDA bezüglich der Hirnentwicklung des Fetus und des Früh- und Neugeborenen vor [11], der jedoch zugleich äußert, dass einzelne bzw. kurze (<3 h) Anästhesien wahrscheinlich keinen negativen Effekt auf Verhalten und Lernen des Kindes haben. Die FDA ergänzte, dass schwangere Frauen bei gegebener Indikation und kurzer Anästhesiedauer (<3 h) einen notwendigen Eingriff nicht verzögern sollten [12]. Letztlich ist die klinische Evidenz unzureichend, um einen neurotoxischen Effekt prolongierter oder wiederholter Anwendung von Anästhetika in Schwangerschaft und Neugeborenenperiode beim Menschen ausschließen zu können [25]. Eine größere prospektive Multicenter-RCT ließ keine signifikant häufigeren Auffälligkeiten mit 2 bzw. 5 Jahren nach Narkoseinterventionen erkennen [17], wobei diese Studie keine Behandlung von Schwangeren und keine Mehrfachnarkosen beinhaltete und somit nur eingeschränkt übertragbar ist.\n\nAufgrund der heterogenen Datenbasis und Schlussfolgerungen der Übersichtsarbeiten zu EKT in der Schwangerschaft ist es weiterhin sinnvoll, entsprechende Fallberichte und Fallserien zu publizieren. Zur besseren kausalen Einordnung möglicher unerwünschter Ereignisse bei Mutter und Fetus bzw. Kind wären Fall-Kontroll-Studien wünschenswert, die aus methodischen Gründen jedoch schwer zu realisieren sind.\n\nIn Übereinstimmung mit den Leitlinien besteht unter den Autoren interdisziplinärer Konsens hinsichtlich einer engen Indikationsstellung zur EKT in der Schwangerschaft mit besonders sorgfältiger Betrachtung von Diagnose/Indikation, individueller Nutzen-Risiko-Abwägung und therapeutischen Alternativen. Ist dies gegeben und werden die o. g. interdisziplinären Behandlungsvorschläge beachtet, gibt es jedoch nach unserer übereinstimmenden Beurteilung keinen Grund, bei vorliegender Schwangerschaft auf die EKT zu verzichten. Kommt wie im vorliegenden Fall auch noch eine unmittelbare Gefährdung für Mutter und Fetus durch Erregungszustände und selbstverletzendes Verhalten hinzu, sollte das Nutzen-Risiko-Verhältnis deutlich zugunsten der EKT ausfallen.\n\nFazit für die Praxis\nDie EKT kann auch in der Schwangerschaft eine wirksame und sichere Therapieoption bei schweren psychischen Störungen sein.\n\nEine Indikation zur EKT in der Schwangerschaft besteht bei schwerer affektiver oder psychotischer Symptomatik, daraus resultierender Gefährdung von Mutter und/oder Fetus sowie fehlender Wirksamkeit, Verträglichkeit oder Umsetzbarkeit anderer Therapien.\n\nDie kasuistisch beschriebenen unerwünschten Ereignisse entsprechen qualitativ den allgemeinen Risiken bei schwerer psychischer Störung in der Schwangerschaft und sind daher in ihrer Kausalität unklar.\n\nEin abgestimmtes interdisziplinäres Management zwischen Psychiatrie, Gynäkologie, Anästhesiologie und Neonatologie ist grundlegend für die sichere Durchführung.\n\nDie Publikation von weiteren Fallberichten und -serien erscheint zur Verbesserung der Evidenzgrundlage sinnvoll.\n\n\n\nFunding\nOpen Access funding provided by Projekt DEAL.\n\nEinhaltung ethischer Richtlinien\nInteressenkonflikt\nD. Zilles-Wegner, S. Trost, K. Walliser, L. Saager, S. Horn und M. Ernst geben an, dass kein Interessenkonflikt besteht.\n\nFür diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.\n==== Refs\nLiteratur\n1. Anderson EL Reti IM ECT in pregnancy: a review of the literature from 1941 to 2007 Psychosom Med 2009 71 235 242 10.1097/PSY.0b013e318190d7ca 19073751 \n2. Bader A Frisch U Wirz-Justice A Riecher-Rössler A Depression during pregnancy and its treatment Nervenarzt 2010 81 267 276 10.1007/s00115-009-2821-2 19707735 \n3. Berger R Abele H Bahlmann F Prevention and therapy of preterm birth. Guideline of the DGGG, OEGGG and SGGG (S2k level, AWMF registry number 015/025, february 2019)—part 2 with recommendations on the tertiary prevention of preterm birth and the management of preterm premature rupture of membranes Geburtshilfe Frauenheilkd 2019 79 813 833 10.1055/a-0903-2735 31423017 \n4. Coshal S Jones K Coverdale J Livingston R An overview of reviews on the safety of electroconvulsive therapy administered during pregnancy J Psychiatr Pract 2019 25 2 6 10.1097/PRA.0000000000000359 30633726 \n5. DGBS e. V. DGPPN e. V. S3-Leitlinie zur Diagnostik und Therapie Bipolarer Störungen. Langversion 2019 \n6. DGPPN BÄK KBV AWMF S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression – Langfassung 2015 2 \n7. DGPPN e. V. (Hrsg) (2019) S3-Leitlinie Schizophrenie. Langfassung, 2019, Version 1.0, zuletzt geändert am 15. März 2019. https://www.awmf.org/leitlinien/detail/ll/038-009.html (für die Leitliniengruppe). 14. Febr. 2020\n8. Grözinger M Conca A Nickl-Jockschat T Elektrokonvulsionstherapie kompakt. Für Zuweiser und Anwender 2013 Heidelberg Springer \n9. Grundmann U Schneider SO Narkose zur Elektrokrampftherapie Anaesthesist 2013 62 311 322 10.1007/s00101-013-2152-3 23558716 \n10. https://www.awmf.org/uploads/tx_szleitlinien/087-001l_S1_Perinatologische_Versorgung_2015-05.pdf. Zugegriffen: 14. Febr. 2020\n11. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-review-results-new-warnings-about-using-general-anesthetics-and. Zugegriffen: 14. Febr. 2020\n12. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-approves-label-changes-use-general-anesthetic-and-sedation-drugs. Zugegriffen: 14. Febr. 2020\n13. Kibret B Premaratne M Sullivan C Electroconvulsive therapy (ECT) during pregnancy: quantifying and assessing the electric field strength inside the foetal brain Sci Rep 2018 8 4128 10.1038/s41598-018-22528-x 29515221 \n14. Kurki T Hiilesmaa V Raitasalo R Depression and anxiety in early pregnancy and risk for preeclampsia Obstet Gynecol 2000 95 487 490 10725477 \n15. Leiknes KA Cooke MJ Jarosch-von Schweder L Electroconvulsive therapy during pregnancy: a systematic review of case studies Arch Womens Ment Health 2015 18 1 39 10.1007/s00737-013-0389-0 24271084 \n16. Loh N Nickl-Jockschat T Sheldrick AJ Grözinger M Accessibility, standards and challenges of electroconvulsive therapy in Western industrialized countries: a German example World J Biol Psychiatry 2013 14 432 440 10.3109/15622975.2012.665176 22409536 \n17. McCann ME de Graaff JC Dorris L Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial Lancet 2019 393 664 677 10.1016/S0140-6736(18)32485-1 30782342 \n18. Miller LJ Use of electroconvulsive therapy during pregnancy Hosp Community Psychiatry 1994 45 444 450 8045538 \n19. NICE (2014) Antenatal and postnatal mental health: clinical management and service guidance. NICE clinical guideline 192. www.nice.org.uk/guidance/cg192. 14. Febr. 2020\n20. Pinheiro EA Wisner KL Clark CT Quetiapine dose adjustments in pregnant and postpartum women with bipolar disorder J Clin Psychopharmacol 2018 38 89 91 10.1097/JCP.0000000000000820 29194089 \n21. Pompili M Dominici G Giordano G Electroconvulsive treatment during pregnancy: a systematic review Expert Rev Neurother 2014 14 1377 1390 10.1586/14737175.2014.972373 25346216 \n22. Rocke DA Murray WB Rout CC Gouws E Relative risk analysis of factors associated with difficult intubation in obstetric anesthesia Anesthesiology 1992 77 67 73 10.1097/00000542-199207000-00010 1610011 \n23. Sinha P Goyal P Andrade C A meta-review of the safety of electroconvulsive therapy in pregnancy J ECT 2017 33 81 88 10.1097/YCT.0000000000000362 28009621 \n24. Vigod SN Wilson CA Howard LM Depression in pregnancy BMJ 2016 352 i1547 10.1136/bmj.i1547 27013603 \n25. Vlisides P Xie Z Neurotoxicity of general anesthetics: an update Curr Pharm Des 2012 18 6232 6240 10.2174/138161212803832344 22762477 \n26. Ward HB Fromson JA Cooper JJ Recommendations for the use of ECT in pregnancy: literature review and proposed clinical protocol Arch Womens Ment Health 2018 21 715 722 10.1007/s00737-018-0851-0 29796968 \n27. Westin AA Brekke M Molden E Treatment with antipsychotics in pregnancy: changes in drug disposition Clin Pharmacol Ther 2018 103 477 484 10.1002/cpt.770 28643331 \n28. Zhong QY Gelaye B Fricchione GL Adverse obstetric and neonatal outcomes complicated by psychosis among pregnant women in the United States BMC Pregnancy Childbirth 2018 18 120 10.1186/s12884-018-1750-0 29720114\n\n",
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"abstract": "The drive to prescribe to alleviate symptoms and ease suffering is prevalent in health care. In psychiatry, it is no different. Although monotherapy remains the preferred approach to treating psychiatric disorders, especially when combined with nonpharmacological approaches, in practice, a focus on remission of symptoms over patient preferences and quality of life can result in higher doses than necessary and polypharmacy from the addition of drugs for augmentation or treatment of adverse effects. This is especially concerning for older adults who are likely to have comorbid medical disorders, eventually leading to prescribing cascades as different providers address different symptoms. Whereas we generally look to best practice guidelines to treat identified disorders, the approach to treating older adults with multimorbidities requires collaboration among the patient, the family (if appropriate), and the provider to re-evaluate goals based on the patient's priorities, and to examine tradeoffs, reduce medication overload, and simplify care. Fortunately, many resources are available to help the clinician in this process. [Journal of Psychosocial Nursing and Mental Health Services, 58(8), 12-16.].",
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"abstract": "Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.",
"affiliations": "Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.",
"authors": "Lo|Shih-Hsing|SH|;Liu|Yi-Ching|YC|;Dai|Zen-Kong|ZK|;Chen|I-Chen|IC|;Wu|Yen-Hsien|YH|;Hsu|Jong-Hau|JH|",
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"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.639551\nPediatrics\nCase Report\nCase Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy\nLo Shih-Hsing 1\n\nLiu Yi-Ching 1\nDai Zen-Kong 12\nChen I-Chen 12\nWu Yen-Hsien 1*\n\nHsu Jong-Hau 12*\n\n1Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan\n2Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan\nEdited by: Giorgia Grutter, Bambino Gesù Children Hospital (IRCCS), Italy\n\nReviewed by: Michiel Dalinghaus, Erasmus Medical Center, Netherlands; Ashish Garg, Washington State University Tri-Cities, United States; Robert Shaddy, Children's Hospital of Los Angeles, United States\n\n*Correspondence: Yen-Hsien Wu eddiewu1986@gmail.com\nJong-Hau Hsu jhh936@yahoo.com.tw\nThis article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Pediatrics\n\n25 2 2021\n2021\n9 63955109 12 2020\n28 1 2021\nCopyright © 2021 Lo, Liu, Dai, Chen, Wu and Hsu.\n2021\nLo, Liu, Dai, Chen, Wu and Hsu\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.\nValsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.\n\npediatric heart failure\nvalsartan/sacubitril\ncardiomyopathy\ntreatment\nchemotherapy\n==== Body\nIntroduction\n\nThe importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.\n\nCase Description\n\nAcute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.\n\nCyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.\n\nHowever, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.\n\nUnfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.\n\nFigure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.\n\nFigure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.\n\nDiscussion\n\nPediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.\n\nIn adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.\n\nValsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.\n\nCurrently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).\n\nIn our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.\n\nTo date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.\n\nData Availability Statement\n\nThe original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nInformed consent was obtained from the parents for publication of this case report.\n\nAuthor Contributions\n\nJ-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1. Rossano JW Kim JJ Decker JA Price JF Zafar F Graves DE . Prevalence, morbidity, and mortality of heart failure-related hospitalizations in children in the United States: a population-based study. J Card Fail. 18 :459–70. 10.1016/j.cardfail.2012.03.001 22633303\n2. Ponikowski P Voors AA Anker SD Bueno H Cleland JGF Coats AJS . 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 :2129–200. 10.1093/eurheartj/ehw128 27206819\n3. Yancy CW Jessup M Bozkurt B Butler J Casey DE Jr Colvin MM . ACC/AHA/HFSA focused 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. (2017) 70 :776–803. 10.1016/j.jacc.2017.04.025 28461007\n4. McMurray JJ Packer M Desai AS Gong J Lefkowitz MP Rizkala AR . Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 371 :993–1004. 10.1056/NEJMoa1409077 25537439\n5. Kemp CD Conte JV . The pathophysiology of heart failure. Cardiovasc Pathol. 21 :365–71. 10.1016/j.carpath.2011.11.007\n6. Das BB . Current state of pediatric heart failure. Children (Basel). 5 :88. 10.3390/children5070088 29958420\n7. Volpe M Carnovali M Mastromarino V . The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci (Lond). 130 :57–77. 10.1042/cs20150469 26637405\n8. Shaddy R Canter C Halnon N Kochilas L Rossano J Bonnet D . Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study). Am Heart J. (2017) 193 :23–34. 10.1016/j.ahj.2017.07.006 29129252\n9. Adminisitration UFaD . Entresto (Valsartan and Sacubitril). US FDA (2019). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207620s013lbl.pdf (accessed December 08, 2020).\n10. Hu J Wu Y Zhou X Wang X Jiang W Huo J . Beneficial effects of sacubitril/valsartan at low doses in an Asian real-world heart failure population. J Cardiovasc Pharmacol. (2020) 76 :445–51. 10.1097/FJC.0000000000000873 PMID: 33030857.33030857\n11. De Vecchis R Ariano C Di Biase G Noutsias M . In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization: a retrospective cohort study. Herz. (2019) 44 :651–8. 10.1007/s00059-018-4690-6 29520644\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-2360",
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"journal": "Frontiers in pediatrics",
"keywords": "cardiomyopathy; chemotherapy; pediatric heart failure; treatment; valsartan/sacubitril",
"medline_ta": "Front Pediatr",
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"title": "Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.",
"title_normalized": "case report low dose of valsartan sacubitril leads to successful reversal of acute heart failure in chemotherapy induced cardiomyopathy"
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"abstract": "BACKGROUND\nCystinosis is a rare genetic disorder characterized by the abnormal accumulation of cystine in the lysosomes of various tissues and organs leading to their dysfunction. The most common type is the infantile nephropathic cystinosis which without treatment leads to renal failure and before the introduction of cysteamine was the cause of death before puberty.\n\n\nMETHODS\nA 27-year-old female patient with infantile cystinosis developed end-stage renal disease at the age of 10. The first kidney transplantation from patient's father was carried out at the age of 12. The recurrent urinary tract infections led to the graft failure after 6 years. Following the removal of right appendages due to the ovarian tumor, the patient underwent the second kidney transplantation from her mother at the age of 19. After the transplantation, the cysteamine treatment was irregular due to limited availability of the medicine. When it became regular in 2017 the patient did not tolerate full doses. Despite elevated blood levels of cystine and the removal of right appendages, the patient naturally became pregnant in August 2017. Except for recurrent urinary tract infections, the renal parameters remained normal throughout the entire pregnancy. However, in the 32nd week of gestation, due to preeclampsia a caesarean section was performed. A healthy daughter was born, 1400/41 and with a 9 point Apgar score.\n\n\nCONCLUSIONS\nDue to the possibility of treatment with cysteamine and kidney transplantations, patients with cystinosis live longer and their quality of life improves. These female patients can even naturally become pregnant and give birth to healthy children.",
"affiliations": "Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. Electronic address: jola-md@go2.pl.;Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.;Department of Nephrology, Kidney Transplantation, and Arterial Hypertension, Children's Memorial Health Institute, Warsaw, Poland.;Department of General and Endocrinological Surgery, Medical University of Warsaw, Warsaw, Poland.;Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland.;Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.",
"authors": "Kuczborska|K|K|;Gozdowska|J|J|;Lewandowska|D|D|;Grenda|R|R|;Gałązka|Z|Z|;Nazarewski|S|S|;Durlik|M|M|",
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"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D003543:Cysteamine; D065104:Cystine Depleting Agents; D003554:Cystinosis; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome",
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"title": "Therapeutic Problems and Pregnancy in a Patient With Infantile Nephropathic Cystinosis: A Case Report.",
"title_normalized": "therapeutic problems and pregnancy in a patient with infantile nephropathic cystinosis a case report"
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"abstract": "Autoimmune and allergic diseases cause morbidity and diminished quality of life in pediatric organ transplant recipients. We hypothesize that younger age at transplantation and immunosuppression regimen play a role in the development of immune-mediated disease following heart transplant. A single institution retrospective review identified all patients undergoing heart transplant at ≤18 yr of age from 1987 to 2010 who survived ≥1 yr. Using medical record and database review, patients were evaluated for development of autoimmune or severe allergic disease. Of 129 patients who met criteria, seven patients (5.4%) with autoimmune or severe atopic disease were identified. Immune-mediated diseases included inflammatory bowel disease (n = 3), eosinophilic esophagitis/colitis (n = 4), and chronic bullous disease of childhood (n = 1). Patients <1 yr of age at transplant were at greater risk of developing autoimmune disease than patients 1-18 yr at transplant (OR = 9.3, 95% CI 1.1-79.2, p = 0.02). All affected patients underwent thymectomy at <1 yr of age (7/71 vs. 0/58, p = 0.02). In our experience, heart transplantation in infancy is associated with the development of immune-mediated gastrointestinal and dermatologic diseases. Further study is needed to determine risk factors for the development of immune-mediated disease to identify best practices to decrease incidence.",
"affiliations": "Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.",
"authors": "Mouledoux|Jessica H|JH|;Albers|Erin L|EL|;Lu|Zengqi|Z|;Saville|Benjamin R|BR|;Moore|Daniel J|DJ|;Dodd|Debra A|DA|",
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"keywords": "atopic disease; autoimmune disease; immunosuppression; infant heart transplantation; pediatric heart transplantation; thymectomy",
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"mesh_terms": "D000293:Adolescent; D001327:Autoimmune Diseases; D002648:Child; D002675:Child, Preschool; D005260:Female; D006333:Heart Failure; D016027:Heart Transplantation; D006801:Humans; D006969:Hypersensitivity, Immediate; D007166:Immunosuppressive Agents; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D012189:Retrospective Studies; D012307:Risk Factors",
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"title": "Clinical predictors of autoimmune and severe atopic disease in pediatric heart transplant recipients.",
"title_normalized": "clinical predictors of autoimmune and severe atopic disease in pediatric heart transplant recipients"
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"abstract": "18F-labelled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is used extensively in the setting of cancer staging and in assessing cancer treatment response. Oncology patients have a sevenfold risk of developing pulmonary embolism (PE) due to underlying activation of the haemostatic system and anti-cancer therapy inducing a hypercoagulable state. The diagnosis of PE on 18F-FDG PET/CT is challenging, particularly in the absence of intravenous contrast. The case of a female patient undergoing treatment for advanced diffuse large B-cell lymphoma is presented. The ancillary signs of PE are illustrated on consecutive non-contrast-enhanced 18F-FDG PET/CT scans. The signs include the \"rim sign\" relating to regions of pulmonary infarction and abnormal cardiac uptake indicating right heart strain. The diagnosis was confirmed on CT pulmonary angiography which demonstrated extensive PE, including a saddle embolus.",
"affiliations": "Department of Nuclear Medicine Qscan Radiology Clinics Brisbane Australia.;Department of Nuclear Medicine Qscan Radiology Clinics Brisbane Australia.;Department of Nuclear Medicine Qscan Radiology Clinics Brisbane Australia.;Department of Nuclear Medicine Qscan Radiology Clinics Brisbane Australia.;Department of Nuclear Medicine Qscan Radiology Clinics Brisbane Australia.",
"authors": "Singh|Dalveer|D|https://orcid.org/0000-0001-5509-8322;Foessel|Roslyn|R|;Nagra|Navjot|N|;Lau|Pauline|P|;Brauchli|Damian|D|",
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"fulltext": "\n==== Front\nRespirol Case RepRespirol Case Rep10.1002/(ISSN)2051-3380RCR2Respirology Case Reports2051-3380John Wiley & Sons, Ltd Chichester, UK 10.1002/rcr2.476RCR2476Case ReportCase ReportsAcute saddle pulmonary embolism on 18F‐FDG PET/CT: diagnosis by functional imaging Functional imaging of PE on 18F‐FDG PET/CTD. Singh et al.Singh Dalveer https://orcid.org/0000-0001-5509-8322dalveer.singh@qscan.com.au \n1\n\n2\nFoessel Roslyn \n1\nNagra Navjot \n1\nLau Pauline \n1\nBrauchli Damian \n1\n\n1 \nDepartment of Nuclear Medicine\nQscan Radiology Clinics\nBrisbane\nAustralia\n\n2 \nSchool of Medicine\nUniversity of Queensland\nBrisbane\nAustralia\n* Correspondence\n\nDalveer Singh, Department of Nuclear Medicine, Qscan Radiology Clinics, College Junction 2‐12 Wagner Road, Clayfield, Queensland 4011, Australia. E‐mail: dalveer.singh@qscan.com.au\n20 8 2019 11 2019 7 8 10.1002/rcr2.v7.8e0047606 7 2019 24 7 2019 26 7 2019 © 2019 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of RespirologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n18F‐labelled fluoro‐2‐deoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) is used extensively in the setting of cancer staging and in assessing cancer treatment response. Oncology patients have a sevenfold risk of developing pulmonary embolism (PE) due to underlying activation of the haemostatic system and anti‐cancer therapy inducing a hypercoagulable state. The diagnosis of PE on 18F‐FDG PET/CT is challenging, particularly in the absence of intravenous contrast. The case of a female patient undergoing treatment for advanced diffuse large B‐cell lymphoma is presented. The ancillary signs of PE are illustrated on consecutive non‐contrast‐enhanced 18F‐FDG PET/CT scans. The signs include the “rim sign” relating to regions of pulmonary infarction and abnormal cardiac uptake indicating right heart strain. The diagnosis was confirmed on CT pulmonary angiography which demonstrated extensive PE, including a saddle embolus.\n\nPositron emission tomography/computed tomographypulmonary embolusright heart strainrim sign source-schema-version-number2.0component-idrcr2476cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:21.08.2019\n\n\nSingh , D \n, \nFoessel , R \n, \nNagra , N \n, \nLau , P \n, \nBrauchli , D \n. (2019 ) Acute saddle pulmonary embolism on 18F‐FDG PET/CT: diagnosis by functional imaging . Respirology Case Reports , 7 (8 ), e00476. 10.1002/rcr2.476 \n\n\n\nAssociate Editor: James Ho\n==== Body\nIntroduction\nPulmonary embolism (PE) is the second leading cause of death in patients with cancer 1. Overall, the risk of PE is sevenfold in oncology patients compared with the general population 2, which is attributable to inherent cancer‐mediated mechanisms and anti‐cancer therapies inducing a hypercoagulable state. Cancers that are at particularly high risk are haematological, lung, and gastrointestinal (28‐fold, 22‐fold, and 20‐fold risk, respectively). Coincidentally, 18F‐labelled fluoro‐2‐deoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) is an extremely useful tool in this subset of cancers and is performed in the majority of patients for staging and to assess treatment response. In the setting of non‐contrast‐enhanced 18F‐FDG PET/CT, it is important to recognize the indirect signs of PE so that patients can be appropriately treated. We present a case illustrating typical non‐contrast‐enhanced 18F‐FDG PET/CT findings of PE in a patient undergoing treatment for diffuse large B cell lymphoma (DLBCL).\n\nCase Report\nA middle‐aged female presented for a non‐contrast 18F‐FDG PET/CT scan for restaging of advanced DLBCL post completion of R‐CHOP (rituximab cyclophosphamide doxorubicin) chemotherapy. She had known widespread nodal and extra‐nodal disease (including brain), and documented episodes of acute tachycardia and dyspnoea seven weeks earlier. The non‐contrast CT images demonstrated a peripheral area of ground glass with surrounding consolidation in the posterior right lower lobe. The PET data confirmed a corresponding rim of low‐level 18F‐FDG uptake with central photopaenia, consistent with the “rim sign” (Fig. 1).\n\nFigure 1 Right lower lobe opacity demonstrating the “rim sign” (arrow).\n\nFour weeks later while the patient was undergoing whole brain radiation for residual intracranial DLBCL, the patient returned for an 18F‐FDG PET/CT surveillance scan. Peripheral ground glass with a rim of low‐level 18F‐FDG uptake was again demonstrated, this time within the left lower lobe (Fig. 2) with the additional finding of four‐chamber cardiac 18F‐FDG uptake.\n\nFigure 2 Left lower lobe “rim sign” (short arrow) and four‐chamber cardiac uptake (best appreciated on the whole body maximal intensity projection (long arrow).\n\nThe patient deteriorated with acute tachycardia, dyspnoea, and left pleuritic chest pain three hours after the scan. A CT pulmonary angiography (CTPA) was performed, diagnosing extensive lobar, segmental, subsegmental, and saddle PE. There were no features of right heart strain (RHS) on the CTPA.\n\nAfter four weeks of oral anticoagulants and completion of therapy for DLBCL, a follow‐up 18F‐FDG PET/CT scan showed complete resolution of the pulmonary changes and complete metabolic response to therapy.\n\nDiscussion\nIncidental PE was found in 0.32% of contrast‐enhanced 18F‐FDG PET/CT scans in one retrospective study 3. Protocolling for 18F‐FDG PET/CT depends on practice‐specific preferences and patient contraindications such as renal impairment and prior contrast reaction. Many patients will undergo a non‐contrast study which poses even greater challenge for diagnosing PE. Nonetheless, the importance of recognizing potential PE cannot be overstated given the high pre‐test probability in the at‐risk population of oncology patients and the potential for catastrophic outcomes in undiagnosed PE. In these patients there is a reliance on secondary signs of PE. In addition, where contrast is used it is typically acquired with contrast in an arterial phase and during free respiration, which is far from ideal when attempting to detect small and/or basal emboli. Therefore, even when contrast‐enhanced 18F‐FDG PET/CT is used, an understanding of the indirect signs of PE is invaluable.\n\nThe two most distinguishable signs of a PE on a non‐contrast‐enhanced 18F‐FDG PET/CT scan are the “rim sign” which indicates a pulmonary infarction and abnormal cardiac uptake associated with RHS. Other signs include hypermetabolism and hypometabolic filling defects in the pulmonary artery, but these are less reliable. A pulmonary infarction manifests as an area of geographical coagulative necrosis in the subpleural region with islands of viable lung parenchyma and a reparative margin of granulation tissue with a well‐defined edge consisting of palisading histiocytes and foamy macrophages 4. The peripheral inflammation demonstrates variable FDG uptake resulting in the “rim sign.” As pulmonary infarctions are absent in the majority of cases of PE, the absence of “rim sign” in no way reliably excludes the diagnosis 5. Additionally, a centrally necrotic tumour can mimic the appearance of the “rim sign” and the degree of uptake similar to low‐grade primary lung neoplasm such as adenocarcinoma. In our case, observing the pulmonary infarct on CT may have prompted search for PE via CTPA earlier; however, this requires astute interpretation and high index of suspicion.\n\nThe presence of alternative indirect signs for PE such as RHS in this case report can greatly increase diagnostic confidence. Under normal physiological circumstances, only the left ventricle will typically show FDG uptake. In the setting of PE, increased pulmonary arterial resistance and tachycardia contribute to increased metabolic demand, which can alter the distribution of FDG within the heart. Uptake within the right ventricular wall and both atria has been described 3, 6. It should be noted that RHS is not specific to PE and can also present due to underlying heart or lung disease.\n\nIn this case, the patient had moderate right atrial uptake and only very subtle right ventricular uptake. This is a different pattern to the case reported by Franceschi et al. 6 describing intense right atrial and ventricular uptake. In this case, the patient was asymptomatic at the time of the scan and subsequently deteriorated. This raises the possibility that right atrial uptake is an earlier sign of RHS than right ventricular uptake, although this would require further study to confirm. Indeed observing a new finding of RHS should prompt the interpreting physician to enquire to the clinical status of the patient, communication with the referring clinician to ascertain the need for urgent CTPA.\n\nPE is a challenging diagnosis on non‐contrast‐enhanced 18F‐FDG PET/CT. While many cases of PE will remain undetectable, awareness of indirect signs such as the “rim sign” and abnormal cardiac FDG uptake may prevent potentially catastrophic outcomes in at‐risk oncology patients.\n\nDisclosure Statement\nAppropriate written informed consent was obtained for publication of this case report and accompanying images.\n==== Refs\nReferences\n1 \n\nNoble \nS \n, and \nPasi \nJ \n. 2010 \nEpidemiology and pathophysiology of cancer‐associated thrombosis . Br. J. Cancer \n102 (S1):S2 –S9 .20386546 \n2 \n\nBlom \nJW \n, \nDoggen \nCJM \n, \nOsanto \nS \n, et al. 2005 \nMalignancies, prothrombotic mutations, and the risk of venous thrombosis . JAMA \n293 :715 –722 .15701913 \n3 \n\nFlavell \nRR \n, \nBehr \nSC \n, \nBrunsing \nRL \n, et al. 2014 \nThe incidence of pulmonary embolism and associated FDG‐PET findings in IV contrast‐enhanced PET/CT . Acad. Radiol. \n21 :718 –725 .24809314 \n4 \n\nYousem \nSA \n. 2009 \nThe surgical pathology of pulmonary infarcts: diagnostic confusion with granulomatous disease, vasculitis and neoplasia . Mod. Pathol. \n22 :679 –685 .19287460 \n5 \n\nSoussan \nM \n, \nRust \nE \n, \nPop \nG \n, et al. 2012 \nThe rim sign: FDG‐PET/CT pattern of pulmonary infarction . Insights Imaging \n3 (6 ):629 –633 .22903456 \n6 \n\nFranceschi \nAM \n, \nMatthews \nR \n, \nMankes \nS \n, et al. 2012 \nFour chamber FDG uptake in the heart: an indirect sign of pulmonary embolism . Clin. Nucl. Med. \n37 :687 –691 .22691515\n\n",
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"title": "Acute saddle pulmonary embolism on 18F-FDG PET/CT: diagnosis by functional imaging.",
"title_normalized": "acute saddle pulmonary embolism on 18f fdg pet ct diagnosis by functional imaging"
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"abstract": "BACKGROUND\nStenotrophomonas maltophilia is an uncommon gram-negative bacterium often found in individuals with long-standing broad-spectrum antibiotic use or catheter use; individuals undergoing hemodialysis; and individuals with prolonged respiratory disease, specifically, cystic fibrosis. To our knowledge, there are few reported cases of S maltophilia being the causative pathogen of infection in a diabetic foot wound.\n\n\nMETHODS\nFollowing multiple surgical procedures and deep tissue cultures, S maltophilia was determined to be a secondary opportunistic colonizer of the wound, necessitating a change in antibiotic therapy.\n\n\nRESULTS\nThe cultured pathogen was sensitive to ceftazidime, levofloxacin, and trimethoprim-sulfamethoxazole. The treatment team chose to use ceftazidime, as it also provided antibiotic coverage for the initial wound and blood cultures. Change in antibiotic therapy was initiated following multiple surgical procedures and angioplasty of the lower limb. The patient was discharged with a peripheral intravenous central catheter for outpatient antibiotic therapy.\n\n\nCONCLUSIONS\nProlonged exposure to broad-spectrum antibiotics in individuals with multiple comorbidities including diabetes mellitus provides an advantageous environment for growth of uncommon multidrug-resistant organisms. Stenotrophomonas maltophilia may complicate the treatment of diabetic foot infections as an opportunistic pathogen. Understanding the implication of long-term broad-spectrum antibiotic treatment in the diabetic patient is important in managing postoperative complications and determining the correct course of treatment. The emergence of atypical pathogens in diabetic wounds must be managed appropriately.",
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"authors": "Huchital|Michael J|MJ|;Kim|Jason|J|;Mantzoukas|Argirios|A|;Lucido|Jeffrey V|JV|",
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"mesh_terms": "D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D003920:Diabetes Mellitus; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D020615:Stenotrophomonas maltophilia",
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"title": "Insights for the Growth of Stenotrophomonas maltophilia in a Diabetic Patient with Long-Term Antibiotic Use: A Case Study.",
"title_normalized": "insights for the growth of stenotrophomonas maltophilia in a diabetic patient with long term antibiotic use a case study"
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"abstract": "Drug hypersensitivity syndrome (DHS) is a severe medication reaction involving multiple organ systems that is characterized by rash, lymphadenopathy, and laboratory aberrations, including hepatic enzyme changes. Viral reactivation in the setting of DHS can significantly affect the course of disease. We report two children in whom parvovirus infection prolonged and complicated their course of DHS. Most other DHS-complicating viruses are herpesviruses; this report broadens the scope of DHS-modifying infections to include activation of Parvoviridae.",
"affiliations": "Division of Dermatology, Departments of Medicine and Pediatrics, Washington University School of Medicine, St. Louis, Missouri.;Section of Pediatric Dermatology, Division of General Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Division of Dermatology, Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington.",
"authors": "Coughlin|Carrie C|CC|;Jen|Melinda V|MV|;Boos|Markus D|MD|",
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"mesh_terms": "D000293:Adolescent; D002648:Child; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D008297:Male; D010322:Parvoviridae Infections; D000637:Transaminases; D014775:Virus Activation",
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"title": "Drug Hypersensitivity Syndrome with Prolonged Course Complicated by Parvovirus Infection.",
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"abstract": "The comorbidity between multiple sclerosis (MS) and progressive familial intrahepatic cholestasis type-3 (PFIC3) has never been described yet. ABCB4 gene encodes the multidrug resistant protein 3 (MDR3) and its mutations induce PFIC3 as well as intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). We describe the case of a 32-year-old female with MS and PFIC3 who was effectively treated with natalizumab and ursodeoxycholic acid (UCDA), in contrast to glatiramer acetate, dimethylfumarate, and IFNb1a associated with DILI. Our findings clarify the pharmacodynamics of MS therapies and suggest natalizumab plus UDCA as the effective treatment of PFIC3/MS phenotype, unlike the others that should be avoided.",
"affiliations": "Laboratory of Neuroproteomics, Multiple Sclerosis Centre, \"F. Ferrari\" Hospital, 73042, Casarano - Lecce, Italy.;Laboratory of Neuroproteomics, Multiple Sclerosis Centre, \"F. Ferrari\" Hospital, 73042, Casarano - Lecce, Italy.;Laboratory of Hygiene, Department of Biological and Environmental Sciences and Technologies, University of the Salento, Lecce, Italy.",
"authors": "De Masi|Roberto|R|0000-0002-7587-8112;Orlando|Stefania|S|;De Donno|Antonella|A|",
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"fulltext": "\n==== Front\nAnn Clin Transl NeurolAnn Clin Transl Neurol10.1002/(ISSN)2328-9503ACN3Annals of Clinical and Translational Neurology2328-9503John Wiley and Sons Inc. Hoboken 10.1002/acn3.50883ACN350883Case StudyCase StudyProgressive familial intrahepatic cholestasis type‐3 and multiple sclerosis: lessons from comorbidity PFIC3 and MSR. De Masi et al.De Masi Roberto https://orcid.org/0000-0002-7587-8112\n1\n\n2\ndmsrrt@gmail.com Orlando Stefania \n1\n\n3\nDe Donno Antonella \n3\n\n1 \nLaboratory of Neuroproteomics\nMultiple Sclerosis Centre\n“F. Ferrari” Hospital\n73042\nCasarano – Lecce\nItaly\n\n2 \nComplex Operative Unit of Neurology\n“F. Ferrari” Hospital\n73042\nCasarano – Lecce\nItaly\n\n3 \nLaboratory of Hygiene, Department of Biological and Environmental Sciences and Technologies\nUniversity of the Salento\nLecce\nItaly\n* Correspondence\n\nRoberto De Masi, Laboratory of Neuroproteomics, Multiple Sclerosis Centre, “F. Ferrari” Hospital, 73042 Casarano – Lecce, Italy. Tel/Fax: +39 0833 508323; E‐mail: dmsrrt@gmail.com\n30 9 2019 11 2019 6 11 10.1002/acn3.v6.112347 2350 24 6 2019 31 7 2019 10 8 2019 © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.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 comorbidity between multiple sclerosis (MS) and progressive familial intrahepatic cholestasis type‐3 (PFIC3) has never been described yet. ABCB4 gene encodes the multidrug resistant protein 3 (MDR3) and its mutations induce PFIC3 as well as intrahepatic cholestasis of pregnancy (ICP) and drug‐induced liver injury (DILI). We describe the case of a 32‐year‐old female with MS and PFIC3 who was effectively treated with natalizumab and ursodeoxycholic acid (UCDA), in contrast to glatiramer acetate, dimethylfumarate, and IFNb1a associated with DILI. Our findings clarify the pharmacodynamics of MS therapies and suggest natalizumab plus UDCA as the effective treatment of PFIC3/MS phenotype, unlike the others that should be avoided.\n\n source-schema-version-number2.0cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:15.11.2019\n==== Body\nIntroduction\nThe timely recognition of comorbidities in clinical practice is paramount to individualize effective treatment and to minimize adverse effects in treating multiple sclerosis (MS).1 In particular, the comorbidity between MS and progressive familial intrahepatic cholestasis type‐3 (PFIC3) has never been described to date.\n\nPFIC represents a heterogeneous group of autosomal recessive cholestasis diseases of childhood. Mutations in the same genes responsible for PFIC lead to other nonprogressive cholestasis diseases in adults, including intrahepatic cholestasis of pregnancy (ICP) and drug‐induced liver injury (DILI).\n\nThe underlying gene that is defective in PFIC3 is ABCB4 (7q21) that encodes the multidrug resistance protein 3 (MDR3).2 MDR3 is a 12‐domain transmembrane plasmalemmal translocator, responsible for actively flipping phospholipids, particularly phosphatidylcholine, on the interface hepatocyte‐bile ducts. This molecule, belonging to the P‐glycoprotein (P‐gp) superfamily of translocases, is expressed at the blood–brain barrier and secretory/absorptive tissues such as the gastrointestinal tract, kidneys, and liver.\n\nFurthermore, MDR3 can also bind a number of synthetic molecules, conferring resistance to chemotherapy, even though worldwide efforts to identify its selective inhibitors have not been successful.3\n\n\nCase Presentation\nP. L., a 32‐year‐old woman, was admitted to our neurological department in May 2012, presenting with right face and arm paresis that had started about 6 days before. MRI brain demonstrated contrast enhancing and nonenhancing lesions in the periventricular and juxtacortical white matter sites, typical for MS.\n\nThe isoelectric focusing of the cerebrospinal fluid (CSF) showed seven oligoclonal bands not expressed in the serum. CSF showed normal protein concentration and the link index was 1.2, without pleocytosis, suggesting blood–brain barrier breakdown process.\n\nBlood test for MS mimics was negative and the patient was diagnosed with relapsing remitting MS according to the 2011 McDonald criteria. She underwent treatment with 5 days of intravenous high‐dose methylprednisolone.\n\nAt the hospital discharge, we recommended as first‐line MS therapy three times weekly subcutaneous administration of glatiramer acetate, as well as follow‐up every 3 months at the local MS center. The expanded disability status scale (EDSS), improved by one point compared to baseline, was 2.0. Routine blood tests were normal.\n\nDuring the first few weeks of treatment, the patient experienced a moderate increase in liver transaminases, to about four to five times the normal values (n.v.). Three months after starting therapy, the patient had an intense allergic reaction, with breathing difficulties and a diffuse rash. Glatiramer acetate was discontinued in favor of three times weekly subcutaneous administrations of high‐dose IFNb1a. However, elevated transaminases persisted, with a moderate increase in level, even after switching to low‐dose weekly administration of IFNb1a 3 months later.\n\nAt this point, the patient was lost to the follow‐up for about 2 years, after which she reappeared in our department with two children in apparent good health.\n\nMedical records provided evidence of elevated transaminases of five to six times the n.v. and ICP during both pregnancies. By then, however, the woman had only a mild increase of transaminases, about twice the n.v., with stable neurological conditions and no jaundice or pruritus. Six months after starting dimethylfumarate (orally 240 mg bid), increase of transaminases was moderate, but a brain MRI revealed a significant increase in lesion load (LL) with respect to the pretreatment baseline. The EDSS remained stable. Autoimmune, viral, alcohol, and storage liver diseases were excluded. We suspected a diagnosis of PFIC due to the history of DILI and ICP, and the PFIC type‐3 was confirmed with a liver biopsy and specific genetic tests.\n\nThe genetic profile exhibited a double heterozygosis for the ABCB4 gene with the following mutations: p.Arg652Gly (c.1954A > G) and p.Ile237= (c.711A > T); moreover, an intronic variant of TJP2 that is p.Lys16Glu (c.46A > G).\n\nFigure 1 shows the LL and gamma‐glutamyl transferase (GGT) levels during the pregnancies and therapies. Note the increase of LL during the whole first‐line treatment period. Figure 2 shows the loss of MDR3, compared to the healthy control; positive immunostaining of the bile salt export pump (BSEP) and the “hepatocytic rosette”. In Figure 3, protein sequence annotation of FIC‐selected nonsynonymous mutation and annotation on available 3D structure are displayed (only for ABCB4, as TJP2 mutation map to unstructured region).\n\nFigure 1 The graphic representation of the hepatic cytolytic indexes expressed as multiples of gamma‐glutamyl transferase (GGT) normal value (n.v.) during the first pregnancy (IPr), the second pregnancy (IIPr), and the drug administration: glatiramer acetate, interferon (IFNb1a), dimethylfumarate, and natalizumab (Ty). Note the magnetic resonance imaging of the brain with its lesion load (LL) expressed in milliliters (mL) at the start therapy and the last therapy before the natalizumab\n\nFigure 2 Immunohistochemical and histological staining of the liver biopsy. (A) focal loss of the multi‐drug resistant protein 3 (MDR3) at the hepatocytic ductal pole and its residual immunoreaction (black arrows); (B) MDR3 representation at the hepatocytic ductal pole in healthy control; (C) positive immunostaining of the bile salt export pump (BSEP); (D) the “hepatocytic rosette” in reticulus staining (black arrows in the little view) and hematoxylin‐eosin staining (black arrows in the large view)\n\nFigure 3 Protein sequence annotation of FIC‐selected nonsynonymous ABCB4 mutation displayed as red lollipop (R652G). Blue and green lollipops indicate phosphorylation and acetylation sites, respectively. Nonsynonymous mutation annotation on available 3D structure as assessed through Mechismo is displayed following the same color scheme regarding the ABCB4 gene\n\nFinally, the patient was treated with oral ursodeoxycholic acid (UCDA) (10 mg/kg/die), plus natalizumab therapy. She continues to receive monthly infusions with unchanged MRI LL. Transaminases are now stable at 1.5–2 times the n.v., with no pruritus or jaundice.\n\nDiscussion and Conclusions\nWe described a case of a MS patient with DILI and ICP history, who has ABCB4 involvement causing PFIC3, resulting in the PFIC3/MS clinical phenotype. Given its genomic basis, this comorbidity represents an “experimentum naturae”, because it explains the kinetics and dynamics of drugs tested in the mutant patient having MDR3 loss. Normal BSEP function excluded also the non‐PFIC conditions, as resulting by immunostaining. The drugs tested are disease‐modifying therapies (DMTs) that are considered first‐line (dimethylfumarate, glatiramer acetate, and IFNb1a) and second‐line therapies (natalizumab). DILI has been frequently described in literature, but its exact mechanisms are still not understood.4 For DMTs in MS, as with other drugs, liver toxicity is attributed to the direct effect of the therapeutic molecule, as well as its idiosyncratic or autoimmune effects, the frequency of which depends on the specific drug.\n\nThe cause of hepatic injury from DMTs is not known, but it may be reversible following drug discontinuation. In the case of interferon, it may be dose‐related. The postulated mechanism is an autoimmune reaction for IFNb1a and glatiramer acetate, and an idiosyncratic reaction for dimethylfumarate. For natalizumab, the mechanism of liver injury is probably also immunologically mediated, resulting from a dose‐dependent leukocytes compartmentalization into the bloodstream.5\n\n\nUnlike these reversible conditions, the hepatotoxicity described here was not resolved completely at drug discontinuation, but was persistent nonprogressive.\n\nThe persistent DILI with reduced expression of MDR3 protein can be sustained by the lack of translocation of phosphatidylcholine across the canalicular membrane into bile, causing proliferation of bile ducts and altered cytoarchitecture resulting in “hepatocytic rosette”. On the other hand, the accentuation of hepatotoxicity during administration of IFNb1a, glatiramer acetate, and dimethylfumarate is caused by hepatocyte back accumulation of the unbound drug to translocator.\n\nThis study suggests that the therapeutic activity of natalizumab is not linked to MDR3 and is not associated with serum aminotransferase elevation, unlike IFNb1a, glatiramer acetate, and dimethylfumarate that all link MDR3, contributing to hepatotoxicity in PFIC3/MS phenotype. For these reasons, natalizumab plus UDCA should be considered in the future as first‐line therapy in patients with this comorbidity, while the other DMTs described here should be avoided.\n\nAuthor Contributions\nRoberto De Masi was a major contributor in conception and design, acquisition of data, analysis, and interpretation of data of this manuscript. Stefania Orlando has been involved in drafting the manuscript and revising it critically for important intellectual content. Antonella De Donno has given final approval of the version to be published. All authors read and approved the final manuscript.\n\nConflict of Interest\nAll authors declare no conflict of interest.\n==== Refs\nReferences\n1 \n\nMarrie \nRA \n. Comorbidity in Multiple Sclerosis: some answers. more questions . Int J MS Care \n2016 ;18 :271 –272 .27999520 \n2 \n\nDegiorgio \nD \n, \nColombo \nC \n, \nSeia \nM \n, et al. Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3) . Eur J Hum Genet \n2007 ;15 :1230 –1238 .17726488 \n3 \n\nMellor \nHR \n, \nCallaghan \nR \n. Resistance to chemotherapy in cancer: a complex and integrated cellular response . Pharmacology \n2008 ;81 :275 –300 .18259091 \n4 \n\nDavid \nS \n, \nHamilton \nJP \n. Drug‐induced Liver Injury . US Gastroenterol Hepatol Rev \n2010 ;6 :73 –80 .21874146 \n5 \n\nAntezana \nA \n, \nSigal \nS \n, \nHerbert \nJ \n, \nKister \nI \n. Natalizumab‐induced hepatic injury: a case report and review of literature . Mult Scler Relat Disord \n2015 ;4 :495 –498 .26590653\n\n",
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"mesh_terms": "D018435:ATP Binding Cassette Transporter, Subfamily B; D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D002780:Cholestasis, Intrahepatic; D015897:Comorbidity; D000069462:Dimethyl Fumarate; D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents; D000068556:Interferon beta-1a; D020529:Multiple Sclerosis, Relapsing-Remitting; D009154:Mutation; D000069442:Natalizumab; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "101623278",
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"title": "Progressive familial intrahepatic cholestasis type-3 and multiple sclerosis: lessons from comorbidity.",
"title_normalized": "progressive familial intrahepatic cholestasis type 3 and multiple sclerosis lessons from comorbidity"
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"abstract": "OBJECTIVE\nTo report two cases of young immunocompetent males with herpes simplex acute retinal necrosis (HSV ARN) with initial diagnosis of unilateral disc swelling.\n\n\nMETHODS\nRetrospective case series.\n\n\nRESULTS\nTwo young immunocompetent males who were diagnosed to have unilateral disc swelling were treated as presumed optic neuritis and started on systemic steroids. On dilated fundal examination, unilateral retinitis and vasculitis was found after 2-3 days of systemic steroids and the diagnosis of ARN was made. Tetraplex vitreous tap subsequently returned as HSV-2 and HSV for the first and second patient, respectively. Both patients had no significant systemic medical history and tested negative for human immunodeficiency virus (HIV). Despite aggressive treatment, both patients developed profound visual morbidity.\n\n\nCONCLUSIONS\nClose monitoring of patients with unilateral disc swelling and dilated fundus evaluation is critical, particularly upon initiation of systemic steroid therapy, even if immunocompetent, as misdiagnoses can result in potentially devastating consequences.",
"affiliations": "a National Healthcare Group Eye Institute, Tan Tock Seng Hospital , Singapore.;a National Healthcare Group Eye Institute, Tan Tock Seng Hospital , Singapore.;a National Healthcare Group Eye Institute, Tan Tock Seng Hospital , Singapore.;a National Healthcare Group Eye Institute, Tan Tock Seng Hospital , Singapore.;a National Healthcare Group Eye Institute, Tan Tock Seng Hospital , Singapore.",
"authors": "Koh|Yan Tong|YT|;Ang|Bryan Chin-Hou|BC|;Ho|Su Ling|SL|;Beng Teoh|Stephen Charn|SC|;Agrawal|Rupesh|R|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2016.1175643",
"fulltext": null,
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"issn_linking": "0927-3948",
"issue": "25(6)",
"journal": "Ocular immunology and inflammation",
"keywords": "Disc swelling; herpes simplex acute retinal necrosis; immunocompetent; optic neuritis; steroids",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D015828:Eye Infections, Viral; D005451:Fluorescein Angiography; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human; D018258:Herpesvirus 2, Human; D006801:Humans; D007121:Immunocompetence; D016867:Immunocompromised Host; D008297:Male; D009902:Optic Neuritis; D010211:Papilledema; D015882:Retinal Necrosis Syndrome, Acute; D012189:Retrospective Studies; D014822:Vitreous Body",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "797-801",
"pmc": null,
"pmid": "27230575",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Herpes Simplex Acute Retinal Necrosis Presenting as Unilateral Disc Swelling in Young Immunocompetent Patients.",
"title_normalized": "herpes simplex acute retinal necrosis presenting as unilateral disc swelling in young immunocompetent patients"
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"abstract": "A 65-year-old woman with rheumatoid arthritis treated by tocilizumab (TCZ) presented with tongue squamous cell carcinoma. While surgery was performed without any complications the aspiration pneumonia rapidly worsened by postoperative day 2 and severe pulmonary suppuration in the right lung field with infection-induced systemic inflammatory response syndrome (SIRS) was diagnosed. Antibiotic and respirator treatment improved her condition. The anti-inflammatory effect of TCZ may mask the symptoms and signs of severe infection with SIRS.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Emergency and Critical Care, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Emergency and Critical Care, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.",
"authors": "Yamagata|Kenji|K|;Shimojo|Nobutake|N|;Ito|Hiroyuki|H|;Ijima|Junya|J|;Hasegawa|Shogo|S|;Yanagawa|Toru|T|;Mizutani|Taro|T|;Bukawa|Hiroki|H|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2014/649086",
"fulltext": "\n==== Front\nCase Rep DentCase Rep DentCRIDCase Reports in Dentistry2090-64472090-6455Hindawi Publishing Corporation 10.1155/2014/649086Case ReportSevere Pulmonary Suppuration with Infection-Induced Systemic Inflammatory Response Syndrome following Tongue Cancer Surgery in a Patient Undergoing Tocilizumab Therapy for Rheumatoid Arthritis Yamagata Kenji \n1\n*Shimojo Nobutake \n2\nIto Hiroyuki \n1\nIjima Junya \n1\nHasegawa Shogo \n1\nYanagawa Toru \n1\nMizutani Taro \n2\nBukawa Hiroki \n1\n1Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan2Department of Emergency and Critical Care, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan*Kenji Yamagata: y-kenji@md.tsukuba.ac.jpAcademic Editor: Vlaho Brailo\n\n2014 29 4 2014 2014 64908620 3 2014 16 4 2014 Copyright © 2014 Kenji Yamagata 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 65-year-old woman with rheumatoid arthritis treated by tocilizumab (TCZ) presented with tongue squamous cell carcinoma. While surgery was performed without any complications the aspiration pneumonia rapidly worsened by postoperative day 2 and severe pulmonary suppuration in the right lung field with infection-induced systemic inflammatory response syndrome (SIRS) was diagnosed. Antibiotic and respirator treatment improved her condition. The anti-inflammatory effect of TCZ may mask the symptoms and signs of severe infection with SIRS.\n==== Body\n1. Introduction\n\nAlthough the etiologies of rheumatoid arthritis (RA) are not fully understood, proinflammatory cytokines such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1, and IL-6 have been shown to play a role in the pathology of RA and, as such, are potential therapeutic targets [1]. Tocilizumab (TCZ) is a humanized anti-IL-6 receptor monoclonal antibody that binds to both circulating soluble IL-6 receptor and membrane-bound IL-6 receptors, thereby inhibiting IL-6 binding to both forms of its receptor [2]. Because IL-6 has a pivotal role in the host defense reaction against microorganisms [3], patients treated with TCZ should be closely monitored for signs of infection. Pneumonia is a common problem in head and neck cancer (HANC) postsurgical patients [4]. A search of the literature revealed only four cases of organizing pneumonia induced by TCZ [5–7], while no account of aspiration pneumonia following HANC surgery could be found. We describe here the first case of severe pulmonary suppuration from aspiration pneumonia complicated by infection-induced systemic inflammatory response syndrome (SIRS) in a postsurgical patient with tongue cancer who had received TCZ treatment for RA.\n\n2. Case Report\nA 65-year-old woman came to the Department of Oral and Maxillofacial Surgery, University of Tsukuba Hospital, complaining of a painful mass on the right side of her tongue existing for 1 year. She had suffered from RA for 11 years and took Methotrexate for 3 years starting in 2008. Subsequently, TCZ was administered at a dose of 400 mg/month from November 2011 until December 2012, at which time the frequency of the dose was decreased to every 2 months. The last infusion of TCZ was about 1 month before the surgery. She had no rheumatoid lung. The social and family histories were unremarkable. Examination of the oral cavity showed an elastic hard mass on the right side of the tongue measuring approximately 40 × 20 mm (Figure 1). Biopsy of the tongue indicated that the mass was a well-differentiated squamous cell carcinoma. The regional lymph nodes were normal, and a chest radiograph disclosed no metastasis or occult disease. A partial glossectomy and supraomohyoid neck dissection were performed under general anesthesia without any complications as a diagnosis of tongue cancer (T2N0M0). The surgery lasted 4 hours and 32 minutes, and the blood loss was 110 mL. The nasal intubation tube was removed after the patient was wakened in the operating room. The patient's postsurgical clinical course is shown in Figure 2.\n\nOn postoperative day (POD) 1, the white blood cells (WBC) count rose to 18.5 × 103/μL and the neutrophil count rose to 17.2 × 103/μL, whereas the concentration of C-reactive protein (CRP) was 0.74 mg/dL. There was a significant discrepancy between the pre- and postoperative numbers for WBC and CRP. The vital signs on POD 2 were as follows: blood pressure 145/72 mmHg, pulse rate 102/min, respiratory rate 25/min, and body temperature (BT) 38.5°C. The lab data showed a WBC content of 3.6 × 103/μL and a CRP level of 1.0 mg/dL. These results led to a diagnosis of SIRS. SIRS criterion is presenting two or more of the following symptoms: (1) BT > 38°C or <36°C, (2) pulse rate > 90/min, (3) respiratory rate > 20/min or PaCO2 < 32 mmHg, and (4) WBC > 12.0 × 103/μL or <4.0 × 103/μL [8]. On POD 3, the patient's BT rose to 39.2°C, and she complained of cough and dyspnea, while the lab data indicated the following: platelet count (PLT) 46 × 103/μL; WBC 1.6 × 103/μL (Seg 2.0%, Band 47.0%); and CRP 8.6 mg/dL. The aspiration pneumonia had rapidly worsened. The patient was moved to an intensive care unit (ICU), a tracheal intubation was performed, and she was placed on a ventilator (FIO2 0.6, PEEP 5 cm H2O) on POD 4. The arterial blood gas analysis revealed hypoxemia (pH 7.425, PaO2 40.5 Torr, PaCO2 65.1 Torr). From POD 4 to 13, the patient received recombinant thrombomodulin to treat the disseminated intravascular coagulation (PLT 9 × 103/μL, PT ratio 1.36, FDP 12.1 μg/mL) and sivelestat for acute respiratory distress syndrome. Platelet concentrate was infused for a total of 40 U over 3 days. A chest X-ray revealed both a cloudy right lung and a severe consolidation in the upper lobe of the lung (Figure 3). A CT scan of the chest on POD 4 revealed a broad infiltrating shadow with air bronchogram mainly on the dorsal side of the right lung (Figure 4(a)). By POD 19, the infiltrating shadow had expanded and showed evidence of liquid storage. The follow-up CT scan taken at this time showed both lungs to have ground glass opacity and a maculate infiltrating shadow (Figure 4(b)). A diagnosis of pulmonary suppuration was made. Microorganism cultures of sputum detected Klebsiella pneumonia. The antibiotic regimen was changed from ampicillin (ABPC) to meropenem (MEPM) until POD 10 and then to tazobactam/piperacillin (TAZ/PIPC) until POD 21. The CRP value fell to the normal range at about PO 1 month, at which time extubation was attempted. However, because the patient's respiratory capacity was still poor, a tracheostomy was performed and another month of mechanical ventilation was added to her follow-up care. ABPC/sulbactam (SBT) was administered for about 1 month starting at PO 1 month, and the patient's BT resolved to less than 37°C. Thereafter, the patient was weaned from the ventilator and was moved from the ICU to a normal ward at about PO 2 months. She was discharged from the hospital at about PO 3 months. A chest X-ray revealed an improved clear field in the right lung (Figure 5) and the patient's respiratory function resolved. While the intraoral healing of the wound was slower than normal, there was no infection at the site of surgery, and the clinical course of the tongue cancer remained uneventful, without any recurrence or metastasis to the neck.\n\n3. Discussion\nIn a clinical trial of IL-6 in patients with malignancies, IL-6 was found to induce fever, chills, and general malaise [9]. Grave adverse events associated with the use of TCZ include serious infections that may lead to hospitalization or death, gastrointestinal perforation, and hypersensitivity reactions including anaphylaxis [2]. The most common adverse events reported in clinical studies were upper respiratory tract infections, nasopharyngitis, headache, high blood pressure, and increased liver enzymes [2]. The rate of serious infections was 3.6 events per 100 patient-years, but the overall rate of fatal infections was low (0.13 events per 100 patient-years) [10].\n\nPneumonia is a common problem in HANC surgical patients. An increased risk of developing pneumonia is associated with advanced comorbidity, weight loss, and major surgical procedures, a heightened chance of infectious pneumonia is associated with chronic pulmonary disease, and an increased risk of aspiration pneumonia is associated with dysphagia [4]. Although only 4 accounts of organizing pneumonia induced by TCZ have been reported [5–7], no case of aspiration pneumonia after HANC surgery has been described as yet. To our knowledge, this is the first report in which an RA patient using TCZ, who underwent surgery for tongue cancer, subsequently developed severe pulmonary suppuration from aspiration pneumonia.\n\nIt is well recognized that the excessive production of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8 by immune-competent cells can induce SIRS and that these cytokines can also play an important role in the development of acute respiratory distress syndrome or multiple organ dysfunction syndrome [11, 12]. The excessive production of proinflammatory cytokines activates neutrophils, the coagulation system, and other mediator cascades, resulting in organ dysfunction. Moreover, blood cytokine levels begin to rise prior to the onset of organ dysfunction [11]. IL-6 induces acute-phase proteins like CRP, fibrinogen, α1-antitrypsin, and serum amyloid protein A in hepatocytes [2, 13]. In our patient, TCZ suppressed IL-6 as well as the early inflammatory symptoms of aspiration pneumonia. A slight increase in CRP (1.0 mg/dL) was observed in the laboratory findings on POD 2, accompanied by a high fever, but these levels quickly rose to 17.1 mg/dL following progression of the aspiration pneumonia on POD 4, suggesting that TCZ may have suppressed the early inflammatory reaction, leading to severe organ dysfunction.\n\nA recent report investigating the relationship between TCZ treatment and joint surgery outcomes found no complications due to infection or delays in wound healing [13]. On the other hand, the guidelines for TCZ use published in 2009 mention that wound healing might be delayed under TCZ therapy. Moreover, these guidelines advise that surgery should be postponed in patients undergoing TCZ treatment until the concentration of the drug in the peripheral blood has fallen, deferring surgery until at least 14 days after the last infusion [14]. In the present case, although TCZ was last administered about 1 month before surgery and there was no infection at the surgical site, the intraoral wound healing was delayed more than expected. An earlier study concluded that TCZ suppressed fever and increased the level of CRP after surgery, whereas it found no influence of the drug on the number of leukocytes before and after surgery [13]. In the current case, the WBC count was high, but the CRP concentration was normal on POD1. Although the WBC and CRP levels were not remarkable, the BT rose on POD 2. The CRP changed later, which was in agreement with the previous report on TCZ-treated patients after surgery [12]. Since TCZ inhibits IL-6's actions, it is possible that these early symptoms of pneumonia were masked by the TCZ treatment.\n\nBecause the anti-inflammatory effect of TCZ may mask the typical symptoms and signs of infection and the possible conversion to severe infection-induced SIRS, surgeons need to be aware of the potential for hidden infections after surgery. This report provides rheumatologists and surgeons with useful information for the treatment and follow-up of rheumatology patients under TCZ treatment.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Examination of the oral cavity. An elastic, hard superficial mass with ulcer that measured approximately 40 × 20 mm is observed on the right side of the tongue.\n\nFigure 2 Clinical course. Measurements of CRP (C-reactive protein), WBC (white blood cells count), PLT (platelet count), and BT (body temperature) are taken before and after surgery. ICU (intensive care unit), PC (platelet concentrate), MAP (mannitol-adenine-phosphate), FFP (fresh frozen plasma), and rTM (recombinant thrombomodulin).\n\nFigure 3 Chest X-ray (POD 4). The chest X-ray reveals a cloudy right lung and severe consolidation in the upper lobe of the lung.\n\nFigure 4 (a) Chest CT (POD 4). The scan shows a broad infiltrating shadow with air bronchogram mainly in the dorsal portion of the right lung, leading to a diagnosis of pulmonary suppuration. (b) Chest CT (POD 19). Two weeks later, the broad infiltrating shadow has expanded and shows storage of liquid. Both lungs have ground glass opacity and contain a maculate infiltrating shadow.\n\nFigure 5 Chest X-ray (PO 4 months). A chest X-ray reveals an improved clear field in the right lung.\n==== Refs\n1 Nishimoto N Interleukin-6 in rheumatoid arthritis Current Opinion in Rheumatology 2006 18 3 277 281 2-s2.0-33646701639 16582692 \n2 Tanaka T Ogata A Narazaki M Tocilizumab for the treatment of rheumatoid arthritis Expert Review of Clinical Immunology 2010 6 6 843 854 2-s2.0-78049445876 20979549 \n3 Kishimoto T Interleukin-6: from basic science to medicine-40 Years in immunology Annual Review of Immunology 2005 23 1 21 2-s2.0-17644368573 \n4 Genther DJ Gourin CG The effect of alcohol abuse and alcohol withdrawal on short-term outcomes and cost of care after head and neck cancer surgery The Laryngoscope 2012 122 9 1994 2004 2-s2.0-84860577272 22777881 \n5 Ikegawa K Hanaoka M Ushiki A Yamamoto H Kubo K A case of organizing pneumonia induced by tocilizumab Internal Medicine 2011 50 19 2191 2193 2-s2.0-80053499547 21963739 \n6 Fujiwara H Nishimoto N Hamano Y Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment: A report of two cases Modern Rheumatology 2009 19 1 64 68 2-s2.0-60149100932 18758893 \n7 Yanagawa Y Hirano Y Kato H Iba T The absence of typical pneumonia symptoms in a patient with rheumatoid arthritis during tocilizumab and steroid treatment BMJ Case Reports 2012 2012 \n8 Herzum I Renz H Inflammatory markers in SIRS, sepsis and septic shock Current Medicinal Chemistry 2008 15 6 581 587 2-s2.0-42049117508 18336272 \n9 Weber J Yang JC Topalian SL Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies Journal of Clinical Oncology 1993 11 3 499 506 2-s2.0-0027461967 7680375 \n10 Patel AM Moreland LW Interleukin-6 inhibition for treatment of rheumatoid arthritis: a review of tocilizumab therapy Drug Design, Development and Therapy 2010 4 263 278 2-s2.0-79951739491 \n11 Oda S Hirasawa H Shiga H Nakanishi K Matsuda KI Nakamua M Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis Cytokine 2005 29 4 169 175 2-s2.0-12344275811 15652449 \n12 Wheeler AP Bernard GR Treating patients with severe sepsis New England Journal of Medicine 1999 340 3 207 214 2-s2.0-0033590515 9895401 \n13 Hirao M Hashimoto J Tsuboi H Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab Annals of the Rheumatic Diseases 2009 68 5 654 657 2-s2.0-66149155108 18519424 \n14 Koike R Harigai M Atsumi T Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis Modern Rheumatology 2009 19 4 351 357 2-s2.0-68549105886 19590933\n\n",
"fulltext_license": "CC BY",
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"issue": "2014()",
"journal": "Case reports in dentistry",
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"title": "Severe Pulmonary Suppuration with Infection-Induced Systemic Inflammatory Response Syndrome following Tongue Cancer Surgery in a Patient Undergoing Tocilizumab Therapy for Rheumatoid Arthritis.",
"title_normalized": "severe pulmonary suppuration with infection induced systemic inflammatory response syndrome following tongue cancer surgery in a patient undergoing tocilizumab therapy for rheumatoid arthritis"
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"abstract": "BACKGROUND\nObesity is a major world-wide epidemic which has led to a surge of various weight loss-inducing medical or surgical treatments. Orlistat is a gastrointestinal lipase inhibitor used as an adjunct treatment of obesity and type 2 diabetes mellitus to induce clinically significant weight loss via fat malabsorption.\n\n\nMETHODS\nWe describe a case of a 76-year-old female with past medical history of chronic kidney disease (baseline serum creatinine was 1.5-2.5 mg/dL), hypertension, gout and psoriatic arthritis, who was admitted for evaluation of elevated creatinine, peaking at 5.40 mg/dL. She was started on orlistat 120 mg three times a day six weeks earlier. Initial serologic work-up remained unremarkable. Percutaneous kidney biopsy revealed massive calcium oxalate crystal depositions with acute tubular necrosis and interstitial inflammation. Serum oxalate level returned elevated at 45 mm/l (normal <27). Timed 24-hour urine collection documented increased oxalate excretion repeatedly (54-96 mg/24 hour). After five renal dialysis sessions in eighth days she gradually regained her former baseline kidney function with creatinine around 2 mg/dL. Given coexisting proton-pump inhibitor therapy, only per os calcium-citrate provided effective intestinal oxalate chelation to control hyperoxaluria.\n\n\nCONCLUSIONS\nOur case underscores the potential of medically induced fat malabsorption to lead to an excessive oxalate absorption and acute kidney injury (AKI), especially in subjects with pre-existing renal impairment. Further, it emphasizes the importance of kidney biopsy to facilitate early diagnosis and treatment.",
"affiliations": "Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.;Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.;Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, USA.;Department of Anesthesiology, University of Mississippi Medical Center, Jackson, Mississippi, USA ; Simulation and Interprofessional Education Center, University of Mississippi Medical Center, Jackson, Mississippi, USA.;Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.",
"authors": "Humayun|Youshay|Y|;Ball|Kenneth C|KC|;Lewin|Jack R|JR|;Lerant|Anna A|AA|;Fülöp|Tibor|T|",
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"fulltext": "\n==== Front\nJ NephropatholJ NephropatholJ NephropatholJ NephropatholJNPJournal of Nephropathology2251-83632251-8819Society of Diabetic Nephropathy Prevention 10.15171/jnp.2016.14Case ReportAcute oxalate nephropathy associated with orlistat Humayun Youshay \n1\n*Ball Kenneth C. \n1\nLewin Jack R. \n2\nLerant Anna A. \n3\n\n4\nFülöp Tibor \n1\n1Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA\n2Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, USA\n3Department of Anesthesiology, University of Mississippi Medical Center, Jackson, Mississippi, USA\n4Simulation and Interprofessional Education Center, University of Mississippi Medical Center, Jackson, Mississippi, USA\n* Corresponding author: Youshay Humayun, M.D, Department of Medicine, University of Mississippi Medical Center, Mississippi, USA. yhumayun@gmail.com4 2016 29 3 2016 5 2 79 83 22 2 2016 21 3 2016 © 2016 The Author(s)2016\nPublished by Society of Diabetic Nephropathy Prevention. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nhttp://nephropathol.com\nBackground: Obesity is a major world-wide epidemic which has led to a surge of various weight loss-inducing medical or surgical treatments. Orlistat is a gastrointestinal lipase inhibitor used as an adjunct treatment of obesity and type 2 diabetes mellitus to induce clinically significant weight loss via fat malabsorption.\n\n\n\nCase Presentation: We describe a case of a 76-year-old female with past medical history of chronic kidney disease (baseline serum creatinine was 1.5-2.5 mg/dL), hypertension, gout and psoriatic arthritis, who was admitted for evaluation of elevated creatinine, peaking at 5.40 mg/dL. She was started on orlistat 120 mg three times a day six weeks earlier. Initial serologic work-up remained unremarkable. Percutaneous kidney biopsy revealed massive calcium oxalate crystal depositions with acute tubular necrosis and interstitial inflammation. Serum oxalate level returned elevated at 45 mm/l (normal <27). Timed 24-hour urine collection documented increased oxalate excretion repeatedly (54-96 mg/24 hour). After five renal dialysis sessions in eighth days she gradually regained her former baseline kidney function with creatinine around 2 mg/dL. Given coexisting proton-pump inhibitor therapy, only per os calcium-citrate provided effective intestinal oxalate chelation to control hyperoxaluria.\n\n\n\nConclusions: Our case underscores the potential of medically induced fat malabsorption to lead to an excessive oxalate absorption and acute kidney injury (AKI), especially in subjects with pre-existing renal impairment. Further, it emphasizes the importance of kidney biopsy to facilitate early diagnosis and treatment.\n\n\nAcute kidney injuryDialysisOrlistatOxalate nephropathyProton-pump inhibitorWeight loss supplement \nPlease cite this paper as: Humayun Y, Ball KC, Lewin JR, Lerant AA, Fülöp T. Acute oxalate nephropathy associated with orlistat. J Nephropathol. 2016;5(2):79-83. DOI: 10.15171/jnp.2016.14\n==== Body\nImplication for health policy/practice/research/medical education:\n Acute oxalate nephropathy may be an under-recognized and important cause of renal failure in patients taking fat malabsorbtive weight loss supplements. Percutaneous kidney biopsy and timed 24-hour urine collections for oxalate excretion may expedite the diagnosis. The oxalate binding properties of per os calcium supplements are not sufficiently studied in advanced renal failure.\n\n1. Introduction\n\nAcute oxalate nephropathy (1-3) may be an under-reported, yet important complication of malabsorption-inducing weight loss supplements (4,5). We report on a patient taking orlistat, a lipase inhibitor, who presented with acute kidney injury (AKI) due to oxalate deposition.\n\n\n2. Case Presentation\n\nOur patient was a 76-year-old white female with a past medical history of chronic kidney disease (CKD), baseline creatinine 1.85 mg/dL (estimated glomerular filtration rate 27 ml/min/1.73 m2; creatinine range 1.5-2.5 mg/dL six months prior to admission), hypertension, gout and psoriatic arthritis, who was admitted to the hospital for evaluation of elevated creatinine (4.83 mg/dL). She had no previous history of major surgeries. She did have a remote history of therapeutic use of arsenic for psoriasis approximately four decades earlier. She also had past history of heavy nonsteroidal anti-inflammatory drugs use up till three years earlier, when she had an episode of AKI. Her family history was unremarkable. She had only a remote history of smoking. Six weeks earlier, she has been started on orlistat 120 mg three times a day for weight loss. The rest of her medications included vitamin-C supplementation (500 mg/day) calcium carbonate, sevelamer hydrochloride and sodium bicarbonate supplementation for CKD, pantoprazole and monthly infliximab infusions for psoriatic arthritis. Physical exam was non-contributory, with a weight of 71 kg, height 1.55 m and blood pressure of 144/61 mm Hg. Her body mass index calculated at 29.5 kg/m2. Urinalysis with microscopy was unremarkable, except for 5 WBCs/high power fields with no crystals or cast formation. Extensive serologic work-up (antinuclear antibody, anti-neutrophil cytoplasmic antibodies, hepatitis-B and C studies, serum protein electrophoresis with measurements of serum free light chains) remained unremarkable. Uric acid was only mildly elevated at 7.2 mg/dL. Parathyroid hormone level returned within normal limits. During the diagnostic work-up, however, renal ultrasound noted multiple non-obstructing stones. Despite appropriate medical therapy, including volume expansion and correction of serum bicarbonate, creatinine rose to 5.40 mg/dL. Due to the ongoing diagnostic uncertainty a percutaneous kidney biopsy was performed, revealing calcium oxalate crystals within tubular lumens with associated interstitial inflammation with associated features of acute tubular necrosis (Figures 1A-C). A subsequent, 24-hour urine collection confirmed increased oxalate excretion (69.5 mg/24 hour; normal for the laboratory: 9.7 - 40.5 mg/24 hour specimen). Heavy metal screen (arsenic, cadmium, lead, mercury) from blood and 24-hour urine collection was unremarkable. Renal replacement therapy with intermittent hemodialysis was initiated for 5 consecutive sessions in eight days, which she tolerated well. Initial serum oxalate was 45 mm/l (normal <27, reporting limit > 10; ARUP Laboratories, Salt Lake City, UT/National Medical Services, Willow Grove, PA); subsequent values returned undetectable after renal dialysis begun. Repeated 24-hour urine collection before discharge documented ongoing excessive oxalate excretion (75 mg/24 hour) (Table 1.).\n\n\nFigure 1 (A) Kidney biopsy tissue under low power, showing birefringent crystals under polarized light (×40, H&amp;E). (B) Kidney biopsy tissue, showing birefringent crystals under polarized light (×100, H&amp;E). (C) Kidney tissue biopsy under high power (×400, H&amp;E).\n\nTable 1 \nSerum and urine biochemistry and clinical therapy review\n\nDate\t\nAdmission (09/2013)\n\t\nDischarge (12 days after admission)\n\t\n09/2013 (7 days after discharge)\n\t\n10/2013\n\t\n11/2013\n\t\n02/2014\n\t\n09/2014\n\t\n05-06/2015\n\t\n07-08/2015\n\t\nCreatinine, mg/dL\t4.8\t2.36\t4.42\t3.02*\t2.9\t2.28\t2.04\t2.30\t2.32\t\nCalcium, mg/dL \t8.2\t9.4\t9.3\t9.2\t\n10.3#\n\t9\t9.5\t9.6\t9.6\t\nPhosphorus, mg/dL\t7.7\t2.2\t4.5\t4.5\t\n4.7#\n\t4.7\t4.1\t3.4\tn/a\t\n\nSerum HCO3-. mM/L\n\t18\t29\t22\t25\t26\t22\t26\t26\t29\t\nOxalate binder therapy\t\n\t\nCaCO3per os 1250 mg, x3/day\n\t\nCaCO3per os 1250 mg, x3/day\n\t\nCaCO3per os 1250 mg, x3/day\n\t\nCaCO3per os 1250 mg, x3/day\n\t\nCaCO3per os 1250 mg, x3/day\n\t\nCalcium citrate per os 1040 mg, x3/day\n\t\nCalcium citrate per os 1040 mg, x3/day\n\t\nCalcium citrate per os 2080 mg, x3/day##\n\t\nTimed urine studies/24 hours\t\nUrine creatinine, gm/24\t0.61**\t\n\t1.39\t0.94*\t1\t\n\t1.31\t1.39\t0.85\t\nUrine volume, L\t0.812\t\n\t5.2\t3.8\t3\t\n\t4.95\t4.85\t2\t\nUrine oxalate, mg/24 hour (normal: 9.7-40.5 mg)\t54.6\t\n\t75\t96\t54\t\n\t\n\t52\t31\t\nUrine citrate, mg/24 hour\t92\t\n\t\n\t95\t111\t\n\t\n\t160\t244\t\nUrine calcium, mg/24 hour (normal: 100-300 mg)\t8\t\n\t36\t\n\t45\t\n\t\n\t\n\t60\t\nProtein, mg \t211\t\n\t\n\t\n\t\n\t\n\t\n\t\n\tNon-measurable (creatinine < 4 mg/dL)\t\n\n*measured creatinine clearance 24.3 cc/min, **performed during admission (09/13-15/2013), #on daily calcitriol ,##also on NaHCO3 650 mg x3/day.\n\n\n\nTo convert creatinine from mg/dL to µmol/l, multiply it by 88.4.\n\n\n\nDuring follow-up, despite good medical compliance, she failed her per os calcium-carbonate therapy to achieve effective gastrointestinal oxalate chelation. Thereafter, being aware of the potential interaction between proton pump inhibitor (PPI) and reduced bioavailability of CaCO3 (6,7), she was changed to calcium citrate 1040 mg three times daily with meals for the purposes of gastrointestinal oxalate binding agent and to decrease urinary oxalate excretion (8). Twenty-two months after her initial hospital presentation she continues to do well and serum creatinine gradually decreased to the 2.01–2.32 mg/dL range (estimated glomerular filtration rate 20-24 ml/min/1.73 m2) ( Table 1). Urine oxalate excretion came under acceptable control with per os calcium-citrate dosed at 2080 mg, to be taken three times a day with meals ( Table 1).\n\n\n3. Discussion\n\nObesity is a major world-wide epidemic linked to a number of chronic health risks such as heart disease, diabetes and high blood pressure (9,10).It has been reported to affect about one-third of the American adult population (9) and a recognized risk factor for kidney disease (10). Orlistat is a gastrointestinal lipase inhibitor used as an adjunct treatment of obesity and type 2 diabetes mellitus, to induce clinically significant weight loss by causing fat malabsorption.Malabsorption of intestinal lipids would, however, lead to increased “saponification” of calcium in the gastrointestinal tract and decreases calcium availability to form insoluble calcium oxalate complexes. The decreased binding of oxalate will lead to excessive oxalate absorption and will also appear in the urine. Due to the low solubility of oxalate, increased concentrations of oxalate in the body can lead deposition of calcium oxalate in the kidney tissue resulting in nephrocalcinosis, nephrolithiasis, and ultimately progressive renal insufficiency1. Both anti-obesity (bariatric) surgery (11) and orlistat administration is known to increase urinary appearance of oxalate (12). Acute oxalate nephropathy (AON) is defined as renal insufficiency in the presence of calcium oxalate crystal deposition in the renal interstitium and renal tubular cells (4,5). Currently, there is very limited data reported regarding orlistat-induced AON in the United States. The first case reported in 2007 described a patient with AON with a temporal relationship to an increased dose of orlistat and the development of increased fat malabsorption (more frequent loose oily stools) (4). Additional case reports have been described since (5,13,14). More comprehensively, a Canadian study of 953 patients reviewed the incidence of AKI twelve months before and after starting orlistat (15).The incidence of AKI twelve months before was 5 cases and 18 cases after. Our case, similar to past reported experience (16), also documented co-existing acute tubular necrosis (ATN) along with the crystal deposition. ATN is a common finding on renal biopsies when an acute rise of creatinine is documented in sick inpatients (17,18). Oxalate depositions are very common in kidney biopsies immediately after renal transplant and dialysis patients are known to have markedly elevated serum and tissue oxalate content (19,20). In our case, early initiation of temporary renal replacement therapy may have contributed to the excellent functional recovery. Other potential cause of oxalate deposition in this case was the intake of vitamin-C, which not an uncommon in complementary and alternative medicine and is also known precursor of oxalate (21,22). However, she has been taking her vitamin-C supplements already for years at the same dose unchanged. Ethylene glycol exposure may result in similar presentation (23), but she had no history of antifreeze exposure and serum anion gap was not elevated on admission. Unlike some of past cases (13), our patient did have a persistently elevated urinary oxalate excretion, even after cessation of orlistat therapy. It is uncertain, whether some or all of the reported individuals in the reported literature to date had an underlying mild or partial enzyme deficiency of alanine: glyoxylate aminotransferase, further aggravated by orlistat administration. Further, it is unclear, whether calcium supplement, originally intended as phosphorus binders do also reduce oxalate absorption and serum oxalate levels to a meaningful degree in advanced (stage 4-5) CKD patients. AON may be an under-recognized and important cause of renal failure in patients taking fat malabsorption-inducing weight loss supplements through hyperoxaluria.\n\n\n4. Conclusions\n\nAcute oxalate nephropathy is an important entity to recognize in patients taking weight loss supplements. If recognized early, acute oxalate nephropathy can be prevented and even may be reversible with discontinuation of offending agent and dietary modifications, including to provide effective gastrointestinal oxalate binders. Further, our case underscores the importance of kidney biopsy to facilitate early diagnosis and treatment.\n\n\nAcknowledgements\n\nParts of this paper has been presented in a poster format in National Kidney Foundation 2014 Spring Clinical Meeting, April 22 - 26, 2014, Las Vegas, NV. Am J Kidney Dis. 2014 (Apr); 63(5):A17\n\n\nAuthors’ contribution\n\nYH; first author, initial draft, correspondence, nephrology care of the patient. KCB; case identification, clinical correlation, general internal medicine care of the patient, review of manuscript. JRL; pathology correlations, review of the manuscript. AAL; critical review, literature.TF; senior author, literature, critical review, coordinating of manuscript revisions, nephrology care of the patient.\n\n\nConflicts of interest\n\nThe authors declared no competing interests.\n\n\nFunding/Support\n\nNo special source of funding.\n==== Refs\nReferences\n1 Nasr SH D’Agati VD Said SM Stokes MB Largoza MV Radhakrishnan J Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure Clin J Am Soc Nephrol 2008 3 6 1676 83 10.2215/cjn.02940608 18701613 \n2 Mascio HM Joya CA Plasse RA Baker TP Flessner MF Nee R An unusual cause of acute kidney injury due to oxalate nephropathy in systemic scleroderma Clin Nephrol 2015 84 8 111 5 10.5414/CN108406 25500295 \n3 Rankin A Walsh S Summers S Owen M Mansell M Acute oxalate nephropathy causing late renal transplant dysfunction due to enteric hyperoxaluria Am J Transplant 2008 8 8 1755 8 10.1111/j.1600-6143.2008.02288.x 18557738 \n4 Singh A Sarkar SR Gaber LW Perazella MA Acute oxalate nephropathy associated with orlistat, a gastrointestinal lipase inhibitor Am J Kidney Dis 2007 49 1 153 7 17185156 \n5 Karamadoukis L Shivashankar G Ludeman L Williams A An unusual complication of treatment with orlistat Clin Nephrol 2009 71 4 430 2 10.5414/CNP71430 19356376 \n6 O’Connell MB Madden DM Murray AM Heaney RP Kerzner LJ Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial Am J Med 2005 118 7 778 81 10.1016/j.amjmed.2005.02.007 15989913 \n7 Targownik LE Lix LM Metge CJ Prior HJ Leung S Leslie WD Use of proton pump inhibitors and risk of osteoporosis-related fractures Can Med Assoc J 2008 179 4 319 26 10.1503/cmaj.071330 18695179 \n8 Harvey JA Zobitz MM Pak CY Calcium citrate: reduced propensity for the crystallization of calcium oxalate in urine resulting from induced hypercalciuria of calcium supplementation J Clin Endocrin Metab 1985 61 6 1223 5 10.1503/cmaj.071330 \n9 Ogden CL Carroll MD Kit BK Flegal KM Prevalence of childhood and adult obesity in the United States, 2011-2012 JAMA 2014 311 8 806 14 10.1503/cmaj.071330 24570244 \n10 Chandra A Biersmith M Tolouian R Obesity and kidney protection J Nephropathol 2014 3 3 91 25093156 \n11 Sinha MK1 Collazo-Clavell ML Rule A Milliner DS Nelson W Sarr MG Hyperoxaluric nephrolithiasis is a complication of Roux-en-Y gastric bypass surgery Kidney Int 2007 72 1 100 7 17377509 \n12 Sarica K Akarsu E Erturhan S Yagci F Aktaran S Altay B Evaluation of urinary oxalate levels in patients receiving gastrointestinal lipase inhibitor Obesity 2008 16 7 1579 84 10.1038/oby.2008.244 18451780 \n13 Chaudhari D Crisostomo C Ganote C Youngberg G Acute oxalate nephropathy associated with orlistat: a case report with a review of the literature Case Reports Nephrol 2013 2013 124604 10.1155/2013/124604 \n14 Coutinho AK Glancey GR Orlistat, an under-recognised cause of progressive renal impairment Nephrol Dial Transplant 2013 28 suppl 4 iv172 4 24049105 \n15 Weir MA Beyea MM Gomes T Juurlink DN Mamdani M Blake PG Orlistat and acute kidney injury: an analysis of 953 patients Arch Intern Med 2011 171 7 703 4 10.1001/archinternmed.2011.103 21482850 \n16 Karamadoukis L Ludeman L Williams AJ Is there a link between calcium oxalate crystalluria, orlistat and acute tubular necrosis? Nephrol Dial Transplant 2008 23 5 1778 79 10.1093/ndt/gfm945 18272781 \n17 Tavares MB \nChagas de Almeida Mda\n \nC\n Martins RT de Sousa AC Martinelli R dos-Santos WL Acute tubular necrosis and renal failure in patients with glomerular disease Ren Fail 2012 34 10 1252 7 10.3109/0886022X.2012.723582 23002699 \n18 Fülöp T Alemu B Dossabhoy NR Safety and Efficacy of Percutaneous Renal Biopsy by Physicians-in-Training in an Academic Teaching Setting South Med J 2014 107 8 520 5 10.14423/SMJ.0000000000000148 25084192 \n19 Hoffman GS Schumacher HR Paul H Cherian V Reed R Ramsay AG Calcium oxalate microcrystalline-associated arthritis in end-stage renal disease Ann Int Med 1982 97 1 36 42 7092004 \n20 Costello JF Sadovnic MJ Cottington EM Plasma oxalate levels rise in hemodialysis patients despite increased oxalate removal J Am Soc Nephrol 1991 1 12 1289 98 1912391 \n21 Baxmann AC Mendonça CD Heilberg IP Effect of vitamin C supplements on urinary oxalate and pH in calcium stone-forming patients Kidney Int 2003 63 3 1066 71 12631089 \n22 Levine M Conry-Cantilena C Wang Y Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance Proc Natl Acad Sci U S A 1996 93 8 3704 9 10.1073/pnas.93.8.3704 8623000 \n23 Alhamad T Blandon J Meza AT Bilbao JE Hernandez GT Acute kidney injury with oxalate deposition in a patient with a high anion gap metabolic acidosis and a normal osmolal gap J Nephropathol 2013 2 2 139 10.5812/nephropathol.10657 24475441\n\n",
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"abstract": "To date, no medication is proven to be effective in treating core symptoms of autism spectrum disorder (ASD). Psychotropic medications are widely used to target emotional and behavioural symptoms in ASD. This article reviewed evidence for pharmacotherapy, novel therapeutic agents, and Complementary and Alternative Medicine (CAM) in children and adolescents with ASD. Currently, only risperidone and aripiprazole have been approved by the US Food and Drug Administration (FDA) for treatment of irritability associated with ASD in children and adolescents. However, associated metabolic side-effects are concerning. Evidence supports use of methylphenidate and atomoxetine for attention deficit hyperactivity disorder (ADHD) symptoms and clonidine and guanfacine ER appear to be helpful. SSRIs are poorly tolerated and lack evidence in reducing restricted repetitive behaviours (RRB), anxiety, and depression. Buspirone shows promise in the treatment of RRB. The evidence is inconsistent for the effectiveness of anti-epileptic medications. Recent studies of glutamatergic, Gamma-aminobutyric acid (GABA)ergic, and cholinergic agents and oxytocin show inconsistent results. Despite wide use of CAM agents, the evidence is inconclusive. Melatonin can be helpful in reducing sleep problems. Overall, the evidence is limited for pharmacotherapy in children with ASD, and side-effects with long-term use can be burdensome.",
"affiliations": "a Department of Psychiatry , Kennedy Krieger Institute , Baltimore , MD , USA.;a Department of Psychiatry , Kennedy Krieger Institute , Baltimore , MD , USA.;a Department of Psychiatry , Kennedy Krieger Institute , Baltimore , MD , USA.;a Department of Psychiatry , Kennedy Krieger Institute , Baltimore , MD , USA.",
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"abstract": "PANIC DISORDER IS THE MOST COMMON TYPE OF ANXIETY DISORDER, AND ITS MOST COMMON EXPRESSION IS PANIC ATTACKS CHARACTERIZED WITH SUDDEN ATTACKS OF ANXIETY WITH NUMEROUS SYMPTOMS, INCLUDING PALPITATIONS, TACHYCARDIA, TACHYPNEA, NAUSEA, AND VERTIGO: ie, cardiovascular, gastroenterologic, respiratory, and neuro-otologic symptoms. In clinical practice, panic disorder manifests with isolated gastroenteric or cardiovascular symptoms, requiring additional clinical visits after psychiatric intervention. The first-line treatment for anxiety disorders, and in particular for panic disorder, is the selective serotonin reuptake inhibitors. However, these drugs can have adverse effects, including sexual dysfunction, increased bodyweight, and abnormal bleeding, that may be problematic for some patients. Here we report the case of a 29-year-old Caucasian woman affected by panic disorder with agoraphobia who was referred to our clinic for recurrent gastroenteric panic symptoms. The patient reported improvement in her anxiety symptoms and panic attacks while on a selective serotonin reuptake inhibitor, but not in her gastric somatic problems, so the decision was taken to start her on duloxetine, a serotonin-norepinephrine reuptake inhibitor. After 6 months of treatment, the patient achieved complete remission of her gastric and panic-related symptoms, and was able to stop triple gastric therapy. Other authors have hypothesized and confirmed that duloxetine has greater initial noradrenergic effects than venlafaxine and is effective in patients with panic disorder. This case report underscores the possibility of tailoring therapeutic strategies for the gastroenteric expression of panic disorder.",
"affiliations": "Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy.",
"authors": "Preve|Matteo|M|;Nisita|Cristiana|C|;Bellini|Massimo|M|;Dell'osso|Liliana|L|",
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"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S35922ndt-9-1811Case ReportDuloxetine in panic disorder with somatic gastric pain Preve Matteo 1Nisita Cristiana 1Bellini Massimo 2Dell’Osso Liliana 11 Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy2 Department of Gastroenterology, Gastrointestinal Unit, University of Pisa, Pisa, ItalyCorrespondence: Matteo Preve, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, via Roma 67, 56100 Pisa, Italy, Fax +39 0509 93267, Email m_preve@yahoo.com2013 2013 21 11 2013 9 1811 1813 © 2013 Preve et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2013The 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.Panic disorder is the most common type of anxiety disorder, and its most common expression is panic attacks characterized with sudden attacks of anxiety with numerous symptoms, including palpitations, tachycardia, tachypnea, nausea, and vertigo: ie, cardiovascular, gastroenterologic, respiratory, and neuro-otologic symptoms. In clinical practice, panic disorder manifests with isolated gastroenteric or cardiovascular symptoms, requiring additional clinical visits after psychiatric intervention. The first-line treatment for anxiety disorders, and in particular for panic disorder, is the selective serotonin reuptake inhibitors. However, these drugs can have adverse effects, including sexual dysfunction, increased bodyweight, and abnormal bleeding, that may be problematic for some patients. Here we report the case of a 29-year-old Caucasian woman affected by panic disorder with agoraphobia who was referred to our clinic for recurrent gastroenteric panic symptoms. The patient reported improvement in her anxiety symptoms and panic attacks while on a selective serotonin reuptake inhibitor, but not in her gastric somatic problems, so the decision was taken to start her on duloxetine, a serotonin-norepinephrine reuptake inhibitor. After 6 months of treatment, the patient achieved complete remission of her gastric and panic-related symptoms, and was able to stop triple gastric therapy. Other authors have hypothesized and confirmed that duloxetine has greater initial noradrenergic effects than venlafaxine and is effective in patients with panic disorder. This case report underscores the possibility of tailoring therapeutic strategies for the gastroenteric expression of panic disorder.\n\nKeywords\nanxiety disorderpanic attackspalpitationstachycardiatachypneanauseavertigo\n==== Body\nIntroduction\nAnxiety disorders are the most common type of psychiatric disorder, with a mean incidence of 18.1% and a lifetime prevalence of 28.8%.1 Panic attacks are the most common type of anxiety disorder, with lifetime prevalence estimates of 22.7% for isolated (ie, without panic disorder) panic attacks without agoraphobia, 0.8% for isolated panic attacks with agoraphobia, 3.7% for panic disorder without agoraphobia, and 1.1% for panic disorder with agoraphobia. All four subgroups have significant comorbidity with other lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) disorders, with the highest rates of comorbidity in panic disorder with agoraphobia and the lowest in isolated panic attacks.2 Panic attacks are characterized by sudden attacks of anxiety with numerous somatic symptoms, including palpitations, tachycardia, tachypnea, nausea, and vertigo (ie, cardiovascular, gastroenterologic, respiratory, and neuro-otologic symptoms). In clinical practice, panic disorder may also be observed with isolated gastroenteric or cardiovascular symptoms requiring further clinical consultations following psychiatric intervention. Selective serotonin reuptake inhibitors are the preferred treatment for anxiety disorders, and for panic disorder in particular. However, these drugs can have adverse effects, including sexual dysfunction,3 increased bodyweight,4 and abnormal bleeding,5 so their use may be problematic in some patients.\n\nCase report\nGV, a 29-year-old Caucasian woman suffering from panic disorder with agoraphobia, was referred to our clinic for recurrent gastroenteric panic symptoms. She had a negative family history for mental illness and had no past history of substance use/abuse. The patient’s psychiatric history dated back to 8 years previously when, at the age of 21 years, she presented with somatic panic symptoms, ie, tachycardia, chest tightness, heartburn, and panic attacks. On her first outpatient visit to the gastroenterology clinic at the age of 26 years, she presented with recurrent heartburn, but tested negative for hiatal hernia, Helicobacter pylori, and esophagogastric reflux. At that time, she was also experiencing isolated panic attacks characterized by palpitations (tachycardia), chest tightness, somatopsychic depersonalization, fear of dying, anticipatory anxiety, harm avoidance, and a fear of being alone. She was not given any psychopharmacologic treatment but was treated with triple gastric therapy comprising a proton pump inhibitor (esomeprazole), antacids (alginic acid and sodium bicarbonate), and an antidopaminergic gastrointestinal prokinetic agent (clebopride).\n\nAt the first outpatient visit, the patient presented primarily with somatic symptoms, including heartburn, chest tightness and pain, somatopsychic depersonalization, tachycardia, and fear of dying and anxiety in the context of asthenia and anergia. We assessed her symptomatology using the Structured Clinical Interview for Panic-Agoraphobic Spectrum lifetime version,6 and the score was 85 at the first visit. We initially prescribed citalopram 20 mg/day, but the patient reported sexual dysfunction (reduction/loss of libido and difficulty achieving orgasm), cognitive impairment, and fatigue. The patient reported improvement in her anxiety symptoms and panic attacks on a selective serotonin reuptake inhibitor, but not in her troublesome gastric somatic symptoms. We therefore decided to gradually reduce the dose of citalopram and introduced escitalopram 7 mg/day, but the patient continued to report loss of libido with no change in her gastric symptoms. We then prescribed duloxetine 30 mg/day, which was subsequently increased to 60 mg/day, with slow withdrawal of escitalopram. After 6 months of treatment, the patient showed complete remission of her gastric and panic-related symptoms, and all three gastric treatments were able to be discontinued.\n\nDiscussion\nThis case report underscores the possibility of tailoring therapeutic strategies for the gastroenteric expression of panic disorder. Selective serotonin reuptake inhibitors remain the first-line treatment for panic disorder, and paroxetine is the gold standard among these psychopharmacologic medications.7,8 However, these drugs can have adverse effects, including sexual dysfunction, increased bodyweight, and abnormal bleeding, leading to problems with continuation of therapy. The opportunity to have another therapeutic option with fewer adverse effects is important and helpful. Other researchers, such as Simon et al, have hypothesized and confirmed that duloxetine, a serotonin-norepinephrine reuptake inhibitor with greater initial noradrenergic effects than venlafaxine, has broad efficacy in individuals with panic disorder.9,10 Our interest in duloxetine lies in the possibility of treatment for panic disorder with the added benefit of resolution of gastric symptoms. As other researchers have pointed out, duloxetine acts on the neuropathic pain caused by fibromyalgia, neuropathic diabetes,11–13 and irritable bowel syndrome,14 and has fewer sexual and cognitive adverse effects. Moreover, descending serotonin and norepineph-rine pathways have been suggested to be modulators of pain perception,15 and duloxetine has been shown to have an analgesic effect on painful physical symptoms that are partially independent of the improvement in major depressive disorder.15,16\n\nOur patient presented with panic disorder and a combination of gastroenteric symptoms in the context of asthe-nia, anergia, and severe adverse effects due to treatment with a selective serotonin reuptake inhibitor, suggesting the possibility that a serotonin-norepinephrine reuptake inhibitor such as duloxetine may be of some value in patients presenting with such symptoms in a psychopatho-logic context. Obviously, further research is warranted to replicate our clinical observations and, in general terms, controlled studies are needed to confirm the efficacy of this treatment.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1 Kessler RC Chiu WT Demler O Merikangas KR Walters EE Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Arch Gen Psychiatry 2005 62 6 617 627 15939839 \n2 Kessler RC Chiu WT Jin R Ruscio AM Shear K Walters EE The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication Arch Gen Psychiatry 2006 63 4 415 424 16585471 \n3 Serretti A Chiesa A Sexual side effects of pharmacological treatment of psychiatric diseases Clin Pharmacol Ther 2011 89 1 142 147 20668442 \n4 Serretti A Mandelli L Antidepressant and body weight: a comprehensive review and meta-analysis J Clin Psychiatry 2010 71 10 1259 1272 21062615 \n5 Andrade C Sandarsh S Chethan KB Nagesh KS Serotonin reuptake inhibitor antidepressant and abnormal bleeding: a review for clinicians and a reconsideration of mechanism J Clin Psychiatry 2010 71 12 1565 1575 21190637 \n6 Shear MK Frank E Rucci P Panic-agoraphobic spectrum: reliability and validity of assessment instruments J Psychiatr Res 2001 35 1 59 66 11287057 \n7 Bakker A van Balkom AJ Spinhoven P SSRIs vs TCAs in the treatment of panic disorder: a meta-analysis Acta Psychiatr Scand 2002 106 3 163 167 12197851 \n8 Sheehan DV Harnett-Sheehan K The role of SSRIs in panic disorder J Clin Psychiatry 1996 57 Suppl 10 51 58 8917132 \n9 Serretti A Chiesa A Calati R Perna G Bellodi L De Ronchi D Novel antidepressants and panic disorder: evidence beyond current guidelines Neuropsychobiology 2011 63 1 1 7 20962541 \n10 Simon NM Kaufman RE Hoge EA Open-label support for duloxetine for the treatment of panic disorder CNS Neurosci Ther 2009 15 1 19 23 19228176 \n11 Chouinard G The search for new off-label indications for antidepressant, antianxiety, antipsychotic and anticonvulsant drugs J Psychiatry Neurosci 2006 31 3 168 176 16699602 \n12 Arnold LM Wang F Ahl J Gaynor PJ Wohlreich MM Improvement in multiple dimensions of fatigue in patients with fibromyalgia treated with duloxetine: secondary analysis of a randomized, placebo-controlled trial Arthritis Res Ther 2011 13 3 R86 21668963 \n13 Wright A Luedtke KE Vandenberg C Duloxetine in the treatment of chronic pain due to fibromyalgia and diabetic neuropathy J Pain Res 2010 4 1 10 21386950 \n14 Brennan BP Fogarty KV Roberts JL Reynolds KA Pope HG Jr Hudson JI Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study Hum Psychopharmacol 2009 24 5 423 428 19548294 \n15 Perahia DG Pritchett YL Desaiah D Raskin J Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol 2006 21 6 311 317 17012978 \n16 Ball SG Desaiah D Spann ME Efficacy of duloxetine on painful physical symptoms in major depressive disorder for patients with clinically significant painful physical symptoms at baseline: a meta-analysis of 11 double-blind, placebo-controlled clinical trials Prim Care Companion CNS Disord 2011 13 6\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "9()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "anxiety disorder; nausea; palpitations; panic attacks; tachycardia; tachypnea; vertigo",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
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"pages": "1811-3",
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"pmid": "24294001",
"pubdate": "2013",
"publication_types": "D002363:Case Reports",
"references": "8917132;16699602;12197851;19228176;21386950;11287057;21190637;20962541;19548294;20668442;15939839;22454807;16585471;17012978;21668963;21062615",
"title": "Duloxetine in panic disorder with somatic gastric pain.",
"title_normalized": "duloxetine in panic disorder with somatic gastric pain"
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"abstract": "The introduction of immunotherapy using an anti-GD2 antibody (dinutuximab, ch14.18) has significantly improved survival rates for high-risk neuroblastoma patients. However, this improvement in survival is accompanied by a substantial immunotherapy-related toxicity burden. The primary objective of this study was to describe treatment-related toxicities during immunotherapy with dinutuximab, IL-2, GM-CSF, and isotretinoin. A retrospective, single center analysis of immunotherapy-related toxicities was performed in twenty-six consecutive high-risk neuroblastoma patients who received immunotherapy as maintenance therapy in the Princess Máxima Center (Utrecht, Netherlands). Toxicities were recorded and graded according to the CTCAE. Particular attention was drawn to pain and fever management and toxicities leading to dose modifications of dinutuximab and IL-2. Twenty-three patients (88%) completed all six courses of immunotherapy. Disease progression, isotretinoin-associated liver toxicity, and catheter-related infection in combination with peripheral neuropathy were reasons for immunotherapy discontinuation. The most common grade ≥3 toxicities for courses 1-5, respectively, were pain, catheter-related infections, and fever. In total, 310 grade ≥3 toxicities were recorded in 124 courses. Thirty-three grade 4 toxicities in 19/26 patients and no grade 5 toxicities (death) were seen. Fifty-nine percent of grade ≥3 toxicities were recorded in the two courses with IL-2. Catheter-related bloodstream infections were identified in 81% of patients. Four of these episodes led to intensive care admission followed by full recovery (grade 4).",
"affiliations": "Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Department of Pediatric Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.",
"authors": "Blom|Thomas|T|;Lurvink|Roosmarijn|R|;Aleven|Leonie|L|;Mensink|Maarten|M|;Wolfs|Tom|T|;Dierselhuis|Miranda|M|;van Eijkelenburg|Natasha|N|;Kraal|Kathelijne|K|;van Noesel|Max|M|;van Grotel|Martine|M|;Tytgat|Godelieve|G|",
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"doi": "10.3389/fonc.2020.601076",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.601076\nOncology\nOriginal Research\nTreatment-Related Toxicities During Anti-GD2 Immunotherapy in High-Risk Neuroblastoma Patients\nBlom Thomas 1*† Lurvink Roosmarijn 1† Aleven Leonie 1 Mensink Maarten 1 Wolfs Tom 2 Dierselhuis Miranda 1 van Eijkelenburg Natasha 1 Kraal Kathelijne 1 van Noesel Max 1 van Grotel Martine 1 Tytgat Godelieve 1 1Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands\n2Department of Pediatric Infectious Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands\nEdited by: Rod Skinner, Newcastle University, United Kingdom\n\nReviewed by: Joseph Louis Lasky, Cure 4 The Kids, United States; Juliet Gray, Southampton General Hospital, United Kingdom\n\n*Correspondence: Thomas Blom, a.j.blom-3@prinsesmaximacentrum.nlThis article was submitted to Pediatric Oncology, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work\n\n\n17 2 2021 \n2020 \n10 60107631 8 2020 30 12 2020 Copyright © 2021 Blom, Lurvink, Aleven, Mensink, Wolfs, Dierselhuis, van Eijkelenburg, Kraal, van Noesel, van Grotel and Tytgat2021Blom, Lurvink, Aleven, Mensink, Wolfs, Dierselhuis, van Eijkelenburg, Kraal, van Noesel, van Grotel and TytgatThis 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.The introduction of immunotherapy using an anti-GD2 antibody (dinutuximab, ch14.18) has significantly improved survival rates for high-risk neuroblastoma patients. However, this improvement in survival is accompanied by a substantial immunotherapy-related toxicity burden. The primary objective of this study was to describe treatment-related toxicities during immunotherapy with dinutuximab, IL-2, GM-CSF, and isotretinoin. A retrospective, single center analysis of immunotherapy-related toxicities was performed in twenty-six consecutive high-risk neuroblastoma patients who received immunotherapy as maintenance therapy in the Princess Máxima Center (Utrecht, Netherlands). Toxicities were recorded and graded according to the CTCAE. Particular attention was drawn to pain and fever management and toxicities leading to dose modifications of dinutuximab and IL-2. Twenty-three patients (88%) completed all six courses of immunotherapy. Disease progression, isotretinoin-associated liver toxicity, and catheter-related infection in combination with peripheral neuropathy were reasons for immunotherapy discontinuation. The most common grade ≥3 toxicities for courses 1–5, respectively, were pain, catheter-related infections, and fever. In total, 310 grade ≥3 toxicities were recorded in 124 courses. Thirty-three grade 4 toxicities in 19/26 patients and no grade 5 toxicities (death) were seen. Fifty-nine percent of grade ≥3 toxicities were recorded in the two courses with IL-2. Catheter-related bloodstream infections were identified in 81% of patients. Four of these episodes led to intensive care admission followed by full recovery (grade 4).\n\nneuroblastomaimmunotherapydinutuximabch14.18anti-GD2 antibodysafetytoxicity\n==== Body\nHighlights\nImmunotherapy-related toxicities after induction and consolidation according to the Dutch Childhood Oncology Group (DCOG) NBL2009 treatment protocol are considerable but manageable. More toxicity is observed in the immunotherapy courses containing IL-2.\n\nIntroduction\nDespite intensive treatment regimens, patients with high-risk neuroblastoma experienced poor survival outcomes (1). The introduction of immunotherapy using a chimeric anti-GD2 monoclonal antibody (dinutuximab, ch14.18) combined with immunostimulatory cytokines [interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF)] has significantly improved survival rates for these patients (2). The disialoganglioside GD2, has relative tumor-selective expression, with only weak expression in normal human tissues like neurons, melanocytes, and peripheral nerve pain fibers (3), making it an attractive target for neuroblastoma-specific immunotherapy. However, as early as in the first clinical reports, the substantial toxicity burden caused by the ch14.18 antibody was recognized (4, 5), with patients suffering from intense, morphine-responsive pain, intermittent fever, allergic reactions (exanthema, urticaria), and changes in blood pressure. To increase antibody-dependent cellular cytotoxicity (ADCC) and the subsequent antitumor effect, the addition of immunostimulatory cytokines (IL-2, GM-CSF) was studied with encouraging results (6, 7). Here, the clinical benefit has to be weighed against the potential toxicity of these cytokines. Treatment-related toxic effects have resulted in treatment discontinuation and even deaths (2, 8, 9).\n\nFrom 2016 onwards, high-risk neuroblastoma patients receive immunotherapy as maintenance therapy in the Princess Máxima Center for Pediatric Oncology (Utrecht, The Netherlands). The aim of this study was to describe treatment-related toxicities from immunotherapy with dinutuximab, cytokines IL-2 and GM-CSF, and isotretinoin in a cohort of 26 high-risk neuroblastoma patients treated with induction and consolidation therapy according to the DCOG (Dutch Childhood Oncology Group) NBL2009 high-risk group protocol (10). Specifically, we studied pain and fever management and treatment-related toxicities leading to dose modifications of dinutuximab and IL-2.\n\nAdditionally, we performed a non-systematic literature review on toxicity associated with ch14.18 antibody-based immunotherapy in patients with neuroblastoma.\n\nMaterials and Methods\nPatient Population\nA retrospective, single center analysis of immunotherapy-related toxicities was performed in twenty-six consecutive high-risk neuroblastoma patients who received dinutuximab-based immunotherapy as maintenance therapy between August 2016 and October 2019 in the Princess Máxima Center for Pediatric Oncology (Utrecht, The Netherlands). The high-risk patient cohort consisted of International Neuroblastoma Risk Group [INRG (11)] stage M and ≥ 12 months at diagnosis, or INRG stage L2 with MYCN amplification. All patients had completed induction and consolidation therapy according to the DCOG NBL2009 treatment protocol (10), which is based on the standard arm of the German GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie) NB2004 high-risk protocol (12). Patients who achieved at least partial response were eligible to receive immunotherapy. Patients with relapse were not included. Other requirements were Lansky Performance Scale score of ≥60%, adequate organ functions, and full recovery from any toxicities from previous treatments.\n\nImmunotherapy Protocol\nAn overview of the six immunotherapy courses is provided in Supplementary Figure 1. The first five patients received dinutuximab (ch14.18/SP2/0; United Therapeutics Corporation, USA) under a named-patient program at a dose of 17.5 mg/m2 per day as a 10 h (20 h maximum) intravenous infusion on 4 consecutive days. After the approval of dinutuximab beta by the European Medicines Agency (EMA) in May 2017, patients received dinutuximab beta (ch14.18/CHO; EUSA Pharma, Netherlands) at a dose of 20 mg/m² per day as an 8 h (16 h maximum) infusion on 5 consecutive days. During courses 1, 3, and 5, GM-CSF was administered for 14 consecutive days. During courses 2 and 4, IL-2 was administered by continuous intravenous infusion at a dose of 3.0 x 106 and 4.5 x 106 IU/m2/day in weeks 1 and 2, respectively. All patients received isotretinoin at a dose of 160 mg/m² per day for 14 days per course. Course 6 solely consisted of isotretinoin.\n\nPain Management and Prophylactic Medication\nPain management consisted of oral gabapentin (15 mg/kg/day in three doses) starting 7 days prior to start of dinutuximab infusion, and intravenous acetaminophen (60 mg/kg/day in four doses, with a maximum of 4 g/day) and morphine (10 µg/kg/h) starting 1 and 2 h before the start of dinutuximab infusion, respectively. Gabapentin and morphine were continued during dinutuximab infusion. Individual patients were closely monitored by the pain anesthesiologist. In case of inadequate pain control, a personalized combination of intermittent IV morphine boluses, esketamine (0.1–0.4 mg/kg/h), clonidine (1–6 µg/kg/day), and amitriptyline (0.5–2 mg/kg/day) was used. When morphine was not tolerated due to side effects or renal failure, piritramide was used instead.\n\nProphylactic treatment for immune-related symptoms with antihistamines consisted of the combination of clemastine, cetirizine, and ranitidine.\n\nToxicity\nVital parameters, laboratory results including blood culture results, and other toxicities were prospectively recorded in patients’ medical and nursing files and retrospectively graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 3.0). In case toxicities were not listed in CTCAE version 3.0 (e.g. Cytokine release syndrome), CTCAE version 5.0 was used. Data from grade 1–2 toxicities are not reported, with the exception of fever and grade 1–2 toxicities that resulted in dose modifications of dinutuximab and/or IL-2.\n\nDuring dinutuximab infusion, pain scores were obtained at least every 4 h. Intensity of pain was assessed using the COMFORT Behavior Scale for patients <3 years of age (13), the Wong–Baker Faces Pain Rating Scale (WB-FPRS) for patients between the age of 3 and 8 (14), and the visual analogue scale (VAS) for children ≥8 years of age (15). COMFORT scores >24 and WB-FPRS and VAS scores ≥7 were considered as severe pain (grade 3). In the case of disabling pain, pain was graded as grade 4.\n\nThe maximum body temperature per day was used to assess fever instances. Acetaminophen and diclofenac were, respectively, used as first- and second-line pharmacologic antipyretic therapy. We defined catheter-related infection (CRI) as blood culture-proven bacteremia in association with (1) clinical evidence of infection (fever, tachycardia, hypotension, etc.), (2) no probable other site of infection or cause for bacteremia, and (3) treated with systemic antibiotic therapy. Pediatric intensive care unit (PICU) admission due to a CRI was graded as grade 4. Empirical antibiotic therapy started after fever and discontinued after normalization of symptoms in combination with negative or contaminated blood cultures were not regarded as infections. For this study, blood culture results were reviewed by a pediatric infectious disease physician and categorized based on identification and pathogenicity of isolated bacteria.\n\nDose Modifications of Dinutuximab and Interleukin-2\nWe collected all dose modifications of dinutuximab and IL-2 from medical and nursing files. We differentiated between a 50% decrease in the infusion rate, temporary interruption and complete cessation of dinutuximab/IL-2 infusion. For every dose reduction, the causative toxicity was recorded. To investigate the effect of dinutuximab dose modifications, we calculated the total administered dose per course per patient as percentage of intended dose.\n\nStatistical Analysis\nMcNemar’s test for paired data was used to compare the incidence of toxicities between courses containing GM-CSF (courses 1, 3, and 5) and IL-2 (courses 2 and 4). An independent sample t-test was used for antibody type, sex, vital status, myeloablative conditioning regimen, and number of grade ≥3 toxicities. Pearson correlation for association was used for age and number of grade ≥3 toxicities. P values <.05 were considered statistically significant. All statistical analysis was performed using SPSS v.25.0 (IBM, USA).\n\nLiterature Review\nA literature search was conducted in PubMed/MEDLINE (January 1980–March 2020) to identify reports addressing toxicity of ch14.18 antibody-based immunotherapy in children treated for neuroblastoma. The search strategy and selection criteria can be found in Supplementary Table 1. To identify rare complications, case reports were included in this non-systematic review.\n\nResults\nLiterature Review\nTo evaluate the toxicity associated with ch14.18 antibody-based immunotherapy in patients with neuroblastoma, we performed a review of the existing literature and identified six studies reporting grade ≥3 toxicities (2, 8, 9, 16–18). The most prevalent reported toxicities in these studies are listed in Table 1. Cross-study comparisons should be made with caution, since differences exists between these studies in antibody origin/manufacturer, concomitant cytokines administered, infusion times, and toxicity criteria used.\n\nTable 1 Literature overview of reported non-hematological immunotherapy-related grade ≥3 toxicities.\n\nStudy - Year\tYu - 2010\tMarachelian – 2016\tMody – 2017\tLadenstein - 2018\tMueller - 2018\tOzkaynak - 2018\t\nPatients\tn = 137\tn = 28\tn = 16a\tn = 406\tn = 53\tn = 105\t\nImmunotherapy composition\t\t\t\t\t\t\n Antibody\tCh14.18/NCI\tCh14.18/UTCbCh14.18/NCIb\tDinutuximab\tDinutuximab beta\tDinutuximab betac\tDinutuximab\t\n Cytokines\tIL-2 + GM-CSF\tIL-2 + GM-CSF\tGM-CSF\tIL-2 (randomized)d\tIL-2\tIL-2 + GM-CSF\t\n Other\tIsotretinoin\tIsotretinoin\tTemozolomide/ Irinotecan\tIsotretinoin\tIsotretinoin\tIsotretinoin\t\nToxicity (%)\t\t\t\t\t\t\t\n Pain\t52\t33 vs.29\t44\t16 vs.26d\t38\t22 – 41e\t\n Fever\t39\t48 vs.44\t25 (+ infection)\t14 vs.40d\t9\t5 – 59e\t\n Infection\t39\tn.r.\tn.r.\t25 vs.33d\tn.r.\tn.r.\t\n CRI\t13\tn.r.\tn.r.\tn.r.\tn.r.\tn.r.\t\n Hypotension\t18\t7 vs.11\t13\t4 vs.17d\t2\t4 – 17e\t\n Hypersensitivity\t25\tn.r.\tn.r.\t10 vs.20d\t2\t2 – 10 e (AR)\t\n Urticaria\t13\tn.r.\tn.r.\t5 vs.10\t8\tn.r.\t\n CLS\t23\tn.r.\t0\t4 vs.15d\t13\t0 – 4e\t\n Hypokalemia\t35\t26 vs.26\t38\tn.r.\tn.r.\tn.r.\t\n Hyponatremia\t23\t19 vs.19\t19\tn.r.\tn.r.\tn.r.\t\n Increased ALT\t23\t15 vs.4\t6\t17 vs.23 d (+AST)\tn.r.\tn.r.\t\n Hypoxia\t13\t4 vs.11\t25\tn.r.\t6\tn.r.\t\n Neurotoxicity\t\t\t\t\t\t\t\n Central\t4\tn.r.\tn.r.\t1.6 vs.5,8d,f\tn.r.\tn.r.\t\n Peripheral\tn.r.\tn.r.\t6\t0.5 vs.3.1d,g\t2\tn.r.\t\nGrade 5 toxicity (%)\t1 (n = 1)\t0\t0\t1 (n = 2)\t0\t1 (n = 1)\t\nAntibody dose reductions (%)\tn.r.\tn.r.\t38 (6/16)\tn.r.\tn.r.\t43 (45/104)\t\nDiscontinuation IT due to toxicity (%)\t15 (16/107)\t7 (2/28)\t13 (2/16)\t5 (9/183) vs.16 (31/188)\tn.r.\t8 (8/104)\t\nCRI, catheter-related infection; CLS, capillary leak syndrome; ALT, Alanine transaminase; AST, Aspartate transaminase; AR, allergic reaction; IT, immunotherapy; n.r., not reported. aMaintenance + relapsed/refractory patients. bRandomized crossover study comparing ch14.18-UTC (United Therapeutics Corporation) with ch14.18-NCI (National Cancer Institute). c24 h continuous infusion. dComparison of immunotherapy with and without IL-2. eReported as range for courses 1–5. fDisorientation/hallucinations, seizures, posterior reversible encephalopathy syndrome, toxic demyelinating encephalopathy + coma. gParesthesia, motor deficits, tetraparesis.\n\nOverall, the most common grade ≥3 toxicity observed is pain with incidence rates ranging from 16% (without IL-2) to 62% (with IL-2) (8, 9). Pain occurred most frequently during the first immunotherapy course and at lower rates in subsequent courses (2, 8, 9, 16, 18). Grade ≥3 infections are reported in a range of 25%–39% (2, 8, 17), and fever in a range of 9%–67% (9, 18), with more grade ≥3 fever occurring in courses containing IL-2 (9). Seventy-seven percent more infections and 86% more catheter-related infections were seen in the immunotherapy group in comparison with standard isotretinoin therapy (2).\n\nIn three studies, grade 5 toxicity (death) was reported with an incidence rate of 1% (2, 8, 9). Causes of death were capillary leak syndrome (2×) (2, 8), in one case after an IL-2 overdose (medication error) (2), sudden cardiac arrest (9), and acute respiratory distress syndrome in the context of an infection (8).\n\nThe number of patients that permanently discontinued immunotherapy due to toxicity ranges from 5% to 16% (2, 8, 9, 16, 17). Half of the treatment discontinuations were caused by allergic reactions (9, 16, 17).\n\nSeveral case reports and series have described rare side effects of ch14.18 antibody-based immunotherapy. Central neurotoxicity ranges in severity from disorientation and confusion (2, 8) to disabling cases of myelitis (19) and encephalopathy (2, 8, 20, 21), which warrant corticosteroid treatment and immediate discontinuation of immunotherapy. Full recovery is most likely to occur, although exceptions have been described (8, 21).\n\nOcular complications as mydriasis and accommodation deficits are frequently encountered and seldomly severe (8, 9, 22). Ocular symptoms are completely reversible in most patients and discontinuation of immunotherapy does not seem to be warranted (22).\n\nUnusual and severe gastrointestinal complications have been associated with ch14.18 antibody-based immunotherapy in the form of necrotizing enterocolitis (23) and small bowel pneumatosis and ischemia (24).\n\nPatient Characteristics\nBetween 2016 and 2019, a cohort of twenty-six consecutive high-risk neuroblastoma patients (11 girls and 15 boys) were treated with dinutuximab-based immunotherapy and were included in this study. Patient characteristics are summarized in Table 2. The median age at diagnosis was 3.5 years (range 4 months–18 years). Most patients were INRG stage M and ≥ 12 months of age at diagnosis (n=22), while some were children with INRG stage L2 with MYCN amplification (n=4). The median time between diagnosis and the start of immunotherapy was 10 months (range 8–23 months). Five patients received dinutuximab, 20 patients received dinutuximab beta, and one patient received both antibodies.\n\nTable 2 Patient characteristics of high-risk neuroblastoma cohort.\n\nPatient characteristics\tn = 26 No.\t(%)\t\nSex\t\t\t\n\tFemale\t11\t42\t\n\tMale\t15\t58\t\nAge at diagnosis (months)\t\t\t\n\tMedian\t41.5\t\t\n\tRange\t4–224\t\t\nAge at start immunotherapy (months)\t\t\t\n\tMedian\t55\t\t\n\tRange\t16–240\t\t\nINRG stage at diagnosisa\t\t\t\n\tStage L2\t4\t15\t\n\tStage M\t22\t85\t\nLocation primary tumor\t\t\t\n\tAdrenal\t19\t73\t\n\tSympathetic side chain\t7\t27\t\nMYCN status\t\t\t\n\tAmplified\t11\t42\t\n\tSingle copy\t15\t58\t\nTreatment – Induction\t\t\t\n\tStandard induction chemotherapy + Surgery\t18\t69\t\n\t\t+ additional (chemo)therapy\t8\t12\t\nTreatment - Consolidation – Myeloablative conditioning regimen\t\n\tCarboplatin/Etoposide/Melphalan (CEM)\t9\t35\t\n\tBusulfan/Melphalan (BuMel)\t17\t65\t\nTreatment – Maintenance - Anti-GD2 antibody\t\n\tDinutuximab\t5\t19\t\n\tDinutuximab beta\t20\t77\t\n\tBoth antibodies\t1\t4\t\nDisease status at start immunotherapyb\t\t\t\n\tComplete response (CR)\t14\t54\t\n\tPartial response (PR)\t12\t46\t\nVital status at end of follow-up\t\t\t\n\tAlive\t20\t77\t\n\tDead\t6\t23\t\nFollow-up (End immunotherapy – Last control; months)\t\n\tMedian\t22\t\t\n\tRange\t9 – 39\t\t\naAs defined by International Neuroblastoma Risk Group (11). bAs defined by International Neuroblastoma Response Criteria (25).\n\nToxicities\nTwenty-three patients completed all six courses of immunotherapy. In two patients, immunotherapy was discontinued after two courses. One patient developed unacceptable toxicities: grade 4 catheter-related infection (CRI) in combination with bilateral mydriasis and severe peripheral sensory and motor neuropathy which improved over time but did not resolve completely. In another patient, immunotherapy was discontinued because of disease progression. In a third patient, isotretinoin was permanently discontinued during course 5 due to liver toxicity (grade 4 elevated AST and ALT).\n\nIn total, 310 grade ≥3 toxicities were recorded during 124 immunotherapy courses (courses 1–5). Grade ≥3 toxicities were not evenly distributed among the five courses; with most toxicities reported in courses 2 and 4 involving IL-2 (20; 36; 12; 23; 10% for courses 1–5, respectively). All 26 patients experienced at least one grade ≥3 toxicity. Thirty-three grade 4 toxicities in 19/26 patients and no grade 5 toxicities (death) were seen. In Figure 1, the most common grade ≥3 toxicities for courses 1–5 are depicted, while all toxicities encountered during the immunotherapy courses are listed in Supplementary Table 2. Here only the highest grade per course per patient is given. Pain was the most common grade ≥3 toxicity observed in 96% (25/26) of patients at some point during immunotherapy (courses 1–5). Sixty-five percent (17/26) of patients suffered from disabling, grade 4 pain. Esketamine and clonidine were used in 88% (23/26) and 50% (13/26) of patients, respectively, due to inadequate pain control. Grade ≥3 pain was most frequent during immunotherapy course 1, occurring in 88% of patients. During course 5 the proportion of patients with grade ≥3 pain decreased to 42% (p=.003).\n\nFigure 1 The most prevalent immunotherapy-related grade ≥3 toxicities per course. Proportion of patients experiencing grade ≥3 toxicities per cycle (1–5) of immunotherapy are displayed. The highest grade of toxicity per patient per course is shown. Please note the different scales of the Y-axis. AST, Aspartate transaminase; ALT, Alanine transaminase.\n\nThe second and third most common grade ≥3 toxicity were CRIs in 19%, 65%, 25%, 54%, 21%, and fever in 19%, 62%, 13%, 42%, 13% of patients in courses 1–5, respectively. Although both toxicities occurred more frequently in immunotherapy courses that contained IL-2 (courses 2 and 4) as compared with courses that contained GM-CSF (courses 1, 3, and 5), a statistically significant difference between IL-2 and GM-CSF courses was only found for catheter-related infections (p=.039), and not for fever (p=.057).\n\nIn Figure 2 and Supplementary Table 3, all grade ≥3 toxicities per patient are shown for courses 1–5. Here toxicities may be documented multiple times per course, with a maximum of once per day. In total, 441 grade ≥3 toxicities were recorded for the 23 patients that completed all six courses of immunotherapy, with a median of 18 (range 10–37) grade ≥3 toxicities per patient. No statistically significant difference in the number of grade ≥3 toxicities per patient were noted between the patients that received dinutuximab or dinutuximab beta (p=.754). The same holds true for sex (p=.275), myeloablative conditioning regimen (p=.708), and vital status at the end of follow-up (p=.948). Age at diagnosis (p=.908) and at the start of immunotherapy (p=.925) were not significantly correlated with the number of grade ≥3 toxicities per patient.\n\nFigure 2 Immunotherapy-related grade ≥ 3 toxicities per patient for courses 1–5. Toxicities may be documented multiple times per course, with a maximum of once per day. The median number of grade ≥3 toxicities per patient is 18 (range 10–37) for the 23 patients who completed all six courses of immunotherapy. The category “Other” comprises toxicities in alphabetical order from the CTCAE categories Allergy; Blood/bone marrow; Constitutional, Cardiac; Gastrointestinal, Infection; Lymphatics; Metabolic/laboratory; Neurology; Ocular/visual; Pulmonary; and Vascular. All individual toxicities encountered are listed in Supplementary Table 2. *Patients 13, 19, and 20 did not complete all cycles of immunotherapy. CRI, catheter-related infections.\n\nFever Management\nAll 26 patients experienced fever during immunotherapy; 81% of patients suffered from fever >40.0°C (grade 3). In 124 courses of immunotherapy (courses 1–5), 341 instances of fever were recorded (Table 3). Sixty-three percent of fever episodes were recorded in the immunotherapy courses with IL-2 (course 2: 34% and course 4: 29%). During these episodes, 274 blood cultures were taken from which 52 CRIs were identified in 81% of patients. Four of these episodes were life-threatening (grade 4) and led to intensive care admission followed by full recovery. All 26 patients received immunotherapy through a Hickman central venous access device (CVAD). Twelve patients (46%) had a Hickman CVAD implanted shortly before the start of immunotherapy, the other patients (54%) received a Hickman CVAD earlier in their treatment history (i.e., induction or consolidation phase). Surgical removal of the CVAD was performed in 54% (28/52) of CRIs. Ten patients (38%) did not require a CVAD removal during immunotherapy.\n\nTable 3 Fever instances, blood cultures, and catheter-related infections.\n\n\tCourse 1 (n = 26)\tCourse 2 (n = 26)\tCourse 3 (n = 24)\tCourse 4 (n = 24)\tCourse 5 (n = 24)\tTotal\t\n\tNo.\tNo. patients\tNo.\tNo. patients\tNo.\tNo. patients\tNo.\tNo. patients\tNo.\tNo. patients\tNo.\t\nFever instances\t56\t25\t115\t26\t40\t20\t99\t24\t31\t18\t341\t\nGrade (in %)\t1\n2\n3\n\t41\n48\n11\t\t23\n55\n23\t\t73\n15\n13\t\t28\n60\n12\t\t68\n23\n10\t\t\t\nBlood cultures\t48\t24\t99\t26\t42\t17\t68\t22\t17\t12\t274\t\nPositive BC\t15\t11\t42\t22\t18\t11\t34\t16\t7\t7\t116\t\nCRI\t6\t5\t20\t17\t7\t6\t14\t13\t5\t5\t52\t\nCVAD out\t3\t\t10\t\t5\t\t7\t\t3\t\t28\t\nPICU admission\t0\t\t1\t\t1\t\t1\t\t1\t\t4\t\nCRI pathogens\t\t\t\t\t\t\t\n Staphylococcus sp.\t1\t\t7\t\t1\t\t5\t\t1\t\t15\t\n Streptococcal sp.\t2\t\t5\t\t1\t\t3\t\t2\t\t13\t\n Gram-negative sp.\t2\t\t2\t\t1\t\t5\t\t2\t\t12\t\n Mixed Gram pos + neg sp.\t0\t\t1\t\t1\t\t1\t\t0\t\t3\t\n Less/non-pathogenic sp.\t1\t\t5\t\t3\t\t0\t\t0\t\t9\t\nThe maximum body temperature per day was used to assess fever. Days with one recorded body temperature of ≥38.0°C were counted as fever instances. Grades 1, 2, 3 indicate the percentual distribution between Fever grades 1, 2, and 3, respectively. BC, blood culture; CRI, catheter-related infections; CVL, central venous access device; PICU, pediatric intensive care unit; pos, positive; neg, negative; sp., species.\n\nStaphylococcus species were identified in 29% (15/52) of CRIs, in 14/15 blood cultures a Staphylococcus aureus was isolated. In 29% (15/52) of CRIs, Gram-negative pathogens were detected. Supplementary Table 4 lists the identified bacteria isolated in all CRIs.\n\nDose Modifications\nTo reduce the toxicity burden of immunotherapy, the infusion rate of dinutuximab may be decreased. In case of more severe toxicity, temporary interruption or permanent discontinuation of infusion may be necessary. In our cohort, the dinutuximab dose was modified in 81% (21/26) of patients (Table 4). Forty-two percent (11/26) of patients did not receive 100% of the intended dinutuximab dose at some point during courses 1–5. In courses 1 and 3, all patients received 100% of the intended dinutuximab dose. In course 2, 19% (5/26) did not receive the planned dinutuximab dose. Here, two patients, both suffering from a CRI, only received <50%. In course 4, 21% (5/24) received ≥50 to <100% of cumulative intended dinutuximab dose. Lastly, in course 5, 8% (2/24) did not receive the planned dinutuximab dose. Here, one patient received <50% of the dinutuximab dose after therapy discontinuation due to severe coughing.\n\nTable 4 Immunotherapy-related toxicities leading to dose modifications of dinutuximab.\n\nCourse(n=)\t100% of cumulative intended dose of dinutuximab administered\t≥ 50 to <100% of cumulative intended dose of dinutuximab administered\t<50% of cumulative intended dose of dinutuximab administered\t\n\tNo. patients\tNo. patients with dose modifications\tIndication for dose modification\tNo. patients\tNo. patients with dose modifications\tIndication for dose modification\tNo. patients\tNo. patients with dose modifications\tIndication for dose modification\t\nCourse 1(26)\t26 (100%)\t8/26\t1× AR\n3× Cough\n2× Pain\n1× Pain + Cough\n1× Pain + Fever\t0 (0%)\t\t\t0 (0%)\t\t\t\nCourse 2(26)\t21 (81%)\t3/21\t3× Cough\t3 (12%)\t3/3\t1× AR + Fever\n1× Cough\n1× Hypertension\t2 (8%)\t2/2\t2× CRI\t\nCourse 3(24)\t24 (100%)\t6/24\t6× Cough\t0 (0%)\t\t\t0 (0%)\t\t\t\nCourse 4(24)\t19 (79%)\t7/19\t5× Cough\n1× Pain + Cough\n1× Hypertension\t5 (21%)\t5/5\t1× AR\n2× CRI\n1× Fever\n1× Hypoxia\t0 (0%)\t\t\t\nCourse 5(24)\t22 (92%)\t4/21\t1× AR\n1× Cough\n1× Fever\n1× Pain\t1 (4%)\t1/1\t1× CRI\t1 (4%)\t1/1\t1× Cough\t\nAR, allergic reaction; CRI, catheter-related infection.\n\nAlthough more patients did not receive 100% of the intended dinutuximab dose in the courses containing IL-2 (n=9) as compared with courses containing GM-CSF (n=2), this difference was not significant (p=.065). Grade ≥3 pain, the most common toxicity overall, led to dose modifications in 5 patients. All five patients, however, received 100% of cumulative intended course dose of dinutuximab.\n\nThe treatment of patients with IL-2 had to be modified due to treatment-related toxicities in 54 and 48% of patients in courses 2 and 4, respectively (Supplementary Table 5). The most prevalent toxicities preceding IL-2 dose modifications were coughing, CRIs, AST/ALT abnormalities, and fever.\n\nDisease Outcome\nAt the last follow-up, six patients (23%) had died of disease after the start of immunotherapy. One patient, with a complete response before the start of immunotherapy, suffered from cerebral metastases and only completed two courses of immunotherapy. The other five patients had a relapse after immunotherapy completion. In four of these patients, skeletal relapses were detected at the response assessment after immunotherapy course 6. In the fifth patient, a mediastinal soft tissue relapse was discovered 8 months after the completion of immunotherapy.\n\nDiscussion\nTreatment-related toxicity during immunotherapy with dinutuximab, cytokines IL-2 and GM-CSF, and isotretinoin after induction and consolidation according to the DCOG NBL 2009 treatment protocol is substantial. All 26 analyzed patients suffered from grade ≥3 toxicities, 73% suffered from grade 4 toxicities and no grade 5 toxicities (death) were seen. Pain, fever, coughing, edema, and liver enzyme abnormalities were among the most common toxicities observed. These results are in line with earlier reports in which comparable immunotherapy regimens were used (2, 9, 16). A large interpatient variability in grade ≥3 toxicity burden was observed, possibly related to the pharmacokinetic variability of dinutuximab in disposition and clearance in children (26, 27). Generally, immunotherapy-related toxicities were transient and resolved with the discontinuation of antibody and/or cytokine infusion, or with appropriate supportive care (pain/fever management). However, 12% of patients (3/26) could not complete all immunotherapy courses due to toxicity, and in one of these patients the peripheral neuropathy did not resolve completely. Peripheral neurotoxicity is a rare, but severe side effect of immunotherapy with a reported prevalence between 2 and 6% (8, 17, 18).\n\nPain was most severe during the first course and significantly improved during subsequent courses. In our results, 88% of patients experienced grade ≥3 pain in course 1, whereas 41% experienced pain in course 5. Comparable reductions in the proportion of patients experiencing grade ≥3 pain between courses 1 and 5 were seen in the studies of Yu et al. (37%–14%) and Ozkaynak et al. (41%–24%) (2, 9). Decreasing pain scores and intravenous morphine usage in time within and between immunotherapy courses were also observed by Mueller et al. in a study evaluating long-term dinutuximab infusion (LTI, continuous 10-day antibody infusion) (18). Accelerated antibody clearance after repeated administration of dinutuximab may explain the observed decreasing proportion of patients experiencing grade ≥3 pain over the courses (27). However, this explanation of accelerated antibody clearance was contested by another, more recent study (26). The improved pain tolerance in subsequent cycles could also be explained by the individualization of pain management. The individual and initial pain response would guide the subsequent pain management, making it more effective in subsequent courses.\n\nEighty-one percent of patients (21/26) suffered from catheter-related infections during anti-GD2 immunotherapy. This percentage is remarkably higher than reported previously (2). Most catheter-related infections (65%) were recorded in the immunotherapy courses containing IL-2 (courses 2 and 4). Previous studies have shown an increase in bacteremia and catheter-related infections in cancer patients receiving IL-2 (28–32). Staphylococcus aureus was cultured in 27% (14/52) of catheter-related infections in our study. This prevalence is strikingly higher than the 5.2% of S. aureus cultured during central line-associated bloodstream infection (CLABSI) episodes in a report on CVAD-related complications in pediatric oncology patients from colleagues at our institution (33). In unpublished data by Van den Bosch et al. on CVAD-related complications in neuroblastoma patients, significantly more S. aureus-CLABSIs and CLABSIs overall were observed in neuroblastoma patients receiving anti-GD2 immunotherapy. Strategies to prevent catheter-related infections have been studied, including the prophylactic use of antibiotics (34, 35) and the use of antibiotic-coated catheters (36). To our knowledge, no studies have examined the benefit of these strategies in this patient population.\n\nThe courses containing dinutuximab with IL-2 (courses 2 and 4) were associated with more toxicity than the courses with GM-CSF (courses 1, 3, 5), a result also encountered in other studies (2, 9). Moreover, 19% and 21% of patients did not receive the intended dose of dinutuximab due to toxicity in courses 2 and 4, respectively. In contrast, in the other three courses only in course 5 did 8% of patients not receive the complete dinutuximab dose. In one study, IL-2 was thought to be the causative agent in the majority of fever instances without documented infection (6). In another study by Ladenstein et al, patients were randomly assigned to receive either dinutuximab beta plus IL-2 or dinutuximab beta alone (8). No evidence was found that addition of IL-2 improved outcome. Furthermore, dinutuximab beta plus IL-2 was associated with greater toxicity, more dose modifications and less treatment completion than dinutuximab beta alone, leading the authors to conclude that dinutuximab immunotherapy without IL-2 should be considered standard of care.\n\nThe major limitation of our study is the small size of the cohort, making detection of rare complications of treatment less probable. Furthermore, early patients were treated with dinutuximab, while after EMA approval in May 2017 patients were treated with dinutuximab beta. We, however, found no difference in number of grade ≥3 toxicities per patient between the two antibodies and evidence exists that both antibodies have comparable toxicity profiles (37). Lastly, the retrospective nature of our study is a potential source of bias. Although, immunotherapy was newly introduced in our center and all healthcare providers involved were instructed in accurate toxicity recordkeeping, information and selection bias cannot be ruled out completely.\n\nThe strength of our study is that all toxicities were uniformly collected, categorized, and graded by a small group with extensive experience in toxicity reporting of cancer treatment in children. We believe that this design in combination with retrospective collection of toxicities from patients’ medical files led to more sensitive toxicity collection, and therefore to higher prevalences of toxicities than previously reported (2, 8, 9, 16–18).\n\nWe conclude in this single center experience of immunotherapy with dinutuximab, cytokines IL-2 and GM-CSF, and isotretinoin after induction and consolidation according to the DCOG NBL 2009 treatment protocol, that immunotherapy-related toxicity is substantial, but manageable. Future studies are warranted to optimize the scheduling, anti-GD2 antibody (38), and additive cytokines of immunotherapy with anti-GD2 monoclonal antibodies in high-risk neuroblastoma.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by the Medical Research Ethics Committee Utrecht (info@metcutrecht.nl).\n\nAuthor Contributions\nTB, RL, LA, MM, TW, MD, NE, KK, MN, MG, and GT contributed to the conception and design of the study. TB, RL, and GT organized the database. TB and RL collected the data. TB performed the statistical analysis. TB, RL, and GT wrote the first draft of the manuscript. LA, MM, and TW wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.601076/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n\n Abbreviations\nGD2, Disialoganglioside 2; IL-2, Interleukin-2; GM-CSF, Granulocyte-macrophage colony-stimulating factor; ADCC, Antibody-dependent cellular cytotoxicity; COG, Children’s Oncology Group; DCOG, Dutch Childhood Oncology Group; INRG, International Neuroblastoma Risk Group; GPOH, Gesellschaft für Pädiatrische Onkologie und Hämatologie; IV, intravenous; CTCAE, Common Terminology Criteria for Adverse Events; WB-FPRS, Wong–Baker Faces Pain Rating Scale; VAS, Visual analogue scale; CRI, Catheter-related infection; PICU, Pediatric intensive care unit; SPSS, Statistical Package for the Social Sciences; ALT, Alanine transaminase; AST, Aspartate transaminase; LTI, long-term infusion; EMA, European Medicines Agency; CVAD, central venous access device; CLABSI, central line-associated bloodstream infection.\n==== Refs\nReferences\n1 \nMatthay KK Reynolds CP Seeger RC Shimada H Adkins ES Haas-Kogan D . 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Inflammatory disease of the central nervous system induced by anti-GD2 monoclonal antibody in a patient with high risk neuroblastoma\n. Pediatr Blood Cancer (2014 ) 61 (8 ):1521–2. 10.1002/pbc.24982 \n\n21 \nLowas SR Lettieri CK . A Case of Anti-NMDA Receptor Encephalitis During Dinutuximab Therapy for Neuroblastoma\n. J Pediatr Hematol Oncol (2019 ) 43 (1 ):e127–9. 10.1097/MPH.0000000000001632 \n\n22 \nKremens B Hero B Esser J Weinel P Filger-Brillinger J Fleischhack G . Ocular symptoms in children treated with human-mouse chimeric anti-GD2 mAb ch14.18 for neuroblastoma\n. Cancer Immunol Immunother (2002 ) 51 (2 ):107–10. 10.1007/s00262-001-0259-x \n\n23 \nLevy G Bonnevalle M Rocourt N Sudour H Defachelles AS . Necrotizing enterocolitis as an adverse effect of recombinant interleukin-2 and Ch14.18 in maintenance therapy for high-risk neuroblastoma\n. J Pediatr Hematol Oncol (2015 ) 37 (4 ):e250–2. 10.1097/MPH.0000000000000304 \n\n24 \nSpencer K Romberg E Pinto N . Extensive small bowel pneumatosis and ischemia during dinutuximab therapy for high-risk neuroblastoma\n. Pediatr Blood Cancer (2020 ) 67 (4 ):e28147. 10.1002/pbc.28147 \n31925911 \n25 \nPark JR Bagatell R Cohn SL Pearson AD Villablanca JG Berthold F . Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting\n. J Clin Oncol (2017 ) 35 (22 ):2580–7. 10.1200/JCO.2016.72.0177 \n\n26 \nDesai AV Fox E Smith LM Lim AP Maris JM Balis FM . Pharmacokinetics of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma\n. Cancer Chemother Pharmacol (2014 ) 74 (5 ):1047–55. 10.1007/s00280-014-2575-9 \n\n27 \nUttenreuther-Fischer MM Huang CS Yu AL . Pharmacokinetics of human-mouse chimeric anti-GD2 mAb ch14.18 in a phase I trial in neuroblastoma patients\n. Cancer Immunol Immunother (1995 ) 41 (6 ):331–8. 10.1007/BF01526552 \n\n28 \nKlempner MS Noring R Mier JW Atkins MB . An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy\n. N Engl J Med (1990 ) 322 (14 ):959–65. 10.1056/NEJM199004053221404 \n\n29 \nLim SH Giles FJ Smith MP Goldstone AH . Bacterial infections in lymphoma patients treated with recombinant interleukin-2\n. Acta Haematol (1991 ) 85 (3 ):135–8. 10.1159/000204875 \n\n30 \nPockaj BA Topalian SL Steinberg SM White DE Rosenberg SA . Infectious complications associated with interleukin-2 administration: a retrospective review of 935 treatment courses\n. J Clin Oncol (1993 ) 11 (1 ):136–47. 10.1200/JCO.1993.11.1.136 \n\n31 \nRichards JM Gilewski TA Vogelzang NJ . Association of interleukin-2 therapy with staphylococcal bacteremia\n. Cancer (1991 ) 67 (6 ):1570–5. 10.1002/1097-0142(19910315)67:6<1570::AID-CNCR2820670619>3.0.CO;2-V \n\n32 \nSnydman DR Sullivan B Gill M Gould JA Parkinson DR Atkins MB . Nosocomial sepsis associated with interleukin-2\n. Ann Intern Med (1990 ) 112 (2 ):102–7. 10.7326/0003-4819-112-2-102 \n\n33 \nvan den Bosch CH van der Bruggen JT Frakking FNJ Terwisscha van Scheltinga CEJ van de Ven CP van Grotel M . Incidence, severity and outcome of central line related complications in pediatric oncology patients; A single center study\n. J Pediatr Surg (2019 ) 54 (9 ):1894–900. 10.1016/j.jpedsurg.2018.10.054 \n\n34 \nBock SN Lee RE Fisher B Rubin JT Schwartzentruber DJ Wei JP . A prospective randomized trial evaluating prophylactic antibiotics to prevent triple-lumen catheter-related sepsis in patients treated with immunotherapy\n. J Clin Oncol (1990 ) 8 (1 ):161–9. 10.1200/JCO.1990.8.1.161 \n\n35 \nKlevens RM Morrison MA Nadle J Petit S Gershman K Ray S . Invasive methicillin-resistant Staphylococcus aureus infections in the United States\n. JAMA (2007 ) 298 (15 ):1763–71. 10.1001/jama.298.15.1763 \n\n36 \nChemaly RF Sharma PS Youssef S Gerber D Hwu P Hanmod SS . The efficacy of catheters coated with minocycline and rifampin in the prevention of catheter-related bacteremia in cancer patients receiving high-dose interleukin-2\n. Int J Infect Dis (2010 ) 14 (7 ):e548–52. 10.1016/j.ijid.2009.08.007 \n\n37 \nLadenstein R Weixler S Baykan B Bleeke M Kunert R Katinger D . Ch14.18 antibody produced in CHO cells in relapsed or refractory Stage 4 neuroblastoma patients: a SIOPEN Phase 1 study\n. MAbs (2013 ) 5 (5 ):801–9. 10.4161/mabs.25215 \n\n38 \nKushner BH Cheung IY Modak S Basu EM Roberts SS Cheung NK . Humanized 3F8 Anti-GD2 Monoclonal Antibody Dosing With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Resistant Neuroblastoma: A Phase 1 Clinical Trial\n. JAMA Oncol (2018 ) 4 (12 ):1729–35. 10.1001/jamaoncol.2018.4005\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "anti-GD2 antibody; ch14.18; dinutuximab; immunotherapy; neuroblastoma; safety; toxicity",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "601076",
"pmc": null,
"pmid": "33680926",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "30442501;30326045;28549783;20201786;24535934;9626218;18562251;11291631;8635190;28471719;15659992;8418224;11904735;19047291;26791869;2403767;20005762;29120699;2404087;31925911;11118469;30415957;28329731;19171716;25212536;2156163;29967609;28748630;20879881;17940231;25730142;31651725;7718335;23924804;32067684;2042446;2001546;9217046",
"title": "Treatment-Related Toxicities During Anti-GD2 Immunotherapy in High-Risk Neuroblastoma Patients.",
"title_normalized": "treatment related toxicities during anti gd2 immunotherapy in high risk neuroblastoma patients"
} | [
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"companynumb": "NL-MYLANLABS-2021M1096846",
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"abstract": "BACKGROUND\nThe effects of dual antiplatelet therapy (DAPT) and triple therapy (TT: DAPT plus oral anticoagulation) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) regarding to CHA2DS2-VASc score remain undefined.We compare the effect of TT vs. DAPT in this setting regarding the CHA2DS2-VASc score.\n\n\nRESULTS\nIn a prospective multicenter registry, 585 patients (75.2% male, 73.2 ± 8.2 years) with AF undergoing PCI were followed up during 1 year. Of them, 157 (26.8%) had a CHA2DS2-VASc=1, and 428 (73.2%) had a CHA2DS2-VASc ≥2. TT was prescribed in 51.6% with CHA2DS2-VASc=1 and in 55.5% with CHA2DS2-VASc ≥ 2. Patients with CHA2DS2-VASc=1 receiving TT had a similar thromboembolism rate to those on DAPT (1.2% vs. 1.3%, P=0.73), but more total (19.5% vs. 6.9%, P=0.01) and a tendency to more major (4.9% vs. 0%, P=0.06) bleeding. However, patients with CHA2DS2-VASc ≥ 2 receiving TT had a lower thromboembolism rate (1.7% vs. 5.3%, P=0.03) and a trend towards more bleeds (21.8% vs. 15.6%, P=0.06), with an excess of major bleeding (8.4% vs. 3.1%, P=0.01). Rates of major adverse cardiac events (MACE) in both CHA2DS2-VASc subgroups were similar, irrespective of treatment. In a Cox multivariate analysis, TT was associated to major bleeding, but not with MACE.\n\n\nCONCLUSIONS\nIn patients with AF and CHA2DS2-VASc=1 undergoing PCI, the use of TT involves a high risk of bleeding without a significant benefit in preventing thromboembolism.",
"affiliations": "Cardiology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona.",
"authors": "Sambola|Antonia|A|;Mutuberría|Maria|M|;García Del Blanco|Bruno|B|;Alonso|Albert|A|;Barrabés|José A|JA|;Alfonso|Fernando|F|;Bueno|Héctor|H|;Cequier|Angel|A|;Zueco|Javier|J|;Rodríguez-Leor|Oriol|O|;Bosch|Eduard|E|;Tornos|Pilar|P|;García-Dorado|David|D|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.1253/circj.CJ-15-0923",
"fulltext": null,
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"issn_linking": "1346-9843",
"issue": "80(2)",
"journal": "Circulation journal : official journal of the Japanese Circulation Society",
"keywords": null,
"medline_ta": "Circ J",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D006801:Humans; D008297:Male; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D019106:Postoperative Hemorrhage; D011446:Prospective Studies; D012042:Registries; D018570:Risk Assessment; D013923:Thromboembolism",
"nlm_unique_id": "101137683",
"other_id": null,
"pages": "354-62",
"pmc": null,
"pmid": "26725763",
"pubdate": "2016",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effects of Triple Therapy in Patients With Non-Valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention Regarding Thromboembolic Risk Stratification.",
"title_normalized": "effects of triple therapy in patients with non valvular atrial fibrillation undergoing percutaneous coronary intervention regarding thromboembolic risk stratification"
} | [
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"abstract": "A 76-year-old man presented with gross hematuria and reported the use of anticoagulant for deep vein thrombosis (DVT). Blood tests revealed eosinophilia and thrombocytopenia. Urine cytology revealed a class I specimen with a few eosinophils in the urine. We performed cystoscopy, which revealed bladder masses with friable mucosa diffusely throughout the bladder. Magnetic resonance imaging revealed possible invasion of the bladder muscle by the masses. We performed transurethral resection of the bladder masses, and histopathological examination revealed eosinophilic infiltration of the bladder wall stroma without cancerous tissue. Therefore, the patient was diagnosed with eosinophilic cystitis.Eosinophilia and thrombocytopenia promptly resolved, and the bladder masses disappeared following the administration of prednisolone for eosinophilic cystitis. DVT also improved without recurrence of eosinophilic cystitis.",
"affiliations": "Department of Urology, Toranomon Hospital.;Department of Urology, Toranomon Hospital.;Department of Urology, Toranomon Hospital.;Department of Urology, Toranomon Hospital.;Department of Urology, Toranomon Hospital.;Department of Urology, Toranomon Hospital.;Department of Urology, Toranomon Hospital.;Department of Urology, Toranomon Hospital.",
"authors": "Hayashida|Michikata|M|;Yano|Akihiro|A|;Hagiwara|Kiichi|K|;Nagamoto|Shoichi|S|;Ogawa|Kohei|K|;Sakaguchi|Kazushige|K|;Urakami|Shinji|S|;Okaneya|Toshikazu|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5980/jpnjurol.110.266",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5287",
"issue": "110(4)",
"journal": "Nihon Hinyokika Gakkai zasshi. The japanese journal of urology",
"keywords": "Bladder masses; Deep vein thrombosis; Eosinophilic cystitis",
"medline_ta": "Nihon Hinyokika Gakkai Zasshi",
"mesh_terms": null,
"nlm_unique_id": "2984841R",
"other_id": null,
"pages": "266-269",
"pmc": null,
"pmid": "33087690",
"pubdate": "2019",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A CASE REPORT: EOSINOPHILIC CYSTITIS PRESENTED WITH DEEP VEIN THROMBOSIS.",
"title_normalized": "a case report eosinophilic cystitis presented with deep vein thrombosis"
} | [
{
"companynumb": "JP-DSJP-DSJ-2019-144869",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLMESARTAN MEDOXOMIL"
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"drugadditional": "3",... |
{
"abstract": "The cases discussed highlight the atypical presentation and diagnostic dilemmas of toxoplasmosis with fulminant retinal necrosis and the potentially devastating visual outcomes of toxoplasma chorioretinitis following local corticosteroid exposure.\nWe report a series of three patients who presented with toxoplasmosis mimicking severe acute retinal necrosis. Patients were between 59 and 77 years old and had been exposed to local corticosteroids preceding our evaluation. All patients demonstrated diffuse retinal whitening with severe vision loss on presentation. Polymerase chain reaction testing (PCR) was diagnostic in two patients, and histopathologic examination of a vitrectomy specimen was diagnostic in one patient. All cases of retinitis resolved with anti-parasitic medication; however, visual acuity failed to improve in all patients due to disease severity and presentation.\nLocal corticosteroid injection may trigger or exacerbate toxoplasmosis chorioretinitis, leading to fulminant retinal necrosis and severe vision loss. Toxoplasma chorioretinitis should be considered in the differential diagnosis of patients presenting with clinical features of acute retinal necrosis, particularly following local corticosteroid injection regardless of their baseline systemic immune status. Diagnostic vitrectomy may be helpful in patients in whom PCR testing is negative and ocular toxoplasmosis is suspected.",
"affiliations": "Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.;Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.;Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.;Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.;Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.;Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.;Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.;Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA.",
"authors": "Crosson|Jason N|JN|;Kuthyar|Sanjana|S|;Shantha|Jessica G|JG|;Debiec|Matthew R|MR|;Laird|Philip W|PW|;Hwang|Cindy S|CS|;Grossniklaus|Hans E|HE|;Yeh|Steven|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40942-020-00225-0",
"fulltext": "\n==== Front\nInt J Retina Vitreous\nInt J Retina Vitreous\nInternational Journal of Retina and Vitreous\n2056-9920 BioMed Central London \n\n225\n10.1186/s40942-020-00225-0\nCase Report\nToxoplasmosis chorioretinitis mimicking acute retinal necrosis associated with local corticosteroid\nCrosson Jason N. Kuthyar Sanjana Shantha Jessica G. Debiec Matthew R. Laird Philip W. Hwang Cindy S. Grossniklaus Hans E. Yeh Steven steven.yeh@emory.edu Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd, Atlanta, GA 30322 USA \n3 6 2020 \n3 6 2020 \n2020 \n6 2126 2 2020 27 5 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\nThe cases discussed highlight the atypical presentation and diagnostic dilemmas of toxoplasmosis with fulminant retinal necrosis and the potentially devastating visual outcomes of toxoplasma chorioretinitis following local corticosteroid exposure.\n\nCase presentation\nWe report a series of three patients who presented with toxoplasmosis mimicking severe acute retinal necrosis. Patients were between 59 and 77 years old and had been exposed to local corticosteroids preceding our evaluation. All patients demonstrated diffuse retinal whitening with severe vision loss on presentation. Polymerase chain reaction testing (PCR) was diagnostic in two patients, and histopathologic examination of a vitrectomy specimen was diagnostic in one patient. All cases of retinitis resolved with anti-parasitic medication; however, visual acuity failed to improve in all patients due to disease severity and presentation.\n\nConclusions\nLocal corticosteroid injection may trigger or exacerbate toxoplasmosis chorioretinitis, leading to fulminant retinal necrosis and severe vision loss. Toxoplasma chorioretinitis should be considered in the differential diagnosis of patients presenting with clinical features of acute retinal necrosis, particularly following local corticosteroid injection regardless of their baseline systemic immune status. Diagnostic vitrectomy may be helpful in patients in whom PCR testing is negative and ocular toxoplasmosis is suspected.\n\nKeywords\nToxoplasmosisAcute retinal necrosisCorticosteroidsNational Institutes of Health (US)P30EY006360RO1 EY029594K23EY030158Shantha Jessica G. Yeh Steven Research to Prevent Blindness (US)Unrestricted Grant to Emory Eye CenterEmory University School of Medicinehttp://dx.doi.org/10.13039/100005426Association for Research in Vision and OphthalmologyMallinckrodt Research FellowshipYeh Steven issue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nOcular toxoplasmosis is a common cause of infectious uveitis that most commonly presents with unilateral retinitis adjacent to a chorioretinal scar; however, systemically immunosuppressed individuals may present with atypical lesions consisting of large areas of retinal necrosis without adjacent retinal scarring [1, 2]. Patients who have received local or systemic corticosteroid without concomitant anti-parasitic therapy have also been reported to develop severe retinal necrosis from toxoplasmosis [3]. We describe three patients with fulminant necrotizing retinitis with features mimicking acute retinal necrosis following corticosteroid administration and were subsequently diagnosed with toxoplasmosis. These cases highlight the atypical presentation, diagnostic difficulties, and severe visual morbidity associated with diffuse toxoplasmosis chorioretinitis, which may occur in patients without a prior documented history of systemic or ocular toxoplasmosis.\n\nResults: report of cases\nCase 1\nA 59-year-old female with advanced glaucoma underwent a bleb revision with bleb needling, mitomycin C, and subtenons triamcinolone for a failed trabeculectomy in the left eye. Three days after her bleb revision, she experienced floaters, pain, and acute loss of vision. She had no prior history of ocular or systemic toxoplasmosis. She was started on oral prednisone and was referred for an evaluation 1 week later when her vision failed to improve. Visual acuities were 20/25 in the right eye and hand motions in the left eye. A relative afferent pupillary defect of the left eye was observed. Slit lamp exam demonstrated a triamcinolone depot in the inferior fornix (Fig. 1) and 2+ anterior chamber cell and vitreous cell in the left eye. Dilated examination of the left eye demonstrated 2+ vitreous haze and patchy retinal whitening temporally in association with sclerotic-appearing vessels within the inferotemporal quadrant. Examination of the right eye was unremarkable. An anterior chamber paracentesis was performed and polymerase chain reaction (PCR) testing for herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV) and toxoplasmosis was negative. Toxoplasmosis IgG, toxoplasmosis IgM, and syphilis IgG were also negative. Ceftazidime (2.25 mg/0.1 cc), vancomycin (1 mg/0.1 cc), and foscarnet (2.4 mg/0.1 cc) were injected intravitreally and the patient was started on trimethoprim/sulfamethoxazole (800 mg/160 mg). Five days later, a combined tractional and rhegmatogenous retinal detachment developed, prompting pars plana vitrectomy, endolaser, silicone oil instillation, injection of vancomycin, ceftazidime, voriconazole and foscarnet, and excision of subtenons triamcinolone acetonide. Vitreous specimens were obtained for bacterial and fungal cultures, PCR testing, and cytology. Histopathologic analysis showed bradyzoites consistent with toxoplasmosis (Fig. 1). Therapy with trimethoprim/sulfamethoxazole was continued. The toxoplasmosis chorioretinitis improved, but the visual acuity remained hand motions at the final six-month follow-up.Fig. 1 Slit lamp photograph of patient one shows the sub-Tenons triamcinolone acetonide (Kenalog) prior to the development of severe chorioretinitis (a). Histopathologic analysis showing toxoplasmosis bradyzoites at 250 × magnification (b, arrows). Color fundus photo montage of patient one shows a hazy view secondary to vitritis, disc edema, and patchy retinal whitening (c). While the vitreous inflammation and retinal whitening has improved, optic nerve pallor and retinal vascular attenuation are observed (d)\n\n\n\nCase 2\nA 77-year-old male with diabetes mellitus and no prior history of ocular or systemic toxoplasmosis underwent pars plana vitrectomy, membrane peel and intravitreal triamcinolone for an epiretinal membrane in the left eye at an outside institution. He reported significant improvement in his distortion symptoms immediately following surgery. However, one month after surgery, the patient complained of floaters and severe vision loss and was referred to the Emory Eye Center for an evaluation. Presenting visual acuities were 20/20 in the right eye and counting fingers in the left eye. Slit lamp exam revealed 2+ anterior chamber cell and trace anterior vitreous cell in the left eye. Funduscopic exam demonstrated retinitis involving the posterior pole of the left eye (Fig. 2). Examination of the right eye was unremarkable. Due to an initial concern for herpetic acute retinal necrosis, the patient was started oral valacyclovir 1 g three times daily. A vitreous tap for gram stain and culture, as well as PCR testing for HSV, VZV, CMV and toxoplasmosis was performed. Intravitreal foscarnet (2.4 mg/0.1 cc), vancomycin (1 mg/0.1 cc), and ceftazidime (2.25 mg/0.1 cc) were administered. Toxoplasmosis PCR was positive while PCR testing for VZV, HSV, and CMV was negative. Serologic testing showed toxoplasmosis IgG positive at > 250 IU/mL (Normal reference: 0–6.4 IU/mL) and Toxoplasmosis IgM normal at < 0.90 titer. An FTA-ABS was negative. Because of prior sulfa allergy precluding trimethoprim/sulfamethoxazole or sulfadiazine therapy, the patient was treated with a combination of oral azithromycin (500 mg initially, then 250 mg/day) and clindamycin (300 mg four times daily). He also received six intravitreal injections of clindamycin (1 mg/0.1 cc) for a total of six doses over the ensuing month. The retinitis improved, but visual acuity was unimproved with hand motions at the patient’s final 6-month follow-up.Fig. 2 Color fundus photo montage of the left eye of patient two shows diffuse retinal whitening involving the posterior pole and severe vascular attenuation (a). With oral and intravitreal anti-parasitic medication, the majority of the retinitis has improved but optic nerve pallor, diffuse retinal pigment epithelial atrophy and severe vascular attenuation are seen (b)\n\n\n\nCase 3\nA 74 year-old female with dermatomyositis managed with azathioprine and intravenous immunoglobulin was treated by her ophthalmologist with topical prednisolone acetate 1% for iritis of the right eye. She later developed panuveitis with retinal whitening of the right eye. Because of findings consistent with viral retinitis, the patient was started on valacyclovir, 1 g three times daily and oral prednisone (60 mg). A subtenons triamcinolone injection (40 mg/1 cc) was administered. She was subsequently referred to our institution when her vision continued to deteriorate.\n\nThe patient’s presenting visual acuities were 20/600 in the right eye and 20/15 in the left eye. A relative afferent pupillary defect was present in the right eye. Slit lamp exam demonstrated 2+ anterior chamber and 1+ vitreous cell in the right eye. Dilated examination of the right eye showed 2+ vitreous haze and diffuse retinal whitening. The left eye was normal. Intravitreal foscarnet was administered, and an aqueous sample was obtained for PCR for HSV, VZV, CMV, and toxoplasmosis. Prednisone was tapered over to 10 mg/day over a 1 week period. Serologic testing showed toxoplasmosis IgG of 21.2 IU/mL and Toxoplasmosis IgM positive at 1.2 antibody titer (Normal reference < 0.9). An FTA-ABS was negative. One week later, PCR testing of the aqueous humor was negative for viruses and positive for toxoplasmosis DNA. While awaiting PCR testing results, the retinitis had continued to worsen with intravitreal foscarnet and ganciclovir injections (Fig. 3). Trimethoprim/sulfamethoxazole therapy was initiated, and clindamycin was injected intravitreally; however, the patient developed a combined tractional and rhegmatogenous retinal detachment, which was repaired with vitrectomy, endolaser, membrane peel, and silicone oil instillation. Postoperatively, she was treated with pyrimethamine, clindamycin, and folinic acid. Clindamycin was elected at this point in the patient’s treatment instead of trimethoprim/sulfamethoxazole because of concerns that the patient was developing chronic kidney disease with an elevation of creatinine to 1.2 mg/dL and glomerular filtration rate of 45 mL/min/1.73 m2. The patient’s retinitis remained inactive, but her vision remained hand motions at 18-month follow-up (Fig. 3).Fig. 3 Color fundus photo montage of the right eye of patient three demonstrates a hazy view secondary to vitritis and diffuse, fulminant retinal necrosis (a). Following anti-toxoplasmosis therapy and retinal detachment repair, the retina is attached although there is severe vascular attenuation, optic nerve pallor, and fibrosis with chorioretinal scarring superonasally (b)\n\n\n\nDiscussion\nOcular toxoplasmosis in immunocompromised patients may present with greater severity and a diffuse, necrotizing appearance that differs from the typical “headlight in a fog” appearance. Local corticosteroids may reduce the ocular immune response and lead to the rapid evolution of ocular toxoplasmosis to a fulminant retinal necrosis [3]. These patients represent a diagnostic challenge, and the differential diagnosis should include herpetic retinitis, cytomegalovirus retinitis, syphilis, bacterial or fungal endophthalmitis, as well as toxoplasmosis. Because of the broad differential diagnosis and the potential for vision loss, prompt evaluation with aqueous PCR for CMV, HSV, VZV, and toxoplasmosis along with early initiation of empiric therapy are essential [4]. Ocular fluid may be analyzed with immunoglobulin assays, but PCR may be more sensitive for pathogen diagnosis, particularly in immunocompromised patients who may have a reduced host antibody response.\n\nIn our series, PCR was diagnostic in two of three cases presented, one from the aqueous fluid (patient three) and one from a vitreous sample (patient two). Prior studies of aqueous PCR for toxoplasmosis have reported a range of positivity from 18 to 67% [2, 5]. The sensitivity of PCR testing for toxoplasmosis may be greater with vitreous samples compared to aqueous humor.\n\nInterestingly, our series of patients showed a range of toxoplasmosis serologic testing results, which may confound the diagnosis in some cases. Patient 1 showed no serologic evidence of Toxoplasmosis IgG or IgM and was only diagnosed via histopathologic evaluation of vitreous fluid. Given her negative toxoplasmosis PCR from the aqueous humor, a high index of suspicion and detailed ophthalmic pathologic evaluation were eventually needed to identify toxoplasmosis bradyzoites. Patient 3 showed an extremely high IgG level, as well as a positive IgM response. While it is unclear whether this represents a true, acute infection, the antibody response was reflective of a robust systemic antibody response targeting high levels of toxoplasmosis antigen, despite the patient receiving multiple immunosuppressive medications.\n\nBesides serology and PCR testing, histopathologic assessment of vitreous samples may also be extremely helpful to establish a diagnosis of toxoplasmosis in select cases. Patient 1 demonstrated progressive chorioretinitis, which was suspicious for toxoplasmosis and a diagnostic vitrectomy was elected. Clear communication with the ophthalmic pathologist is essential in these scenarios to detect the pathogen and initiate appropriate therapy.\n\nConclusion\nIn summary, we recommend consideration of toxoplasmosis in the differential of necrotizing retinitis in immunocompromised patients and elderly patients, particularly if local corticosteroids have recently been administered. A systematic approach that includes aqueous or vitreous PCR and potentially diagnostic vitrectomy for histopathologic evaluation may be beneficial to establish a diagnosis in these challenging cases.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nJC, SY, SK, and JGS provided funding, drafted and revised the manuscript. MD, PL, CH, and HG contributed data and revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nSupported by an unrestricted grant from Research to Prevent Blindness to the Emory Eye Center and National Eye Institute, National Institutes of Health Core Grant to Emory University (P30EY006360). Research reported in this publication was supported by the National Eye Institute of the National Institutes of Health (Awards: RO1 EY029594 and K23EY030158). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Gagliuso DJ Teich SA Friedman AH Orellana J Ocular toxoplasmosis in AIDS patients Trans Am Ophthalmol Soc 1990 LXXXVII 63 88 \n2. Fardeque C Romand S Narsing RA Cassoux N Diagnosis of toxoplasmic retinochoroiditis with atypical clinical features Am J Ophthalmol 2002 134 196 203 10.1016/S0002-9394(02)01500-3 12140026 \n3. Bosch-Driessen EH Rothova A Sense and nonsense of corticosteroid administration in the treatment of ocular toxoplasmosis Br J Ophthalmol 1998 82 858 860 10.1136/bjo.82.8.858 9828766 \n4. Moshfeghi DM Dodds EM Couto CA Santos CI Diagnostic approaches to severe, atypical toxoplasmosis mimicking acute retinal necrosis Ophthalmology 2004 111 716 725 10.1016/j.ophtha.2003.07.004 15051204 \n5. Harper TW Miller D Schiffman JC Davis JL Polymerase chain reaction analysis of aqueous and vitreous specimens in the diagnosis of posterior segment infectious uveitis Am J Ophthalmol 2009 147 140 147 10.1016/j.ajo.2008.07.043 18834576\n\n",
"fulltext_license": "CC BY",
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"issue": "6()",
"journal": "International journal of retina and vitreous",
"keywords": "Acute retinal necrosis; Corticosteroids; Toxoplasmosis",
"medline_ta": "Int J Retina Vitreous",
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"title": "Toxoplasmosis chorioretinitis mimicking acute retinal necrosis associated with local corticosteroid.",
"title_normalized": "toxoplasmosis chorioretinitis mimicking acute retinal necrosis associated with local corticosteroid"
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"abstract": "Rheumatoid arthritis (RA) is a common autoimmune disease primarily affecting small joints which leads to crippling erosion of the articular cartilage and bone. It is associated with complications related to both its disease course and treatment. Methotrexate (MTX) is a folate antagonist responsible for modulating cell-specific signaling pathways and inhibiting the proinflammatory properties of major cell lineages involved in the pathogenesis of RA. It is considered to be the first-line agent in RA because of its disease-modifying ability and safety profile at low doses. This case report discusses how a middle-aged female presented with severe bone marrow suppression secondary to MTX toxicity, an unusual presentation at the usual low-dose regimen. Her presentation overlapped with several other conditions, especially with Felty's syndrome, a rare complication of RA, characterized by the triad of splenomegaly, neutropenia, and RA. Other differentials included hemophagocytic lymphohistiocytosis, hematologic neoplasms, drug reaction, and infection. Therefore, it was essential to exclude all possible differentials before initiating therapy. We found the corrected reticulocyte count coupled with a good response to leucovorin to be an effective way to differentiate MTX-induced pancytopenia from other possible hematologic diagnoses without the use of a bone marrow biopsy. Additionally, our case incidentally demonstrated a potential interaction between piperacillin/tazobactam and MTX.",
"affiliations": "Medical Intensive Care Unit, Darul Sehat Hospital, Karachi, PAK.",
"authors": "Hassan|Syed Wajih Ul|SWU|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.15193\nInternal Medicine\nRheumatology\nHematology\nPancytopenia Resulting From Low-Dose Methotrexate Use: A Diagnostic Challenge\nMuacevic Alexander\nAdler John R\nHassan Syed Wajih Ul 1\n1 Medical Intensive Care Unit, Darul Sehat Hospital, Karachi, PAK\nSyed Wajih Ul Hassan wajih321994@gmail.com\n23 5 2021\n5 2021\n13 5 e1519323 5 2021\nCopyright © 2021, Hassan et al.\n2021\nHassan et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/58209-pancytopenia-resulting-from-low-dose-methotrexate-use-a-diagnostic-challenge\nRheumatoid arthritis (RA) is a common autoimmune disease primarily affecting small joints which leads to crippling erosion of the articular cartilage and bone. It is associated with complications related to both its disease course and treatment. Methotrexate (MTX) is a folate antagonist responsible for modulating cell-specific signaling pathways and inhibiting the proinflammatory properties of major cell lineages involved in the pathogenesis of RA. It is considered to be the first-line agent in RA because of its disease-modifying ability and safety profile at low doses. This case report discusses how a middle-aged female presented with severe bone marrow suppression secondary to MTX toxicity, an unusual presentation at the usual low-dose regimen. Her presentation overlapped with several other conditions, especially with Felty’s syndrome, a rare complication of RA, characterized by the triad of splenomegaly, neutropenia, and RA. Other differentials included hemophagocytic lymphohistiocytosis, hematologic neoplasms, drug reaction, and infection. Therefore, it was essential to exclude all possible differentials before initiating therapy. We found the corrected reticulocyte count coupled with a good response to leucovorin to be an effective way to differentiate MTX-induced pancytopenia from other possible hematologic diagnoses without the use of a bone marrow biopsy. Additionally, our case incidentally demonstrated a potential interaction between piperacillin/tazobactam and MTX.\n\nreticulocyte count\nrheumatoid arthritis\nfelty’s syndrome\nbone marrow suppression\nnsaid\nhemophagocytic lymphohistiocytosis (hlh)\nbone marrow biopsy\nmethotrexate-induced pancytopenia\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nRheumatoid arthritis (RA) is an autoimmune disease causing inflammatory polyarthritis primarily of the small joints leading to crippling erosion of the articular cartilage and bone. Common complications include joint deformity and immobility; however, extraarticular manifestations are also possible. An uncommon extraarticular complication of this disease is Felty’s syndrome (FS), which is characterized by the triad of neutropenia, splenomegaly, and RA. It occurs in less than 1% of the people with RA [1]. However, the extraarticular manifestations of RA are generally associated with higher mortality [2]. Therefore, accurate recognition and treatment of the disease are vital to patient survival.\n\nMethotrexate (MTX) is a folate antagonist responsible for modulating cell-specific signaling pathways and inhibiting the proinflammatory properties of major cell lineages involved in the pathogenesis of RA. It is considered to be the first-line agent in RA because of its disease-modifying ability and safety profile at low doses. However, at higher doses, it is known to cause adverse effects such as pancytopenia, liver toxicity, and renal failure [3].\n\nOur patient was a middle-aged female on low-dose MTX therapy for RA, who presented with pancytopenia, an unusual presentation at the standard low-dose regimen. The presence of neutropenia and splenomegaly complicated the diagnosis for this case as FS had become a possibility. The fever and pancytopenia also begged the exclusion of hematologic malignancies and sepsis as possible causes.\n\nA common practice is to use a bone marrow biopsy to identify the cause of low cell counts and the enlarged spleen. Unfortunately, this practice can be cumbersome and cause the patient undue pain.\n\nI hope to discuss the use of “corrected reticulocyte count” and the initiation of filgrastim and leucovorin rescue therapy as an initial effort that can potentially defer the use of bone marrow biopsy in cases presenting with fever and pancytopenia, such as ours. In addition, I aim to briefly discuss the incidental findings of this case and its implications.\n\nCase presentation\n\nA 45-year-old female presented to the emergency department with complaints of fever, diarrhea, vomiting, and anuria. She was a known case of seropositive RA since 2008. Her list of regular medications comprised injection MTX 15 mg weekly, oral leflunomide (LFE) 20 mg daily, oral prednisolone 5 mg daily, oral folic acid 5 mg daily, oral pantoprazole 40 mg daily, and vitamin D supplementation. She occasionally used non-steroidal anti-inflammatory drugs (NSAIDs) to control any additional joint pains.\n\nOn examination, she had a temperature of 102°F but was otherwise vitally stable and oriented. She had subconjunctival pallor, yellowish sclera, stomatitis, and a 7 × 7 cm carbuncle on her left scapular region. Abdominal examination revealed a tender liver that was palpable 2 cm below the costal margin, but the spleen could not be palpated. Musculoskeletal examination revealed stiffness in bilateral wrists and metacarpophalangeal and interphalangeal joints. Per vaginal examination revealed multiple superficial ulcers on the vulva.\n\nHer initial blood workup showed hemoglobin (Hb) of 7.7 g/dL, mean corpuscular volume of 75 fl, total leucocyte count (TLC) of 2,100/µL (absolute neutrophil count: 1,680/µL), platelets of 133,000/µL, hematocrit of 25%, and corrected reticulocyte count of <2%. Her renal functions demonstrated urea 60 mg/dL and creatinine 3.5 mg/dL. Baseline creatinine was 0.7 mg/dL. Her liver function tests showed total bilirubin at 4.8 mg/dL, direct bilirubin 2.8 mg/dL, indirect bilirubin 2.0 mg/dL, serum glutamic pyruvic transaminase (SGPT) 11 U/L, alkaline phosphatase (ALP) 477 U/L, and gamma-glutamyl transferase (GGT) 70 U/L. Her viral markers for hepatitis A, B, C, and E were non-reactive. Additional blood tests revealed HbA1c of 10.4%, lactate dehydrogenase (LDH) 475 U/L, ferritin 1,398 µg/L, vitamin B12 354.9 pg/mL, red blood cell folate 4.92 ng/mL, lactic acid 11.0 mg/dL, and 24-hour urinary protein 90 mg. Direct Coombs test and antinuclear antibody (ANA) were positive. Peripheral smear revealed normochromic, anisocytosis, dimorphic picture with no abnormal cells. Her electrocardiogram (ECG), echocardiography (ECHO), and chest X-ray were all unremarkable. Urinalysis was positive for glucose, epithelial cells, and yeast cells; however, bile pigments were negative and urobilinogen levels were normal. Urine culture and sensitivity showed growth of Candida species, but blood cultures showed no growth after 48 hours of incubation. Ultrasound showed a liver measuring 21.8 cm with an altered parenchymal echo pattern and a bulky spleen measuring 13.7 cm.\n\nGiven the patient history, physical examination, and investigations, a provisional diagnosis of MTX-induced pancytopenia secondary to NSAID-induced acute kidney injury (AKI) was made. MTX and LFE were immediately stopped, and she was started on injection leucovorin 15 mg thrice daily. Given the presence of fever, carbuncle, and yeast cells on urinalysis, she was provided broad-spectrum antibiotic and antifungal cover as per the hospital protocol, which included injection piperacillin/tazobactam 4.5 g thrice daily, injection imipenem 250 mg thrice daily, and oral fluconazole 50 mg once daily. She was also transfused two red blood pack cells and started on intravenous (IV) hydration.\n\nOn day two, TLC reduced to 900/µL, and injection filgrastim 300 mg subcutaneously once daily was started. Piperacillin/tazobactam was switched to injection clindamycin 600 mg thrice daily as per expert consultant opinion. Following two days of IV hydration, she began to produce approximately 1,600 mL of urine per day. Her cell counts improved by day five (Hb: 9.4 g/dL, TLC: 4,600/µL, absolute neutrophil count: 3,772/µL, and platelets: 167,000/µL) of therapy and filgrastim was stopped. As cell counts improved following therapy, bone marrow biopsy was deferred. Her carbuncle was excised on day 10 of her hospital stay. On day 13, her labs showed urea 32 mg/dL, creatinine 2.0 mg/dL, total bilirubin 1.1 mg/dL, direct bilirubin 0.6 mg/dL, indirect bilirubin 0.5 mg/dL, SGPT 11 U/L, ALP 552 U/L, and GGT 45 U/L.\n\nDiscussion\n\nThe presence of fever and splenomegaly presented a diagnostic challenge in our patient. The fever might have been a result of RA, an infection, drug reaction, hemophagocytic lymphohistiocytosis (HLH), or hematologic neoplasms. These differential diagnoses had to be carefully considered and logically excluded given their high mortality and morbidity.\n\nOur patient was provisionally diagnosed as MTX-induced pancytopenia secondary to AKI given the absence of splenomegaly on clinical examination and the presence of risk factors such as polypharmacy and irregular follow-up. The incidental finding of splenomegaly on ultrasound, however, cast the diagnosis in doubt. The diagnostic triad for FS includes RA, splenomegaly, and neutropenia, which were all present in our patient. The presence of a high LDH, elevated indirect bilirubin, ANA, and a positive direct Coombs test gave an initial impression of hemolytic anemia which was in line with FS. However, a low corrected reticulocyte count clarified that the low Hb was due to underproduction instead of increased lysis. A peripheral smear with no schistocytes, spherocytes, or any other abnormal cells supported these findings. A decrease in red cell production was in line with MTX-induced pancytopenia instead of FS and allowed us to safely discontinue MTX, thereby avoiding any unwarranted therapies with biological disease-modifying antirheumatic drug (DMARD).\n\nThe presence of fever, splenomegaly, pancytopenia, and high serum ferritin also alerted us to the possibility of HLH and a possible hematologic neoplasm. The HLH-2004 criteria include either a genetic diagnosis or five out of eight clinical and lab parameters: fever, splenomegaly, bicytopenia, hyperferritinemia, hypertriglyceridemia, hypofibrogenimea, and sIL2r of >2,400 U/mL. However, our patient only met four out of eight of the HLH-2004 diagnostic criteria, and the decreasing C-reactive protein (CRP) essentially excluded the diagnosis. The possibility of lymphoma or leukemia was excluded based on the absence of weight loss, lymphadenopathy, low lymphocyte counts, and lack of abnormal cells on the peripheral smear.\n\nThe diagnosis of MTX-induced pancytopenia was proven by the effective response to leucovorin and filgrastim therapy and withholding MTX. Improving cell counts and decreasing CRP were used as trends to monitor the effectiveness of therapy. Although a bone marrow biopsy is an important step in the diagnostic pathway to exclude myeloid or lymphoid proliferation in patients with pancytopenia, it can be a painful procedure with potentially unnecessary complications in a low-risk individual such as our patient [4]. The bone marrow biopsy was deferred given the positive response to therapy.\n\nMTX is considered the first-line DMARD for treating RA. When given at the standard 7.5-25 mg weekly dose, adverse drug reactions are rare [5]. However, hypoalbuminemia, renal failure, and polypharmacy were risk factors for developing MTX toxicity, which were present in our patient [6]. MTX toxicity occurs as both an idiosyncratic reaction and dose-dependent reaction. Given the chronic history and risk factors of our patient, this reaction most likely occurred due to cumulative doses of the drug. The MTX drug level was not obtained as the literature shows adverse effects are a function of the duration of suprathreshold levels instead of peak levels achieved [7]. Our case demonstrated the findings of fever, vomiting, diarrhea, stomatitis, mucocutaneous ulcers, and pancytopenia, which are classical findings of MTX-induced toxicity [8].\n\nCombination therapy of MTX and LFE has been propagated for recalcitrant disease [9]. Given the possibility of pharmacodynamic synergism, one would assume the combination therapy to have worse side effects than monotherapy. However, studies showed otherwise, with the combination only eliciting mild side effects such as gastrointestinal upset and liver enzyme elevation [10]. A few case reports demonstrated the presence of pancytopenia like ours [11]. No case reports were found demonstrating renal toxicity of low-dose MTX or LFE.\n\nMTX-induced renal injury results from using MTX at high doses as in the treatment of malignant neoplasms. AKI secondary to low-dose MTX is uncommon and usually the result of concomitant use of NSAIDs [12]. NSAIDs reduce blood flow to the kidney and make them vulnerable to a pre-renal insult such as hypovolemia resulting from diarrhea. Initially, it seemed like this might have been the case in our patient. Given that her blood pressure never acutely dropped, and serum lactic acid levels were normal, a pre-renal injury seemed unlikely. A more plausible explanation might be interstitial nephritis given her use of NSAID, amoxicillin, and pantoprazole [13]. Other supportive findings included the presence of sub-nephrotic proteinuria and improvement of renal function after drug withdrawal over two weeks.\n\nThere are no formal guidelines on how to treat MTX-induced pancytopenia. However, according to a literature review, leucovorin plays a significant role in reversing MTX-induced myelosuppression [14]. Likewise, a review found filgrastim to improve cell counts in febrile neutropenia [15]. The average time to recovery of cell counts was five days in a case report [16]; however, a duration of four days was noted in this study. This might be explained by the fact that our patient had sufficient folate levels on presentation and was initiated immediately on leucovorin rescue after clinical suspicion. I also recognize that the use of piperacillin/tazobactam as an initial empiric antibiotic might have had a negative impact on our therapy, as cell counts drastically dropped following a single dose. Only a handful of case reports have highlighted this potential drug-drug interaction between high-dose MTX and piperacillin/tazobactam [17], none with low-dose MTX.\n\nIn this case, an unusual finding was the presence of a cholestatic pattern of liver function tests, with a normal SGPT. MTX has been implicated in causing elevation of aminotransferases, portal fibrosis, and cirrhosis. The presence of jaundice, elevated ALP, and GGT along with splenomegaly was suggestive of liver fibrosis; however, an ultrasound revealed a normal common bile duct, intrahepatic duct, and portal vein diameter. Furthermore, risk factors for the development of liver fibrosis include diabetes and obesity, both of which were present in our patient. The patient should ideally have been evaluated with ultrasound elastography for further classification; however, this was not available in our facility. Bilirubin levels and GGT showed a gradual improvement along the course of the patient’s stay.\n\nConclusions\n\nFever and pancytopenia secondary to MTX can present a diagnostic challenge in patients with splenomegaly who are known cases of RA. However, corrected reticulocyte count is a simple yet effective test in differentiating FS from bone marrow suppression secondary to MTX. An adequate response to filgrastim and leucovorin and a low lymphocyte count on complete blood count essentially ruled out other remaining hematologic diagnoses and the need for bone marrow biopsy. It is worth noting that piperacillin/tazobactam has potentially serious drug-drug interactions with MTX and should be avoided in patients already on MTX. Concomitant use of NSAIDs should also be avoided as much as possible in MTX users given the potential for AKI and secondary bone marrow suppression even at low doses of MTX.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Extra-articular manifestations of rheumatoid arthritis: a hospital-based study Ann Saudi Med Al-Ghamdi A Attar SM 189 193 29 2009 19448378\n2 Extra-articular rheumatoid arthritis Curr Opin Rheumatol Turesson C 360 366 25 2013 23425964\n3 Preventing and managing toxicities of high-dose methotrexate Oncologist Howard SC McCormick J Pui CH Buddington RK Harvey RD 1471 1482 21 2016 27496039\n4 Pain during bone marrow aspiration: prevalence and prevention J Pain Symptom Manage Vanhelleputte P Nijs K Delforge M Evers G Vanderschueren S 860 866 26 2003 12967736\n5 Low-dose methotrexate (LD-MTX) in rheumatology practice - a most widely misunderstood drug Curr Rheumatol Rev Malaviya AN 168 176 12 2016 27964706\n6 Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients Autoimmun Rev Kivity S Zafrir Y Loebstein R Pauzner R Mouallem M Mayan H 1109 1113 13 2014 25172240\n7 Therapeutic drug monitoring in rheumatic diseases: utile or futile? Rheumatology (Oxford) Stamp LK Barclay M 988 997 53 2014 24196384\n8 Methotrexate-induced pancytopenia: a case series of 46 patients Int J Rheum Dis Ajmani S Preet Singh Y Prasad S 846 851 20 2017 28261918\n9 Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis Scand J Rheumatol Lee SS Park YW Park JJ 11 14 38 2009 19191187\n10 The SMILE study -- safety of methotrexate in combination with leflunomide in rheumatoid arthritis J Rheumatol Bird P Griffiths H Tymms K 228 235 40 2013 23322457\n11 The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate Pharmacoepidemiol Drug Saf McEwen J Purcell PM Hill RL Calcino LJ Riley CG 65 73 16 2007 16634119\n12 Concomitant use of low-dose methotrexate and NSAIDs and the risk of serious adverse events among patients with rheumatoid arthritis Pharmacoepidemiol Drug Saf Svanström H Lund M Melbye M Pasternak B 885 893 27 2018 29797447\n13 Biopsy-proven acute interstitial nephritis, 1993-2011: a case series Am J Kidney Dis Muriithi AK Leung N Valeri AM Cornell LD Sethi S Fidler ME Nasr SH 558 566 64 2014 24927897\n14 Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis Cochrane Database Syst Rev Shea B Swinden MV Tanjong Ghogomu E 0 5 2013\n15 Filgrastim in patients with neutropenia: potential effects on quality of life Drugs Lyman GH Kuderer NM 65 78 62 Suppl 1 2002 12479595\n16 How should we manage low-dose methotrexate-induced pancytopenia in patients with rheumatoid arthritis? Clin Rheumatol Cansu DÜ Teke HÜ Bodakçi E Korkmaz C 3419 3425 37 2018 30056523\n17 Pharmacokinetic interaction between methotrexate and piperacillin/tazobactam resulting in prolonged toxic concentrations of methotrexate J Antimicrob Chemother Zarychanski R Wlodarczyk K Ariano R Bow E 228 230 58 2006 16717053\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(5)",
"journal": "Cureus",
"keywords": "bone marrow biopsy; bone marrow suppression; felty’s syndrome; hemophagocytic lymphohistiocytosis (hlh); methotrexate-induced pancytopenia; nsaid; reticulocyte count; rheumatoid arthritis",
"medline_ta": "Cureus",
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"pubdate": "2021-05-23",
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"title": "Pancytopenia Resulting From Low-Dose Methotrexate Use: A Diagnostic Challenge.",
"title_normalized": "pancytopenia resulting from low dose methotrexate use a diagnostic challenge"
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"abstract": "BACKGROUND\nBlinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19- disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood.\n\n\nMETHODS\nThis study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure.\n\n\nRESULTS\nThe overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD.\n\n\nCONCLUSIONS\nA history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure.\nExtramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. Most extramedullary failure cases retain CD19 expression.",
"affiliations": "Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Duarte, California.;Department of Clinical and Translational Project Development, City of Hope National Medical Center, Duarte, California.;Department of Pharmacy, City of Hope National Medical Center, Duarte, California.;Department of Clinical Supportive Care, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.",
"authors": "Aldoss|Ibrahim|I|https://orcid.org/0000-0001-9564-4498;Otoukesh|Salman|S|;Zhang|Jianying|J|;Mokhtari|Sally|S|;Ngo|Dat|D|;Mojtahedzadeh|Mona|M|;Al Malki|Monzr M|MM|;Salhotra|Amandeep|A|;Ali|Haris|H|;Aribi|Ahmed|A|;Sandhu|Karamjeet S|KS|;Arslan|Shukaib|S|;Koller|Paul|P|;Ball|Brian|B|;Stewart|Forrest|F|;Curtin|Peter|P|;Artz|Andrew|A|;Nakamura|Ryotaro|R|;Marcucci|Guido|G|;Forman|Stephen J|SJ|;Stein|Anthony S|AS|;Pullarkat|Vinod|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.33967",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": null,
"journal": "Cancer",
"keywords": "acute lymphoblastic leukemia (ALL); blinatumomab; extramedullary; refractory; relapse",
"medline_ta": "Cancer",
"mesh_terms": null,
"nlm_unique_id": "0374236",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34633671",
"pubdate": "2021-10-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia.",
"title_normalized": "extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia"
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"abstract": "The authors retrospectively reviewed the clinical records of 196 patients with dementia treated with memantine for at least 6 months. Eleven (5.6%) developed treatment-induced agitation. At chi-square analysis, they were significantly more likely to have a history of similar side effects from other medications acting on the central nervous system in comparison with the group without agitation, suggesting neurochemical susceptibility. A trend toward a significantly greater prevalence was also present for ischemic cardiopathy and neuroimaging evidence of chronic small vessel disease. Ischemic brain and heart disease might contribute through anatomical and functional alterations within the glutamatergic system.",
"affiliations": "From the Neurology Section, S. Gerardo Hospital, Monza, University of Milan, Bicocca, Italy.",
"authors": "Da Re|Fulvio|F|;Rucci|Francesco|F|;Isella|Valeria|V|",
"chemical_list": "D018691:Excitatory Amino Acid Antagonists; D008559:Memantine",
"country": "United States",
"delete": false,
"doi": "10.1176/appi.neuropsych.13100226",
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"issue": "27(1)",
"journal": "The Journal of neuropsychiatry and clinical neurosciences",
"keywords": null,
"medline_ta": "J Neuropsychiatry Clin Neurosci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003704:Dementia; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D011595:Psychomotor Agitation; D012189:Retrospective Studies",
"nlm_unique_id": "8911344",
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"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective study on agitation provoked by memantine in dementia.",
"title_normalized": "retrospective study on agitation provoked by memantine in dementia"
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"companynumb": "IT-MYLANLABS-2015M1037873",
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"abstract": "An elderly Singaporean male with no travel history was hospitalized for fever and altered mental status. Blood cultures grew Enterococcus faecalis, and given a preceding history of steroid use and peripheral eosinophilia, Strongyloides hyperinfection was suspected. Stool specimens were positive for Strongyloides stercoralis larvae over four days, and larvae were also isolated in an early morning nasogastric aspirate specimen prior to initiation of ivermectin. A cerebrospinal fluid examination was consistent with partially treated bacterial meningitis and ventriculitis was demonstrated on neuroimaging. In view of a persistent fever, a further imaging evaluation was performed, which demonstrated bilateral pneumonia as well as the unusual finding of gas-forming emphysematous spondylodiscitis and left psoas abscesses. Despite the early suspicion of Strongyloides hyperinfection, commencement of appropriate antibiotics and anti-helminthics, microbiological clearance of bacteremia as well as clearance of S. stercoralis from the stool, the patient still succumbed to infection and passed away 11 days after admission.",
"affiliations": "Singhealth Infectious Diseases Residency, Singapore 168753, Singapore.;Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore.;Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore.;Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore 308433, Singapore.",
"authors": "Wee|Liang En|LE|0000-0001-6428-9999;Hnin|Su Wai Khin|SWK|;Xu|Zheyu|Z|;Lee|Lawrence Soon-U|LS|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3390/tropicalmed5010044",
"fulltext": "\n==== Front\nTrop Med Infect Dis\nTrop Med Infect Dis\ntropicalmed\nTropical Medicine and Infectious Disease\n2414-6366 MDPI \n\n10.3390/tropicalmed5010044\ntropicalmed-05-00044\nCase Report\nStrongyloides Hyperinfection Associated with Enterococcus faecalis Bacteremia, Meningitis, Ventriculitis and Gas-Forming Spondylodiscitis: A Case Report\nhttps://orcid.org/0000-0001-6428-9999Wee Liang En 1* Hnin Su Wai Khin 2 Xu Zheyu 2 Lee Lawrence Soon-U 34 1 Singhealth Infectious Diseases Residency, Singapore 168753, Singapore\n2 Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore; hninsuwai.khin@mohh.com.sg (S.W.K.H.); xu.zhe.yu@singhealth.com.sg (Z.X.)\n3 Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore 308433, Singapore; Lawrence_lee@ttsh.com.sg or \n4 Department of Medicine, National University of Singapore, Singapore 119077, Singapore\n* Correspondence: ian.wee@mohh.com.sg; Tel.: +65-9677-7651\n12 3 2020 \n3 2020 \n5 1 4423 2 2020 06 3 2020 © 2020 by the authors.2020Licensee 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/).An elderly Singaporean male with no travel history was hospitalized for fever and altered mental status. Blood cultures grew Enterococcus faecalis, and given a preceding history of steroid use and peripheral eosinophilia, Strongyloides hyperinfection was suspected. Stool specimens were positive for Strongyloides stercoralis larvae over four days, and larvae were also isolated in an early morning nasogastric aspirate specimen prior to initiation of ivermectin. A cerebrospinal fluid examination was consistent with partially treated bacterial meningitis and ventriculitis was demonstrated on neuroimaging. In view of a persistent fever, a further imaging evaluation was performed, which demonstrated bilateral pneumonia as well as the unusual finding of gas-forming emphysematous spondylodiscitis and left psoas abscesses. Despite the early suspicion of Strongyloides hyperinfection, commencement of appropriate antibiotics and anti-helminthics, microbiological clearance of bacteremia as well as clearance of S. stercoralis from the stool, the patient still succumbed to infection and passed away 11 days after admission.\n\nStrongyloideshyperinfectionenterococcusemphysematous spondylodiscitis\n==== Body\n1. Introduction\nStrongyloides is common in tropical and subtropical regions, although the distribution of this intestinal nematode can occur worldwide. Chronically infected patients are at risk of developing Strongyloides hyperinfection, especially with immunosuppression and steroid use [1]. The unique autoinfective lifecycle of this intestinal nematode allows for infection to persist in the host for a prolonged duration [1,2]; thus, the index of suspicion for this condition needs to be high, particularly as epidemiological exposures may be distant in time. Early suspicion and detection of Strongyloides hyperinfection is crucial, given its high mortality rates up to 90% [1]. Strongyloides hyperinfection is characterized by the dissemination of gut flora into the bloodstream, typically leading to bacteremia, pneumonia and involvement of the central nervous system; concomitant bone and deep soft tissue infection is less commonly reported [1,2,3]. Here we present a case of Strongyloides hyperinfection associated with Enterococcus faecalis bacteremia, gas-forming spondylodiscitis, and psoas abscess—a less common presentation—in a patient with previous steroid use.\n\n2. Case Report\nAn 82-year-old Singaporean Chinese male was admitted to our institution with one day’s history of generalized lethargy, malaise and fever. His pre-existing medical conditions included hypertension, hyperlipidemia and atrial fibrillation. On initial presentation, the patient was noted to have a fever of 38.2 °C, with stable vital signs. In the emergency department, he developed a generalized tonic–clonic seizure, which was aborted with intravenous lorazepam. On physical examination, the patient had an initial Glasgow Coma Scale (GCS) of E1V1M2. Gaze was central; the neck was supple. There was no rash. The white blood cell (WBC) count on presentation was elevated at 19.2 × 109/L (normal 4.0–9.6) with 93.8% neutrophils, 2.2% lymphocytes and 1.3% eosinophils. The patient was empirically started on intravenous (IV) ceftriaxone, ampicillin and acyclovir to cover for meningoencephalitis, as well as phenytoin. Blood cultures from admission grew E. faecalis, which was susceptible to penicillin. \n\nOn the third day of hospitalization, the patient was referred to infectious diseases for a further opinion as he still remained febrile despite the blood cultures from day two of hospitalization, demonstrating clearance of E. faecalis bacteremia. The repeat WBC count was still elevated at 20.4 × 109/L (normal 4.0–9.6); however, significant peripheral eosinophilia was also noted, with 8.1% eosinophils, 83.8% neutrophils and 4.1% lymphocytes. The eosinophil count was 1.65 × 109/L (normal 0.0–0.6). In light of the significant peripheral eosinophilia, suspicion of meningoencephalitis and isolation of a microorganism less typically associated with meningitis, stool specimens were sent for ova, cyst and parasite (OCP) examination, due to suspicion of hyperinfection with Strongyloides stercoralis.\n\nOn the fourth day of hospitalization, the lumbar puncture was successfully performed under radiological guidance. Cerebrospinal fluid (CSF) findings were in keeping with a partially treated pyogenic meningitis, with an elevated CSF protein of >2.00 g/L (normal 0.10–0.40), low CSF glucose of 2.3 mmol/L(normal 2.5–5.5) and a white cell count of 173 cells/microliter (normal 0–5); however, CSF cultures were negative, likely because of prior antibiotic treatment. Cytology showed a mixed inflammatory yield of mononuclear cells and neutrophils; polymerase chain reaction (PCR) tests for cytomegalovirus, herpes simplex virus, varicella zoster virus, human herpes-virus 6, enterovirus and parechovirus were all negative, and PCR tests for typical bacterial pathogens causing meningitis, including E. coli, H. influenzae, L. monocytogenes, N. meningitidis, S. agalactiae, S. pneumoniae, were also negative. Fungal cultures and acid-fast-bacilli smears and cultures were also negative. Intravenous acyclovir was stopped; IV ceftriaxone and ampicillin were continued. Subsequently, Strongyloides stercoralis larvae were detected on microscopic examination of a stool specimen on the fourth day of hospitalization, as well as on microscopic examination of early morning nasogastric aspirate specimens. Direct smear and formalin–ether concentration examinations were conducted on the stool samples. Multiple smears were made for each technique, followed by systematic microscopic examination.\n\nGiven the suspicion of hyperinfection with Strongyloides stercoralis, oral ivermectin was started at 200 mcg/kg/day daily and administered via a nasogastric tube. Additional history was obtained: The patient was born in Singapore and had grown up in a rural village in the 1930s with no other travel history. Other family members did not recollect any history of passing worms per-rectum in childhood. He previously worked in a lumber mill but had retired more than 30 years ago. In the 1970s, the patient had moved out of his village to live in an apartment block, and at the point of admission, was staying in an apartment block in western Singapore. He did not have any exposure to soil. Although prednisolone was stopped two months prior to his current admission, he had instead continued taking prednisolone up to the day of admission. For the past two decades, he was noted to have intermittent peripheral eosinophilia but did not undergo further evaluation (Table 1). On review of previous blood tests, he was first noted to have peripheral eosinophilia 17 years prior to presentation (eosinophil count of 0.81 × 109/L); three years ago, when he was first diagnosed with adrenal insufficiency secondary to exogenous steroid usage, the peripheral eosinophil count still remained raised (eosinophil count of 3.88 × 109/L). He continued to have intermittent eosinophilia on follow up. He was initiated on steroids for the adrenal insufficiency, while the endocrinologist had stopped prescribing prednisolone three months prior to presentation; it became apparent during medication reconciliation that the patient had inadvertently continued on both prednisolone 5 mg as well as hydrocortisone 10 mg once-daily up to the point of his admission.\n\nOn the fifth day of hospitalization, magnetic resonance imaging (MRI) of the brain demonstrated ventriculitis. There was no evidence of brain abscesses. On the seventh day of hospitalization, in view of persistent pyrexia, a computed tomography (CT) scan of the thorax, abdomen and pelvis was performed, which showed gas locules within the L3/L4 intervertebral disc with asymmetric thickening of the left psoas muscle, suggestive of a psoas abscess and concurrent spondylodiscitis (Figure 1a,b). There were also bilateral patchy airspace changes and moderate pleural effusions suggestive of pneumonia (Figure 1c) and small pericardial effusion. The transthoracic echocardiogram was negative for vegetations. In view of the prolonged hospitalization and persistent fever, his antibiotic coverage was changed to IV cefepime, metronidazole and ampicillin, to provide broader empiric nosocomial cover. Repeated blood cultures remained negative. An MRI scan of the lumbar spine showed left psoas myositis with phlegmon and small gas-containing abscesses. However, as the abscesses were small and the patient was coagulopathic, drainage of the abscesses was deemed infeasible. \n\nStrongyloides stercoralis was persistently detected on microscopic examination of daily stool specimens from the fourth to eighth day of admission. However, although Strongyloides was also detected on early morning nasogastric aspirates on the fourth day admission, after ivermectin was initiated, subsequent sampling of nasogastric aspirates was persistently negative. Microscopy of urine specimens for Strongyloides was also negative. Strongyloides IgG returned as positive; testing for antibodies against human immunodeficiency virus (HIV) and human T-lymphotrophic virus (HLTV) were negative. IgE levels were significantly elevated (1064 kU/L; normal < 113 kU/L). The patient was treated with daily ivermectin, and on Day 10 of admission was also given a single dose of 400 mg albendazole. However, he continued to deteriorate and passed away on Day 11 of admission. Blood cultures done just prior to his demise were negative, and two consecutive microscopic examinations of his stool, as well as sputum/early morning nasogastric aspirates, were negative for Strongyloides stercoralis. A final diagnosis of Strongyloides hyperinfection, in the context of exogenous steroid usage, complicated by E. faecalis bacteremia, bacterial meningitis/ventriculitis as well as gas-forming spondylodiscitis and a psoas abscess was made. \n\n3. Discussion\nWhile Strongyloides is common in the tropical and subtropical regions, few cases have been reported in Singapore, a highly-urbanized city state. However, cases of Strongyloides hyperinfection have been reported in immunocompromised elderly individuals, who were most likely exposed in childhood prior to the rapid urbanization of Singapore in the 1960s–1970s [4,5,6]. Cases of Strongyloides hyperinfection have been previously reported in British veterans of the Second World War who were exposed during their service in Southeast Asia, demonstrating the long latent period and potential chronicity of infection [7]. In our patient, given his lack of a travel history and lack of recent soil exposure, we speculate that his infection was likely acquired earlier in life and had persisted for decades, with steroid exposure being a known risk factor for progression to Strongyloides hyperinfection [1,2]. He had a documented history of peripheral eosinophilia for almost two decades prior to his presentation. While the majority of patients with chronic S. stercoralis infection may have peripheral eosinophilia, in the situation of hyperinfection, eosinophil counts may potentially be suppressed [2]. In this patient, while the initial full blood count did not show eosinophilia, subsequent development of eosinophilia, the clinical suspicion of meningitis and isolation of E. faecalis from the blood prompted a search for Strongyloides. While Strongyloides hyperinfection is typically associated with Gram-negative bacteremia and meningitis, there have been case reports of hyperinfection associated with Enterococcus spp. [8,9,10]. \n\nAlthough our patient presented with the triad of bacteremia, central nervous system involvement and pneumonia typical of Strongyloides hyperinfection [1,2,3], he also had unusual features of gas-forming spondylodiscitis and psoas abscesses. Seeding of the spine might potentially have occurred through hematogenous spread of the bacteria, or through dissemination of the Strongyloides larvae. However, while larva currens and cutaneous manifestations of Strongyloides hyperinfection are well-documented [5], dissemination to deep soft tissue and spinal involvement is less commonly reported [1,2,3]. Gas-forming spondylodiscitis is an uncommon radiological finding [11,12,13,14,15]. Common causes of emphysematous osteomyelitis include anaerobes, Gram-negative organisms (e.g., K. pneumoniae, E. coli) and Staphylococcus aureus [12,13,14,15]; though, E. faecalis has previously been reported as a cause of gas-forming spinal epidural abscess [11]. In our patient, the only positive microbiology was E. faecalis isolated from the bloodstream. Gas-forming osteomyelitis was associated with a higher mortality rate compared to vertebral osteomyelitis with non-gas-forming organisms [12]. Despite early suspicion of Strongyloides hyperinfection, commencement of appropriate antibiotics, anti-helminthics and microbiological clearance of both E. faecalis from the bloodstream and clearance of S. stercoralis from the stool (demonstrated by two consecutive negative microscopic examinations of both stool and early morning nasogastric aspirates), our patient still succumbed to his infection. This highlights the high mortality associated with Strongyloides hyperinfection [1,2] and the high index of suspicion required to establish early diagnosis and institute appropriate treatment. \n\nAcknowledgments\nAs the patient eventually demised and did not recover consciousness, written informed consent from the patient for publication could not be feasibly obtained. Consent was obtained from the patient’s family for publication and no identifying details of the patient were included in the publication in order to preserve anonymity.\n\nAuthor Contributions\nL.E.W., S.W.K.H., Z.X. and L.S.-U.L. wrote the manuscript, managed the patient and provided clinical history. All authors have read and agree to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest. \n\nFigure 1 Strongyloides hyperinfection associated with gas-forming spondylodiscitis and E. faecalis bacteremia. (a) Transverse view of the computed tomography scan of the abdomen, demonstrating gas-forming spondylodiscitis. (b) Coronal view of the computed tomography scan of the abdomen, demonstrating gas-forming spondylodiscitis. (c) Bilateral pulmonary infiltrates noted on the computed tomography scan of the thorax.\n\ntropicalmed-05-00044-t001_Table 1Table 1 Eosinophil trend, clinical events and history of steroid usage prior to presentation.\n\nDate\t2002\t2004\tMarch–April 2016\t2018\tJanuary 2019\tJuly 2019\tDecember 2019\t\nEosinophil count (×109/L)\t0.8\t0.8\t3.9\t2.8\t0.8\t0.6\t0.5\t0.0\t0.8\t0.2\t0.3\t1.7\t2.2\t1.1\t0.8\t\nEosinophil %\t9.5\t6.5\t25.4\t31.1\t4.7\t6.3\t4.2\t0.1\t8.4\t1.9\t1.3\t8.1\t16.6\t12\t5.4\t\nEvent\tRoutine primary care visit\tAdmitted for bleeding gastric ulcer\tAdmitted for left upper limb cellulitis and deconditioning in March 2016; transferred to a community hospital for rehabilitation in April 2016. Had two documented episodes of E.coli urinary tract infection\tRoutine primary care visit\tRoutine primary care visit\tRoutine primary care visit\tRoutine primary care visit \tAdmitted in mid-December 2019 for fever and altered mental status, diagnosed with Strongyloides hyperinfection (stool positive from D4-D8 of admission)\nStarted on daily oral ivermectin from D4-D11 of admission. \t\nSteroid usage\tNot known\tTraditional Chinese medicine\tStarted on hydrocortisone 20 mg once every morning, 10 mg once every evening for adrenal insufficiency on 16/3/16; dose subsequently reduced further to 10 mg daily\tRemains on maintenance hydrocortisone 10 mg once daily\tSwitched to prednisolone 5 mg once daily from June 2019 and stopped from September 2019, but patient inadvertently took hydrocortisone 10 mg once daily and prednisolone 5 mg once daily up till December 2019 admission.\n==== Refs\nReferences\n1. Vasquez-Rios G. Pineda-Reyes R. Pineda-Reyes J. Marin R. Ruiz E.F. Terashima A. Strongyloides stercoralis hyperinfection syndrome: A deeper understanding of a neglected disease J. Parasit. Dis. 2019 43 167 175 10.1007/s12639-019-01090-x 31263320 \n2. Nutman T.B. Human infection with Strongyloides stercoralis and other related Strongyloides species Parasitology 2017 144 263 273 10.1017/S0031182016000834 27181117 \n3. Buonfrate D. Requena-Mendez A. Angheben A. Muñoz J. Gobbi F. Van Den Ende J. Bisoffi Z. Severe strongyloidiasis: A systematic review of case reports BMC Infect. Dis. 2013 13 78 10.1186/1471-2334-13-78 23394259 \n4. Koh M.S. Leng P.H. Eng P. Hwang J. An unusual cause of pulmonary haemorrhage in a patient with rheumatoid arthritis Ann. Acad. Med. Singap. 2004 33 365 367 15175782 \n5. Oh C.C. Ong T.H. Busmanis I. Wijaya L. An 81-year-old man with cutaneous periumbilical purpura Chest 2012 141 818 821 10.1378/chest.11-1878 22396570 \n6. Seet R.C. Lau L.G. Tambyah P.A. Strongyloides hyperinfection and hypogammaglobulinemia Clin. Diagn. Lab. Immunol. 2005 12 680 682 10.1128/CDLI.12.5.680-682.2005 15879034 \n7. Robson D. Beeching N.J. Gill G.V. Strongyloides hyperinfection syndrome in British veterans Ann. Trop. Med. Parasitol. 2009 103 145 148 10.1179/136485909X385009 19208298 \n8. Zeana C. Kubin C.J. Della-Latta P. Hammer S.M. Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: Case report and review of the literature Clin. Infect. Dis. 2001 33 477 482 10.1086/321896 11462183 \n9. Abu Omar M. Abu Ghanimeh M. Kim S. Howell G. Strongyloides hyperinfection syndrome and VRE pneumonia BMJ Case Rep. 2017 bcr2016216634 10.1136/bcr-2016-216634 28093424 \n10. Schein F. Fouillet L. Lutz M.F. Daguenet E. Botelho-Nevers E. Cornillon J. Recurrent Enterococcus faecalis meningitis in a patient presenting with Strongyloides hyperinfection syndrome during HTLV-1-induced T-cell lymphoma Med. Mal. Infect. 2018 48 428 430 10.1016/j.medmal.2018.04.389 29884325 \n11. Bang J.H. Cho K.T. Rapidly Progressive Gas-containing Lumbar Spinal Epidural Abscess Korean J. Spine 2015 12 139 142 10.14245/kjs.2015.12.3.139 26512268 \n12. Ono R. Uehara K. Kitagawa I. Emphysematous Osteomyelitis of the Spine: A Case Report and Literature Review Intern. Med. 2018 57 2081 2087 10.2169/internalmedicine.0219-17 29526940 \n13. Khanduri S. Singh M. Goyal A. Singh S. Emphysematous osteomyelitis: Report of two cases and review of literature Indian J. Radiol. Imaging 2018 28 78 80 29692532 \n14. Kim Y.K. Jo K.M. Jang J.H. Heo C.M. Lee J.H. Park J.H. Kim S. Jang H.J. Kim H.K. Kiem S. Rapidly Fatal Emphysematous Osteomyelitis with Multiple Septic Emboli and Liver Abscess Caused by Klebsiella pneumoniae Infect. Chemother. 2018 50 268 273 10.3947/ic.2018.50.3.268 30270587 \n15. Aghaei Lasboo A. Walker M.T. Hijaz T.A. An unusual appearance of discitis due to gas-forming Escherichia coli with associated pneumocephalus Spine 2010 35 E257 E259 10.1097/BRS.0b013e3181bca12f 20228705\n\n",
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"issue": "5(1)",
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"keywords": "Strongyloides; emphysematous spondylodiscitis; enterococcus; hyperinfection",
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"pubdate": "2020-03-12",
"publication_types": "D002363:Case Reports",
"references": "19208298;28093424;15175782;29526940;11462183;22396570;23394259;27181117;29884325;15879034;26512268;29692532;30270587;20228705;31263320",
"title": "Strongyloides Hyperinfection Associated with Enterococcus faecalis Bacteremia, Meningitis, Ventriculitis and Gas-Forming Spondylodiscitis: A Case Report.",
"title_normalized": "strongyloides hyperinfection associated with enterococcus faecalis bacteremia meningitis ventriculitis and gas forming spondylodiscitis a case report"
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"companynumb": "SG-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-244492",
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"abstract": "We present the case of a patient who presented to the emergency department complaining of diffuse myalgias, severe jaw pain and chills. She met criteria for severe sepsis and received treatment including analgesia, antibiotics, intravenous fluids, and antipyretics. Workup revealed an elevated lactate and leukocytosis however, did not reveal any infectious source. The patient had a history of Crohn's disease and had received an infusion of infliximab ten days prior to the onset of her symptoms. After ruling out other potential causes of lactic acidemia, her final diagnosis was determined to be the rare presentation of an infliximab infusion reaction. On reviewing the literature, we could not find another documented case of a lactic acidemia caused by an infliximab infusion reaction. The key to the treatment of this patient was steroids, antihistamines, and supportive treatment. Emergency physicians do not often encounter infliximab infusion reactions because they occur so infrequently. Along with more common diagnoses such as sepsis, emergency physicians should include infliximab infusion reactions on the differential diagnosis in patients receiving this medication.",
"affiliations": "Department of Emergency Medicine, Good Samaritan Hospital Medical Center, West Islip, NY, United States. Electronic address: nvigh@nyit.edu.;Department of Emergency Medicine, Good Samaritan Hospital Medical Center, West Islip, NY, United States.",
"authors": "Vigh|Nicole|N|;Levy|David|D|",
"chemical_list": "D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.11.005",
"fulltext": null,
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"issn_linking": "0735-6757",
"issue": "38(4)",
"journal": "The American journal of emergency medicine",
"keywords": "Drug reaction; Infliximab; Lactic acidemia; Reaction",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000140:Acidosis, Lactic; D000328:Adult; D018501:Antirheumatic Agents; D018771:Arthralgia; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D000069285:Infliximab",
"nlm_unique_id": "8309942",
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"pages": "850.e1-850.e3",
"pmc": null,
"pmid": "31831342",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Lactic acidemia due to an infliximab infusion reaction.",
"title_normalized": "lactic acidemia due to an infliximab infusion reaction"
} | [
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"companynumb": "US-JNJFOC-20200827396",
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"abstract": "BACKGROUND\nPurpuric drug eruption (PDE) is an uncommon, clinically distinct side effect of epidermal growth factor receptor (EGFR) inhibitors.\nUnlike acneiform eruption, which arises from hair follicles mainly in the head and neck area, PDE starts from xerosis cutis, primarily in the lower extremities and is not associated with hair follicles. Herein, we report 3 cases of 3 patients who had received EGFR inhibitor and were hospitalized for PDE later. The cases were characterized by painful late-onset palpable purpura with identifiable bacterial pathogens.\n\n\nMETHODS\nThe patients were diagnosed with characteristic clinical presentations, that is, late onset, PDE locations mainly in the lower extremities, nonfollicular centricity, and laboratory findings with identifiable bacterial pathogens.\n\n\nMETHODS\nSystemic antibiotics and intensive moisturizer application were prescribed.\n\n\nRESULTS\nAll the patients were successfully treated within 6 to 9 days without discontinuation of EGFR inhibitors.\n\n\nCONCLUSIONS\nSystemic antibiotics, topical emollient, and skin barrier repair should be included in the treatment regimens for PDE.",
"affiliations": "Department of Dermatology, Kaohsiung Veterans General Hospital.;Department of Dermatology, Kaohsiung Veterans General Hospital.;Department of Dermatology, E-Da Hospital & I-Shou University, Graduate Institute of Science Education and Environmental Education, National Kaohsiung Normal University, Kaohsiung, Taiwan.;Department of Dermatology, Kaohsiung Veterans General Hospital.",
"authors": "Fang|Szu-Yun|SY|;Wu|Chieh-Shan|CS|;Liu|Yi-Shan|YS|;Wei|Kai-Che|KC|",
"chemical_list": "C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000018112",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31764850MD-D-19-0171510.1097/MD.0000000000018112181125700Research ArticleClinical Case ReportEpidermal growth factor receptor (EGFR) inhibitor induced purpuric drug eruption Three case reportsFang Szu-Yun MDaWu Chieh-Shan MDaLiu Yi-Shan MDbWei Kai-Che MDa∗NA. a Department of Dermatology, Kaohsiung Veterans General Hospitalb Department of Dermatology, E-Da Hospital & I-Shou University, Graduate Institute of Science Education and Environmental Education, National Kaohsiung Normal University, Kaohsiung, Taiwan.∗ Correspondence: Kai-Che Wei, Department of Dermatology, Kaohsiung Veterans General Hospital, No.386, Dazhong 1st Rd, Zuoying Dist, Kaohsiung City 81362, Taiwan (e-mail: kaiche92@gmail.com).11 2019 22 11 2019 98 47 e181129 3 2019 9 10 2019 24 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nPurpuric drug eruption (PDE) is an uncommon, clinically distinct side effect of epidermal growth factor receptor (EGFR) inhibitors.\n\nPatient concerns:\nUnlike acneiform eruption, which arises from hair follicles mainly in the head and neck area, PDE starts from xerosis cutis, primarily in the lower extremities and is not associated with hair follicles. Herein, we report 3 cases of 3 patients who had received EGFR inhibitor and were hospitalized for PDE later. The cases were characterized by painful late-onset palpable purpura with identifiable bacterial pathogens.\n\nDiagnosis:\nThe patients were diagnosed with characteristic clinical presentations, that is, late onset, PDE locations mainly in the lower extremities, nonfollicular centricity, and laboratory findings with identifiable bacterial pathogens.\n\nInterventions:\nSystemic antibiotics and intensive moisturizer application were prescribed.\n\nOutcomes:\nAll the patients were successfully treated within 6 to 9 days without discontinuation of EGFR inhibitors.\n\nConclusion:\nSystemic antibiotics, topical emollient, and skin barrier repair should be included in the treatment regimens for PDE.\n\nKeywords\nacneiform eruptionepidermal growth factor receptorepidermal growth factor receptor inhibitorlung cancerpurpuric drug eruptionOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nEpidermal growth factor receptor (EGFR) inhibitors block the signal transduction pathway to inhibit cancer cell proliferation and survival and are widely used to treat non-small cell lung cancer.[1,2] Because of the distribution of EGFR, the most common side effects of EGFR inhibitors are cutaneous adverse events that are crucially dependent on EGFR signaling for normal function, and these adverse events affect 50% to 100% of patients, in a dose-dependent manner.[3] Skin-related side effects can result in decreased quality of life and may require decrease in the dose of EGFR inhibitors or interruption or discontinuation of cancer treatment. Thus, proper management and prevention of possible skin-related side effects are important for continuing EGFR inhibitor treatment.[4,5]\n\nThe most common skin toxic side effect is acneiform eruption, and other common events include pruritus, xerosis, and paronychia.[6] Less common adverse effects include mucositis, trichomegaly, and hypersensitivity. Purpuric drug eruption (PDE) has been reported as a rare complication.[7] However, the prevalence of PDE may not be as rare as expected. Recently, we encountered 3 hospitalized PDE patients. They were treated successfully with both systemic antibiotics and intensive skin care, without a decrease or discontinuation of EGFR inhibitor. By sharing these cases, we can increase clinicians’ awareness of PDE to provide timely and appropriate treatment in order to improve patient quality of life and avoid interruption of treatment with EGFR inhibitors.\n\n2 Case presentation\n(Each of following 3 patients has provided informed consent for publication of the case.)\n\nCase 1: A 61-year-old man had stage IB lung adenocarcinoma with EGFR mutation (+), exon 21 L858R, and received erlotinib 150 mg daily. Two and a half months after erlotinib was started, he initially experienced xerotic (dry) change over his bilateral lower extremities. Then, purpuric macules and papules were noted, and some papules turned into pustules days later. Clinical inspection showed multiple purpuric papules and pustules that were topped with crust, and erythematous-to-violaceous plaques and erosions over his bilateral thighs and legs (Fig. 1 A and B). Histopathology showed epidermal atrophy, parakeratosis, exudate with bacterial colonies on the surface, and neutrophil and lymphocyte inflammatory cell infiltration into the upper dermis (Fig. 1C). The dermis also showed telangiectatic changes with erythrocyte extravasation and fibrin deposition into the vascular wall of blood vessels (Fig. 1C). No fungus was found in the periodic acid-Schiff stain. The laboratory examination showed normal platelet counts, prothrombin time, and partial thromboplastin time. Pus and tissue cultures yielded oxacillin-susceptible Staphylococcus aureus (OSSA) and Pseudomonas aeruginosa. Systemic treatment with cefepime for 1 week and skin care with topical emollient were given. The patient continued erlotinib treatment during the treatment course, and the skin eruption subsided after 9 days of therapy. During the following 3 months, if he did not apply topical emollient, xerotic skin and subsequent tender pustules appeared within days. And this kind of attack was experienced 3 times.\n\nFigure 1 Case 1. (A) Multiple purpuric papules and pustule on erythematous to violaceous patches and erosions over his bilateral thighs and legs. (B) Xerosis skin over his thigh. (C) Histopathology showed telangiectasia, erythrocyte extravasation, and a perivascular inflammatory infiltration composed with neutrophils and lymphocytes in the superficial dermis without vasculitis. (100×; hematoxylin and eosin stain).\n\nCase 2: An 82-year-old woman was diagnosed with stage IV lung adenocarcinoma with an EGFR mutation (exon 21 L858R) and was treated with oral gefitinib 250 mg daily. After 3 months of gefitinib treatment, multiple erythematous and purpuric macules, papules, and stinging erosions appeared over her buttocks, bilateral inner thighs, knee fossae, and bilateral inner legs, especially at her bilateral inner thigh regions. No mucosal lesions were observed. Skin biopsy showed epidermal atrophy, necrosis, spongiosis, and marked neutrophilic infiltration and erythrocyte extravasation into the superficial dermis, with vasculitis changes of small blood vessels that showed fibrinoid deposition and neutrophils with predominant vascular infiltration. Suprabasal and subcorneal acantholysis were also noted. A direct immunofluorescence study showed negative results, and the laboratory tests, including platelet count and coagulation profiles, were within normal limits. Bacterial culture from the erosions yielded oxacillin-resistant Staphylococcus aureus (ORSA). Treatments with oral minocycline and potent topical corticosteroids (fluocinolone acetonide) and emollient were given without the discontinuation of gefitinib therapy. One week later, the skin eruption subsided with hyperpigmentation without recurrence during the following 6 months.\n\nCase 3: A 63-year-old woman was diagnosed with stage IV lung adenocarcinoma with an EGFR mutation (+) (exon 21 L858R) and received erlotinib treatment 150 mg daily. Two and half months later, multiple severe painful and itchy discrete erythematous to purpuric papules, pustules, and crusted ulcers on her chest, abdomen, pubic area, back, and 4 limbs were noted. The skin biopsy revealed parakeratosis, basal cell vacuolization, perivascular lymphocytic, and neutrophilic infiltration, with erythrocyte extravasation into the superficial dermis and gram-positive cocci in small clusters that were compatible with the culture result. Amyloid deposition was noted at the papillary dermis. The periodic acid-Schiff stain showed negative results for fungus. Her platelet count and coagulation profiles were within normal limits, and the pus culture yielded OSSA. She received treatment with systemic cefazolin and topical petrolatum without discontinuation of erlotinib treatment. The skin eruption subsided after 6 days of treatment.\n\n3 Discussion\nPDE is clinically distinct from acneiform skin eruption. Although there is no large-scale epidemiologic study to explore the incidence of PDE, PDE seems not as rare as expected, according to our experiences. Among the skin toxicities that are associated with EGFRIs, acneiform eruption is the most common. The link between acneiform eruption and the development of PDE is not clear. The 3 patients presented here all had grade 2 acneiform eruptions on the face, chest, and back 10 to 21 days after starting EGFR inhibitor treatment, and all of the acneiform lesions subsided within 2 weeks of proper treatment (Table 1). The time frame of PDE is quite different from that of acneiform eruption. The median interval between the development of PDE and EGFR inhibitor commencement is 2.5 to 3 months in our patients and 3.5 months in 1 previous report.[7] This is longer than that of acneiform eruption, of which the median time to onset ranges from 1 to 2 weeks,[4,5] often reaching a maximum at 2 to 3 weeks following therapy initiation.[3]\n\nTable 1 Summary of characteristics in these 3 purpuric drug eruption patients.\n\nThe cutaneous manifestations of PDE are multiple purpuric erythematous papules, which frequently present various sized pustules and can even become coalesced purpuric erosions. These lesions are not follicular centric while acneiform eruptions invariably arise from hair follicles. PDE shows a predominant distribution in the lower extremities, and other less frequent locations include the upper extremities and trunk. The face is usually spared, while acneiform eruption invariably involves seborrheic (oily) area, including the face, scalp, and chest.[7,8]\n\nThe pathogenesis of PDE involves a mixture of different pathways. Skin barrier and bacteria may play an important role, and the bacterial cultures from our 3 hospitalized patients all yielded S aureus, and one also showed P aeruginosa. The result is consistent with previous studies, which revealed S aureus was the most common bacterial pathogen in patients treated with EGFR inhibitors, and the second was P aeruginosa.[7,9] Treatment with systemic antibiotics is effective. On the contrary, bacterial cultures of acneiform eruption lesions usually show negative results, except in cases of secondary superinfection.[8]\n\nFurthermore, we observed PDE lesions invariably started from the xerosis skin. Eczema craquelé (asteatotic dermatitis) appears initially (Fig. 1B); then, purpuric eruptions appear in the dry cracking skin and finally turn into tender and painful pustules rapidly within several days when proper treatment is not given.[10] Xerosis is a common cutaneous adverse effect of EGFR inhibitors and appears relatively late, about 1 to 2 months after the start of EGFR inhibitor.[11] Since there is a close association between skin xerosis and PDE, proper skin care with emollient and skin barrier repair should be crucial parts of the treatment for PDE.\n\nThe histopathologic findings of PDE showed a subcorneal pustule without folliculitis in a pustule lesion. Epidermal atrophy, parakeratosis, focal hydropic degeneration, or spongiosis could be found in some of the reported cases. The superficial dermis in a purpuric papule commonly shows perivascular neutrophilic and lymphocytic infiltration and telangiectatic changes with abundant erythrocyte extravasations (Fig. 1C). Some cases also revealed leukocytoclastic vasculitis changes; however, these changes may be secondary to ulcer-induced inflammation.[7,10] In Case 2, there were both suprabasal and subcorneal acantholysis (loss of cohesion between keratinocytes). Acantholysis can appear in autoimmune blister disease, such as pemphigus, but can be incidentally found in many inflammatory dermatoses, such as staphylococcal scalded skin syndrome. Acantholysis in PDE is an uncommon histological presentation that has only been reported in 3 cases.[12,13] In our case, the direct immunofluorescence study showed negative results; thus, autoimmune bullous diseases were less likely. The mechanism may involve S aureus exfoliative toxin A targeting desmoglein 1, which results in subcorneal acantholysis.[14] Another possible hypothesis is that activated neutrophils that are induced by EGFR inhibitors may release proteases that contribute to further tissue destruction, with the loss of intercellular attachments in the epidermis, basal keratinocyte degeneration, and destruction of the basement membrane.[15] Amyloid deposition in papillary dermis was found incidentally in case 3, and there was no related clinical change.\n\nEGFR is expressed on basal epidermal keratinocytes, the outer root sheath cells of hair follicles, sebaceous and eccrine sweat gland cells, some endothelial cells, smooth muscle cells of dermal vessels, and various cancer cells.[2] Disruption of the normal EGFR pathway of basal keratinocytes can give rise to growth arrest and premature differentiation, leading to impaired stratum corneum, interference of sebaceous gland function, and reduced expression of major components of cornified cell envelopes, which results in loss of the water-retaining function of the epidermis, and then xerosis skin develops.[15] Additionally, the release of inflammatory cell chemoattractants may recruit leukocytes that release enzymes, resulting in apoptosis and tissue damage with subsequent apoptotic keratinocytes, vascular dilation, and increased permeability.[15] The purpuric change may be involved in a similar mechanism. The EGFR on endothelial cells and dermal vessel smooth muscle cells and EGFR inhibitors can result in inflammation of the endothelium, loss of vessel wall structural support, increased permeability, and red blood cell extravasation. In addition, xerosis with disturbed barrier function also increases susceptibility to injuries and facilitates microbial invasion. In human skin, antimicrobial peptides such as human β-defensins (hBDs) serve as the first line of defense against infections by pathogenic microorganisms. EGFR inhibitor could dampen the innate immune system and suppress hBD2 expression,[7,16] which allows bacterial infection and further results in aggravating tissue inflammation, recruiting neutrophils, and the subsequent formation of pustules.\n\nAccording to the speculated mechanisms described as the above, factors including impaired barrier function, perivascular inflammation, and pathogen invasion can result in a clinical presentation that includes xerosis skin, purpuric change, and pustule formation. Therefore, we recommend routine microorganism surveys for purpuric and pustules lesions, that is, for doctors to treat such findings with definitive antibiotic therapy, based on the culture report. Before the final culture report, an antibiotic should be selected to treat OSSA, ORSA, and P aeruginosa. Our experiences strongly suggest that intensive skin care is as important as antibiotic treatment for controlling and reestablishing normal skin components and preventing microorganism invasion, which avoid further inflammation and pustule formation. Besides, the moisture contents of the horny layer and cutaneous sebum levels increased after moisturizer application, which is effective against dry skin and skin toxicities due to EGFR inhibitors.[17,18] All of the patients in our case report were successfully treated with systemic antibiotics with intensive moisturizer, without decreasing or discontinuing EGFR inhibitors. The median clinical treatment course in our 3 cases was 6 to 9 days.\n\nIn summary, we share 3 cases of EGFR-induced PDE who were successfully treated with systemic antibiotics for 6 to 9 days with intensive moisturizer, without decreasing or discontinuing EGFR inhibitors. The median clinical treatment course in our 3 cases was 6 to 9 days. The clinical manifestations of PDE differ from those of acneiform eruptions with regard to late onset, location mainly at the lower extremities, nonfollicular centricity, and identifiable bacterial pathogens. It should be emphasized the importance of timely treatment with systemic antibiotics, topical application moisturizer, and avoiding discontinuation of EGFR inhibitors to achieve better clinical outcomes of cancer treatment.\n\nAuthor contributions\nConceptualization: Szu-Yun Fang, Kai-Che Wei.\n\nSupervision: Yi-Shan Liu, Kai-Che Wei.\n\nWriting – original draft: Szu-Yun Fang, Kai-Che Wei.\n\nWriting – review & editing: Chieh-Shan Wu.\n\nAbbreviations: EGFR = epidermal growth factor receptor, EGFRI = epidermal growth factor receptor inhibitor, hBDs = human β-defensins, LCV = leukocytoclastic vasculitis, OSSA = oxacillin-sensitive Staphylococcus aureus, ORSA = oxacillin-resistant Staphylococcus aureus, PDE = purpuric drug eruption.\n\nHow to cite this article: Fang SY, Wu CS, Liu YS, Wei KC. EGFR inhibitor induced purpuric drug eruption: three case reports. Medicine. 2019;98:47(e18112).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Baselga J \nNew therapeutic agents targeting the epidermal growth factor receptor . J Clin Oncol \n2000 ;18 : 21 Suppl : 54S –9S .11060328 \n[2] Nanney LB Magid M Stoscheck CM \nComparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages . J Invest Dermatol \n1984 ;83 :385 –93 .6092481 \n[3] Segaert S Van Cutsem E \nClinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors . Ann Oncol \n2005 ;16 :1425 –33 .16012181 \n[4] Chanprapaph K Pongcharoen P Vachiramon V \nCutaneous adverse events of epidermal growth factor receptor inhibitors: a retrospective review of 99 cases . Indian J Dermatol Venereol Leprol \n2015 ;81 :547 .\n[5] Kiyohara Y Yamazaki N Kishi A \nErlotinib-related skin toxicities: treatment strategies in patients with metastatic non-small cell lung cancer . J Am Acad Dermatol \n2013 ;69 :463 –72 .23602600 \n[6] Agero AL Dusza SW Benvenuto-Andrade C \nDermatologic side effects associated with the epidermal growth factor receptor inhibitors . J Am Acad Dermatol \n2006 ;55 :657 –70 .17010747 \n[7] Cho YT Chen KL Sheen YS \nPurpuric drug eruptions caused by epidermal growth factor receptor inhibitors for non-small cell lung cancer: a clinicopathologic study of 32 cases . JAMA Dermatol \n2017 ;153 :906 –10 .28538945 \n[8] Roe E Garcia Muret MP Marcuello E \nDescription and management of cutaneous side effects during cetuximab or erlotinib treatments: a prospective study of 30 patients . J Am Acad Dermatol \n2006 ;55 :429 –37 .16908348 \n[9] Eilers RE JrGandhi M Patel JD \nDermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy . J Natl Cancer Inst \n2010 ;102 :47 –53 .20007525 \n[10] Sheen YS Hsiao CH Chu CY \nSevere purpuric xerotic dermatitis associated with gefitinib therapy . Arch Dermatol \n2008 ;144 :269 –70 .18283195 \n[11] Owczarek W Slowinska M Lesiak A \nThe incidence and management of cutaneous adverse events of the epidermal growth factor receptor inhibitors . Postepy Dermatol Alergol \n2017 ;34 :418 –28 .29507555 \n[12] Busam KJ Capodieci P Motzer R \nCutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225 . Br J Dermatol \n2001 ;144 :1169 –76 .11422037 \n[13] Chen KL Cho YT Yang CW \nA patient with acantholytic pustular purpuric eruption due to gefitinib successfully treated with systemic antibiotics . Dermatol Sin \n2016 ;34 :166 –7 .\n[14] Amagai M Matsuyoshi N Wang ZH \nToxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1 . Nat Med \n2000 ;6 :1275 –7 .11062541 \n[15] Lacouture ME \nMechanisms of cutaneous toxicities to EGFR inhibitors . Nat Rev Cancer \n2006 ;6 :803 –12 .16990857 \n[16] Park K Ommori R Imoto K \nEpidermal growth factor receptor inhibitors selectively inhibit the expressions of human beta-defensins induced by Staphylococcus epidermidis . J Dermatol Sci \n2014 ;75 :94 –9 .24831548 \n[17] Grande R Narducci F Bianchetti S \nPre-emptive skin toxicity treatment for anti-EGFR drugs: evaluation of efficacy of skin moisturizers and lymecycline. A phase II study . Support Care Cancer \n2013 ;21 :1691 –5 .23314653 \n[18] Watanabe S Nakamura M Takahashi H \nDermopathy associated with cetuximab and panitumumab: investigation of the usefulness of moisturizers in its management . Clin Cosmet Investig Dermatol \n2017 ;10 :353 –61 .\n\n",
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"issn_linking": "0025-7974",
"issue": "98(47)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D003875:Drug Eruptions; D066246:ErbB Receptors; D006801:Humans; D008297:Male; D008875:Middle Aged; D011537:Pruritus",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e18112",
"pmc": null,
"pmid": "31764850",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epidermal growth factor receptor (EGFR) inhibitor induced purpuric drug eruption: Three case reports.",
"title_normalized": "epidermal growth factor receptor egfr inhibitor induced purpuric drug eruption three case reports"
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"companynumb": "TW-ASTELLAS-2020US004585",
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"occurcountry": "TW",
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"activesubstance": {
"activesubstancename": "ERLOTINIB"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nFibrolamellar carcinoma (FLC) has been considered a distinct clinical entity vs. hepatocellular carcinoma, with respect to its epidemiology, etiology, and prognosis.\n\n\nMETHODS\nWe describe the unusual case of a 23-year-old female patient with FLC and ovarian (Krukenberg) and peritoneal metastases, clinically mimicking an ovarian carcinoma. Multiple recurrences occurred despite initial R0 resection and chemotherapy, requiring surgical treatment. The patient survived five years and died from generalized disease.\n\n\nCONCLUSIONS\nThe particularities of our case are discussed by comparison with the other two similar cases and other date from the literature.\n\n\nCONCLUSIONS\nTo our knowledge, the ovarian involvement encountered in our case is the third case published in literature, being explained by the superficial location of the liver tumor.",
"affiliations": "Center of General Surgery and Liver Transplantation, \"Fundeni\" Clinical Institute, Bucharest, Romania; emmatei@yahoo.com.",
"authors": "Ciurea|Silviu Horia|SH|;Matei|Emil|E|;Stănescu|CodruŢ Silvian|CS|;Lupescu|Ioana Gabriela|IG|;Boroş|Mirela|M|;Herlea|Vlad|V|;Luca|Niculina Ioana|NI|;DorobanŢu|Bogdan Mihail|BM|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1220-0522",
"issue": "58(1)",
"journal": "Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie",
"keywords": null,
"medline_ta": "Rom J Morphol Embryol",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "9112454",
"other_id": null,
"pages": "187-192",
"pmc": null,
"pmid": "28523316",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fibrolamellar hepatocellular carcinoma with ovarian metastasis - an unusual presentation.",
"title_normalized": "fibrolamellar hepatocellular carcinoma with ovarian metastasis an unusual presentation"
} | [
{
"companynumb": "RO-BAYER-2017-178800",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SORAFENIB"
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"abstract": "Allergic bronchopulmonary aspergillosis (ABPA) is a severe hypersensitivity reaction to aspergillus species colonizing the airways of patients with asthma or cystic fibrosis. Biologics including anti-IgE and anti-IL5 antibodies have strongly changed the treatment of severe asthmatics and have partly been reported to be effective in the treatment of ABPA. Recently, dupilumab, an anti-IL4-Rα antibody which inhibits signaling by the Th2-cytokines IL4 and IL13, has been approved for the treatment of severe asthma.\nHere, we report the case of a 49-year-old woman with severe asthma and ABPA, who was uncontrolled despite maximum inhalative therapy, anti-IL5-Rα antibody and continuous oral steroid therapy. Moreover, trials of itraconazole as well as omalizumab showed insufficient efficacy. Lung function revealed peripheral obstruction. FeNO and IgE were increased, eosinophils were suppressed under treatment while marked increases had been documented previously. Switching to dupilumab led to a complete resolution of pulmonary symptoms, resolution of exacerbations and complete withdrawal of oral steroids. A drastic improvement in lung function was noted, with an increase in FEV1 of almost 1 l. FeNO was normalized and IgE strongly reduced.\nOur case highlights that a patient may exhibit differential treatment responses to the currently available asthma biologics and suggests switching treatment if outcome is insufficient. A potential role for dupilumab in the treatment of ABPA warrants future studies.",
"affiliations": "Department of Internal Medicine V, Ludwig-Maximilians-University of Munich (LMU), Marchioninistr.15, 81377 Munich, Germany.;Pneumologie an der Münchner Freiheit, Munich, Germany.;Department of Internal Medicine V, Ludwig-Maximilians-University of Munich (LMU), Marchioninistr.15, 81377 Munich, Germany.;Department of Internal Medicine V, Ludwig-Maximilians-University of Munich (LMU), Marchioninistr.15, 81377 Munich, Germany.;Department of Internal Medicine V, Ludwig-Maximilians-University of Munich (LMU), Marchioninistr.15, 81377 Munich, Germany.",
"authors": "Mümmler|Carlo|C|;Kemmerich|Bernd|B|;Behr|Jürgen|J|;Kneidinger|Nikolaus|N|;Milger|Katrin|K|0000-0003-2914-8773",
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"fulltext": "\n==== Front\nAllergy Asthma Clin Immunol\nAllergy Asthma Clin Immunol\nAllergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology\n1710-1484 1710-1492 BioMed Central London \n\n454\n10.1186/s13223-020-00454-w\nCase Report\nDifferential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?\nMümmler Carlo 12 Kemmerich Bernd 3 Behr Jürgen 12 Kneidinger Nikolaus 12 http://orcid.org/0000-0003-2914-8773Milger Katrin Katrin.Milger@med.uni-muenchen.de 12 1 grid.5252.00000 0004 1936 973XDepartment of Internal Medicine V, Ludwig-Maximilians-University of Munich (LMU), Marchioninistr.15, 81377 Munich, Germany \n2 Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany \n3 Pneumologie an der Münchner Freiheit, Munich, Germany \n26 6 2020 \n26 6 2020 \n2020 \n16 5530 4 2020 22 6 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\nAllergic bronchopulmonary aspergillosis (ABPA) is a severe hypersensitivity reaction to aspergillus species colonizing the airways of patients with asthma or cystic fibrosis. Biologics including anti-IgE and anti-IL5 antibodies have strongly changed the treatment of severe asthmatics and have partly been reported to be effective in the treatment of ABPA. Recently, dupilumab, an anti-IL4-Rα antibody which inhibits signaling by the Th2-cytokines IL4 and IL13, has been approved for the treatment of severe asthma.\n\nCase presentation\nHere, we report the case of a 49-year-old woman with severe asthma and ABPA, who was uncontrolled despite maximum inhalative therapy, anti-IL5-Rα antibody and continuous oral steroid therapy. Moreover, trials of itraconazole as well as omalizumab showed insufficient efficacy. Lung function revealed peripheral obstruction. FeNO and IgE were increased, eosinophils were suppressed under treatment while marked increases had been documented previously. Switching to dupilumab led to a complete resolution of pulmonary symptoms, resolution of exacerbations and complete withdrawal of oral steroids. A drastic improvement in lung function was noted, with an increase in FEV1 of almost 1 l. FeNO was normalized and IgE strongly reduced.\n\nConclusion\nOur case highlights that a patient may exhibit differential treatment responses to the currently available asthma biologics and suggests switching treatment if outcome is insufficient. A potential role for dupilumab in the treatment of ABPA warrants future studies.\n\nKeywords\nABPAAspergillosisAsthmaDupilumabIL13IL4issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAllergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to aspergillus species that predominantly affects cystic fibrosis and asthma patients [1]. Aspergillus colonization of the bronchial mucus leads to an activation of the innate immune system with a Th2-predominant T cell response [2–5]. Clinical features of ABPA comprise frequent asthma exacerbations, productive cough, airway obstruction, fever, and finally leads to end-stage lung disease. Diagnostic criteria are a predisposing condition, high total serum IgE levels, aspergillus-specific IgE or positive aspergillus skin test, aspergillus-specific IgG, peripheral blood eosinophilia and imaging findings consistent with ABPA [1, 6]. Clinical management involves oral corticosteroids and systemic therapy with azoles. In recent years, several studies and case reports showed efficacy for anti-IgE antibody and IL5/IL5-Rα antibodies in the treatment of ABPA [7–11]. Dupilumab is a novel IL4-Rα-antibody that has been approved for the treatment of atopic dermatitis, severe asthma and chronic rhinosinusitis with nasal polyps. Here, we describe a case of a pronounced treatment response to dupilumab in a patient with severe asthma and ABPA previously refractory to therapy.\n\nCase presentation\nA 49-year old female patient, never-smoker, presented to our outpatient clinic with a 20-year history of severe asthma. The patient reported poor asthma control with an asthma control test (ACT) score of 5/25 points. During the last 3 years her symptoms had deteriorated with increasing dyspnea, productive cough and nocturnal symptoms. She further experienced two asthma exacerbations during the last 12 months. At that time, her medication included high-dose ICS, LABA, oral prednisolone at 20 mg per day and anti-IL5-Rα treatment with benralizumab. She reported side effects from oral corticosteroid use including weight gain, osteopenia and steroid acne. Three years prior, she was diagnosed with ABPA based on bronchiectasis and pulmonary infiltrates (Fig. 1), eosinophilia of 950/µl (13%), total serum IgE of up to 7000 IU/ml, specific aspergillus IgE of 31.4 U/ml and specific aspergillus IgG of more than 200 mg/l. A trial of itraconazol had been performed but was stopped due to inefficacy. Pulmonary function testing during benralizumab showed peripheral obstruction with an FEV1 of 2.46 l (74% pred.), FEV1/FVC of 73%, small airway disease with MMEF of 1.76 l (50%) and increased RV of 157%. Fraction of exhaled nitric oxide (FeNO) was elevated at 56 ppb. Latest lab values during benralizumab revealed increased IgE of 6700 IU/ml and suppressed eosinophils of 0/µl. Benralizumab was discontinued after 6 months of treatment due to lack of improvement and no biologic was applied in the following 3 months. In this interval no change in symptoms was observed. As a potential therapeutic effect for omalizumab in the treatment of ABPA has been reported [9], a trial of omalizumab at 600 mg subcutaneously every 2 weeks was undertaken. However, again, no change in symptoms was seen after 5 months of treatment and omalizumab was stopped. Instead, 6 weeks later a trial of dupilumab was initiated with a loading dose of 600 mg and further 300 mg doses subcutaneously every 2 weeks.Fig. 1 Chest CT demonstrating pulmonary infiltrates, bipulmonary bronchiectasis and bronchial wall thickening consistent with ABPA\n\n\n\nAt reevaluation 4 months after treatment initiation, the patient reported complete resolution of symptoms. ACT score had increased to 25/25 points. Oral steroid medication had been tapered completely and the patient experienced improvements of former steroid side effects (Fig. 2a). Lung function improved drastically with an FEV1-increase of almost 1000 ml to 3.43 l (99.6%), normalization of RV to 98% (Fig. 2b), and strong improvement in small airway obstruction (increase in MMEF from 1.76 to 2.87 l/s). FeNO decreased to a normal value of 10 ppb. Lung function improvements were sustained at 8 months follow-up (Fig. 2b). Laboratory analysis demonstrated a marked decrease in IgE to currently 940 IU/ml (reduction of 86%). Eosinophils at 4 months follow-up were increased to 1056/µl (16%), however normalized to 200/µl at 8 months follow-up (Fig. 2c). There were no changes in home or work environment during the reported period.Fig. 2 a Course of asthma control test (ACT) score and prednisolone dose over time. b Course of lung function parameters FEV1 and RV over time. c Course of FeNO, eosinophil count and IgE over time\n\n\n\nDiscussion\nABPA is a complication of bronchial asthma that renders disease management more difficult, often necessitating oral steroid treatment. High eosinophil counts are an important finding in the diagnosis of ABPA and initially eosinophils were markedly elevated in our patient. Thus, benralizumab had been started, which led to depletion of eosinophils, but did not improve symptoms, exacerbations or OCS dose. After discontinuation of benralizumab there was no change in symptoms underlining that the patient did not benefit from this treatment. Soeda et al. reported a case of asthma and ABPA with similar eosinophilia that responded well to benralizumab [11]. In contrast to our patient, that patient had less advanced disease without bronchiectasis and much lower total IgE of 537 IU/ml. Omalizumab decreased exacerbations in asthmatic patients with ABPA in a small prospective trial despite very high total IgE levels and a moderate omalizumab dose of 375 mg biweekly. However, improvement in lung function could not be demonstrated in that trial, and oral steroid tapering was not performed [9]. Our patient received a high dose of omalizumab (600 mg biweekly) but remained highly symptomatic and dependent on continuous OCS. In contrast, dupilumab led to a complete resolution of symptoms, discontinuation of OCS and normalization of lung function.\n\nEosinophils increased transiently after the initiation of dupilumab, however this was not associated with clinical symptoms and returned to a normal level during follow-up. In phase III trials of dupilumab in asthmatic patients, hypereosinophilia of more than 3000/µl was seen in 14% and 4.1% of dupilumab-treated patients, respectively and only led to discontinuation of dupilumab in few cases [12, 13]. It is hypothesized that dupilumab blocks the migration of eosinophils into (lung) tissues and therefore increases blood eosinophils transiently. The differential response to targeted biologic treatment suggests that in the present case the disease was mainly driven by IL4/IL13. Preclinical studies on APBA support a key role for IL4/IL13 signaling in ABPA. Dietschmann et al. showed that in a mouse model of ABPA, T-cells released huge amounts of IL4, IL5 and IL13 upon stimulation with Aspergillus fumigatus conidia. They further demonstrated that T cell-specific IL4/IL13-deficient-knockout mice exhibited reduced peripheral and lung eosinophilia, suggesting that IL4 and IL13 signaling leads to recruitment of eosinophils to the lung and blood from the bone marrow [3].\n\nAs comparative trials of different biologics in asthma and differential predictive biomarkers are currently lacking, guidelines recommend the trial of an antibody switch if the initial treatment did not show sufficient efficacy. This approach is supported by the presented case and previous treatment failures should not refrain clinicians from further trials of biologics that have different targets. It should be noted that the sequence in which the different biologics were applied here was mainly due to availability and licensing status of the drugs: dupilumab had only just become licensed for severe asthma when therapy was started in this patient.\n\nConclusion\nAltogether, this case report suggests that biological treatment should be switched to a drug with a different target, if treatment outcome under the previous biologic was insufficient. Further trials are needed to explore whether there is a general role for dupilumab in the treatment of ABPA.\n\nPatient perspective\n\n“After nearly 50 years of breathlessness, therapy with dupilumab changed my life from one day to the next: to breathe without resistance is really a new quality of life! Perhaps there are two things in my case, which are special to this success. First, I am doing at minimum one hour of sport each day (bicycling, rowing) since 35 years, even when this was hard to practice. And second: I lost, after starting with dupilumab and stopping cortisone, 17 kg of weight within three months with a fasting cure. Altogether, this is giving me a reliable and hopeful perspective for my future.”\n\n\n\n\nAbbreviations\nABPAAllergic broncho-pulmonary aspergillosis\n\nAnti-IgEAnti-immunoglobin E\n\nAnti-Il4RαAnti-interleukin5-receptor-alpha\n\nAnti-Il5RαAnti-interleukin5-receptor-alpha\n\nFeNOFractional exhaled nitric oxide\n\nFEV1Forced expiratory volume in 1 s\n\nOCSOral corticosteroid\n\nRVResidual volume\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nAll authors were involved in the treatment of the patient. CM, KM and BK designed the study and analyzed the data. CM and KM wrote the manuscript. JB and NK provided critical feedback and proofread the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe authors declare that they did not receive any form of funding for the writing of this clinical case.\n\nAvailability of data and materials\nThe data used during the current report are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nThe patient has given written informed consent for the case report to be published. Additionally she formulated a patient perspective in her own words which has been included in the report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Agarwal R Chakrabarti A Shah A Gupta D Meis JF Guleria R Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria Clin Exp Allergy 2013 43 8 850 873 10.1111/cea.12141 23889240 \n2. Rathore VB Johnson B Fink JN Kelly KJ Greenberger PA Kurup VP T cell proliferation and cytokine secretion to T cell epitopes of Asp f 2 in ABPA patients Clin Immunol. 2001 100 2 228 235 10.1006/clim.2001.5056 11465952 \n3. Dietschmann A Schruefer S Krappmann S Voehringer D Th2 cells promote eosinophil-independent pathology in a murine model of allergic bronchopulmonary aspergillosis Eur J Immunol. 2020 10.1002/eji.201948411 32108934 \n4. Walker C Bauer W Braun RK Menz G Braun P Schwarz F Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia Am J Respir Crit Care Med 1994 150 4 1038 1048 10.1164/ajrccm.150.4.7921434 7921434 \n5. Skov M Poulsen LK Koch C Increased antigen-specific Th-2 response in allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis Pediatr Pulmonol 1999 27 2 74 79 10.1002/(SICI)1099-0496(199902)27:2<74::AID-PPUL2>3.0.CO;2-L 10088929 \n6. Buckingham SJ Hansell DM Aspergillus in the lung: diverse and coincident forms Eur Radiol 2003 13 8 1786 1800 10.1007/s00330-002-1813-4 12783174 \n7. Li JX Fan LC Li MH Cao WJ Xu JF Beneficial effects of Omalizumab therapy in allergic bronchopulmonary aspergillosis: a synthesis review of published literature Respir Med 2017 122 33 42 10.1016/j.rmed.2016.11.019 27993289 \n8. van der Ent CK Hoekstra H Rijkers GT Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody Thorax 2007 62 3 276 277 10.1136/thx.2004.035519 17329558 \n9. Voskamp AL Gillman A Symons K Sandrini A Rolland JM O’Hehir RE Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis J Allergy Clin Immunol Pract. 2015 3 2 192 199 10.1016/j.jaip.2014.12.008 25640470 \n10. Terashima T Shinozaki T Iwami E Nakajima T Matsuzaki T A case of allergic bronchopulmonary aspergillosis successfully treated with mepolizumab BMC Pulm Med. 2018 18 1 53 10.1186/s12890-018-0617-5 29587693 \n11. Soeda S Kono Y Tsuzuki R Yamawaki S Katsube O To M Allergic bronchopulmonary aspergillosis successfully treated with benralizumab J Allergy Clin Immunol Pract 2019 7 5 1633 1635 10.1016/j.jaip.2018.11.024 30513359 \n12. Castro M Corren J Pavord ID Maspero J Wenzel S Rabe KF Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma N Engl J Med 2018 378 26 2486 2496 10.1056/NEJMoa1804092 29782217 \n13. Rabe KF Nair P Brusselle G Maspero JF Castro M Sher L Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma N Engl J Med 2018 378 26 2475 2485 10.1056/NEJMoa1804093 29782224\n\n",
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"title": "Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?",
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"abstract": "Case reports and small case series suggest increased central nervous system (CNS) toxicity, especially convulsions, after overdose of mefenamic acid, compared with other nonsteroidal anti-inflammatory drugs (NSAIDs), although comparative epidemiological studies have not been conducted. The current study compared rates of CNS toxicity after overdose between mefenamic acid, ibuprofen, diclofenac and naproxen, as reported in telephone enquiries to the UK National Poisons Information Service (NPIS).\n\n\n\nNPIS telephone enquiries related to the four NSAIDs, received between January 2007 and December 2013, were analysed, comparing the frequency of reported CNS toxicity (convulsions, altered conscious level, agitation or aggression, confusion or disorientation) using multivariable logistic regression.\n\n\n\nOf 22 937 patient-specific telephone enquiries, 10 398 did not involve co-ingestion of other substances (mefenamic acid 461, ibuprofen 8090, diclofenac 1300, naproxen 547). Patients taking mefenamic acid were younger and more commonly female than those using other NSAIDs. Those ingesting mefenamic acid were more likely to experience CNS toxicity than those ingesting the other NSAIDs combined [adjusted odds ratio (OR) 7.77, 95% confidence interval (CI) 5.68, 10.62], especially convulsions (adjusted OR 81.5, 95% CI 27.8, 238.8). Predictors of CNS toxicity included reported dose and age, but not gender.\n\n\n\nMefenamic acid overdose is associated with a much larger and dose-related risk of CNS toxicity, especially convulsions, compared with overdose of other NSAIDs. The benefit-risk profile of mefenamic acid should now be re-evaluated in light of effective and less toxic alternatives.",
"affiliations": "National Poisons Information Service, Newcastle Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Wolfson Unit, Claremont Place, Newcastle upon Tyne, NE2 4HH, UK.;Department of Primary Care and Public Health, King's College London, Capital House, London, SE1 3QD, UK.;National Poisons Information Service, Cardiff Unit, University Hospital Llandough, Penlan Road, Penarth, Vale of Glamorgan, CF64 2XX, UK.;National Poisons Information Service, Edinburgh Unit, Royal Infirmary of Edinburgh, 51 Little France Crescent, Old Dalkeith Road, Edinburgh, EH16 4SA, UK.;National Poisons Information Service, Edinburgh Unit, Royal Infirmary of Edinburgh, 51 Little France Crescent, Old Dalkeith Road, Edinburgh, EH16 4SA, UK.;National Poisons Information Service, Birmingham Unit, City Hospital, Dudley Road, Birmingham, B18 7QH, UK.;National Poisons Information Service, Cardiff Unit, University Hospital Llandough, Penlan Road, Penarth, Vale of Glamorgan, CF64 2XX, UK.;National Poisons Information Service, Newcastle Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Wolfson Unit, Claremont Place, Newcastle upon Tyne, NE2 4HH, UK.",
"authors": "Kamour|Ashraf|A|;Crichton|Siobhan|S|;Cooper|Gill|G|;Lupton|David J|DJ|;Eddleston|Michael|M|;Vale|J Allister|JA|;Thompson|John P|JP|;Thomas|Simon H L|SH|",
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"keywords": "CNS toxicity; convulsions; mefenamic acid; nonsteroidal anti-inflammatory drug; overdose; poisoning",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002648:Child; D002675:Child, Preschool; D004008:Diclofenac; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D008528:Mefenamic Acid; D008875:Middle Aged; D015999:Multivariate Analysis; D009288:Naproxen; D020258:Neurotoxicity Syndromes; D011039:Poison Control Centers; D012737:Sex Factors; D006113:United Kingdom; D055815:Young Adult",
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"title": "Central nervous system toxicity of mefenamic acid overdose compared with other NSAIDs: an analysis of cases reported to the United Kingdom National Poisons Information Service.",
"title_normalized": "central nervous system toxicity of mefenamic acid overdose compared with other nsaids an analysis of cases reported to the united kingdom national poisons information service"
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"abstract": "Xeroderma pigmentosum (XP) is a genetic disease in which DNA repair mechanisms are impaired. Cisplatin (CDDP) exerts cytotoxic effects by forming mainly intrastrand DNA cross-links, and sensitivity to CDDP depends on the DNA repair system. Several in vitro studies have suggested that treatment with CDDP may cause enhanced adverse events as well as anti-tumor activity in cancer patients with XP. This article is the first to describe two cancer patients with XP showing severe adverse events following CDDP-based chemotherapy. Physicians should pay attention when administering CDDP in cancer patients with XP.",
"affiliations": "Department of Respiratory Medicine, Sasebo City General Hospital, Japan.;Department of Respiratory Medicine, Sasebo City General Hospital, Japan.;Department of Surgery, Saiseikai Fukuoka General Hospital, Japan.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.;Department of Respiratory Medicine, Sasebo City General Hospital, Japan.;Department of Respiratory Medicine, Sasebo City General Hospital, Japan.;Department of Respiratory Medicine, Sasebo City General Hospital, Japan.;Department of Respiratory Medicine, Sasebo City General Hospital, Japan.;Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.",
"authors": "Sumiyoshi|Makoto|M|;Soda|Hiroshi|H|;Sadanaga|Noriaki|N|;Taniguchi|Hirokazu|H|;Ikeda|Takaya|T|;Maruta|Hiroshi|H|;Dotsu|Yosuke|Y|;Ogawara|Daiki|D|;Fukuda|Yuichi|Y|;Mukae|Hiroshi|H|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2842085010.2169/internalmedicine.56.7866Case ReportAlert Regarding Cisplatin-induced Severe Adverse Events in Cancer Patients with Xeroderma Pigmentosum Sumiyoshi Makoto 1Soda Hiroshi 1Sadanaga Noriaki 2Taniguchi Hirokazu 3Ikeda Takaya 3Maruta Hiroshi 1Dotsu Yosuke 1Ogawara Daiki 1Fukuda Yuichi 1Mukae Hiroshi 31 Department of Respiratory Medicine, Sasebo City General Hospital, Japan2 Department of Surgery, Saiseikai Fukuoka General Hospital, Japan3 Second Department of Internal Medicine, Nagasaki University School of Medicine, JapanCorrespondence to Dr. Hiroshi Soda, h-souda@hospital.sasebo.nagasaki.jp\n\n15 4 2017 56 8 979 982 16 6 2016 5 8 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Xeroderma pigmentosum (XP) is a genetic disease in which DNA repair mechanisms are impaired. Cisplatin (CDDP) exerts cytotoxic effects by forming mainly intrastrand DNA cross-links, and sensitivity to CDDP depends on the DNA repair system. Several in vitro studies have suggested that treatment with CDDP may cause enhanced adverse events as well as anti-tumor activity in cancer patients with XP. This article is the first to describe two cancer patients with XP showing severe adverse events following CDDP-based chemotherapy. Physicians should pay attention when administering CDDP in cancer patients with XP. \n\nCDDPxeroderma pigmentosumDNA repair systemmultiple organ failure\n==== Body\nIntroduction\nXeroderma pigmentosum (XP) is a genetic disorder that is associated with an increased incidence of ultraviolet radiation-induced skin cancer (1). XP variant is a subtype of XP involving mutations in the POLH gene encoding DNA polymerase η. DNA polymerase η is involved in the translesion DNA synthesis (TLS) pathway, which bypasses damaged DNA and repairs DNA in an error-free or error-prone manner (1, 2). In contrast, the other subtypes of XP involve a genetic defect in the nucleotide excision repair (NER) pathway, which removes damaged DNA from the genome and replicates DNA (1, 3).\n\nCisplatin (CDDP) is a widely used chemotherapeutic agent that exerts cytotoxic effects by forming mainly intrastrand cross-linked DNA adducts, which block DNA replication and induce apoptosis (4). Resistance to CDDP is, at least in part, associated with the NER and TLS pathways (5-7). Several in vitro studies have suggested that treatment with CDDP may cause enhanced adverse events as well as anti-tumor activity in cancer patients with XP. To the best of our knowledge, however, there has been no clinical report regarding the effects of CDDP on cancer or normal cells in patients with XP. We herein report for the first time two cancer patients with XP variant that experienced severe adverse events with multiple organ failure following CDDP-based chemotherapy.\n\nCase Reports\nCase 1\nA woman in her 70s with a medical history of an XP variant was referred to us for investigation of a nodule that was seen on chest radiography. The diagnosis of XP variant had been made based on the clinical features and a genetic test approximately 20 years ago at a university hospital. The patient had shown weak photosensitivity and undergone surgical resection more than 10 times for repeated skin cancers, but not chemotherapy. She had a family history of a relative with XP and esophageal cancer. On a physical examination, irregular dark spots on the skin were seen all over the body. Chest computed tomography (CT) showed a 2-cm solid nodule in the apical segment (S6) of the right lower lobe. Bronchoscopic examinations pathologically revealed atypical cells in the nodule, and 18F-fluorodeoxyglucose positron emission tomography with integrated CT showed only the lung nodule with high uptake of 18F-fluorodeoxyglucose. Since the nodule was strongly suspected of being lung cancer, the patient underwent right lower lobe resection. Pathological examinations revealed the tumor, measuring 23 mm in diameter, to be papillary-predominant adenocarcinoma. Although no tumor cells were seen in the hilar lymph nodes, single-station metastasis to the subcarinal lymph node (#7) was observed. The patient was diagnosed with stage IIIA lung adenocarcinoma (pT1bN2M0).\n\nThe patient received adjuvant chemotherapy one month after the operation. A combination of CDDP at 80 mg/m2 and vinorelbine at 25 mg/m2 was administered on the first day of adjuvant chemotherapy. Fig. 1 shows the time course of the major adverse events experienced following chemotherapy. On the second day, the patient complained of grade 1 diarrhea and grade 2 vomiting according to the Common Terminology Criteria for Adverse Events, version 4.0. On the third day, blood tests revealed grade 4 liver enzyme elevation (alanine aminotransferase [ALT] level: 1,179 IU/L), grade 2 bilirubin elevation (1.7 mg/dL), and grade 2 creatinine elevation (1.11 mg/dL). On the 5th day, the patient suffered from a grade 3 hearing impairment, leading to grade a 4 complete loss of hearing ability. On the 8th day, the acute kidney injury progressed to grade 4 (creatinine level: 3.62 mg/dL), and intermittent hemodialysis was performed. Myelosuppression was also observed, and recombinant human granulocyte colony-stimulating factor was administered to prevent febrile neutropenia. The nadir of the neutrophil and platelet counts was 1,630/μL (grade 1) on the 14th day and 19,000/μL (grade 4) on the 10th day, respectively. A systemic survey including CT of the brain, chest, and abdomen showed no recurrence of lung cancer. Irrespective of intensive treatment, multiple organ failure and systemic infection progressed, and the patient died on the 59th day after the initiation of chemotherapy.\n\nFigure 1. The time course of major adverse events in the lung cancer patient with xeroderma pigmentosum after receiving adjuvant chemotherapy: cisplatin at 80 mg/m2 and vinorelbine at 25 mg/m2 on day 1. Bold line: alanine aminotransferase (ALT) levels, thin line: total bilirubin levels, broken line: creatinine levels.\n\nCase 2\nDuring the above-described clinical course, the family members of the first patient reported that similar severe adverse events had been seen in a male relative in his 70s with XP who received chemotherapy for esophageal cancer in another hospital. The relative had been clinically diagnosed with a possible XP variant because of the family history, strong photosensitivity leading to burn-like rashes since childhood, and irregular dark spots of the skin all over the body. With the approval of the family members, his medical information was obtained from the hospital in order to utilize the information for treatment of the first patient. On reviewing his chart, upper gastrointestinal endoscopy at a medical checkup had revealed an ulcerative and localized type of squamous cell carcinoma in the lower portion of the esophagus. The relative had then received subtotal esophagectomy with gastric tube reconstruction for esophageal cancer. Histologically, the tumor, measuring 2.4 cm, had invaded the submucosal layer of the esophagus. The relative had been diagnosed with stage IIB basoloid-squamous cell carcinoma (pT1bN1M0).\n\nAdjuvant chemotherapy had been performed one and a half months after operation. The relative had been scheduled to receive CDDP at 80 mg/m2 on the first day and 5-fluorouracil at 800 mg/m2/day as a continuous infusion on the first day through the fifth day. Diarrhea, nausea, and hearing impairment unexpectedly developed on the third day, and the infusion of 5-fluorouracil was discontinued on the 4th day. The time course of the major adverse events experienced following chemotherapy is shown in Fig. 2. The hearing impairment resulted in the use of a hearing aid (grade 3). Liver dysfunction (grade 4 ALT level: 1,009 IU/L; grade 3 bilirubin level: 3.6 mg/dL) and acute kidney injury (grade 4 creatinine level: 6.8 mg/dL) progressed on the 6th day, and hemodialysis was performed. Thereafter, myelosuppression was observed, and platelet transfusion and recombinant human granulocyte colony-stimulating factor were administered. The nadir of the neutrophil and platelet counts was 20/μL (grade 4) and 5,000/μL (grade 4) on the 18th day, respectively. Despite intensive treatment, multiple organ failure progressed, and the relative died on the 21st day after the initiation of chemotherapy.\n\nFigure 2. The time course of major adverse events in the esophageal cancer patient with xeroderma pigmentosum after receiving adjuvant chemotherapy: cisplatin at 80 mg/m2 on day 1 and 5-fluorouracil continuous infusion at 800 mg/m2/day on day 1 through day 3. The infusion of 5-fluouracil was discontinued on day 4. Bold line: alanine aminotransferase (ALT) levels, thin line: total bilirubin levels; broken line: creatinine levels.\n\nDiscussion\nIn Japan, the prevalence of XP is 1 in 22,000 individuals, showing that it is not necessarily a rare disease (8). The major subtypes of XP include XP group A, which involves a defect in the XPA protein of the NER pathway, and XP variant, which involves a defect in DNA polymerase η of the TLS pathway (8). Although impairment of the NER and TLS pathways leads to the inability to repair ultraviolet radiation-induced DNA damage, patients with XP variant show mild photosensitivity and a moderately increased risk of developing skin cancer compared to those with XP group A (1, 8). Since the NER and TLS pathways also repair DNA damage induced by chemotherapeutic agents such as CDDP, the effects of DNA-damaging agents on cancer and normal cells may be different between patients with and without XP. To the best of our knowledge, however, there has been no clinical report or any guideline regarding the usage of DNA-damaging agents in cancer patients with XP.\n\nSeveral in vitro studies have shown that defective XPA protein and DNA polymerase η reduce the proliferation and viability of cancer and normal cells. Lung cancer A549 cells transfected with XPA antisense RNA show a reduction in cell viability after CDDP treatment (6). Ovarian cancer cells with small interfering RNA-induced knockdown of POLH encoding DNA polymerase η exhibit high sensitivity to CDDP (5). In contrast, XPA-deficient GM04312 fibroblasts derived from a patient with XP group A showed moderate sensitivity to CDDP. Additionally, DNA polymerase η-deficient XP30RO fibroblasts from a patient with XP variant were highly sensitive to CDDP (7). These in vitro findings suggest that CDDP treatment may have enhanced cytotoxic effects on normal cells as well as cancer cells in patients with XP.\n\nIn the present cases, we were unable to completely exclude the possibility that unknown mechanisms, aside from the impairment of DNA repair systems, may exist. For example, DNA polymerase η-deficient GM13154 and GM13155 cells derive from the same patient with XP variant; the GM13154 and GM13155 cells originate from B-lymphocytes and fibroblasts, respectively. While the GM13154 cells are more sensitive to CDDP, the GM13155 cells are less sensitive (9). Factors other than the loss of DNA polymerase η activity may account for the difference in cytotoxicity of CDDP.\n\nThere remains a possibility that vinorelbine and 5-fluorouracil might have induced severe adverse events in these two patients. Both patients shared certain characteristics of severe adverse events: rapid ototoxicity followed by acute kidney injury that needed hemodialysis within one week after chemotherapy. Among chemotherapeutic agents, ototoxicity is characteristic of platinum-containing agents such as CDDP (10). Several randomized studies have shown that all grades and grade 3 or worse ototoxicity are seen in 18% and 4% of patients treated with single-agent CDDP, respectively (11). In contrast, all grades and grade 3 or worse ototoxicity are observed in 1% and 0% of those treated with single-agent vinorelbine, respectively (12). The combination of vinorelbine with CDDP does not increase the frequency and severity of ototoxicity compared with those treated with single-agent CDDP (11). There has been no report of ototoxicity with 5-fluorouracil. Furthermore, acute kidney injury is a dose-limiting toxicity of CDDP that needs a large quantity of fluid replacement for prevention, whereas acute kidney injury is rarely observed in the treatment with vinorelbine or 5-fluorouracil. In general, vinorelbine interferes with microtubule assembly. 5-fluorouracil is an analogue of uracil, and the metabolites inhibit the synthesis of DNA and RNA. The cytotoxic mechanisms of vinorelbine and 5-fluorouracil are not directly associated with DNA repair systems. Based on these findings, the severe adverse events in the present cases probably resulted from CDDP.\n\nAn additional limitation of our report is that a genetic test was not performed in the second patient. The diagnosis of XP is usually based on the clinical findings, family history, and genetic tests; however, there are no established diagnostic criteria for XP (13). Recently, the diagnostic criteria for XP were reported by the Research Committees of the Ministry of Health, Labor of Japan and the Japanese Dermatology Association (8). In brief, a definite diagnosis of XP is established when typical skin manifestations or a family history of XP is present along with a positive genetic test. When a genetic test is not performed, a probable diagnosis requires all of the following: acute photosensitivity, freckle-like pigmentation, and early-onset skin malignancies. A possible diagnosis is given when a patient shows both acute photosensitivity and freckle-like pigmentation. Other diseases with photosensitivity, such as erythropoietic protoporphilia, must be ruled out. Patients with XP do not always show distinctive skin manifestations, and early protection from the sunlight decreases the appearance of skin lesions. The genetic tests are becoming increasingly important for the diagnosis of XP and the management of patients.\n\nBefore cancer treatment is started, a genetic diagnosis of XP should be made in patients with clinical findings suggestive of XP. By not selecting CDDP-based chemotherapy, patients with XP may avoid severe adverse events. However, CDDP is a pivotal chemotherapeutic agent in a variety of malignancies. As such, by not selecting CDDP-based chemotherapy, patients with XP may lose an opportunity for long-term survival or achieving a cure. Whether or not cancer patients with XP should receive CDDP-based chemotherapy is a major controversial issue. Our experience with two patients encourages further studies to clarify the association between the underlying biology in XP and the effects of CDDP, which may help in the management of cancer patients with XP.\n\nThe results of in vitro studies suggest that the adverse effects caused by CDDP on normal cells is, at least in part, protected by DNA repair systems. XP is known to involve the impairment of DNA repair systems. Physicians should therefore be aware that CDDP can potentially induce severe adverse events in patients with XP.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\n\nA consent was obtained from the patients' family representative for the publication of this case report.\n==== Refs\n1. \nMenck CF , Munford V \nDNA repair diseases: What do they tell us about cancer and aging? \nGenet Mol Biol \n37 : 220 -233 , 2014 .24764756 \n2. \nAlt A , Lammens K , Chiocchini C , et al \nBypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta . Science \n318 : 967 -970 , 2007 .17991862 \n3. \nFadda E \nRole of the XPA protein in the NER pathway: A perspective on the function of structural disorder in macromolecular assembly . Comput Struct Biotechnol J \n14 : 78 -85 , 2015 .26865925 \n4. \nRose MC , Kostyanovskaya E , Huang RS \nPharmacogenomics of cisplatin sensitivity in non-small cell lung cancer . Genomics Proteomics Bioinformatics \n12 : 198 -209 , 2014 .25449594 \n5. \nSrivastava AK , Han C , Zhao R , et al \nEnhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells . Proc Natl Acad Sci USA \n112 : 4411 -4416 , 2015 .25831546 \n6. \nWu X , Fan W , Xu S , Zhou Y \nSensitization to the cytotoxicity of cisplatin by transfection with nucleotide excision repair gene xeroderma pigmentosun group A antisense RNA in human lung adenocarcinoma cells . Clin Cancer Res \n9 : 5874 -5879 , 2003 .14676109 \n7. \nAlbertella MR , Green CM , Lehmann AR , O'Connor MJ \nA role for polymerase eta in the cellular tolerance to cisplatin-induced damage . Cancer Res \n65 : 9799 -9806 , 2005 .16267001 \n8. \nMoriwaki S , Kanda F , Hayashi M , Yamashita D , Sakai Y , Nishigori C \nClinical practice guideline on xeroderma pigmentosum . The Japanese Jounal of Dermatology \n125 : 2013 -2022 , 2015 (in Japanese).\n9. \nGregory MT , Park GY , Johnstone TC , Lee YS , Yang W , Lippard SJ \nStructural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage . Proc Natl Acad Sci USA \n111 : 9133 -9138 , 2014 .24927576 \n10. \nCallejo A , Sedó-Cabezón L , Domènech Juan I , Llorens J \nCisplatin-induced ototoxicity: effects, mechanisms and protection strategies . Toxics \n3 : 268 -293 , 2015 .\n11. \nWozniak AJ , Crowley JJ , Blcerzak SP , et al \nRandomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: a Southwest Oncology Group study . J Clin Oncol \n16 : 2459 -2465 , 1998 .9667264 \n12. \nLe Chevalier T , Brisgand D , Douillard JY , et al \nRandomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small-cell lung cancer: results of a European multicenter trial including 612 patients . J Clin Oncol \n12 : 360 -367 , 1994 .8113844 \n13. \nKraemer KH, DiGiovanna JJ.\nXeroderma pigmentosum.\nGeneReviews (the online database on the National Center for Biothechnology Information), February 13, 2014 [Internet]. [cited 2016 July 17]. Available from URL\n:\nhttp://www.ncbi.nlm.nih.gov/books/NBK1397/\n.\n\n",
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"keywords": "CDDP; DNA repair system; multiple organ failure; xeroderma pigmentosum",
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"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002945:Cisplatin; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure; D009369:Neoplasms; D014983:Xeroderma Pigmentosum",
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"title": "Alert Regarding Cisplatin-induced Severe Adverse Events in Cancer Patients with Xeroderma Pigmentosum.",
"title_normalized": "alert regarding cisplatin induced severe adverse events in cancer patients with xeroderma pigmentosum"
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"abstract": "Statin-induced necrotizing autoimmune myopathy (SINAM) is a rare side effect of statin use which manifests as progressive muscle weakness. Because statins are a widely prescribed medication for coronary artery disease, hyperlipidemia, and many other diseases, many patients are at risk of developing SINAM or one of the many other statin-induced myopathies. Due to identification of an antibody specific to this disease, we were able to diagnose SINAM in a patient whose symptoms had progressed to the extent that they were debilitating. Our case describes SINAM in a patient undergoing treatment with a statin for an extended period of time, diagnosis of the disease process, treatment, and resolution of symptoms.",
"affiliations": "Icahn School of Medicine at Mount Sinai-Queens Hospital Center, Queens, NY, USA.;Icahn School of Medicine at Mount Sinai-Queens Hospital Center, Queens, NY, USA.",
"authors": "Dixit|Ayushi|A|0000-0001-9678-5428;Abrudescu|Adriana|A|",
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"doi": "10.1155/2018/5931046",
"fulltext": "\n==== Front\nCase Rep RheumatolCase Rep RheumatolCRIRHCase Reports in Rheumatology2090-68892090-6897Hindawi 10.1155/2018/5931046Case ReportA Case of Atorvastatin-Associated Necrotizing Autoimmune Myopathy, Mimicking Idiopathic Polymyositis http://orcid.org/0000-0001-9678-5428Dixit Ayushi ayuushii@gmail.comAbrudescu Adriana Icahn School of Medicine at Mount Sinai-Queens Hospital Center, Queens, NY, USAAcademic Editor: Remzi Cevik\n\n2018 20 6 2018 2018 593104626 1 2018 18 4 2018 22 5 2018 Copyright © 2018 Ayushi Dixit and Adriana Abrudescu.2018This 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.Statin-induced necrotizing autoimmune myopathy (SINAM) is a rare side effect of statin use which manifests as progressive muscle weakness. Because statins are a widely prescribed medication for coronary artery disease, hyperlipidemia, and many other diseases, many patients are at risk of developing SINAM or one of the many other statin-induced myopathies. Due to identification of an antibody specific to this disease, we were able to diagnose SINAM in a patient whose symptoms had progressed to the extent that they were debilitating. Our case describes SINAM in a patient undergoing treatment with a statin for an extended period of time, diagnosis of the disease process, treatment, and resolution of symptoms.\n==== Body\n1. Introduction\nStatins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and are some of the most widely prescribed medications for treating atherosclerotic disease in order to reduce the morbidity and mortality for both coronary and cerebral vascular diseases. Most statin-induced myotoxicity is self-limiting with myalgia and transient elevation of muscle enzymes followed by complete recovery within weeks to months upon the discontinuation of the statin. Statin-induced necrotizing autoimmune myopathy (SINAM) is a rare side effect reported in about 2-3 out of 100,000 people who use statins. We present a case of SINAM manifested in a patient with over ten years of simvastatin use who was recently switched to atorvastatin.\n\n2. Case Presentation\nA 66-year-old female with a medical history of hypertension, hyperlipidemia, diabetes mellitus type 2, and obesity presented with hip pain after a fall. Radiograph of the hip was negative for dislocation or fracture. On physical exam, she had proximal muscle weakness greater in the lower extremities, and the rest of her examination was negative for skin rashes, lymphadenopathy, joints inflammation, and pedal edema. Her EKG showed normal sinus rhythm with no ST-T changes. Blood work showed elevated CPK (9767), CKMB (101.50), and aldolase (60) levels and LFT derangement (AST-302 and ALT404) (Tables 1 and 2). Other lab findings were negative for ANA, anti-Jo antibody, and antimitochondrial antibody. Thyroid function tests were normal. At that time the patient was taking atorvastatin 80 mg which recently replaced simvastatin for better hyperlipidemia control. Atorvastatin was discontinued, and the patient was followed closely in the medical clinic. The proximal muscle weakness continued to progress rapidly during the following month with significant impairment of her walking and rising from a chair without support. The physical exam revealed a decrease to 2 out of 5 motor strength of the proximal upper extremities and 3 out 5 of the proximal lower extremities, and the rest of the physical examination remained normal. Laboratory results with persisting elevated muscle enzyme (CPK, CKMB, and aldolase) levels remained elevated. Testing for anti-HMGCR antibody with ELISA was positive at 34 (reference value: greater than 20 is positive). Muscle biopsy was consistent with necrotizing myopathy (Figures 1 and 2). Taken with the antibody results, the final diagnosis of statin-induced necrotising autoimmune myopathy was performed. Findings were consistent with diagnosis of necrotizing autoimmune myositis. Prednisone therapy started at 1 mg/kg per day and tapered over the next three months. The patient's proximal upper and lower strength and mobility improved back to her baseline with normalization of the muscle enzymes and the liver function tests. Upon further review of the patient's chart it was found that she had been taking simvastatin for at least thirteen years which was recently discontinued after which she was switched to atorvastatin. Due to necrotizing myopathy's high association with malignancy, cancer screening reports were reviewed. The patient had a normal colonoscopy in 2014, cervical cancer screening was negative, and calcifications on serial mammograms remained stable. The patient started complaining of weakness one month after initiation of the new therapy with atorvastatin. Liver function tests recorded during treatment with simvastatin were within normal limits.\n\n3. Discussion\nSince their introduction over 20 years ago, statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have been one of the most widely prescribed medications, and treatment with statins has effectively reduced the cardiovascular morbidity and mortality. Evidence presented by the American College of Cardiology/American Heart Association Blood Cholesterol Treatment Task Force solidified statins as the only cholesterol-lowering agent that showed mortality benefit. The new guidelines have expanded the statin-eligible population in the United States from 43 to 56 million, a total increase of 13 million. This number further approaches 1 billion worldwide [1]. Muscular side effects of statins are diverse, ranging from common mild myalgia with localized weakness to life-threatening rhabdomyolysis [2]. Myopathic symptoms produced by statins generally resolve within weeks to several months of stopping the medication [3]. Recently a new entity called statin-induced necrotizing autoimmune myopathy (SINAM) was identified and has led to identification of an autoantibody against 3-hydroxy-3-methylglutaryl coenzyme A reductase [4]. The novel anti-HMGCR antibody, which was discovered in 2010, is a promising diagnostic marker for statin-associated NAM. Almost all patients with statin-induced necrotizing autoimmune myopathy have tested positive for anti-HMGCR antibodies. The sensitivity and specificity of the anti-HMGCR antibodies are 94.4% and 99.3%, respectively [5, 6]. This new entity was recently described by Mammen et al. who first identified a group of 16 patients with necrotizing myopathy associated with a new antibody recognizing 200 kD and 100 kD proteins [5]. SINAM is an autoimmune disease that requires specific therapy and possibly long-term immunosuppression. Different statins have varied propensities for causing self-limited myopathy, with atorvastatin and simvastatin associated with higher rates of myopathy than rosuvastatin; however, there is no established association between specific statins and the occurrence of SINAM [7, 8]. A study by Troyanov involving 12 patients with exposure to atorvastatin and diagnosed with atorvastatin-induced autoimmune myopathy reported that the mean interval between atorvastatin discontinuation and diagnosis of the myopathy was 17.8 months (range of 0–79 months) [9]. His study was performed at a tertiary care center, and response to steroid therapy was inadequate subsequently resulting in therapy with methotrexate and azathioprine. Our patient's dramatic response and improvement may be attributed to the fact that SINAM was identified two months after initiation of atorvastatin. Our case is the second one reporting a diagnosis of SINAM after changing simvastatin to atorvastatin, the first being reported by Nichols et al. [5]. As of yet, there are no control trials to guide treatment. In the past, treatments with high doses of steroids, methotrexate, and azathioprine have been given with variable responses. Our patient responded to a three-month course of steroids. We believe our case is unique because the early recognition of HMGCR antibodies and prompt treatment resulted in full recovery.\n\n4. Conclusion\nAs statins are an extensively used class of drugs, clinicians should be aware of SINAM and patients should be promptly evaluated at the earliest signs of inflammatory muscle disease which mimics polymyositis. It is important to differentiate statin-associated inflammatory myopathies from other self-limited myopathies, because the disease will not subside following discontinuation of the statin [10]. Muscle biopsy is crucial for differentiation; however, in the future, larger studies could prove whether using the HMGCR antibodies alone would be sufficient to make the diagnosis and implement the immunosuppressive or intravenous immunoglobulin therapy. Our case report illustrates the importance of early recognition of SINAM and that the treatment requires immunosuppressive agents to prevent permanent damage and it can result in complete recovery. Upon our review of literature, atorvastatin use was reported in cases of SINAM; however, there is still speculation about whether any one statin is linked with the disease. Further studies should be done to determine whether the use of atorvastatin, when compared with other statins, is more likely to result in a positive HMGCR antibody test.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Surgical pathology report.\n\nFigure 2 Microscopic right quadriceps muscle biopsy showing necrotic muscle fibers and regenerating fibers. (a) Arrow pointing at necrotic muscle fiber (magnification 20x with alkaline phosphatase stain). (b) Arrow pointing at regenerating muscle fiber (magnification 20x with alkaline phosphatase stain).\n\nTable 1 Muscle enzyme trend from diagnosis to resolution of disease process.\n\n \tReference range and units\t3/24/2017\t3/29/2017\t6/20/2017\t8/8/2017\t\nAldolase\tNormal: 3.3–10.3 U/L\t60.0\t31.2\t8.4\t7.7\t\nCK\tNormal: 20–170 U/L\t9767\t6114\t653\t88\t\nCKMB\tNormal: 0.00–3.77 ng/ml\t101.50\t73.33\t9.00\t \t\nTable 2 Liver function enzyme trend from diagnosis to resolution of disease process.\n\n \tReference range and units\t3/11/2017\t3/12/2017\t3/13/2017\t3/15/2017\t3/16/2017\t4/25/2017\t8/8/2017\t\nAlkaline phosphatase\tNormal: 40–120 U/L\t105\t110\t117\t109\t102\t71\t79\t\nALT\tNormal: 10–45 U/L\t404\t347\t356\t363\t331\t349\t23\t\nAST\tNormal: 10–40 U/L\t302\t274\t322\t323\t273\t120\t17\n==== Refs\n1 Young J. B. Ghobrial Autoimmune statin-induced myopathy: a case report Journal of Community Hospital Internal Medicine Perspectives 2015 5 4 p. 28374 10.3402/jchimp.v5.28374 \n2 Joy T. R. Hegele R. A. Narrative review: statin-related myopathy Annals of Internal Medicine 2009 150 12 858 868 10.7326/0003-4819-150-12-200906160-00009 19528564 \n3 Hansen K. E. Hildebrand J. P. Ferguson E. E. Outcomes in 45 patients with statin-associated myopathy Archives of Internal Medicine 2005 165 2671 2676 10.1001/archinte.165.22.2671 2-s2.0-28944444047 16344427 \n4 Christopher-Stine L. Casciola-Rosen L. A. Hong G. A novel autoantibody recognizing 200 and 100 kDa proteins is associated with an immune-mediated necrotizing myopathy Arthritis and Rheumatism 2010 62 9 2757 2766 10.1002/art.27572 2-s2.0-77953373228 20496415 \n5 Nichols L. Pfeifer K. Mammen A. L. An unusual case of statin-induced myopathy: anti-HMGCoA necrotizing autoimmune myopathy Journal of General Internal Medicine 2015 30 12 1879 1883 10.1007/s11606-015-3303-9 2-s2.0-84946499756 25855481 \n6 Ngo L. Q. Wu A. G. Nguyen M. A. A case report of autoimmune necrotizing myositis presenting as dysphagia and neck swelling BMC Ear, Nose, and Throat Disorders 2016 16 1 p. 7 10.1186/s12901-016-0027-3 2-s2.0-84969560146 \n7 Molokhia M. McKeigue P. Curcin V. Majeed A. Statin induced myopathy and myalgia: time trend analysis and comparison of risk associated with statin class from 1991–2006 PLoS One 2008 3 6 e2522 10.1371/journal.pone.0002522 2-s2.0-49649119693 \n8 Grable-Esposito P. Katzberg H. D. Greenberg S. A. Srinivasan J. Katz J. Amato A. A. Immune-mediated necrotizing myopathy associated with statins Muscle Nerve 2010 41 2 185 190 19813188 \n9 Troyanov Y. Landon-Cardinal O. Fritzler M. J. Atorvastatin-induced necrotizing autoimmune myositis Medicine 2017 96 3 p. e5694 10.1097/MD.0000000000005694 2-s2.0-85010297851 \n10 Kanth R. Shah M. S. Flores R. M. Statin-associated polymyositis following omeprazole treatment Clinical Medicine and Research 2013 11 2 91 95 10.3121/cmr.2012.1110 2-s2.0-84879384314 23580790\n\n",
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"title": "A Case of Atorvastatin-Associated Necrotizing Autoimmune Myopathy, Mimicking Idiopathic Polymyositis.",
"title_normalized": "a case of atorvastatin associated necrotizing autoimmune myopathy mimicking idiopathic polymyositis"
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"abstract": "BACKGROUND\nCOVID-19-associated pulmonary aspergillosis (CAPA) has emerged as an invasive fungal disease, often affecting previously immunocompetent, mechanically ventilated, intensive care unit (ICU) patients. Incidence rates of 3.8%-33.3% have been reported depending on the geographic area, with high (47%) mortality.\n\n\nOBJECTIVE\nHere, we describe a single-centre prospective case series with CAPA cases from both the first (March-May, n = 5/33) and second (mid-September through mid-December, n = 8/33) COVID-19 wave at a 500-bed teaching hospital in the Netherlands.\n\n\nMETHODS\nIn the first COVID-19 wave, a total of 265 SARS-CoV-2 PCR-positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, 508 SARS-CoV-2 PCR-positive patients were admitted of whom 33 needed mechanical ventilation. Data were prospectively collected.\n\n\nRESULTS\nWe found a significant decrease in COVID-19 patients needing mechanical ventilation in the ICU in the second wave (p < .01). From these patients, however, a higher percentage were diagnosed with CAPA (24.2% vs 15.2%), although not significant (p = .36). All CAPA patients encountered in the second wave received dexamethasone. Mortality between both groups was similarly high (40%-50%). Moreover, we found environmental TR34 /L98H azole-resistant Aspergillus fumigatus isolates in two separate patients.\n\n\nCONCLUSIONS\nIn this series, 19.7% (n = 13/66) of mechanically ventilated SARS-CoV-2 patients were diagnosed with CAPA. In addition, we found a significant reduction in COVID-19 patients needing mechanical ventilation on the ICU in the second wave. Numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS-CoV-2 therapy.",
"affiliations": "Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands.;Department of Intensive Care Medicine, Canisius Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands.;Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.",
"authors": "Meijer|Eelco F J|EFJ|https://orcid.org/0000-0002-0226-024X;Dofferhoff|Anton S M|ASM|;Hoiting|Oscar|O|;Meis|Jacques F|JF|https://orcid.org/0000-0003-3253-6080",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.13254",
"fulltext": "\n==== Front\nMycoses\nMycoses\n10.1111/(ISSN)1439-0507\nMYC\nMycoses\n0933-7407\n1439-0507\nJohn Wiley and Sons Inc. Hoboken\n\n33569857\n10.1111/myc.13254\nMYC13254\nOriginal Article\nOriginal Articles\nCOVID‐19–associated pulmonary aspergillosis: a prospective single‐center dual case series\nMEIJER et al.\nMeijer Eelco F. J. https://orcid.org/0000-0002-0226-024X\n1 2 3 eelco.meijer@radboudumc.nl\n\nDofferhoff Anton S. M. 3 4\nHoiting Oscar 5\nMeis Jacques F. https://orcid.org/0000-0003-3253-6080\n1 2 3 6\n1 Department of Medical Microbiology Radboud University Medical Center Nijmegen The Netherlands\n2 Center of Expertise in Mycology Radboudumc/CWZ Nijmegen The Netherlands\n3 Department of Medical Microbiology and Infectious Diseases Canisius Wilhelmina Hospital (CWZ) Nijmegen The Netherlands\n4 Department of Internal Medicine Canisius Wilhelmina Hospital (CWZ) Nijmegen The Netherlands\n5 Department of Intensive Care Medicine Canisius Wilhelmina Hospital (CWZ) Nijmegen The Netherlands\n6 Bioprocess Engineering and Biotechnology Graduate Program Federal University of Paraná Curitiba Brazil\n* Correspondence\nEelco F. J. Meijer, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.\nEmail: eelco.meijer@radboudumc.nl\n\n16 2 2021\n4 2021\n64 4 10.1111/myc.v64.4 457464\n01 2 2021\n02 2 2021\n© 2021 The Authors. Mycoses published by Wiley‐VCH GmbH.\nThis 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.\n\nAbstract\n\nBackground\n\nCOVID‐19–associated pulmonary aspergillosis (CAPA) has emerged as an invasive fungal disease, often affecting previously immunocompetent, mechanically ventilated, intensive care unit (ICU) patients. Incidence rates of 3.8%–33.3% have been reported depending on the geographic area, with high (47%) mortality.\n\nObjectives\n\nHere, we describe a single‐centre prospective case series with CAPA cases from both the first (March‐May, n = 5/33) and second (mid‐September through mid‐December, n = 8/33) COVID‐19 wave at a 500‐bed teaching hospital in the Netherlands.\n\nPatients/Methods\n\nIn the first COVID‐19 wave, a total of 265 SARS‐CoV‐2 PCR‐positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, 508 SARS‐CoV‐2 PCR‐positive patients were admitted of whom 33 needed mechanical ventilation. Data were prospectively collected.\n\nResults\n\nWe found a significant decrease in COVID‐19 patients needing mechanical ventilation in the ICU in the second wave (p < .01). From these patients, however, a higher percentage were diagnosed with CAPA (24.2% vs 15.2%), although not significant (p = .36). All CAPA patients encountered in the second wave received dexamethasone. Mortality between both groups was similarly high (40%–50%). Moreover, we found environmental TR34/L98H azole‐resistant Aspergillus fumigatus isolates in two separate patients.\n\nConclusions\n\nIn this series, 19.7% (n = 13/66) of mechanically ventilated SARS‐CoV‐2 patients were diagnosed with CAPA. In addition, we found a significant reduction in COVID‐19 patients needing mechanical ventilation on the ICU in the second wave. Numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS‐CoV‐2 therapy.\n\nAspergillus fumigatus\nCAPA\ndexamethasone\nICU\npulmonary aspergillosis\nTR34L98H\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.1 mode:remove_FC converted:01.04.2021\nMeijer EFJ , Dofferhoff ASM , Hoiting O , Meis JF . COVID‐19–associated pulmonary aspergillosis: A prospective single‐center dual case series. Mycoses. 2021;64 :457–464. 10.1111/myc.13254 33569857\n==== Body\n1 INTRODUCTION\n\nCOVID‐19–associated pulmonary aspergillosis (CAPA) is a recently described disease entity being mainly reported in the Intensive Care Unit (ICU), also affecting immunocompetent patients. Recently published small case series describe an overall high incidence of CAPA in SARS‐CoV‐2‐positive patients admitted to the ICU with acute respiratory distress syndrome requiring mechanical ventilation. The United Kingdom, 1 , 2 The Netherlands, 3 , 4 Belgium, 5 Germany, 6 Italy 7 and France 8 , 9 report incidences of 12.3%–33.3%. In Denmark, 10 a 25% (n = 2/8) incidence of invasive aspergillosis in COVID‐19 patients undergoing extracorporeal membrane oxygenation (ECMO) was described, totalling 7.4% when adding the non‐ECMO ICU population (n = 19). China, 11 Mexico 12 and Switzerland 13 report incidences of 8%, 9.7% and 3.8% in mechanically ventilated patients, respectively. In addition, Spain 14 and Pakistan 15 reported CAPA incidences of 3.3% and 21.7% in single studies, respectively, although patient data describing the use of mechanical ventilation were incomplete. Altogether, CAPA is associated with a high mortality of approximately 50% in these series, underscoring the importance of global awareness and early diagnosis.\n\nThe above‐mentioned percentages of CAPA are alarming, keeping in mind that novel and mixed existing definitions 16 , 17 , 18 , 19 are used in diagnosing cases, often not confirmed by histopathology. The higher percentages are comparable with observations made in influenza, which is an independent risk factor for invasive pulmonary aspergillosis in the ICU setting. 20 , 21 However, clinically and mechanistically, influenza‐associated pulmonary aspergillosis (IAPA) and CAPA are clearly distinct clinical entities. 16 , 22 More published data are needed to delineate the true incidence of CAPA in the ICU setting. Fortunately, the recently published CAPA 2020 ECMM/ISHAM consensus criteria 23 should provide clinical guidance and uniformity in classifying patients. Here, we report prospective findings from CAPA patients admitted to the ICU of a 500‐bed teaching hospital in the Netherlands during the first and second waves of the COVID‐19 pandemic during the year 2020.\n\n2 PATIENTS AND METHODS\n\nIn the first COVID‐19 wave during a 2‐month‐period from March until May 1 2020, a total of 265 SARS‐CoV‐2 PCR‐positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, a 3‐month‐period from mid‐September through mid‐December 2020, 508 SARS‐CoV‐2 PCR‐positive patients were admitted of whom 33 needed mechanical ventilation due to respiratory insufficiency. Data were prospectively collected in a study named ‘Clinical course and prognostic factors for COVID‐19’, approved March 2020 by the Canisius Wilhelmina hospital medical ethics committee CWZ‐nr 027‐2020. CAPA classification (possible/probable) was performed by using the 2020 ECMM/ISHAM consensus criteria, 23 using a combination of microbiology, imaging and clinical factors. Statistical analyses were performed with SPSS statistics (IBM version 25). For the unpaired two‐tailed t tests, a p‐value of less than .05 was considered statistically significant.\n\n2.1 Diagnostics\n\nSARS‐CoV‐2 PCR was performed by in‐house PCR or by Cepheids GeneXpert Xpress SARS‐CoV‐2 PCR as described by Wolters et al. 24 Triazole susceptibility screening was done using VIPcheck™ (Mediaproducts BV). MICs of Aspergillus fumigatus isolates were determined with broth microdilution using CLSI standards. 25 Fungal PCR targeting the Cyp51A gene was done using AsperGenius™ (PathoNostics). 1‐3 β‐d‐glucan (BDG) testing was done using the Fungitell assay (Associates of Cape Cod Inc). Galactomannan (GM) testing was done using Platelia Aspergillus (Bio‐Rad) and/or Aspergillus lateral flow device (AspLFD, OLM Diagnostics).\n\n3 RESULTS\n\nCase characteristics and diagnostics performed are presented in Table 1. Of the 33 admitted patients to our ICU in the first wave, 15.2% (n = 5) developed possible or probable CAPA. In the second wave out of 33 patients, 24.2% (n = 8) developed possible or probable CAPA, totalling 19.7% (13/66) in both waves combined. We found a significantly lower percentage of admitted COVID‐19 patients needing mechanical ventilation on the ICU in the second wave (33/265 vs 33/508; p‐value < .01) with a non‐significant increase in CAPA patients in the second wave (5/33 vs 8/33; p‐value = .36). Mortality between groups was similar (2/5 vs 4/8; p‐value = .75). We found two patients (15.4%) with an environmental TR34/L98H azole‐resistant Aspergillus fumigatus isolate.\n\nTABLE 1 CAPA patient cohort characteristics and diagnostics\n\nFirst wave COVID‐19, March through May 2020\t\nCharacteristics\tPatient #1\tPatient #2\tPatient #3\tPatient #4\tPatient #5\t\nCAPA classification. 23\tPossible\tPossible\tPossible\tPossible\tProbable\t\nGender\tMale\tMale\tMale\tFemale\tMale\t\nAge (years)\t70\t74\t68\t74\t65\t\nMedical history\t‐Diabetes mellitus type 2\n\n‐Proctitis ulcerosa\n\n‐Lacunar infarction left hemisphere\n\n\t‐Hypertension\n\n‐Colitis ulcerosa\n\n‐3rd degree AV block (pacemaker)\n\n\t‐Diabetes mellitus type 2\n\n‐Mitral valve insufficiency\n\n‐Hyperthyroidism\n\n\tPolyarthrosis\tNone\t\nImmuno‐compromising condition\tNone\tNone\tNone\tNone\tNone\t\nSymptom onset (days before ICU admission)\tDay‐13: fever, dyspnoeic\tDay‐5: fever, dry cough, malaise\tDay‐15: fever, dry cough, muscle ache, dyspnoeic\tDay‐16: fever, dry cough, dyspnoeic.\n\nDay‐13: diarrhoea\n\n\tDay‐7: malaise, dyspnoeic\t\nICU admission duration\t23 days\t18 days (death)\t32 days\t18 days (death)\t30 days\t\nAcute renal failure\tYes: CVVH\tYes: CVVH\tYes: CVVH\tYes: CVVH\tNo\t\nImaging\tX‐ray findings related to COVID‐19\tCT chest findings related to COVID‐19\tCT chest findings related to COVID‐19\tCT chest findings related to COVID‐19\tCT chest findings related to COVID‐19.\n\nAdditional developing cavitary lesion right lower lobe suspect for fungal disease\n\n\t\nARDS\t\t\t\t\t\t\nProne positioning\tYes\tNo\tYes\tYes\tYes\t\nECMO\tNo\tNo\tNo\tNo\tNo\t\nMicrobiology\t\t\t\t\t\t\nSerum GM (>0.5)\tNegative (<0.1)\tNegative (0.2)\tNegative (<0.1)\tNegative (<0.1)\tNegative (<0.1)\t\nFungal culture\tTA Aspergillus fumigatus\tTA Aspergillus fumigatus\tTA Aspergillus fumigatus\tTA Aspergillus fumigatus\tBAL: Aspergillus fumigatus\t\nSusceptibility\tAzole susceptible (VIPcheck™ negative)\tAzole susceptible (VIPcheck™ negative)\tAzole susceptible (VIPcheck™ negative)\tVIPcheck™ positive: Voriconazole I, Itraconazole R, Posaconazole I\tAzole susceptible (VIPcheck™ negative)\t\nFungal PCR\tN/A\tN/A\tN/A\tPCR TA: Aspergillus fumigatus TR34/L98H\tN/A\t\nTA/BAL GM (≥1)\tTA: positive (4.7)\tTA: positive (4.7)\tTA: negative (0.5)\tTA: positive (>3.0)\tBAL: negative (0.3)\t\nTA/BAL AspLFD\tTA: positive (<15 min)\tTA: negative (45 min)\tTA: positive (<15 min)\tTA: positive (<15 min)\tBAL: negative\t\nBDG\tN/A\tN/A\tN/A\t1590 pg/ml\tN/A\t\nVirology\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\t\nSARS‐CoV‐2 therapy\tHydroxychloroquine\tNone\tHydroxychloroquine\tHydroxychloroquine\tHydroxychloroquine\t\nAntifungal therapy\tVoriconazole\tVoriconazole\tVoriconazole\tEmpiric caspofungin/voriconazole; L‐amphotericin B\tVoriconazole\t\nSecond wave COVID‐19, mid‐September through mid‐December 2020\t\nCharacteristics\tPatient #1\tPatient #2\tPatient #3\tPatient #4\tPatient #5\tPatient #6\tPatient #7\tPatient #8\t\nCAPA classification 23\tPossible\tProbable\tProbable\tProbable\tProbable\tProbable\tProbable\tProbable\t\nGender\tMale\tMale\tMale\tMale\tMale\tFemale\tMale\tFemale\t\nAge (years)\t67\t56\t77\t65\t54\t59\t68\t78\t\nMedical history\tNone\tNone\t‐Angina pectoris\n\n‐Hypertension\n\n‐Diabetes mellitus\n\ntype 2\n\n\t‐Myocardial infarction\t‐Carotid endarterectomy\n\n‐Fontaine 3 peripheral arterial disease\n\n\t‐COPD gold II\t‐Multiple myocardial infarctions\n\n‐Heart failure\n\n‐Impaired renal function\n\n\tNone\t\nImmuno‐compromising condition\tNone\tNone\tNone\tNone\tNone\tNone\tNone\tNone\t\nSymptom onset (days before ICU admission)\tDay‐5: malaise, sore throat, headache\tDay‐21: fever, dry cough, dyspnoeic\tDay‐4: fever, dry cough, dyspnoeic\tDay‐12: fever, dry cough, dyspnoeic\tDay‐6: fever, dry cough, dyspnoeic\tDay‐7: malaise, dry cough, dyspnoeic\tDay‐17: fever, malaise, dyspnoeic\tDay‐7: fever, malaise, throat ache, dyspnoeic\t\nICU admission duration\t29 days (still admitted)\t56 days\t41 days\t41 days (death)\t13 days (death)\t40 days (death)\t30 days (death)\t42 days\t\nAcute renal failure\tNo\tNo\tNo\tNo\tYes: CVVH\tNo\tYes: CVVH\tNo\t\nImaging\tX‐ray findings related to COVID‐19\tCT chest findings related to COVID‐19. Additional developing nodular lesions suspect for fungal disease\tCT chest findings related to COVID‐19\tCT chest findings related to COVID‐19\tCT chest findings related to COVID‐19\tCT chest findings related to COVID19\tCT chest findings related to COVID‐19\tCT chest findings related to COVID‐19\t\nARDS\t\nProne positioning\tYes\tYes\tYes\tYes\tYes\tYes\tYes\tYes\t\nECMO\tNo\tNo\tNo\tNo\tNo\tNo\tNo\tNo\t\nMicrobiology\t\nSerum GM (>0.5)\tNegative (<0.1)\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\t\nFungal culture\tTA: Aspergillus fumigatus\tBAL: Aspergillus fumigatus\tBAL: Aspergillus fumigatus\tBAL: Aspergillus fumigatus\tBAL: Aspergillus fumigatus\tBAL: Aspergillus fumigatus\tBAL: Aspergillus fumigatus\tBAL: Aspergillus fumigatus\t\nSusceptibility\tAzole susceptible (VIPcheck™ negative)\tVIPcheck™ positive: Voriconazole R, Itraconazole R, Posaconazole I\tAzole susceptible (VIPcheck™ negative)\tAzole susceptible (VIPcheck™ negative)\tAzole susceptible (VIPcheck™ negative)\tAzole susceptible (VIPcheck™ negative)\tAzole susceptible (VIPcheck™ negative)\tAzole susceptible (VIPcheck™ negative)\t\nFungal PCR\tPCR TA: Aspergillus fumigatus\tPCR BAL: Aspergillus fumigatus TR34/L98H\tN/A\tPCR BAL: Aspergillus fumigatus\tN/A\tPCR BAL: Negative\tPCR BAL: Aspergillus fumigatus\tPCR BAL: Aspergillus fumigatus\t\nTA/BAL GM (≥1)\tTA: positive (3.5)\tBAL: negative 0.3\tBAL: negative 0.5\tBAL: positive > 5.9\tN/A\tBAL: negative 0.1\tBAL: negative 0.2\tBAL: positive 4.3\t\nTA/BAL AspLFD\tTA: negative\tBAL: Positive (<15 min)\tBAL: positive (<15 min)\tBAL: positive (<15 min)\tBAL: positive (<15 min)\tBAL: negative\tBAL: positive (<15 min)\tBAL: positive (<15 min)\t\nBDG\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\tN/A\t\nVirology\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\tSARS‐CoV‐2 positive\t\nSARS‐CoV‐2 therapy\tDexamethasone\n\nRemdesivir\n\n\tDexamethasone\tDexamethasone\n\nRemdesivir\n\n\tDexamethasone\tDexamethasone\tDexamethasone\tDexamethasone\tDexamethasone\n\nRemdesivir\n\n\t\nAntifungal therapy\tVoriconazole\tEmpiric caspofungin/voriconazole; L‐amphotericin B\tEmpiric caspofungin/voriconazole; L‐amphotericin B\tL‐amphotericin B; voriconazole\tVoriconazole\tVoriconazole\tEmpiric caspofungin/voriconazole; Voriconazole\tEmpiric caspofungin/voriconazole; L‐amphotericin B\t\nNote\n\nBDG testing: Fungitell assay, Associates of Cape Cod Inc, East Falmouth, MA, USA; Fungal PCR: AsperGenius™, PathoNostics, Maastricht, the Netherlands; GM testing: Platelia Aspergillus, Bio‐Rad, Marnes‐La‐Coquette, France; Triazole susceptibility testing: VIPcheck™, Mediaproducts BV, Groningen, The Netherlands; Aspergillus lateral flow device: AspLFD, OLM diagnostics, Dagenham, United Kingdom.\n\nAbbreviations: BAL, Bronchoalveolar lavage; BDG, 1‐3 β‐d‐glucan; CVVH, continuous venovenous hemofiltration; ECMO, extracorporeal membrane oxygenation; GM, galactomannan; TA, Tracheal aspirate.\n\nJohn Wiley & Sons, Ltd\nThis article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.\n\n4 DISCUSSION\n\nIn this series, we found a significant reduction in COVID‐19 patients needing mechanical ventilation on the ICU in the second wave. This reduction is probably partly attributable 26 to the 10‐day 6 mg intravenous dexamethasone SARS‐CoV‐2 therapy 27 introduced after the first wave, indicated for patients with severe COVID‐19 and associated symptoms longer than 7 days. From these patients, however, a larger percentage were diagnosed with CAPA in the second wave (24.2% vs 15.2%), although not significant. Prolonged use of corticosteroids is known to be a risk factor for invasive fungal disease. 17 However, numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS‐CoV‐2 therapy. None of the CAPA patients in this case series had prior immuno‐compromising conditions, and diabetes mellitus was not overrepresented in either group.\n\nIn the first COVID‐19 wave, tracheal aspirates were used instead of bronchoalveolar lavage (BAL) as the use of bronchoscopy had been restricted in the COVID‐19 setting. 28 , 29 This likely explains the difference in possible versus probable CAPA classification in patients from the first and second waves. The consensus case definition of IAPA/CAPA from Verweij and colleagues were adapted for clinical decision making before the 2020 ECMM/ISHAM consensus criteria 23 were published, and yielded a similar number of CAPA patients in our cohort. 16 In line with the majority of other published case series, the EORTC/MSGERC consensus definition 17 and AspICU algorithm 18 for diagnosing invasive aspergillosis were unsuitable. 19 , 20 , 30 The 15.2% incidence of CAPA in our ICU in the first wave is comparable to the 19.4% 3 and 21.4% 4 published recently from other Dutch centres. These centres employ similar treatment regimes, and avoid empiric fungal prophylaxis. Of note, van Biesen et al. 4 used a novel, non‐directed, BAL method and did not apply existing diagnostic algorithms, making direct comparison with this study difficult.\n\nBy combining published case series, 16.5% (n = 151/917) of all SARS‐CoV‐2 patients requiring mechanical ventilation in the ICU developed CAPA (Table 2). The 47% (n = 62/132) mortality found in these case series is comparable to a recent study who report 52.5% mortality including both case series and case reports. 31 Not all patients were discharged from the hospital in several studies, possibly underestimating mortality. In IAPA, a similar overall mortality has been described (51%), 21 with a subset of IAPA tracheobronchitis patients having a reported mortality of over 90%. 32 To our knowledge, invasive tracheobronchitis has not been reported in CAPA patients, underscoring how IAPA and CAPA are mechanistically distinct clinical entities.\n\nTABLE 2 Overview of CAPA patients in published case series\n\nCountry\tDiagnostic criterium CAPA\tPatients CAPA/total cohort (%)\tSerum GM positive/tested (%)\tSerum BDG positive/tested (%)\tMortality (%)\t\nBelgium 5\tVerweij et al.\t7/34 (20.6)\t0/3 (0)\tN/A\t4/7 (57.1)\t\nChina 11\tEORTC/MSGERC\t4/50 (8)\tN/A\tN/A\tN/A\t\nDenmark 10\tAspICU algorithm\t2/27 (7.4)\t0/2 (0)\tN/A\t2/2 (100)\t\nFrance 8\tAspICU algorithm\t19/106 (17.9)\t1/12 (8.3)\tN/A\t7/19 (36.8)\t\nFrance 9\tN/A a\t9/27 (33.3)\t1/9 (11.1)\t4/8 (50)\t4/9 (44.4)\t\nGermany 6\tAspICU algorithm\t5/19 (26.3)\t2/5 (40)\tN/A\t3/5 (60)\t\nItaly 7\tVerweij et al.\t30/108 (27.8)\t1/16 (6.3)\tN/A\t13/30 (43.3)\t\nMexico 12\tAspICU algorithm\t14/144 (9.7)\t6/14 (42.9)\tN/A\t8/14 (57.1)\t\nSwitzerland 13\tVerweij et al.\t3/80 (3.8)\t1/3 (33)\t1/2 b (50)\t1/3 (33.3)\t\nThe Netherlands 3\tVerweij et al.\t6/31 (19.4)\t0/3 (0)\tN/A\t4/6 (66.7)\t\nThe Netherlands 4\tN/A a\t9/42 (21.4)\tN/A\tN/A\t2/9 (22.2)\t\nThe Netherlands ‐ this case series\tECMM/ISHAM consensus criteria\t13/66 (19.7)\t0/6 (0)\t1/1 (100)\t6/13 (46.2)\t\nUnited Kingdom 1\tVerweij et al. a\t15/ 122(12.3)\t2/3 (66.7)\t7/7 (100)\t8/15 (53.3)\t\nUnited Kingdom 2\tAspICU algorithm\t15/61 (24.6)\t5/15 (33.3)\t12/15 (80)\tN/A\t\nTotal\t\t151/917 (16.5)\t19/91 (20.9)\t25/33 (75.8)\t62/132 (47.0)\t\nNote\n\nFor better comparison, only mechanically ventilated patients were included from listed case series. Studies not adequately describing if patients were mechanically ventilated were excluded from this table.\n\nAbbreviations: BDG, 1‐3 β‐d‐glucan; CAPA, COVID‐19–associated pulmonary aspergillosis; GM, Galactomannan.\n\na Novel criteria are discussed in these publications.\n\nb Unpublished: personal communication with the authors, with gratitude.\n\nJohn Wiley & Sons, Ltd\nThis article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.\n\nIn diagnosing CAPA, little was known on the performance of serum GM and the ‘panfungal’ marker BDG. Serum GM testing in neutropenic non‐CAPA patients with proven invasive aspergillosis has been shown to have a sensitivity of around 70%, and 25% in the non‐neutropenic host. 33 CAPA patients are generally non‐neutropenic and sensitivity of serum GM reported in these patients are similarly low (15.6%–21%). 30 , 31 Whilst BDG testing is nonspecific, its sensitivity in the ICU population for invasive fungal disease has been shown to be high (88%). 34 Combining the case series reported, we found that only 20.9% had a positive serum GM (Table 2). In contrast, serum BDG was reported positive in 75.8% of CAPA patients tested (Table 2) albeit infrequently reported. Altogether, only 60.2% and 21.8% of mechanically ventilated suspected CAPA patients were tested for serum GM and serum BDG, respectively. In the first wave of our prospective case series, none of the patients had a positive serum GM. Because of the apparent low sensitivity of serum GM in this cohort and the lacking specificity of serum BDG, our hospital decided to limit the use of serum GM and BDG in the second wave.\n\nEpidemiological data dominate the choice of primary antifungal therapy, whilst development of resistance to antifungals in Aspergillus species is a growing concern. 35 Based on surveillance data, azole‐resistance in the Netherlands has been estimated to be around 11%, 36 , 37 in line with our findings in this series. Therefore, if A fumigatus susceptibility is unknown, empiric treatment is started with an echinocandin plus voriconazole or liposomal amphotericin B if toxicity or co‐infection with Mucorales is suspected. From our cohort, two patients had an environmental TR34/L98H azole‐resistant isolate, one of these elsewhere published as a case report. 20 This mutation has also been identified in CAPA patients in Ireland, 38 France 39 and the UK 2 underscoring the challenges faced in patient management, the importance of early diagnostics and (inter)national surveillance programs.\n\nCONFLICT OF INTEREST\n\nThe authors declare no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nEelco Meijer: Conceptualization (equal); Formal analysis (lead); Writing‐original draft (equal). Anton Dofferhoff: Conceptualization (equal); Data curation (equal); Writing‐review & editing (equal). Oscar Hoiting: Conceptualization (equal); Data curation (equal); Investigation (lead); Writing‐review & editing (equal). Jacques F. Meis: Conceptualization (equal); Resources (lead); Supervision (lead); Writing‐original draft (equal).\n==== Refs\nREFERENCES\n\n1 White PL , Dhillon R , Cordey A , et al. A national strategy to diagnose COVID‐19 associated invasive fungal disease in the ICU. Clin Infect Dis. 2020; 10.1093/cid/ciaa1298\n2 Borman AM , Palmer MD , Fraser M , et al. COVID‐19‐associated invasive Aspergillosis: data from the UK National Mycology Reference Laboratory. J Clin Microbiol. 2021;59 (1 ):e02136‐20.\n3 van Arkel ALE , Rijpstra TA , Belderbos HNA , van Wijngaarden P , Verweij PE , Bentvelsen RG . COVID‐19‐associated pulmonary aspergillosis. Am J Respir Crit Care Med. 2020;202 (1 ):132‐135.32396381\n4 Van Biesen S , Kwa D , Bosman RJ , Juffermans NP . Detection of invasive pulmonary aspergillosis in COVID‐19 with non‐directed bronchoalveolar lavage. Am J Respir Crit Care Med. 2020;202 (8 ):1171‐1173.\n5 Rutsaert L , Steinfort N , Van Hunsel T , et al. COVID‐19‐associated invasive pulmonary aspergillosis. Ann Intensive Care. 2020;10 (1 ):71.32488446\n6 Koehler P , Cornely OA , Böttiger BW , et al. COVID‐19 associated pulmonary aspergillosis. Mycoses. 2020;63 (6 ):528‐534.32339350\n7 Bartoletti M , Pascale R , Cricca M , et al. Epidemiology of invasive pulmonary aspergillosis among COVID‐19 intubated patients: a prospective study. Clin Infect Dis. 2020; 10.1093/cid/ciaa1065\n8 Dupont D , Menotti J , Turc J , et al. Pulmonary aspergillosis in critically ill patients with Coronavirus Disease 2019 (COVID‐19). Med Mycol. 2020;59 (1 ):110‐114.\n9 Alanio A , Dellière S , Fodil S , Bretagne S , Mégarbane B . Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID‐19. Lancet Respir Med. 2020;8 (6 ):e48‐e49.32445626\n10 Helleberg M , Steensen M , Arendrup MC . Invasive aspergillosis in patients with severe COVID‐19 pneumonia. Clin Microbiol and Infect. 2021;27 (1 ):147‐148.32768493\n11 Wang J , Yang Q , Zhang P , Sheng J , Zhou J , Qu T . Clinical characteristics of invasive pulmonary aspergillosis in patients with COVID‐19 in Zhejiang, China: a retrospective case series. Crit Care. 2020;24 (1 ):299.32503617\n12 Roman‐Montes ACM , Martinez‐Gamboa A , Diaz‐Lomelí P , et al. Accuracy of galactomannan testing on tracheal aspirates in COVID‐19‐associated pulmonary aspergillosis. Mycoses. 2020; 10.1111/myc.13216\n13 Lamoth F , Glampedakis E , Boillat‐Blanco N , Oddo M , Pagani JL . Incidence of invasive pulmonary aspergillosis among critically ill COVID‐19 patients. Clin Microbiol Infect. 2020;26 (12 ):1706‐1708.32659385\n14 Segrelles‐Calvo G , Araújo GRS , Llopis‐Pastor E , et al. Prevalence of opportunistic invasive aspergillosis in COVID‐19 patients with severe pneumonia. Mycoses. 2021;64 :144‐151.33217071\n15 Nasir N , Farooqi J , Mahmood SF , Jabeen K . COVID‐19‐associated pulmonary aspergillosis (CAPA) in patients admitted with severe COVID‐19 pneumonia: an Observational Study from Pakistan. Mycoses. 2020;63 (8 ):766‐770.32585069\n16 Verweij PE , Rijnders BJA , Brüggemann RJM , et al. Review of influenza‐associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. Intensive Care Med. 2020;46 (8 ):1524‐1535.32572532\n17 Donnelly JP , Chen SC , Kauffman CA , et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2020;71 (6 ):1367‐1376.31802125\n18 Blot SI , Taccone FS , Van den Abeele A‐M , et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2012;186 (1 ):56‐64.22517788\n19 Mohamed A , Rogers TR , Talento AF . COVID‐19 associated invasive pulmonary aspergillosis: diagnostic and therapeutic challenges. J Fungi (Basel). 2020;6 (3 ):115.\n20 Meijer EFJ , Dofferhoff ASM , Hoiting O , Buil JB , Meis JF . Azole‐resistant COVID‐19‐associated pulmonary aspergillosis in an immunocompetent host: a case report. J Fungi (Basel). 2020;6 (2 ):79.\n21 Schauwvlieghe A , Rijnders BJA , Philips N , et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a Retrospective Cohort Study. Lancet Respir Med. 2018;6 (10 ):782‐792.30076119\n22 Costantini C , van de Veerdonk FL , Romani L . Covid‐19‐associated pulmonary aspergillosis: The other side of the coin. Vaccines (Basel). 2020;8 (4 ):713.\n23 Koehler P , Bassetti M , Chakrabarti A , et al. Defining and managing COVID‐19‐associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis. 2020; 10.1016/s1473-3099(20)30847-1\n24 Wolters F , van de Bovenkamp J , van den Bosch B , et al. Multi‐center evaluation of Cepheid xpert® xpress SARS‐CoV‐2 point‐of‐care test during the SARS‐CoV‐2 pandemic. J Clin Virol. 2020;128 :104426.32417674\n25 Clinical and Laboratory Standards Institute . Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi. M38th‐Ed3. Wayne, PA: CLSI; 2017.\n26 Tomazini BM , Maia IS , Cavalcanti AB , et al. Effect of dexamethasone on days alive and ventilator‐free in patients with moderate or severe acute respiratory distress syndrome and COVID‐19: The CoDEX randomized clinical trial. JAMA. 2020;324 (13 ):1307‐1316.32876695\n27 Horby P , Lim WS , Emberson JR , et al. Dexamethasone in hospitalized patients with Covid‐19: preliminary report. N Engl J Med. 2020; 10.1056/NEJMoa2021436\n28 Wahidi MM , Lamb C , Murgu S , et al. American Association for Bronchology and Interventional Pulmonology (AABIP) statement on the use of bronchoscopy and respiratory specimen collection in patients with suspected or confirmed COVID‐19 infection. J Bronchology Interv Pulmonol. 2020;27 (4 ):e52‐e54.32195687\n29 Verweij PE , Gangneux J‐P , Bassetti M , et al. Diagnosing COVID‐19‐associated pulmonary aspergillosis. Lancet Microbe. 2020;1 (2 ):e53‐e55.32835328\n30 Arastehfar A , Carvalho A , van de Veerdonk FL , et al. COVID‐19 associated pulmonary aspergillosis (CAPA): From immunology to treatment. J Fungi (Basel). 2020;6 (2 ):91.\n31 Salmanton‐Garcia J , Sprute R , Stemler J , et al. COVID‐19 associated pulmonary aspergillosis: an analysis of epidemiological and clinical characteristics of 186 international cases from FungiScope® Registry and the literature. Emerg Infect Dis. 2021;27 (4 ). 10.3201/eid2704.204895\n32 Nyga R , Maizel J , Nseir S , et al. Invasive tracheobronchial aspergillosis in critically ill patients with severe influenza. A clinical trial. Am J Respir Crit Care Med. 2020;202 (5 ):708‐716.32407157\n33 Meersseman W , Lagrou K , Maertens J , et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med. 2008;177 (1 ):27‐34.17885264\n34 Lahmer T , Neuenhahn M , Held J , Rasch S , Schmid RM , Huber W . Comparison of 1,3‐β‐D‐glucan with galactomannan in serum and bronchoalveolar fluid for the detection of Aspergillus species in immunosuppressed mechanical ventilated critically ill patients. J Crit Care. 2016;36 :259‐264.27475024\n35 Wiederhold NP , Verweij PE Aspergillus fumigatus and pan‐azole resistance: who should be concerned? Curr Opin Infect Dis. 2020;33 (4 ):290‐297.32657965\n36 Lestrade PPA , Buil JB , van der Beek MT , et al. Paradoxal trends in azole‐resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013–2018. Emerg Infect Dis. 2020;26 (7 ):1447‐1455.32568033\n37 Buil JB , Meijer EFJ , Denning DW , Verweij PE , Meis JF . Burden of serious fungal infections in the Netherlands. Mycoses. 2020;63 (6 ):625‐631.32297377\n38 Mohamed A , Hassan T , Trzos‐Grzybowska M , et al. Multi‐triazole‐resistant Aspergillus fumigatus and SARS‐CoV‐2 co‐infection: a lethal combination. Med Mycol Case Rep. 2020; 10.1016/j.mmcr.2020.06.005\n39 Ghelfenstein‐Ferreira T , Saade A , Alanio A , et al. Recovery of a triazole‐resistant Aspergillus fumigatus in respiratory specimen of COVID‐19 patient in ICU – A case report. Med Mycol Case Rep. 2020; 10.1016/j.mmcr.2020.06.006\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "64(4)",
"journal": "Mycoses",
"keywords": "\nAspergillus fumigatus\n; CAPA; ICU; TR34L98H; dexamethasone; pulmonary aspergillosis",
"medline_ta": "Mycoses",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D009426:Netherlands; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D055732:Pulmonary Aspergillosis; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D000086402:SARS-CoV-2",
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"pages": "457-464",
"pmc": null,
"pmid": "33569857",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": "32657965;33539721;32876695;32914189;32339350;32195687;33217071;32768493;33271780;32719848;32860682;32568033;33217784;32837880;32599813;33569857;22517788;32585069;32678530;32668167;32417674;32445626;32707965;32488446;32835328;33333012;32407157;32837879;32396381;31802125;32503617;32659385;32517166;32297377;32572532;30076119;17885264;33087440;27475024",
"title": "COVID-19-associated pulmonary aspergillosis: a prospective single-center dual case series.",
"title_normalized": "covid 19 associated pulmonary aspergillosis a prospective single center dual case series"
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"abstract": "OBJECTIVE\nTo report a patient who had developed reversible hypocortisolism during the use of quetiapine.\n\n\nMETHODS\nEarly morning cortisol levels were measured on two separate days. In addition, the patient underwent testing with intravenous synthetic adrenocorticotropic hormone (1 mcg tetracosactide) before and after tapering of quetiapine. Pituitary function was assessed and magnetic resonance imaging (MRI) was performed.\n\n\nRESULTS\nThe patient had low early morning cortisol levels at presentation when using quetiapine. Tetracosactide testing indicated hypocortisolism. A MRI of the pituitary was unremarkable. The patient was treated temporarily with hydrocortisone and quetiapine was tapered. After quetiapine had been discontinued, the patient's cortisol production had returned to normal.\n\n\nCONCLUSIONS\nAlthough lowering cortisol levels has been previously reported, this is the first report of hypocortisolism associated with the use of quetiapine. It is possible symptoms of malaise in patients who use quetiapine could be attributed to quetiapine-related hypocortisolism.",
"affiliations": "Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands Section of Endocrinology, University Medical Center Utrecht, Utrecht, The Netherlands.",
"authors": "Dreijerink|Koen M A|KM|;Kampschreur|Linda M|LM|;Lentjes|Eef G W M|EG|;Lokhorst|Bianca|B|;Zelissen|Pierre M J|PM|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D003366:Cosyntropin; D000069348:Quetiapine Fumarate; D006854:Hydrocortisone",
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"doi": "10.4158/EP12415.CR",
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"issue": "19(5)",
"journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists",
"keywords": null,
"medline_ta": "Endocr Pract",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003366:Cosyntropin; D003987:Dibenzothiazepines; D006801:Humans; D006854:Hydrocortisone; D008297:Male; D010902:Pituitary Gland; D000069348:Quetiapine Fumarate",
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"pages": "e112-4",
"pmc": null,
"pmid": "23757611",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical hypocortisolism.",
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"abstract": "Hypothyroidism occurs relatively common and is a significant cause of morbidity and mortality during the course of chronic kidney disease. Rhabdomyolysis is a potentially life-threatening condition characterised by necrosis of muscular tissue and rarely associates with hypothyroidism. Here we describe a case of rhabdomyolysis due to severe hypothyroidism in a 56-year-old female hemodialysis patient.",
"affiliations": "Division of Nephrology, Izmir Bozyaka Education and Research Hospital, 9035170 Izmir, Turkey.;Department of Internal Medicine, Izmir Bozyaka Education and Research Hospital, 9035170 Izmir, Turkey.;Division of Nephrology, Izmir Bozyaka Education and Research Hospital, 9035170 Izmir, Turkey.;Division of Nephrology, Izmir Bozyaka Education and Research Hospital, 9035170 Izmir, Turkey.;Division of Nephrology, Izmir Bozyaka Education and Research Hospital, 9035170 Izmir, Turkey.",
"authors": "Tatar|Erhan|E|;Isikyakar|Tolgay|T|;Yeniay|Kezban Pinar|KP|;Uzuner|Hasan Huseyin|HH|;Sevinc Ok|Ebru|E|",
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"doi": "10.1155/2014/501890",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/501890Case ReportHypothyroidism Induced Severe Rhabdomyolysis in a Hemodialysis Patient Tatar Erhan \n1\n*Isikyakar Tolgay \n2\nYeniay Kezban Pinar \n1\nUzuner Hasan Huseyin \n1\nSevinc Ok Ebru \n1\n1Division of Nephrology, Izmir Bozyaka Education and Research Hospital, 9035170 Izmir, Turkey2Department of Internal Medicine, Izmir Bozyaka Education and Research Hospital, 9035170 Izmir, Turkey*Erhan Tatar: etatar@hotmail.comAcademic Editor: W. Zidek\n\n2014 7 4 2014 2014 50189018 1 2014 12 3 2014 Copyright © 2014 Erhan Tatar 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.Hypothyroidism occurs relatively common and is a significant cause of morbidity and mortality during the course of chronic kidney disease. Rhabdomyolysis is a potentially life-threatening condition characterised by necrosis of muscular tissue and rarely associates with hypothyroidism. Here we describe a case of rhabdomyolysis due to severe hypothyroidism in a 56-year-old female hemodialysis patient.\n==== Body\n1. Introduction\n\nThyroid dysfunction is relatively common in patients with chronic kidney disease (CKD) when compared to general population [1, 2]. Both hormonal changes including alterations in TRH, TSH, and iodine clearance as well as presence of associating autoimmune disorders (type 1 diabetes mellitus or systemic lupus erythematosus) and comorbidities such as HCV infection or treatment with drugs having adverse thyroid effects (e.g., amiodarone) are thought to be responsible for thyroid dysfunction [2–4]. Thyroid dysfunction particularly hypothyroidism is a significant cause of cardiovascular mortality and morbidity in CKD patients [5–10]. In hemodialysis patients, however, the frequency of acute complications and neuromuscular effects of hypothyroidism are not known.\n\nRhabdomyolysis is a rapid breakdown of skeletal muscle tissue leading to release of its contents into systemic circulation [11]. Rhabdomyolysis, a life-threatening condition, may occur due to physical factors including trauma, convulsions, or overexertion as well as to chemical and hormonal causes [11]. Hypothyroidism associated rhabdomyolysis is rare in nonuremic patients. Hypothyroidism induced rhabdomyolysis in dialysis patients has not been reported as far as we know. Here we present a case of rhabdomyolysis in a hemodialysis patient on amiodarone treatment receiving antithyroid therapy for subclinical hyperthyroidism.\n\n2. Case Presentation\nA 56-year-old female with a past medical history of end stage diabetic nephropathy, interstitial pulmonary disease, congestive heart failure, and atrial fibrillation presented to nephrology outpatient clinics with complaints of nausea and fatigue. She was back on routine hemodialysis 4 times a week for 18 months (she underwent a renal transplantation 10 years ago). She provided a history of subclinical hyperthyroidism detected six months ago for which antithyroid treatment was started because of the diagnosis of a thyroid nodule. She stated that she missed her follow-up appointments. Her medications included warfarin 5 mg, diltiazem 30 mg, amiodarone 400 mg (started for atrial fibrillation with rapid ventricular response), propylthiouracil 300 mg, theophylline 300 mg, acetylsalicylic acid 100 mg, olanzapine 2.5 mg, citalopram 10 mg, and calcium acetate 1500 mg daily.\n\nOn admission her blood pressure was 80/50 mmHg, body temperature was 36.7°C, pulse rate was 50 beats/min, and respiratory rate was 12/min. Physical examination revealed bilateral rales at the lung bases. Electrocardiogram showed atrial fibrillation with slow ventricular response with 45–50 bpm. Upon initial assessment laboratory studies revealed the following: hemoglobin: 10.8 g/dL, mean corpuscular volume (MCV): 78, total leukocyte count: 13,700/mm3, and platelet count: 289 × 109/L; random blood sugar: 117 mg/dL, blood urea: 142 mg/dL, serum creatinine: 6.61 mg/dL, serum albumin: 4.06 g/dL, serum aspartate amino transferase (AST): 400 (0–31) U/L, serum alanine amino transferase (ALT): 71 (0–31) U/L, creatine phosphokinase (CPK): 6314 (26–192) U/L, CPK-MB: 12 (2–24) U/L, troponin I: 0.252 ng/mL (0–0.06), serum lactate dehydrogenase (LDH): 3643 (135–214) U/L, serum sodium: 132 mEq/L, and serum potasium: 7.2 mEq/L; TSH: >100 uIU, free T3: 1.5 pg/mL, and free T4: 0.4 (repeated twice). Antithyroglobulin and antithyroid peroxidase antibody were negative. Basal serum cortisol level was 32.97 ug/dL (6.7–22.6). Thyroid gland size was measured to be normal on thyroid ultrasound while a heterogeneous appearance was observed including fibrous bands with no nodules. She was diagnosed with hypothyroidism induced rhabdomyolysis. Thyroid function test results during hemodialysis treatment are demonstrated in Table 1. Antithyroid and antiarrhythmic medications were discontinued. Levothyroxine replacement therapy was started with a daily dose of 100 mcg, which then gradually increased up to 200 mcg. The patient underwent daily hemodialysis during the first five days of the hospital stay. On hospital followup the patient's muscle enzymes gradually declined to normal ranges in nearly two weeks (Figure 1). The patient was discharged in good clinical condition after two weeks of hospitalization.\n\n3. Discussion\nHypothyroidism related skeletal muscle involvement is observed in almost 80% of the nonuremic patient population in which muscle serum creatinine kinase is usually slightly elevated [12]. Deterioration of glycogenolysis, mitochondrial oxidative metabolism, and triglyceride turnover in thyroxine deficiency may be the responsible pathogenetic mechanisms. Hypothyroidism associated rhabdomyolysis, on the other hand, is quite rare [13]. Hypothyroidism induced rhabdomyolysis, depending on its severity, may be complicated with acute kidney injury [14]. Rhabdomyolysis tends to occur more frequently in a portion of comorbid patients particularly receiving antihyperlipidemics (i.e., statins and fibrates) [15, 16]. In the literature, however, there have been no reports regarding hypothyroidism induced rhabdomyolysis in a hemodialysis patient. Hemodialysis patients are likely to have an increased risk for hypothyroidism induced rhabdomyolysis regarding the presence of comorbidities such as electrolyte imbalances, diabetes mellitus, medications received, and drug-drug interactions (i.e., antihyperlipidemics, antihypertensives, and antiarrhythmics).\n\nKidneys play a significant role in thyroid hormone metabolism. Deterioration in kidney functions may lead to important alterations in thyroid functions for which a variety of mechanisms have been suggested [3, 4]. The most common thyroid function abnormality in patients with CKD is euthyroid sick syndrome (i.e., low T3 syndrome) and hypothyroidism frequency of which increases with the severity of CKD [1, 2]. The frequency of subclinical hyperthyroidism, on the other hand, is the same as the general population [3, 17]. However, there is not enough information about whether to start antithyroid treatment in CKD patients with subclinical hyperthyroidism. The decision to start antithyroid treatment should be given carefully considering that thyroid function parameters in case of comorbid situations tend to vary during the course of followup, and that these medications are likely to interact with others in CKD patients, who usually are on multiple drugs. In our patient, hypothyroidism is likely to have developed due to antithyroid treatment started for subclinical hyperthyroidism.\n\nAmiodarone, a class III antiarrhythmic drug, potentially interferes with normal thyroid function owing to its high iodine content [18, 19]. It inhibits both peripheral conversion of T3 to T4 via blocking 1–5′ deiodinase and the entry of thyroid hormone into peripheral tissues, thereby increasing serum fT4 levels while lowering serum fT3 levels. Amiodarone alters pituitary synthesis and release of TSH and inhibits the activity of 2–5′ deiodinase resulting in elevated serum TSH concentrations [18, 20]. The majority of the patients treated with amiodarone remain euthyroid whereas the treatment sometimes may lead to thyrotoxic or hypothyroid states. Amiodarone induced clinical hypothyroidism is seen in only 5% of the patients receiving the treatment. The predisposing factors are coexisting Hashimoto's thyroiditis and/or presence of autoantibodies as well as living in iodine-sufficient areas [19]. Long-term amiodarone treatment is not likely to be solely responsible for the severe hypothyroidism in our patient. The antithyroid medication, kidney disease, and decreased clearance of iodine are possible contributors. Amiodarone, which is metabolized by cytochrome P-450 (CYP) 3A4 in the liver, may interact with concurrent drugs (i.e., antihyperlipidemics) by interfering with their metabolism and this may lead to adverse events including rhabdomyolysis [21]. Our patient, although denied a medical history of use of antihyperlipidemic drugs, was on multidrugs, and we think that potential drug interactions could have contributed to development of rhabdomyolysis.\n\nIn conclusion, thyroid dysfunction is an important problem in hemodialysis patients. Hypothyroidism induced rhabdomyolysis may be seen, although rarely, in these patients. Hypothyroidism must be questioned in the etiological assessment of rhabdomyolysis in hemodialysis patients.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests.\n\nFigure 1 Rhabdomyolysis parameters of the patient during the hospital stay.\n\nTable 1 Thyroid function test results during hemodialysis treatment.\n\n \tEighteen months prior to admission\tSix months prior to admission \n(on propylthiouracil treatment)\t Upon admission \tOne month after admission\n(on levothyroxine treatment)\t\nTSH (normal range)\n(0.41–4.25 uIU/mL)\t0.80\t0.04↓\t>100↑↑\t2.44\t\nfT3 (normal range)\n(2.5–3.9 pg/mL)\t2.40↓\t2.30↓\t1.5↓↓\t2.09↓\t\nfT4 (normal range)\n(0.61–1.06 ng/dL)\t1.05\t0.98\t0.4↓↓\t1.53↑\t\nAntithyroglobulin\n(0–100 IU/mL)\t \tneg\t0 (neg)\t \t\nAnti-TPO\n(0–100 IU/mL)\t \tneg\t0.9 (neg)\t \n==== Refs\n1 Lo JC Chertow GM Go AS Hsu C-Y Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease Kidney International 2005 67 3 1047 1052 2-s2.0-20844439910 15698444 \n2 Chonchol M Lippi G Salvagno G Zoppini G Muggeo M Targher G Prevalence of subclinical hypothyroidism in patients with chronic kidney disease Clinical Journal of the American Society of Nephrology 2008 3 5 1296 1300 2-s2.0-53749105339 18550654 \n3 Kaptein EM Thyroid hormone metabolism and thyroid diseases in chronic renal failure Endocrine Reviews 1996 17 1 45 63 2-s2.0-0030051476 8641223 \n4 Disthabanchong S Treeruttanawanich A Oral sodium bicarbonate improves thyroid function in predialysis chronic kidney disease American Journal of Nephrology 2010 32 6 549 556 2-s2.0-77958527094 21042013 \n5 Rhee CM Alexander EK Bhan I Brunelli SM Hypothyroidism and mortality among dialysis patients Clinical Journal of the American Society of Nephrology 2013 8 4 593 601 23258793 \n6 Zoccali C Benedetto F Mallamaci F Low triiodothyronine and cardiomyopathy in patients with end-stage renal disease Journal of Hypertension 2006 24 10 2039 2046 2-s2.0-33748623395 16957565 \n7 Tatar E Kircelli F Asci G Associations of triiodothyronine levels with carotid atherosclerosis and arterial stiffness in hemodialysis patients Clinical Journal of the American Society of Nephrology 2011 6 9 2240 2246 2-s2.0-80052605638 21836150 \n8 Tatar E Demirci MS Kircelli F The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients International Urology and Nephrology 2012 44 601 606 21779917 \n9 Carrero JJ Qureshi AR Axelsson J Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease Journal of Internal Medicine 2007 262 6 690 701 2-s2.0-36248953130 17908160 \n10 Tatar E Kircelli F Ok E The contribution of thyroid dysfunction on cardiovascular disease in patients with chronic kidney disease Atherosclerosis 2013 227 1 26 31 23206977 \n11 Khan FY Rhabdomyolysis: a review of the literature Netherlands Journal of Medicine 2009 67 9 272 283 2-s2.0-70350438980 19841484 \n12 Duyff RF van den Bosch J Laman DM Potter van Loon B-J Linssen WHJP Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study Journal of Neurology Neurosurgery and Psychiatry 2000 68 6 750 755 2-s2.0-0034065086 \n13 Monzani F Caraccio N Siciliano G Manca L Murri L Ferrannini E Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism Journal of Clinical Endocrinology and Metabolism 1997 82 10 3315 3318 2-s2.0-0030884984 9329360 \n14 Altay M Duranay M Ceri M Rhabdomyolysis due to hypothyroidism Nephrology Dialysis Transplantation 2005 20 4 847 848 2-s2.0-17144384434 \n15 Kiernan TJ Rochford M McDermott JH Simvastatin induced rhabdomyolysis and an important clinical link with hypothyroidism International Journal of Cardiology 2007 119 3 374 376 2-s2.0-34250316660 17098308 \n16 Satarasinghe RL Ramesh R Riyaaz AAA Gunarathne PAKG de Silva AP Hypothyroidism is a predisposing factor for fenofibrate-induced rhabdomyolysis—patient report and literature review Drug Metabolism and Drug Interactions 2007 22 4 279 283 2-s2.0-40149088288 18447003 \n17 Kaptein EM Wilcox RB Nelson JC Assessing thyroid hormone status in a patient with thyroid disease and renal failure: from theory to practice Thyroid 2004 14 5 397 400 2-s2.0-2942592170 15186619 \n18 Basaria S Cooper DS Amiodarone and the thyroid American Journal of Medicine 2005 118 7 706 714 2-s2.0-21244452633 15989900 \n19 Batcher EL Tang XC Singh BN Singh SN Reda DJ Hershman JM Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation American Journal of Medicine 2007 120 10 880 885 2-s2.0-34548823481 17904459 \n20 Franklyn JA Davis JR Gammage MD Littler WA Ramsden DB Sheppard MC Amiodarone and thyroid hormone action Clinical Endocrinology 1985 22 3 252 264 2-s2.0-0021992135 \n21 Marot A Morelle J Chouinard VA Jadoul M Lambert M Demoulin N Concomitant use of simvastatin and amiodarone resulting in severe rhabdomyolysis: a case report and review of the literature Acta Clinica Belgica 2011 66 2 134 136 2-s2.0-79960961358 21630612\n\n",
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"abstract": "Sclerosing extramedullary hematopoietic tumors (SEMHTs) are associated with chronic myeloproliferative neoplasms. These extremely rare mass lesions were first described in kidney and peritoneum. On histopathology, they are characterized by sclerosis, entrapped fat, atypical megakaryocytes with myeloid and erythroid elements. Only approximately ten cases have been subsequently reported in orbit, lacrimal system, liver, omentum, and skin. The authors present a case of SEMHTs as incidentally detected omental nodules, while the patient was undergoing splenectomy for Janus kinase-2 negative myelofibrosis. The authors postulate their origin in omentum-associated lymphoid tissue; and highlight the diagnostic dilemma presented by SEMHTs at frozen section.",
"affiliations": "Department of Pathology, B.Y.L. Nair Hospital, Mumbai, Maharashtra, India.",
"authors": "Shinde|Sweety V|SV|;Shenoy|Asha S|AS|;Balsarkar|Dharmesh J|DJ|;Shah|Vinaya B|VB|",
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"title": "Omental sclerosing extramedullary hematopoietic tumors in Janus kinase-2 negative myelofibrosis: caveat at frozen section.",
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"abstract": "A 60 years old chinese male scheduled for a removal of an intracardiac mass occupying majority of right ventricular space, right ventricular outflow tract and pulmonary artery. The giant cardiac mass was later diagnosed pathologically as metastatic liposarcoma. The patient had a history of surgical removal of myxoid liposarcoma from his left thigh many years ago. It is extremely rare for liposarcoma to metastatize to right ventricle and pulmonary artery. The anesthetic management of the surgical procedure to remove this kind of intracardiac mass poses significant challenges to anesthesia providers. Our patient developed refractory hypotension after induction of general anesthesia which necessitated urgent cardiopulmonary bypass. The surgical procedure was successful and the patient recovered from the surgery and was discharged home without significant complication. Accurate preoperative diagnosis and assessment of patient's functional status, appropriate preoperative volume status, emergency cardiopulmonary bypass readiness, smooth and gentle induction of general anesthesia with less myocardial depressing agent, and closely monitoring patient's vitals and hemodynamic parameters are imperative in managing this kind of patients.",
"affiliations": "Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China. smzhu20088@163.com.",
"authors": "Xu|Jianhong|J|;Zheng|Yueying|Y|;Wang|Liqing|L|;Feng|Qiang|Q|;Yu|Ceyan|C|;Zhu|Shengmei|S|",
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"fulltext": "\n==== Front\nJ Cardiothorac SurgJ Cardiothorac SurgJournal of Cardiothoracic Surgery1749-8090BioMed Central 1749-8090-9-562465532910.1186/1749-8090-9-56Case ReportAnesthetic management of the removal of a giant metastatic cardiac liposarcoma occupying right ventricle and pulmonary artery Xu Jianhong 1xujh1969@163.comZheng Yueying 1mariezju2004@126.comWang Liqing 1wangliqingzju@163.comFeng Qiang 2fengqiang1088@126.comYu Ceyan 2yuceyan@163.comZhu Shengmei 1smzhu20088@163.com1 Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China2 Department of Thoracicardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China2014 22 3 2014 9 56 56 29 8 2013 17 3 2014 Copyright © 2014 Xu et al.; licensee BioMed Central Ltd.2014Xu et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.A 60 years old chinese male scheduled for a removal of an intracardiac mass occupying majority of right ventricular space, right ventricular outflow tract and pulmonary artery. The giant cardiac mass was later diagnosed pathologically as metastatic liposarcoma. The patient had a history of surgical removal of myxoid liposarcoma from his left thigh many years ago. It is extremely rare for liposarcoma to metastatize to right ventricle and pulmonary artery. The anesthetic management of the surgical procedure to remove this kind of intracardiac mass poses significant challenges to anesthesia providers. Our patient developed refractory hypotension after induction of general anesthesia which necessitated urgent cardiopulmonary bypass. The surgical procedure was successful and the patient recovered from the surgery and was discharged home without significant complication. Accurate preoperative diagnosis and assessment of patient’s functional status, appropriate preoperative volume status, emergency cardiopulmonary bypass readiness, smooth and gentle induction of general anesthesia with less myocardial depressing agent, and closely monitoring patient’s vitals and hemodynamic parameters are imperative in managing this kind of patients.\n\nLiposarcomaCardiac tumorHypotensionCardiopulmonary bypassTransesophageal echocardiography\n==== Body\nBackground\nMetastatic tumors to cardiac chamber(s) are uncommon. If it occurs, mostly it is due to renal cancer and metastasized to right atrium. Liposarcoma from lower extremity metastasized into right ventricle (RV) and protruded into pulmonary artery (PA) is extremely rare [1-4]. We report this case with the metastatic neoplasm occupying most RV chamber space and protruding into pulmonary artery. When we induced general anesthesia, the patient collapsed hemodynamically. Emergency cardiopulmonary bypass (CPB) was established. The patient underwent a successful removal of the metastatic tumor and recovered smoothly postoperatively. The complete resection of tumor is a recognized therapy with documented favorable prognosis [5]. The scheduled procedure in this kind of patient poses unique challenges to the anesthesiologist(s). We will discuss what we have learned from this case and the potential challenges anesthesia provider(s) will face.\n\nCase presentation\nA 60 years old chinese male was admitted to our hospital with chest tightness, dyspnea, systemic edema, and abdominal distension for more than 1 week. Physical examination is within normal limits except mild systematic edema. Electrocardiography (ECG) showed complete right bundle branch block and RV hypertrophy. The chest X-ray revealed cardiomegaly (cardiothoracic ratio: 60%). The transthoracic echocardiography detected a large echogenic mass (10.4*4.1 cm) which occupied most chamber space of RV and RV outflow tract (RVOT), was attached to the RV free wall, and extended into the main pulmonary artery and its bifurcations. A small pericardial effusion and left ventricular diastolic dysfunction were also detected. Computerized tomography (CT) with contrast of the chest confirmed the presence of the mass, which caused obvious obstruction of the RVOT (Figure 1). Laboratory results were unremarkable. The patient had a right bundle branch block for about 10 years and a surgical removal of a left thigh liposarcoma 20 years ago. With the preoperative diagnosis of intracardia tumor, the patient was scheduled for excision of the mass with CPB. On arrival to operating theatre, O2 (5 L/min) via face mask was administered and all American Society of Anesthesiologists (ASA) standard monitors were started. Pulse oxygen saturation (SpO2) was 98%, and heart rate 100 beats/min. The left radial arterial and large-bore intravenous access was obtained. The invasive blood pressure was 120/85 mmHg (mean blood pressure, MBP, 100 mmHg). A double-lumen central venous catheter (14, 18gauge, 13 cm length from the catheter tip to the skin; Arrow International, USA) was inserted to the right internal jugular vein before the induction of general anesthesia. Then the central venous pressure (CVP) was measured as 31 mmHg. Lactate Ringer’s solution 1000 ml was administrated, and then the induction of general anesthesia was performed slowly with midazolam 2 mg iv, etomidate 8 mg iv, rocuronium 50 mg iv, sufentanyl 30 μg iv, and scopolamine 0.3 mg iv. During induction, blood pressure fell about 40 mmHg from baseline, which responded to phenylephrine (40 μg, iv) and fluid administration. The results from arterial blood gas revealed pH 7.30, PaCO2 37, PaO2 89 (FiO2 at 50%). General anesthesia was maintained with propofol (200 mg/h) and cis-atracurium (10 mg/h), and sufentanyl (iv, intermittently according to hemodynamic changes). Meanwhile, dopamine (3-8 μg/kg/min) was given continuously. MBP decreased below 60 mmHg after sternal retraction, unresponsive to intravenous fluid and phenylephrine administration. Heart rates fluctuated around 90 beats/min. SpO2 maintained at 95-100%. CVP increased to 35 mmHg. The medication for maintenance of general anesthesia was turned down temporarily. About 24 minutes after induction of general anesthesia, urgent CPB was initiated after intravenous heparine was given. Ulinastatin (30,000 U) and methylprednisolone (40 mg) were also administrated. Then the surgery team removed the neoplasm successfully from the RV, RVOT and pulmonary artery. Total CPB and aortic cross-clamp times were 90 and 24 minutes, respectively. The patient was weaned from CPB easily with pace-maker and epinephrine infusion of 6 μg/min. At the termination of CPB, the pH was 7.30, PaCO2 44 mmHg, PaO2 276 mmHg with FiO2 80%. After CPB, the patient’s heart rate was maintained at around 90 beats/min, blood pressure 90-100/50-60 mmHg, and CVP 9-11 mmHg. The patient was extubated at postoperative day one in surgical ICU (intensive care unit) and he was discharged home in a good condition 11 days postoperatively. The final histopathology report of the tumor mass revealed myxoid liposarcoma. The post-operative ECG indicated no residual mass was inside the heart chambers.\n\nFigure 1 Iodine enhanced computerized tomography of the patient’s chest. Sagittal view confirmed a large filling defect in the right ventricle extended into the right pulmonary artery (arrow), rending almost complete occlusion of the right ventricular outflow tract.\n\nDiscussion\nThe occurrence of metastatic liposarcoma to the heart is rare. Metastatic liposarcoma occurs most likely in the lungs, liver, lymph node, brain and skeletal system [6]. Only 20 cases of metastatic cardiac liposarcoma were reported in the literature prior to our report [4,7-9]. Diagnosis of the isolated heart tumor as being metastatic is unusual unless the primary site is discovered. Liposarcoma is one of the most common soft tissue sarcomas, usually found in the lower extremities. The myxoid of histological classification accounts about 50% in liopsarcoma subgroups, which is characterized by a slow growth and a low risk for the metastasis. Some authors believe that it may take 3-25 years to present at a metastatic location [6]. In our patient, the interval between the appearance of primary tumor and metastasis was about 20 years.\n\nClinically, the symptoms of cardiac metastasis are basically nonspecific. Pericardium is usually involved and pericardial effusion often exists. Heart failure is a common clinical feature. And cardioembolic stroke, myocardial infarction and even death from malignant arrhythmia may be its serious complications. Generally, cardiac symptoms appear slowly in onset. Nevertheless, in our case, symptoms on admission were 1-week history of clinical symptoms related to the right heart failure. Two-dimensional ECG and CT of the chest are reportedly very accurate in making the diagnosis and assessing the extent of a cardiac mass preoperatively, though angiocardiography would better provide spatial and temporal resolution in this kind of patients [10]. The prognosis of the metastatic liposarcoma is usually poor. Surgery is indicated when complete resection of tumor is feasible and/or relieving intracardiac obstruction is necessary [11].\n\nThe concerns in anesthetizing these patients with tumors involved in the RV, the RVOT, and even PA include acute RV failure, hypoxemia, low cardiac output, tamponade, and potential pulmonary emboli. There is no “standard method” for the anesthetic management of this kind of surgical procedures. We believe the following strategies will help manage these patients:\n\n1. Preoperative evaluation: accurate preoperative diagnosis, assessment of tumor size, location, involvement of cardiac valves, tumor mobility, degree of obstruction to blood flow etc and evaluation of patient’s overall cardiac functional status and comorbidities;\n\n2. Preoperative volume replacement is very important, hypovolemia should be avoided;\n\n3. Monitoring: non-thermodilution technique for cardiac output measurement should be used, because we cannot insert a pulmonary artery catheter for these patients. CVP is possible, but the catheter cannot be too close to superior vena cava-right atrium junction; Transesophageal ECG will be very helpful in multiple aspects: confirming diagnosis, assessment of the mass, evaluation of blood volume status, cardiac function and comorbidities, monitoring the evolving process of the surgical procedure. In addition, it is useful in detecting the tumor fragmentation, dislodgement or embolism [12,13]. Unfortunately we did not use TEE (transesophageal echocardiography) due to technical difficulties.\n\n4. Emergency CPB readiness: sedating patient for preoperative invasive line placement, or inducing general anesthesia can all cause hemodynamic collapse, so emergency CPB readiness is mandatory. Surgical sterilizing and draping before the initiation of induction of anesthesia is also mandatory. In some report, some authors even suggested to prepare for femoral-femoral cannulation and bypass [12].\n\n5. Smooth and slow-titration induction of general anesthesia with less myocardial depressing agent, and closely monitoring patient’s vitals and hemodynamic parameters are imperative in managing this kind of patients. Avoidance of sedating these patients outside of operation room (OR) is also very important because if patient’s hemodynamic parameters worsen, emergency CPB is necessary, it is more favorable if patient is inside the OR.\n\n6. Judicious use of inotropes: inotropes are double-sides sword for these kinds of patients. When using appropriately, inotropes can enhance myocardial contractility and improve hemodynamics. On the other hand, inotropes can also cause increased contractility which leads to narrower passage for intracardiac blood flow.\n\nWe supplemented the patient with 1000 ml of crystalloid before the initiation of induction. However, we were not sure whether the RV preload was full, since the CVP monitoring might not accuratly reflect the RV volume status due to the RV mass. Despite of the slow and careful induction of anesthesia and intravenous infusion of dopamine for improving RV contractility, hypotension happened after induction and exacerbated after sternotomy. This hypotension might be related to decreased systemic vascular resistance (SVR), which caused decreased venous return, thus lower cardiac output and hypotension. Another potential mechanism is the sudden dilatation of RV. Flexman AM et al reported with TEE monitoring that the distended RV in the condition of acute RV failure forced the interventricular septum to be shifted the left, which reduced the left ventricle volume further [12]. In our case, the surgeon did find the heart congestion during the exploration. Undoubtedly, TEE measurements would be significantly useful and helpful for cardiac assessment and monitoring. In addition, delicate performance during surgery is also crucial for the patient. The surgery team adopted a special technique of suctioning tumor instead of excision avoid tumor fragmentation, thus reducing the chance of residual tumor or tumor migration to other tissue or organs. Post-operative ECG assesses the completeness of surgical removal and may reveal some unexpected findings.\n\nConclusions\nGiant metastatic cardiac liposarcoma occupying right ventricle and pulmonary artery is extremely rare. The anesthetic management of the surgical procedure to remove this kind of tumor poses significant challenges to anesthesia providers. Accurate preoperative diagnosis and assessment of patient’s functional status, appropriate preoperative volume status, emergency CPB readiness, smooth and gentle induction of general anesthesia with less myocardial depressing agent, and closely monitoring patient’s vitals and hemodynamic parameters are imperative in managing this kind of patients.\n\nConsent statement\nWritten informed consent was obtained from the patient 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\nAbbreviations\nASA: American society of anesthesiologists; CPB: Cardiopulmonary bypass; CT: Computerized tomography; CVP: Central venous pressure; ECG: Electrocardiography; ICU: Intensive care unit; MBP: Mean blood pressure; OR: Operation room; PA: Pulmonary artery; RV: Right ventricle; RVOT: Right ventricular outflow tract; SpO2: Pulse oxygen saturation; SVR: Systemic vascular resistance; TEE: Transesophageal echocardiography.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nXJH and ZSM carried out the anesthetic management of the patient. ZYY participated in the following-up of this patient and drafted the manuscript. WLQ participated in modify the manuscript and submitted to the journal. FQ and YCY participated in the operation of this patient. All authors read and approved the final manuscript.\n\nAcknowledgement\nAll the people we acknowledge are listed in the authorship. This article is supported by a national clinical key specialty construction projects in CHINA.\n==== Refs\nTong EC Rubenfeld S Cardiac metastasis from myxoid liposarcoma emphasizing its radiosensitivity Am J Roentgenol Radium Ther Nucl Med 1968 9 792 799 10.2214/ajr.103.4.792 5692417 \nLanglard JM Lefévre M Fiche M Chevallier JC Godin O Bouhour JB [Right atrioventricular metastasis of myxoid liposarcoma. Prolonged course after repeated surgery and chemotherapy] Arch Mal Coeur Vaiss 1992 9 1353 1356 1290400 \nKono T Amano J Sakaguchi M Kitahara H Successful resection of cardiac metastatic liposarcoma extending into the SVC, right atrium, and right ventricle J Card Surg 2005 9 364 365 10.1111/j.1540-8191.2005.200389.x 15985140 \nMitomi M Kimura K Iguchi Y Hayashida A Nishimura H Irei I Okawaki M Ikeda H A case of stroke due to tumor emboli associated with metastatic cardiac liposarcoma Intern Med 2011 9 1489 1491 10.2169/internalmedicine.50.5071 21757835 \nHallahan DE Vogelzang NJ Borow KM Bostwick DG Simon MA Cardiac metastases from soft-tissue sarcomas J Clin Oncol 1986 9 1662 1669 3772419 \nRavikumar TS Topulos GP Anderson RW Grage TB Surgical resection for isolated cardiac metastases Arch Surg 1983 9 117 120 10.1001/archsurg.1983.01390010087020 6848063 \nFairman EB Mauro VM Cianciulli TF Rubio M Charask AA Bustamante J Barrero CM Liposarcoma causing left ventricular outflow tract obstruction and syncope: a case report and review of the literature Int J Cardiovasc Imaging 2005 9 513 518 10.1007/s10554-005-0653-0 16175441 \nChughtai A Cronin P Lucas DR Prager R Kazerooni EA Metastatic shoulder liposarcoma to the right ventricle: CT findings J Thorac Imaging 2007 9 195 198 10.1097/01.rti.0000213591.37096.1c 17527130 \nDogan U Zamani A Gormus N Paksoy Y Avunduk MC Demirbas S The first case report of a metastatic myxoid liposarcoma invading the left atrial cavity and pulmonary vein Heart Surg Forum 2011 9 E261 E263 10.1532/HSF98.20111021 21859649 \nGodwin JD Axel L Adams JR Schiller NB Simpson PC JrGertz EW Computed tomography: a new method for diagnosing tumor of the heart Circulation 1981 9 448 451 10.1161/01.CIR.63.2.448 7449067 \nMurphy MC Sweeney MS Putnam JB JrWalker WE Frazier OH Ott DA Cooley DA Surgical treatment of cardiac tumors: a 25-year experience Ann Thorac Surg 1990 9 612 617 discussion 617-618 10.1016/0003-4975(90)90310-3 2322057 \nFlexman AM Del Vicario G Schwarz SK Hemodynamic collapse under anesthesia in a patient with pulmonary artery sarcoma Can J Anaesth 2009 9 604 608 10.1007/s12630-009-9118-6 19466503 \nNath MP Dhawan N Chauhan S Kiran U A large angiosarcoma of the right atrium: anaesthetic management Hellenic J Cardiol 2011 9 273 277 21642079\n\n",
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{
"abstract": "BACKGROUND\nThe aim of this study was to evaluate, in a cohort of haemodialysis patients with atrial fibrillation (AF), the relationship between oral anticoagulant therapy (OAT) and mortality, thromboembolic events and haemorrhage.\n\n\nMETHODS\nTwo hundred and ninety patients with AF were prospectively followed for 4 years. Warfarin and antiplatelet intake, age, dialytic age, comorbidities, CHA2DS2-VASc and HAS-BLED scores were considered as predictors of risk of death, thromboembolism and bleeding events. In patients taking OAT, the international normalized ratio (INR) was assessed and the percentage time in the target therapeutic range (TTR) was calculated.\n\n\nRESULTS\nAt recruitment, 134/290 patients were taking warfarin. During follow-up there were 170 deaths, 28 thromboembolic events and 95 bleedings. After balancing for treatment propensity, intention-to-treat analysis on OAT intake at recruitment did not show differences in total mortality, thromboembolic events and bleedings, while the as-treated analysis, accounting for treatment switch, showed that patients taking OAT at recruitment had a significantly lower mortality than those not taking it [hazard ratio, HR 0.53 (95% confidence interval 0.28-0.90), p = 0.04], with a decrease of thromboembolic events [HR 0.36 (0.13-1.05), p = 0.06], and an increase of bleedings [HR 1.79 (0.72-4.39), p = 0.20], both non-significant. Among patients taking OAT at recruitment, those continuing to take warfarin had a significant reduction in the risk of total [HR 0.28 (0.14-0.53), p < 0.001] and cardiovascular [HR 0.21 (0.11-0.40), p < 0.001] mortality compared to patients stopping OAT.\n\n\nCONCLUSIONS\nIn haemodialysis patients with AF, continuously taking warfarin is associated with a reduction of the risk of total and cardiovascular mortality.",
"affiliations": "Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza (MB), Italy. simonetta.genovesi@unimib.it.;Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.;Nephrology Unit, San Carlo Borromeo Hospital, Milan, Italy.;Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza (MB), Italy.;Nephrology Unit, Infermi Hospital, Rimini, Italy.;Nephrology Unit, S. Uboldo Hospital, Cernusco sul Naviglio, Italy.;Nephrology Unit, S. Maria Nuova Hospital, Reggio Emilia, Italy.;Nephrology Unit, IRCCS Multimedica, Sesto S. Giovanni, Italy.;Nephrology Unit, Ospedali Riuniti, Bergamo, Italy.;Nephrology Unit, S. Anna Hospital, Como, Italy.;Nephrology Unit, Bassini Hospital, Cinisello, Milan, Italy.;Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.;Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.;Nephrology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy.",
"authors": "Genovesi|Simonetta|S|;Rebora|Paola|P|;Gallieni|Maurizio|M|;Stella|Andrea|A|;Badiali|Fabio|F|;Conte|Ferruccio|F|;Pasquali|Sonia|S|;Bertoli|Silvio|S|;Ondei|Patrizia|P|;Bonforte|Giuseppe|G|;Pozzi|Claudio|C|;Rossi|Emanuela|E|;Valsecchi|Maria Grazia|MG|;Santoro|Antonio|A|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin",
"country": "Italy",
"delete": false,
"doi": "10.1007/s40620-016-0364-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": "30(4)",
"journal": "Journal of nephrology",
"keywords": "Atrial fibrillation; Bleeding; Haemodialysis; Mortality; Stroke; Warfarin",
"medline_ta": "J Nephrol",
"mesh_terms": "D000284:Administration, Oral; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D015897:Comorbidity; D005260:Female; D006470:Hemorrhage; D006801:Humans; D057194:Intention to Treat Analysis; D007558:Italy; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D016016:Proportional Hazards Models; D011446:Prospective Studies; D065840:Protective Factors; D006435:Renal Dialysis; D012307:Risk Factors; D013923:Thromboembolism; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "9012268",
"other_id": null,
"pages": "573-581",
"pmc": null,
"pmid": "27834042",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "12644343;20299623;25352571;23114904;19297555;27598317;8470047;12846756;25399274;22894575;24595776;24452752;24430763;22223710;19713308;20803557;19757444;27295351;25500231;25449515;24470482;20054291;23746378;26493621;22922413;18215703;26162653;26680239;23677245;10955409",
"title": "Effect of oral anticoagulant therapy on mortality in end-stage renal disease patients with atrial fibrillation: a prospective study.",
"title_normalized": "effect of oral anticoagulant therapy on mortality in end stage renal disease patients with atrial fibrillation a prospective study"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT22995",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Although the etiology of ICP is not fully understood thus far, some genetic factors might contribute to the development of this condition. Sodium-taurocholate cotransporting polypeptide (NTCP), the protein encoded by the gene Solute Carrier Family 10, Member 1 (SLC10A1), is the primary transporter expressed in the basolateral membrane of the hepatocyte to uptake conjugated bile salts from the plasma. NTCP deficiency arises from biallelic SLC10A1 mutations which impair the NTCP function and cause intractably elevated levels of total bile acids (TBA) in the plasma (hypercholanemia). In this study, all the SLC10A1 exons and their flanking sequences were analyzed by Sanger sequencing to investigate the etiology for hypercholanemia in two male infants aged 2 and 20 months, respectively, from two unrelated families. As a result, both patients are homozygous for the reported pathogenic variant c.800C>T (p.Ser267Phe) that could impair the NTCP function to uptake bile acids, and the diagnosis of NTCP deficiency was thus made. Their mothers are also homozygotes of the same variant and both had been diagnosed to have ICP in the third trimester, with one of them undergoing cesarean section. The father of the first patient in this paper has the same SLC10A1 genotype c.800C>T/c.800C>T, also exhibiting slight hypercholanemia with a plasma TBA level of 21.5 μmol/L. In conclusion, we suggest that with hypercholanemia being a common laboratory change, NTCP deficiency may be a genetic factor leading to ICP and even cesarean section in clinical practice.",
"affiliations": "Department of Pediatrics, The First Affiliated Hospital, Jinan University.;Department of Pediatrics, The First Affiliated Hospital, Jinan University.;Department of Pediatrics, The First Affiliated Hospital, Jinan University.;Department of Pediatrics, The First Affiliated Hospital, Jinan University.;Department of Pediatrics, The First Affiliated Hospital, Jinan University.;Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-Sen University.;Department of Gynecology and Obstetrics, The First Affiliated Hospital, Jinan University.;Department of Pediatrics, The First Affiliated Hospital, Jinan University.",
"authors": "Chen|Rong|R|;Deng|Mei|M|;Rauf|Yaqub-Muhammad|YM|;Lin|Gui-Zhi|GZ|;Qiu|Jian-Wu|JW|;Zhu|Shun-Ye|SY|;Xiao|Xiao-Min|XM|;Song|Yuan-Zong|YZ|",
"chemical_list": "D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter",
"country": "Japan",
"delete": false,
"doi": "10.1620/tjem.248.57",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-8727",
"issue": "248(1)",
"journal": "The Tohoku journal of experimental medicine",
"keywords": "SLC10A1; bile acid; hypercholanemia; intrahepatic cholestasis of pregnancy; sodium taurocholate cotransporting polypeptide deficiency",
"medline_ta": "Tohoku J Exp Med",
"mesh_terms": "D001483:Base Sequence; D002780:Cholestasis, Intrahepatic; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent; D011247:Pregnancy; D011248:Pregnancy Complications; D027981:Symporters",
"nlm_unique_id": "0417355",
"other_id": null,
"pages": "57-61",
"pmc": null,
"pmid": "31142693",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrahepatic Cholestasis of Pregnancy as a Clinical Manifestation of Sodium-Taurocholate Cotransporting Polypeptide Deficiency.",
"title_normalized": "intrahepatic cholestasis of pregnancy as a clinical manifestation of sodium taurocholate cotransporting polypeptide deficiency"
} | [
{
"companynumb": "CN-ALLERGAN-1933541US",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": null,
"d... |
{
"abstract": "Pleuroparenchymal fibroelastosis (PPFE), a new disease entity associated with interstitial pneumonia, is characterized by fibrosis and elastosis involving the pleura and subpleural lung parenchyma, predominantly in the upper lobe. As the awareness of this disease entity has increased, many studies have revealed the prevalence and incidence, clinical and pathological characteristics, and disease course of PPFE. Patients with PPFE reportedly have several unique clinical characteristics-including an extremely low body mass index with a slender body and chest wall deformity, known as \"flat chest\". As this disease progresses, shrinking of the lungs often causes life-threatening complications, such as pneumothorax, and associated air leak syndrome. Lung transplantation is considered the only effective treatment for patients with advanced PPFE; however, little is known about the influences of the characteristics of PPFE on the outcome of lung transplantation. This review focuses on the unique clinicopathologic characteristics of PPFE and associated outcomes of lung transplantation for these patients.",
"affiliations": "Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.;Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.",
"authors": "Shiiya|Haruhiko|H|0000-0003-1766-7736;Sato|Masaaki|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm10050957",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383\nMDPI\n\n10.3390/jcm10050957\njcm-10-00957\nReview\nLung Transplantation for Pleuroparenchymal Fibroelastosis\nhttps://orcid.org/0000-0003-1766-7736\nShiiya Haruhiko 12\nSato Masaaki 1*\nIshii Hiroshi Academic Editor\n1 Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; shiiyah-sur@h.u-tokyo.ac.jp\n2 Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Kita 15 Nishi 7, Kita-ku, Sapporo 060-8638, Hokkaido, Japan\n* Correspondence: satom-sur@h.u-tokyo.ac.jp; Tel.: +81-3-3815-5411; Fax: +81-3-5800-9156\n01 3 2021\n3 2021\n10 5 95725 1 2021\n20 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/).\nPleuroparenchymal fibroelastosis (PPFE), a new disease entity associated with interstitial pneumonia, is characterized by fibrosis and elastosis involving the pleura and subpleural lung parenchyma, predominantly in the upper lobe. As the awareness of this disease entity has increased, many studies have revealed the prevalence and incidence, clinical and pathological characteristics, and disease course of PPFE. Patients with PPFE reportedly have several unique clinical characteristics—including an extremely low body mass index with a slender body and chest wall deformity, known as “flat chest”. As this disease progresses, shrinking of the lungs often causes life-threatening complications, such as pneumothorax, and associated air leak syndrome. Lung transplantation is considered the only effective treatment for patients with advanced PPFE; however, little is known about the influences of the characteristics of PPFE on the outcome of lung transplantation. This review focuses on the unique clinicopathologic characteristics of PPFE and associated outcomes of lung transplantation for these patients.\n\nlung transplantation\npleuroparenchymal fibroelastosis\ninterstitial lung disease\nchest wall\n==== Body\n1. Introduction\n\nPleuroparenchymal fibroelastosis (PPFE) is characterized by fibrosis involving the pleura and subpleural lung parenchyma, predominantly in the upper lobes. PPFE is broadly divided into two types: Idiopathic PPFE (IPPFE) and non-idiopathic PPFE. An associated condition termed idiopathic pulmonary upper lobe fibrosis was first reported by Amitani et al. [1] in 1992 in the Japanese literature. The term “idiopathic pleuroparenchymal fibroelastosis” was first used by Frankel et al. [2] in 2004, and IPPFE was formally included as a rare subtype in the international classification of the idiopathic interstitial pneumonias (IIPs) in 2013 [3]. Since then, the awareness of this disease entity has increased, and several characteristic clinical features have been reported; patients with IPPFE often have a slender body and a low body mass index (BMI) [4], and many develop a chest wall deformity known as “flat chest” [5]. In the advanced stage of the disease, shrinking of the lungs often causes pneumothorax and associated air leak syndrome (ALS) [6,7,8,9]. No medical treatment has been shown to be effective, and lung transplantation (LT) is, therefore, considered a therapeutic option for patients with advanced PPFE. Although few data regarding the outcomes of LT for patients with PPFE are available, complicated post-LT courses associated with the unique features of PPFE have been reported. This narrative review focuses on the difficulties, challenges, and future perspectives of LT for patients with PPFE.\n\n2. Prevalence and Incidence of PPFE\n\nThe number of reports associated with PPFE has increased during the last decade. However, no international consensus regarding the diagnostic criteria has been established, and the accurate prevalence and incidence of PPFE, therefore, remain unknown. Before IPPFE was included in the new classification of IIPs in 2013, PPFE may have been diagnosed as other IIPs, mostly idiopathic pulmonary fibrosis (IPF). Most previous reports describing the prevalence and incidence of IPPFE were reviews of patients with IIPs. The reported prevalence of a PPFE pattern in patients with IIPs is around 5.8–10.4% [10,11,12,13]. Oda et al. [10] reported that 11 (10%) of 110 patients with IPF had radiological PPFE and that 9 (8.2%) of these patients’ conditions fulfilled the histologic criteria for PPFE. Nakatani et al. [11] retrospectively reviewed 205 patients who underwent surgical lung biopsy for interstitial lung diseases (ILDs) and found that 12 (5.8%) had PPFE. They also reported that the frequency of IPPFE among IIPs was 10.4% [11]. Shioya et al. [12] reviewed 375 patients with IIPs and found that 29 (7.7%) met radiological criteria for IPPFE. Lee et al. [13] reviewed 445 patients with IPF and identified PPFE in 28 (6.3%). The frequency of PPFE among patients with ILDs is reportedly higher when the analysis is limited to LT candidates. A Japanese single-institution study showed that among 118 patients with ILDs listed for LT, 30 (25%) were diagnosed with radiological PPFE [14]. We previously reported that 8 (28%) of 29 LT candidates with IIPs were diagnosed with IPPFE [15]. Many previous reports describing the prevalence of IPPFE were from Japanese authors. Whether the prevalence and incidence of IPPFE in the Japanese population are higher than those in Western populations should be investigated further.\n\nNon-idiopathic PPFE reportedly occurs mainly after chemotherapy, allogeneic hematopoietic stem cell transplantation (HSCT), allogeneic bone marrow transplantation (BMT), and LT. Mariani et al. [16] reviewed high-resolution computed tomography examination findings from 700 HSCT recipients and 53 LT recipients. Among them, the imaging findings of two (0.28%) HSCT recipients and four (7.5%) LT recipients were identified as clinically and radiologically consistent with PPFE [16]. PPFE associated with connective tissue disease has also been reported. Enomoto et al. [17] reviewed 113 patients with connective tissue disease-related ILDs and found radiologic PPFE-like lesions in 21 (19%) patients. Recently, Bonifazi et al. [18] identified PPFE in 65 (18.1%) of 359 patients with systemic sclerosis. Most patients with restrictive allograft syndrome, one of the clinical subtypes of chronic lung allograft dysfunction (CLAD), reportedly show a histological PPFE pattern [19]. CLAD is reported to occur in approximately 50% of recipients by five years after LT [20], and restrictive allograft syndrome is reported to account for 25% to 35% of cases of CLAD [21].\n\n3. Clinical Characteristics of PPFE\n\nMany papers have described the characteristic clinical and laboratory findings of PPFE, and excellent review articles have been published [4,22,23]. In the present review, therefore, we focus on the characteristic features and complications that may affect the outcomes after LT.\n\n3.1. BMI\n\nIn general, an underweight status before LT is reportedly associated with worse survival after LT, although the optimal cutoff value of the BMI varies among different reports. Upala et al. [24] reported a significant risk of mortality after LT in candidates with a BMI of <18.5 kg/m2 [relative risk, 1.36; 95% confidence interval (CI), 1.11–1.66]. Singer et al. [25] reported that a BMI of <18.5 kg/m2 was associated with a 35% increased mortality (95% CI, 10–66%). Fernandez et al. [26] reported that a BMI of <20 kg/m2 in a cohort of patients with restrictive lung disease was associated with an increased risk of mortality at one year after LT (odds ratio, 1.23; 95% CI, 1.02–1.48). Komatsu et al. [27] proposed an optimal BMI cutoff of <17.0 kg/m2 as indicative of a pre-LT underweight status.\n\nPatients with IPPFE have been reported to have a lower BMI than patients with IPF [10,12,13,28]. Oda et al. [10] evaluated nine patients with PPFE and a usual interstitial pneumonia (UIP) pattern, and their BMI (mean ± standard deviation) was 18.6 ± 1.8 kg/m2. Shioya et al. [12] reported that the mean BMI of 29 patients with radiological IPPFE was 20.1 ± 3.25 kg/m2. Lee et al. [13] reported that the coexistence of radiological PPFE in patients with IPF was associated with a lower BMI (PPFE, 21.2 ± 3.0 kg/m2 vs. non-PPFE, 24.4 ± 3.1 kg/m2). Enomoto et al. [28] reported that 44 patients with radiological IPPFE had a median BMI of 17.2 kg/m2 [interquartile range (IQR), 14.7–18.5]. We previously reported that the median pre-LT BMI of Japanese recipients with IPPFE was 16.7 kg/m2 [29]. Among patients with connective tissue disease, a radiological PPFE-like region is reportedly associated with a low BMI (median, 19.8 kg/m2; IQR, 17.3–22.4) [17]. Tanizawa et al. [14] reviewed LT candidates with ILDs and reported that the median BMI of 30 patients with radiological PPFE was 15.9 kg/m2 (IQR, 14.8–17.2). Thus, a substantial proportion of patients with PPFE have an extremely low BMI, which might predict worse survival after LT.\n\nNo data regarding the association between the low BMI in patients with PPFE and post-LT outcomes are currently available. In general, severe malnutrition is considered to be a relative contraindication for LT [30]. Given that a substantial proportion of patients with PPFE has a low BMI, the post-LT outcomes in patients with PPFE might be poor; however, the low BMI may not necessarily represent malnutrition and lead to poor outcomes. Indeed, in our previous work, the overall survival after LT in patients with IPPFE was similar to that in patients with IPF [29]. In patients with cystic fibrosis, weight loss often occurs secondary to maldigestion, malabsorption, and associated malnutrition. Malnutrition in patients with cystic fibrosis is reportedly associated with worse survival and pulmonary function after LT [31,32]. Whether the low BMI in patients with PPFE results from malnutrition and affects post-LT outcomes should be investigated in further studies. Other parameters that reflect frailty or the nutritional status, such as the muscle mass [33], bioelectrical impedance analysis results [34], and nutritional risk index [35], should also be evaluated in future studies. Moreover, severe restrictive dysfunction in patients with PPFE might result in increased respiratory effort and energy consumption.\n\n3.2. Flat Chest\n\nPatients with PPFE often develop a flattening of the thoracic cage with the progression of the disease [5] (Figure 1). Chest deformity may result in the restriction of lung expansion after LT, and severe chest wall deformity is often considered an absolute contraindication for LT [30]; however, studies have shown that flat chest is not always associated with a poor outcome after LT. Miyoshi et al. [36] reported that pulmonary function after living-donor LT in patients with flat chest was poorer than that in patients with a normal chest, whereas the post-LT exercise capacity was equivalent, and the flat chest severity improved after LT. Miyahara et al. [37] reported that pulmonary function, exercise capacity, and survival in patients with flat chest after deceased-donor LT were similar to those in patients with a normal chest. Poorer pulmonary function after living-donor LT might be partly attributed to a lower volume of the donor lungs; living-donor LT usually uses two lung lobes, which have a smaller volume than the whole lungs used in deceased-donor LT. These two reports [36,37] were not limited to patients with PPFE; they included patients with other lung diseases and pulmonary hypertension. Patients with advanced ILDs and some congenital conditions, such as pectus excavatum, may show a flattening of the chest wall. Flat chest in patients with PPFE may be slightly different from that in patients with other diseases. In our previous report, pulmonary functions in patients with IPPFE after both deceased-donor and living-donor LT were poorer than those in patients with IPF [29]. These differences between patients with IPPFE and those with other diseases suggest that not only the lung volume itself, but other problems, such as a rigid chest wall, might persist and limit the function of patients with IPPFE even after LT. Yanagiya et al. [38] described a patient who required intensive pulmonary rehabilitation because of chest wall rigidity despite the fact that the chest wall flatness was reversed after LT. The mechanism underlying the development of flat chest in patients with PPFE should be investigated further.\n\n3.3. Pneumothorax and ALS\n\nPneumothorax is one of the major complications in patients with both IPPFE and non-idiopathic PPFE. The incidence of pneumothorax in patients with PPFE is apparently higher than that in other IIPs. Enomoto et al. [28] reported that 8 (18%) of 44 patients with PPFE had a history of pneumothorax at the time of diagnosis. Lee et al. [13] reported that 5 (17.9%) of 28 patients who had IPF with radiological PPFE developed pneumothorax during the median follow-up period of 43.0 months. The incidence of pneumothorax is reportedly higher in LT candidates, who usually have advanced disease. Tanizawa et al. [14] reported that 24 (80%) of 30 patients with radiological PPFE had a history of pneumothorax at the time of registration for LT. We previously reported 31 recipients with IPPFE who underwent LT; among them, 16 (52%) had a history of pneumothorax at the time of LT [29].\n\nPost-transplant ALS, including pneumothorax, subcutaneous emphysema, and pneumomediastinum, is known to occur after allogeneic HSCT or BMT [6,7,8,9]. PPFE-related ALS was recently recognized as a lung complication after allogeneic HSCT and allogeneic BMT [9,39]. Patients with IPPFE can also develop ALS at an advanced stage of the disease (Figure 2). ALS is sometimes life-threatening [6,7], can be recurrent [40], and often leads to fungal infection [6,41], which may result in mortality before LT.\n\nRecurrent or prolonged pneumothorax and ALS sometimes necessitate interventions, such as pleurodesis and surgical repair, including pleural covering [9,42]. Severe adhesion in the chest cavity may lead to prolonged surgical and ischemic times and a higher rate of bleeding, resulting in delayed recovery and poorer outcomes after LT. These conditions may be exacerbated by longer cardiopulmonary bypass times. Drainage or observation may be preferred to pleurodesis in sufficient cases; however, pneumothorax in a future recipient for LT should be given the best immediate management to avoid missing the opportunity to undergo LT [30]. Pleurodesis and previous surgery are usually not contraindications for LT. Recurrent pneumothorax and ALS may cause adhesion even if pleurodesis is avoided.\n\n4. Optimal Timing of LT\n\nThe natural course and prognosis of PPFE are highly variable. An analysis of 85 patients, including patients with both IPPFE and secondary PPFE, demonstrated a relatively long median survival of 11 years [22]. A subsequent study, however, revealed the presence of a rapidly progressing phenotype of IPPFE [43], and several studies have shown worse survival of patients with IPPFE than IPF [12,44]. The differences among these studies may be partly due to the timing of the diagnosis; most patients with IPPFE are diagnosed at the advanced stage. Patients with IPPFE may have a long subclinical stage with only small changes in the upper lobes [22]. Another important matter is the heterogeneity of PPFE. The coexistence of the PPFE pattern and other ILDs is apparently not uncommon [17,45]. Several studies have shown that the coexistence of a UIP pattern predicts a poorer prognosis in patients with IPPFE [13,46,47], although one study failed to show a significant impact of the presence of a UIP pattern on the prognosis of patients with IPPFE [28]. The coexistence of a PPFE pattern in patients with chronic hypersensitivity pneumonitis has also been reported to be associated with increased mortality [48]. In contrast, one study showed that after adjustment for age, sex, percent predicted forced vital capacity (FVC), and 6-min walk distance, patients with IPPFE and late-onset noninfectious pulmonary complications after HSCT and/or chemotherapy with a radiological PPFE pattern had better survival than patients with fibrotic ILDs without a radiological PPFE pattern [14]. Patients with IPPFE often show a disproportionate reduction in the FVC with a relatively preserved diffusing capacity [22]; therefore, the FVC may not always precisely represent the general condition in patients with IPPFE. Our previous small study of LT candidates suggested long-term survival despite unfavorable prognostic factors, including a low BMI and a short 6-min walk distance [15].\n\nThe optimal timing to list patients with PPFE on the waiting list for LT is still unknown. The proposal by the international guideline for the timing of listing patients with ILD for LT is based on a decline in the FVC, diffusing capacity, desaturation, and exercise capacity. The presence of pulmonary hypertension, pneumothorax, and acute exacerbation are also factors associated with the timing of listing [30]. Based on the current knowledge, the disease course of patients with PPFE is not always the same as that of patients with other ILDs, and some patients with PPFE may survive longer than patients with other ILDs; however, the survival of most patients with PPFE after diagnosis is as poor as that of patients with other ILDs.\n\n5. Post-LT Course\n\nFew data are available regarding the outcomes of LT for PPFE. Several authors have reported good post-LT courses without complications (Table 1). Chen et al. [49] described a patient with PPFE after chemotherapy for leukemia who was treated with single LT. The postoperative course was uneventful, and the patient was doing well four months after LT. Hata et al. [50] also reported an uneventful clinical course after living-donor lobar LT (LDLLT) for PPFE associated with chemotherapy. Rasciti et al. [51] described a patient with IPPFE who underwent bilateral LT. Although relapse of PPFE was suspected as a late complication, the postoperative course was uneventful. In contrast, several case reports have described complicated postoperative courses. Shimada et al. [52] reported PPFE associated with allogeneic umbilical cord stem cell transplantation. The patient underwent extracorporeal membrane oxygenation-bridged LDLLT and spent 30 days in the intensive care unit, but thereafter recovered and did well for one year. Yanagiya et al. [38] described a patient with IPPFE and flat chest who underwent LDLLT. The authors reported the necessity of intensive pulmonary rehabilitation for chest wall rigidity [38]. Righi et al. [53] also described a patient with IPPFE who required long-term rehabilitation after LT. We previously reported a case of fatal secondary pulmonary hypertension associated with flat chest in a patient with IPPFE who underwent single LT [54]. Other authors have also reported complicated post-LT courses [55,56,57]; however, after recovery from early complications, such as chylothorax, dysphagia, vocal cord paralysis, pneumonia, and repeated nausea and vomiting for an unknown reason, the patients apparently did well. There are also several case reports of LT for IPPFE or non-idiopathic PPFE without detailed information about the post-LT course [58,59,60]. To the best of our knowledge, our previous study of 31 patients with IPPFE in Japan is the largest study to show the outcomes after LT. In that study, although patients with IPPFE had a longer stay in the intensive care unit and the hospital, and although the low BMI and the low FVC persisted even after LT, the overall survival was similar to that of patients with IPF [29]. Based on the current knowledge, LT can be performed successfully and achieve acceptable survival for patients with PPFE; however, the post-LT course can be complicated, and some functional problems may persist even after LT. Further studies are necessary to obtain accurate knowledge regarding the outcome of LT for PPFE. The incidence of CLAD and other late complications should also be determined in further studies.\n\n6. Conclusions\n\nFew data are available regarding the optimal strategy to achieve the best outcome after LT for patients with PPFE. Further studies are needed to obtain accurate knowledge regarding LT for PPFE. Based on the current knowledge, unique characteristics of patients with PPFE may result in a complicated intraoperative and short-term post-LT course; however, the long-term outcomes are apparently similar to those of patients with other ILDs. As the only therapeutic option for patients with PPFE, LT should be considered in the advanced stage of the disease. Clinicians should consider the distinct characteristics of patients with PPFE when considering the possibility of LT, follow up patients on the waiting list, and follow up patients after LT. Further studies should also address the underlying mechanism of PPFE.\n\nAcknowledgments\n\nWe thank Angela Morben, DVM, ELS, from Edanz Group (https://en-author-services.edanz.com/ac accessed on 25 January 2021), for editing a draft of this manuscript.\n\nAuthor Contributions\n\nConceptualization, M.S. and H.S.; methodology, H.S. and M.S.; validation, H.S. and M.S.; investigation, H.S.; data curation, H.S. and M.S.; writing—original draft preparation, H.S.; writing—review and editing, H.S. and M.S.; visualization, H.S.; supervision, M.S.; project administration, M.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nData Availability Statement\n\nThis study did not report any data.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 3D-CT of a patient with pleuroparenchymal fibroelastosis. (a) 3D-CT with body surface. Flattening of the chest wall is shown. (b) 3D-CT with bone reconstruction. The intercostal spaces are narrow, and the anteroposterior diameter is shortened. Abbreviation: 3D-CT—three-dimensional computed tomography.\n\nFigure 2 Chest CT images of a patient with idiopathic pleuroparenchymal fibroelastosis (IPPFE). (a) Chest CT before the diagnosis of IPPFE at the level of the sixth thoracic vertebra. The bilateral lungs are almost normal. (b) Chest CT 7 years later at the same level. The anteroposterior diameter of the thoracic cage has become shortened. Shrinking of the lungs has resulted in an air space in the right chest cavity (yellow arrow) and pneumomediastinum (blue arrow), indicating air leak syndrome. Abbreviations: CT—computed tomography; IPPFE—idiopathic pleuroparenchymal fibroelastosis.\n\njcm-10-00957-t001_Table 1 Table 1 Published case reports describing lung transplantation for PPFE.\n\nAuthor\tSex\tAge\tUnderlying Condition\tProcedure\tPosttransplant Course\tOutcome\t\nChen et al. (2014)\tMale\t14\tChemotherapy\tLeft single\tuneventful\tAlive\t\nPortillo et al. (2015)\tMale\t25\tCastleman’s disease\tBilateral\tNA\tAlive\t\nHata et al. (2016)\tMale\t19\tChemotherapy\tLDLLT\tuneventful\tAlive\t\nYanagiya et al. (2016)\tFemale\t27\tIdiopathic\tLDLLT\tcomplicated\tAlive\t\nHuan et al. (2017)\tMale\t34\tIdiopathic\tBilateral\tNA\tNA\t\nShimada et al. (2018)\tFemale\t21\tHSCT\tLDLLT\tcomplicated\tAlive\t\nTsubosaka et al. (2018)\tMale\t19\tChemotherapy\tLiving-donor\tNA\tNA\t\nRighi et al. (2018)\tMale\t42\tIdiopathic\tBilateral\tcomplicated\tAlive\t\nAli et al. (2019)\tFemale\t26\tIdiopathic\tBilateral\tcomplicated\tAlive\t\nAljefri et al. (2019)\tMale\t27\tIdiopathic\tBilateral\tcomplicated\tAlive\t\nSekine et al. (2020)\tFemale\t29\tIdiopathic\tLDLLT\tcomplicated\tAlive\t\nRasciti et al. (2020)\tMale\t48\tIdiopathic\tBilateral\tpossible PPFE relapse\tRe-transplant\t\nShiiya et al. (2020)\tFemale\t40\tIdiopathic\tLeft single\tcomplicated\tDead\t\nAbbreviations: HSCT—hematopoietic stem cell transplantation; LDLLT—living-donor lobar lung transplantation; NA—not available; PPFE—pleuroparenchymal fibroelastosis.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Amitani R. Niimi A. Kuse F. Idiopathic pulmonary upper lobe fibrosis Kokyu 1992 11 693 699\n2. Frankel S.K. Cool C.D. Lynch D.A. Brown K.K. 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"issn_linking": "2077-0383",
"issue": "10(5)",
"journal": "Journal of clinical medicine",
"keywords": "chest wall; interstitial lung disease; lung transplantation; pleuroparenchymal fibroelastosis",
"medline_ta": "J Clin Med",
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"pmid": "33804467",
"pubdate": "2021-03-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "32299855;31409884;21419659;31290582;30655147;27257997;28344924;32766429;28315009;25085497;24881083;26781007;29249487;27106430;33354595;24578677;28666014;33148928;18043388;29773298;25441830;31238182;20577219;23018877;25233138;31005872;15596706;30745942;25367470;29173442;26613209;30228893;32147954;16916592;27460284;26380141;30186537;29724400;27108011;30522096;28964412;31303415;31938568;33576927;27645979;24032382;29274246;29986004;21822205;27312041;30165854;30604238;28489801;32917352;30232390;24041590;25700380;31425665;33054813",
"title": "Lung Transplantation for Pleuroparenchymal Fibroelastosis.",
"title_normalized": "lung transplantation for pleuroparenchymal fibroelastosis"
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"abstract": "OBJECTIVE\nTo determine the safety and efficacy of etanercept in a multicenter, randomized, placebo-controlled, double-blind trial of adults with moderate to severe active ankylosing spondylitis (AS).\n\n\nMETHODS\nPatients (n = 277) were treated with either etanercept 25 mg (n = 138) or placebo (n = 139) subcutaneously twice weekly for 24 weeks. The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) at weeks 12 and 24. Other outcome measures included the percentage of patients achieving higher ASAS responses, and the safety of etanercept in patients with AS. All outcome measures were assessed at 2, 4, 8, 12, and 24 weeks.\n\n\nRESULTS\nTreatment with etanercept resulted in dramatic improvement. The ASAS20 was achieved by 59% of patients in the etanercept group and by 28% of patients in the placebo group (P < 0.0001) at week 12, and by 57% and 22% of patients, respectively, at week 24 (P < 0.0001). All individual ASAS components, acute-phase reactant levels, and spinal mobility measures were also significantly improved. The safety profile of etanercept was similar to that reported in studies of patients with rheumatoid arthritis or psoriatic arthritis. The only adverse events that occurred significantly more often in the etanercept group were injection-site reactions, accidental injuries, and upper respiratory tract infections.\n\n\nCONCLUSIONS\nEtanercept is a highly effective and well tolerated treatment in patients with active AS.",
"affiliations": "University of California, San Francisco, CA 94143, USA. jdavis@medicine.ucsf.edu",
"authors": "Davis|John C|JC|;Van Der Heijde|Désirée|D|;Braun|Jurgen|J|;Dougados|Maxime|M|;Cush|John|J|;Clegg|Daniel O|DO|;Kivitz|Alan|A|;Fleischmann|Roy|R|;Inman|Robert|R|;Tsuji|Wayne|W|;|||",
"chemical_list": "D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D002097:C-Reactive Protein; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": "10.1002/art.11325",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-3591",
"issue": "48(11)",
"journal": "Arthritis and rheumatism",
"keywords": null,
"medline_ta": "Arthritis Rheum",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001799:Blood Sedimentation; D002097:C-Reactive Protein; D004311:Double-Blind Method; D000068800:Etanercept; D005260:Female; D006304:Health Status; D006801:Humans; D007074:Immunoglobulin G; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D012720:Severity of Illness Index; D013167:Spondylitis, Ankylosing; D016896:Treatment Outcome",
"nlm_unique_id": "0370605",
"other_id": null,
"pages": "3230-6",
"pmc": null,
"pmid": "14613288",
"pubdate": "2003-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial.",
"title_normalized": "recombinant human tumor necrosis factor receptor etanercept for treating ankylosing spondylitis a randomized controlled trial"
} | [
{
"companynumb": "US-AMGEN-USASP2019174286",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nNeuroleptic malignant syndrome (NMS) is an uncommon condition associated with significant morbidity and mortality. Data on treatment interventions are limited. In this case series, we sought to describe all NMS cases requiring ECT from a large academic institution over a nearly 2-decade period.\n\n\nMETHODS\nWe retrospectively identified all patients with NMS who were treated with ECT over a 17-year period. Patients were included in the study based on chart review using the International Consensus Diagnostic Criteria for NMS. Data were collected related to clinical findings, treatment course, and response to ECT.\n\n\nRESULTS\nWe identified 15 patients meeting the inclusion criteria. Most patients had neurocognitive or schizophrenia spectrum disorders and developed NMS after exposure to multiple antipsychotic drugs. All patients received bitemporal ECT after failed pharmacotherapy for NMS. Electroconvulsive therapy was well tolerated and resulted in a remission rate of 73.3% (n = 11). Patients showed early initial response to ECT (mean of 4.2 treatments), but an average of 17.7 treatments was necessary to minimize recurrence of catatonic signs. One patient died after interruption of the index course of ECT because of severe infection, and another was discharged to hospice care after limited response. These cases highlight the lethality of NMS and its complications despite aggressive treatment measures.\n\n\nCONCLUSIONS\nBitemporal ECT was well tolerated and effective in treating NMS refractory to pharmacotherapy. We suggest that ECT be considered early in cases of NMS that are refractory to pharmacological interventions, especially if the underlying condition is also responsive to ECT.",
"affiliations": "From the Michigan Medicine Department of Psychiatry, The University of Michigan, Ann Arbor, MI.",
"authors": "Morcos|Nicholas|N|;Rosinski|Amy|A|;Maixner|Daniel F|DF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/YCT.0000000000000600",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1095-0680",
"issue": "35(4)",
"journal": "The journal of ECT",
"keywords": null,
"medline_ta": "J ECT",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D008297:Male; D008824:Michigan; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D012189:Retrospective Studies",
"nlm_unique_id": "9808943",
"other_id": null,
"pages": "225-230",
"pmc": null,
"pmid": "31764444",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Electroconvulsive Therapy for Neuroleptic Malignant Syndrome: A Case Series.",
"title_normalized": "electroconvulsive therapy for neuroleptic malignant syndrome a case series"
} | [
{
"companynumb": "NVSC2020US070993",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "We report a 24-year-old man with anti-melanoma differentiation-associated gene-5 (MDA5) antibody-positive dermatomyositis (DM) and interstitial lung disease (ILD) who developed spontaneous pneumomediastinum. By comparing serial thoracic high-resolution computed tomography scans, we demonstrated the distinct time course showing a paradoxical occurrence of pneumomediastinum despite a radiological improvement of ILD. Our case shows that pneumomediastinum in DM can occur regardless of associated ILD and it is a serious complication that should be considered in DM patients presenting with pulmonary manifestations. Cutaneous vasculopathy may be associated with pneumomediastinum and could potentially be a useful indicator of future disease.",
"affiliations": "Division of Rheumatology and Clinical Immunology, Queen Mary Hospital, Hong Kong, China.;Division of Rheumatology and Clinical Immunology, Queen Mary Hospital, Hong Kong, China.;Division of Rheumatology and Clinical Immunology, Queen Mary Hospital, Hong Kong, China.;Division of Rheumatology and Clinical Immunology, Queen Mary Hospital, Hong Kong, China.",
"authors": "Chan|Chiu Wai Shirley|CWS|http://orcid.org/0000-0002-0640-0676;Chung|Ho Yin|HY|;Lau|Chak Sing|CS|;Tsang|Helen H L|HHL|",
"chemical_list": "D001323:Autoantibodies; D007166:Immunosuppressive Agents; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13112",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "22(3)",
"journal": "International journal of rheumatic diseases",
"keywords": "MDA5; dermatomyositis; interstitial lung disease; pneumomediastinum",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D001323:Autoantibodies; D003882:Dermatomyositis; D006801:Humans; D007166:Immunosuppressive Agents; D000072640:Interferon-Induced Helicase, IFIH1; D017563:Lung Diseases, Interstitial; D008297:Male; D008478:Mediastinal Emphysema; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "521-524",
"pmc": null,
"pmid": "28580698",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous pneumomediastinum in a dermatomyositis patient with anti-melanoma differentiation-associated gene-5 antibody and interstitial lung disease despite an initial response to immunosuppressant.",
"title_normalized": "spontaneous pneumomediastinum in a dermatomyositis patient with anti melanoma differentiation associated gene 5 antibody and interstitial lung disease despite an initial response to immunosuppressant"
} | [
{
"companynumb": "HK-BAUSCH-BL-2019-010761",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "This report describes a 48-year-old caucasian male with schizophrenia who developed hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria early in clozapine treatment which resolved on drug discontinuation. The literature on similar cases is reviewed.",
"affiliations": "University of Pittsburgh School of Medicine, PA, USA.",
"authors": "Thompson|J|J|;Chengappa|K N|KN|;Good|C B|CB|;Baker|R W|RW|;Kiewe|R P|RP|;Bezner|J|J|;Schooler|N R|NR|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1097/00004850-199803000-00007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1315",
"issue": "13(2)",
"journal": "International clinical psychopharmacology",
"keywords": null,
"medline_ta": "Int Clin Psychopharmacol",
"mesh_terms": "D014150:Antipsychotic Agents; D001772:Blood Cell Count; D056486:Chemical and Drug Induced Liver Injury; D003024:Clozapine; D004802:Eosinophilia; D006417:Hematuria; D006801:Humans; D006943:Hyperglycemia; D008297:Male; D008875:Middle Aged; D010996:Pleural Effusion; D011507:Proteinuria; D012563:Schizophrenia, Paranoid; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8609061",
"other_id": null,
"pages": "95-8",
"pmc": null,
"pmid": "9669191",
"pubdate": "1998-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria occurring early in clozapine treatment.",
"title_normalized": "hepatitis hyperglycemia pleural effusion eosinophilia hematuria and proteinuria occurring early in clozapine treatment"
} | [
{
"companynumb": "PHEH1998US10771",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": null,
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnu... |
{
"abstract": "Aim: Assess feasibility and perspectives of pharmacogenetic testing/PGx in rural, primary care physician (PCP) practices when PCPs are trained to interpret/apply results and testing costs are covered. Methods: Participants included PCPs who agreed to training, surveys and interviews and eligible patients who agreed to surveys and testing. 51 patients from three practices participated. Results: Prestudy, no PCP had ever ordered a PGx test. Test results demonstrated gene variations in 30% of patients, related to current medications, with PCPs reporting changes to drug management. Poststudy, test cost was still a concern, but now PCPs reported practical barriers, including the utilization of PGx results over time. PCPs and patients had favorable responses to testing. Summary: PGx testing is feasible in rural PCP practices.",
"affiliations": "Mission Health Personalized Medicine & Pharmacogenomics Program; currently Independent Consultant, LGDconsulting 512, Fairview, NC 28730, USA.;Mission Health Personalized Medicine & Pharmacogenomics Program, Asheville, NC 28801, USA.;Mission Health Personalized Medicine & Pharmacogenomics Program, Asheville, NC 28801, USA.;Mission Health Personalized Medicine & Pharmacogenomics Program; currently OneOME, Minneapolis, MN,55405, USA.;Mission Health, Mission Research Institute, Asheville, NC 28801, USA.",
"authors": "Dressler|Lynn G|LG|;Bell|Gillian C|GC|;Abernathy|Pearl M|PM|;Ruch|Karl|K|;Denslow|Sheri|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2018-0200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "20(6)",
"journal": "Pharmacogenomics",
"keywords": "clinical implementation; personalized medicine; pharmacogenetics; pharmacogenomics; primary care; rural health",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005240:Feasibility Studies; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D058007:Physicians, Primary Care; D010865:Pilot Projects; D011320:Primary Health Care; D011446:Prospective Studies; D011795:Surveys and Questionnaires",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "433-446",
"pmc": null,
"pmid": "30983513",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Implementing pharmacogenetic testing in rural primary care practices: a pilot feasibility study.",
"title_normalized": "implementing pharmacogenetic testing in rural primary care practices a pilot feasibility study"
} | [
{
"companynumb": "US-OTSUKA-2019_033260",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nNearly all patients with malignant glioma will have disease recurrence. Our purpose was to define the treatment toxicity and efficacy of concurrent bevazicumab (BVZ) with hypofractionated stereotactic radiosurgery (SRS) of relatively larger targets for patients with recurrent MG.\n\n\nMETHODS\nA retrospective review of 21 patients with recurrent malignant glioma (18 glioblastoma, 3 WHO grade III glioma), treated at initial diagnosis with surgery and standard chemoradiation, was performed. All patients had concurrent BVZ with hypofractionatedSRS, 30 Gy in 5 fractions, with or without concurrent chemotherapy (temozolomide or CCNU).\n\n\nRESULTS\nMedian patient age was 54 years, median Karnofsky Performance Status was 80, and median target size was 4.3 cm (range, 3.4-7.5 cm). Eleven patients (52%) had previously failed BVZ. One patient had grade 3 toxicities (seizures, dysphasia), which resolved with inpatient admission and intravenous steroids/antiepileptics. Treatment-related toxicities were grade 3 (n = 1), grade 2 (n = 9), and grade 0-1 (n = 11). Kaplan-Meier median progression-free survival and overall survival estimates (calculated from start of SRS) for GBM patients (n = 18) were 11.0 and 12.5 months, respectively. Concurrent chemotherapy did not appear to show any statistically significant efficacy benefit or have any propensity for toxicity.\n\n\nCONCLUSIONS\nBVZ concurrent with hypofractionated SRS was well tolerated by this cohort of patients with relatively larger targets. Ongoing randomized trials with more moderate radiotherapy dosing may help establish the efficacy of this regimen, though intricacies of this approach, including patient selection, radiation target volume delineation/size, and optimal radiation dose, will need further evaluation.",
"affiliations": "University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).;University of Alabama at Birmingham Radiation Oncology , Birmingham, Alabama (G.M.C., A.M.M., C.D.W., M.B., J.B.F.); University of Alabama at Birmingham Neuro-Oncology , Birmingham, Alabama (L.B.N., H.F.-S., X.H.); University of Alabama at Birmingham Neurosurgery , Birmingham, Alabama (J.M.M., B.L.G.).",
"authors": "Clark|Grant M|GM|;McDonald|Andrew M|AM|;Nabors|Louis B|LB|;Fathalla-Shaykh|Hassan|H|;Han|Xiaosi|X|;Willey|Christopher D|CD|;Markert|James M|JM|;Guthrie|Barton L|BL|;Bredel|Markus|M|;Fiveash|John B|JB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/nop/npu028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2054-2577",
"issue": "1(4)",
"journal": "Neuro-oncology practice",
"keywords": "bevacizumab; glioblastoma; hypofractionated radiation; radiosurgery; recurrent",
"medline_ta": "Neurooncol Pract",
"mesh_terms": null,
"nlm_unique_id": "101640528",
"other_id": null,
"pages": "172-177",
"pmc": null,
"pmid": "26034629",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "19114704;20479391;20231676;19167838;14765377;17577040;19838627;23725997;21147867;10776976;19066727;21030162;15758009",
"title": "Hypofractionated stereotactic radiosurgery with concurrent bevacizumab for recurrent malignant gliomas: the University of Alabama at Birmingham experience.",
"title_normalized": "hypofractionated stereotactic radiosurgery with concurrent bevacizumab for recurrent malignant gliomas the university of alabama at birmingham experience"
} | [
{
"companynumb": "US-ROCHE-1732628",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Infliximab (Remicade), a chimeric monoclonal antibody to tumor necrosis factor-alpha (anti-TNF-alpha), is being used with increasing frequency in the treatment of Crohn's disease. Infliximab's safety profile to date has been good with reported adverse events being mild to moderate. We report a case of diffuse alveolar hemorrhage after the second infliximab infusion in a patient with Crohn's disease. The mechanism by which infliximab may have caused the observed pulmonary insult remains unknown. Physicians should be aware of the possible association between infliximab treatment and the development of alveolar hemorrhage. Future cases should be reported.",
"affiliations": "Sections of Gastroenterology and Pulmonary Medicine, Department of Medicine, Lenox Hill Hospital, and New York University School of Medicine, New York, NY, USA.",
"authors": "Panagi|Sofia|S|;Palka|Wojciech|W|;Korelitz|Burton I|BI|;Taskin|Metin|M|;Lessnau|Klaus D|KD|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1097/00054725-200405000-00016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "10(3)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D005260:Female; D005765:Gastrointestinal Agents; D006470:Hemorrhage; D006801:Humans; D000069285:Infliximab; D011014:Pneumonia; D011650:Pulmonary Alveoli; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "274-7",
"pmc": null,
"pmid": "15290924",
"pubdate": "2004-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diffuse alveolar hemorrhage after infliximab treatment of Crohn's disease.",
"title_normalized": "diffuse alveolar hemorrhage after infliximab treatment of crohn s disease"
} | [
{
"companynumb": "US-PFIZER INC-2016540622",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Drug-induced vasculitis is an inflammation of small-sized blood vessel caused by the use of drugs. It accounts for approximately 10% of acute cutaneous vasculitis. Propylthiouracil, hydralazine, and allopurinol have been widely known as causative agents. The most common clinical feature of drug-induced vasculitis is palpable purpura on lower extremities. A 66-year-old Korean female presented with erythematous nodules on upper chest and back. She had been on medication for multiple myeloma. Laboratory results showed neutropenia. After a single injection of filgrastim (recombinant granulocyte colony-stimulating factor), she developed cutaneous lesions with concurrent increase in absolute neutrophil count. A skin biopsy revealed leukocytoclastic vasculitis. After discontinuation of filgrastim injection, her skin lesions disappeared spontaneously.",
"affiliations": "Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Yoon|Dokyoung|D|https://orcid.org/0000-0002-1769-4921;Byun|Hyun Jeong|HJ|https://orcid.org/0000-0002-4354-5655;Oh|Se Jin|SJ|https://orcid.org/0000-0001-7525-4740;Park|Ji-Hye|JH|https://orcid.org/0000-0002-6699-5202;Lee|Dong-Youn|DY|https://orcid.org/0000-0003-0765-9812",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5021/ad.2020.32.2.164",
"fulltext": "\n==== Front\nAnn Dermatol\nAnn Dermatol\nAD\nAnnals of Dermatology\n1013-9087\n2005-3894\nThe Korean Dermatological Association; The Korean Society for Investigative Dermatology\n\n10.5021/ad.2020.32.2.164\nCase Report\nA Case of Cutaneous Leukocytoclastic Vasculitis Associated with Granulocyte Colony-Stimulating Factor: An Unusual Presentation\nhttps://orcid.org/0000-0002-1769-4921\nYoon Dokyoung\nhttps://orcid.org/0000-0002-4354-5655\nByun Hyun Jeong\nhttps://orcid.org/0000-0001-7525-4740\nOh Se Jin\nhttps://orcid.org/0000-0002-6699-5202\nPark Ji-Hye\nhttps://orcid.org/0000-0003-0765-9812\nLee Dong-Youn\nDepartment of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.\nCorresponding author: Ji-Hye Park, Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Tel: 82-2-3410-6578, Fax: 82-2-3410-3869, jh1204.park@samsung.com\n4 2020\n11 3 2020\n32 2 164167\n17 1 2019\n29 3 2019\n04 4 2019\nCopyright © 2020 The Korean Dermatological Association and The Korean Society for Investigative Dermatology\n2020\nThe Korean Dermatological Association and The Korean Society for Investigative Dermatology\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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nDrug-induced vasculitis is an inflammation of small-sized blood vessel caused by the use of drugs. It accounts for approximately 10% of acute cutaneous vasculitis. Propylthiouracil, hydralazine, and allopurinol have been widely known as causative agents. The most common clinical feature of drug-induced vasculitis is palpable purpura on lower extremities. A 66-year-old Korean female presented with erythematous nodules on upper chest and back. She had been on medication for multiple myeloma. Laboratory results showed neutropenia. After a single injection of filgrastim (recombinant granulocyte colony-stimulating factor), she developed cutaneous lesions with concurrent increase in absolute neutrophil count. A skin biopsy revealed leukocytoclastic vasculitis. After discontinuation of filgrastim injection, her skin lesions disappeared spontaneously.\n\nCutaneous\nCutaneous small vessel\nGranulocyte colonystimulating factor\nSkin\nVasculitis\n==== Body\nINTRODUCTION\n\nGranulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with many applications in cancer therapy. Various cutaneous adverse events associated with G-CSF have been reported, including Sweet's syndrome and pyoderma gangrenosum1,2. Herein, we present a case of G-CSF induced cutaneous vasculitis with unusual manifestation in a patient with multiple myeloma.\n\nCASE REPORT\n\nA 66-year-old Korean female presented with erythematous nodules and plaques on upper chest and back. She had been treated with bortezomib (proteasome inhibitor) for multiple myeloma for the past three months. Laboratory investigations showed white blood cell (WBC) count of 2,710/µl and absolute neutrophil count (ANC) of 560/mm3. Due to neutropenia, she had received 300 µg of filgrastim two weeks before her visit to our outpatient clinic. Three days after the injection, her laboratory results showed improvement in WBC and ANC count to 8,190/µl and 5,320/mm3 respectively; however, skin lesions started to develop. Multiple, tender, finger-tip to coin-sized red nodules were observed on her upper chest and back (Fig. 1).\n\nSkin biopsy on her back lesion showed vessel destruction, fibrinoid necrosis, and infiltration of neutrophils and lymphocytes with leukocytoclasia around small-sized vessels in the upper dermis, suggestive of leukocytoclastic vasculitis (Fig. 2). After discontinuation of both bortezomib and filgrastim, the skin lesions subsided within two weeks.\n\nDISCUSSION\n\nG-CSF regulates the production of neutrophils within the bone marrow. Recombinant G-CSF (filgrastim) is clinically used for the treatment of neutropenia associated with chemotherapy. Reported adverse events include bone pain, splenomegaly, hepatomegaly, thrombocytopenia, osteopenia/osteoporosis, glomerulonephritis, growth and development, and subfertility3. Cutaneous manifestations associated with recombinant human G-CSF include Sweet's syndrome and bullous pyoderma ganrenosum1,2.\n\nThe biopsy result and the fact that our patient developed the skin lesion after the injection of G-CSF raised the possibility of drug-induced leukocytoclastic vasculitis. However, because this histologic findings of vasculitis can also occur as a secondary phenomenon, it was necessary for us to exclude other possibilities.\n\nSweet's syndrome is one of the most possible causes of neutrophilic dermatoses in cutaneous vascular diseases. Histologic findings include perivascular infiltration of neutrophils in the papillary dermis and various extent of vascular damage can be seen. Histologically, Sweet's syndrome was not favored because prominent edema of upper dermis, one of the characteristic features of Sweet's syndrome, was not seen on our specimen. Moreover, our patient did not have fever or involvement of noncutaneous sites, such as eyes, joints, oral mucosa, and visceral organs. Together with the histologic findings and clinical manifestations, we were able to diagnose our patient's skin lesions as leukocytoclastic vasculitis.\n\nPubMed search of literature was made to retrieve publications about cutaneous vasculitis in association with infusion of G-CSF. G-CSF, cutaneous, adverse events, and vasculitis were terms used for the search. We found 18 cases of vasculitis after infusion of G-CSF. However, one study of 12 patients gave limited information (Table 1)4,5,6,7,8,9. Skin lesions developed within two days to one month after receiving G-CSF. Skin biopsy was performed for 17 cases. Of them, 16 cases showed leukocytoclastic vasculitis while the other case showed vasculitis with dermal infiltration of lymphocytes around blood vessel. Affected areas of the skin were described in five cases. All cases involved lower extremities. Three cases affected upper extremities while two cases showed acral lesion concurrently. Similar to the previous case reports described above, skin lesions in the current case developed three days after the injection of G-CSF. In our case, they subsided after stopping the drug. Although drug-induced vasculitis with palpable purpura usually developed on lower extremities in other literatures, tender multiple erythematous nodules showed up on the chest and upper back of our patient.\n\nThe mechanism of G-CSF-induced vasculitis is currently unclear, although some possible hypotheses have been proposed. Elsner et al.10 who studied neutrophils in patients with congenital neutropenia suggested the involvement of altered fragment constant (FCr) receptor expression in the pathogenesis of G-CSF-induced vasculitis. Their data showed that patterns of FCr receptor expression of neutrophils from patients with severe congenital neutropenia on G-CSF therapy were signs of in vivo activation of these cells. Because interaction between FCr receptors and immune complexes can cause release of lysosomal enzymes, altered FCr receptor expression might be associated with cutaneous vasculitis. Elsner et al.10 demonstrated that interleukin 1α and tumor necrosis factor-α could stimulate smooth muscle cells of blood vessel walls to synthesize G-CSF by enhancing antibody-mediated toxicity of polymorphonuclear cell.\n\nCutaneous leukocytoclastic vasculitis is a rare adverse reaction of G-CSF treatment. Because drug-induced vasculitis is indistinguishable clinically from other causes of small vessel vasculitis, it is easy to be misdiagnosed. Patients might be treated improperly, especially when clinical presentation is unusual as described in the present case 11,12. When the association between G-CSF and leukocytoclastic vasculitis is recognized, the drug should be immediately withdrawn. The eruption may resolve completely without the need of any further treatment. In severe cases, high-dose prednisone treatment may be required11.\n\nFig. 1 Multiple tender finger-tip to coin sized red colored nodules on her upper chest (A) and back (B). We received the patient's consent form about publishing all photographic materials.\n\nFig. 2 Histopathological images of skin biopsy. (A) Perivascular inflammatory cells infiltration in the upper dermis (H&E, ×40). (B) Vessel destruction, fibrinoid necrosis, and neutrophils and lymphocytes infiltration (H&E, ×400).\n\nTable 1 Summary of G-CSF induced vasculitis reported previously in literature\n\nReport\tNumber of cases\tAge (yr)\tSex\tPast medical history\tAffected area\tHistopathology\tG-CSF\tOnset of skin lesion from G-CSF infusion\t\nIppoliti et al.4\t1\t35\tM\tHeart transplantation\tLower extremities\tLeukocytoclastic vasculitis\tFilgrastim\t4 d\t\nEl Husseiny and Mattar5\t1\t64\tM\tChronic lymphatic leukemia\tEar, Hand, Lower extremities\tConfluent necrosis in the epidermis and infiltration of the dermis with lymphocytes around the blood vessels\tLenograstim\t2 d\t\nKilic et al.6\t2\t13\tF\tSevere congenital neutropenia\tUpper extremities, Lower extremities\tLeukocytoclastic vasculitis\tLenograstim\t1 mo\t\n5\tF\tSevere congenital neutropenia\tUpper extremities, Lower extremities\tLeukocytoclastic vasculitis\tLenograstim\t4 d\t\nAndavolu and Logan7\t1\t30\tM\tHemophilia A with arthropathy\tAuricles of both ears, sides of the face, upper extremities, and lower extremities\tLeukocytoclastic vasculitis\tNA\t3 d\t\nJain8\t12\tNA\tNA\tNA\tNA\tLeukocytoclastic vasculitis\tNA\tNA\t\nIto et al.9\t1\t59\tF\tDiffuse large B cell lymphoma\tNA\tNA\tpegfillgrastim\tNA\t\nG-CSF: granulocyte colony-stimulating factor, M: male, F: frmale, NA: not available.\n\nCONFLICTS OF INTEREST: The authors have nothing to disclose.\n==== Refs\n1 White JM Mufti GJ Salisbury JR du Vivier AW Cutaneous manifestations of granulocyte colony-stimulating factor Clin Exp Dermatol 2006 31 206 207 16487091\n2 Ross HJ Moy LA Kaplan R Figlin RA Bullous pyoderma gangrenosum after granulocyte colony-stimulating factor treatment Cancer 1991 68 441 443 1712666\n3 Cottle TE Fier CJ Donadieu J Kinsey SE Risk and benefit of treatment of severe chronic neutropenia with granulocyte colony-stimulating factor Semin Hematol 2002 39 134 140 11957197\n4 Ippoliti G Paulli M Lucioni M Lauriola M D'Armini AM Leukocytoclastic vasculitis as a complication of recombinant granulocyte colony-stimulating factor therapy in a heart transplant patient Case Rep Transplant 2014 2014 160407 24600524\n5 El Husseiny NM Mattar MM Aggressive cutaneous vasculitis in a patient with chronic lymphatic leukemia following granulocyte colony stimulating factor injection: a case report J Med Case Rep 2011 5 88 21362198\n6 Kilic SS Mustafayeva S Ipek K Adim SB Leukocytoclastic vasculitis in patients with severe congenital neutropenia J Trop Pediatr 2010 56 359 362 20100783\n7 Andavolu MV Logan LJ Leukocytoclastic vasculitis as a complication of granulocyte colony-stimulating factor (G-CSF) -- a case study Ann Hematol 1999 78 79 81 10089022\n8 Jain KK Cutaneous vasculitis associated with granulocyte colony-stimulating factor J Am Acad Dermatol 1994 31 2 Pt 1 213 215 7518847\n9 Ito Y Noda K Aiba K Yano S Fujii T [Diffuse large B-cell lymphoma complicated with drug-induced vasculitis during administration of pegfilgrastim] Rinsho Ketsueki 2017 58 2238 2242 Japanese 29212975\n10 Elsner J Roesler J Emmendörffer A Zeidler C Lohmann-Matthes ML Welte K Altered function and surface marker expression of neutrophils induced by rhG-CSF treatment in severe congenital neutropenia Eur J Haematol 1992 48 10 19 1370419\n11 Goldsmith LA Katz SI Gilchrest BA Paller AS Leffell DJ Wolff K Fitzpatrick's dermatology in general medicine 8th ed New York McGraw Hill 2012 456\n12 Goeser MR Laniosz V Wetter DA A practical approach to the diagnosis, evaluation, and management of cutaneous small-vessel vasculitis Am J Clin Dermatol 2014 15 299 306 24756249\n\n",
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"issn_linking": "1013-9087",
"issue": "32(2)",
"journal": "Annals of dermatology",
"keywords": "Cutaneous; Cutaneous small vessel; Granulocyte colonystimulating factor; Skin; Vasculitis",
"medline_ta": "Ann Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8916577",
"other_id": null,
"pages": "164-167",
"pmc": null,
"pmid": "33911730",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": "1370419;7518847;10089022;24600524;1712666;24756249;11957197;20100783;29212975;21362198;16487091",
"title": "A Case of Cutaneous Leukocytoclastic Vasculitis Associated with Granulocyte Colony-Stimulating Factor: An Unusual Presentation.",
"title_normalized": "a case of cutaneous leukocytoclastic vasculitis associated with granulocyte colony stimulating factor an unusual presentation"
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"abstract": "Chronic lymphocytic leukaemia often has a clinical presentation characterised by increased neoplastic lymphocytes which are mostly mature looking due to B lymphocytes. Increased secondary cancer prevalence has been detected among patients with chronic lymphocytic leukaemia diagnosis. In this report, we present three chronic lymphocytic leukaemia patients who developed secondary rare cancers during their follow-up at our clinic. Case 1: A 54-year-old female patient was diagnosed with stage I chronic lymphocytic leukaemia in 2003 and was diagnosed with Merkel cell carcinoma in February 2013. Case 2: A 66-year-old male patient was diagnosed with stage II chronic lymphocytic leukaemia in 2009 and was diagnosed with Kaposi's sarcoma in March 2013. Case 3: A 77-year-old male patient was diagnosed with stage I chronic lymphocytic leukaemia in 2006 and was diagnosed with Kaposi's sarcoma in 2011. In conclusion, secondary cancers are observed in patients diagnosed with chronic lymphocytic leukaemia. Therefore, follow-up of chronic lymphocytic leukaemia requires additional attention in this context.",
"affiliations": "MD (Medical Doctor), Clinic of Hematology, Istanbul Training and Research Hospital, Turkey mhdogu@yahoo.com.;MD (Medical Doctor), Department of Hematology, Pamukkale University Faculty of Medicine, Turkey.;MD (Medical Doctor), Department of Hematology, Pamukkale University Faculty of Medicine, Turkey.;MD (Medical Doctor), Department of Medical Oncology, Pamukkale University Faculty of Medicine, Turkey.;MD (Medical Doctor), Department of Pathology, Pamukkale University Faculty of Medicine, Turkey.;MD (Medical Doctor), Department of Hematology, Pamukkale University Faculty of Medicine, Turkey.",
"authors": "Dogu|Mehmet H|MH|;Sari|Ismail|I|;Hacioglu|Sibel|S|;Degirmencioglu|Serkan|S|;Şen|Nilay|N|;Keskin|Ali|A|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1177/0036933015619590",
"fulltext": null,
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"issn_linking": "0036-9330",
"issue": "61(1)",
"journal": "Scottish medical journal",
"keywords": "Chronic lymphocytic leukaemia; Kaposi’s sarcoma; Merkel cell carcinoma",
"medline_ta": "Scott Med J",
"mesh_terms": "D000368:Aged; D015266:Carcinoma, Merkel Cell; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "2983335R",
"other_id": null,
"pages": "60-3",
"pmc": null,
"pmid": "27334532",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two rare diagnoses during chronic lymphocytic leukaemia follow-up: Kaposi's sarcoma and Merkel cell carcinoma.",
"title_normalized": "two rare diagnoses during chronic lymphocytic leukaemia follow up kaposi s sarcoma and merkel cell carcinoma"
} | [
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"companynumb": "TR-TEVA-2019-TR-1055556",
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"activesubstancename": "FLUDARABINE PHOSPHATE"
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"abstract": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for the current global pandemic, coronavirus disease 2019 (COVID-19). COVID-19 usually presents with respiratory symptoms but can affect multiple organ systems. A wide spectrum of complications can occur depending upon the comorbidities of patients. There is limited literature available regarding the presentation and outcome of COVID-19 in chronic lymphocytic leukaemia (CLL) patients. We report 2 cases of COVID-19-induced hyperleucocytosis (WBC count >100,000/μl) in CLL patients.\nLymphopenia has been associated with severe disease and is a poor prognostic factor in COVID-19 infected patients; however, our cases show COVID-19-induced hyperleucocytosis (WBC count >100,000/μl)/lymphocytosis in CLL patients.Prior reports suggest that ibrutinib may have a protective effect against COVID-19 by decreasing inflammation and preventing progression to ARDS.",
"affiliations": "Saint Joseph's University Medical Center, Peterson, NJ, USA.;Saint Joseph's University Medical Center, Peterson, NJ, USA.;Saint Joseph's University Medical Center, Peterson, NJ, USA.;Saint Joseph's University Medical Center, Peterson, NJ, USA.;Saint Joseph's University Medical Center, Peterson, NJ, USA.;Saint Joseph's University Medical Center, Peterson, NJ, USA.",
"authors": "Singh|Balraj|B|;Ayad|Sarah|S|;Kaur|Parminder|P|;Reid|Ro-Jay|RJ|;Gupta|Sachin|S|;Maroules|Michael|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2021_002348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "8(3)",
"journal": "European journal of case reports in internal medicine",
"keywords": "CLL; COVID-19; SARS-CoV-2; chronic lymphocytic leukaemia; leucocytosis; lymphocytosis; lymphopenia",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "002348",
"pmc": null,
"pmid": "33869094",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "32719750;33098641;32361723;32688395;32991251;9482530;32433778;32616708;32776538;32665936;32918594;32575156;33117480;32753689;32647324;32066541;33043320;32388230;32696264",
"title": "COVID-19-Induced Hyperleucocytosis in Chronic Lymphocytic Leukaemia.",
"title_normalized": "covid 19 induced hyperleucocytosis in chronic lymphocytic leukaemia"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-307044",
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in protumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6.Patients and Methods: Three dosages of andecaliximab monotherapy [200, 600, and 1800 mg i.v. every 2 weeks (q2w)] were investigated in patients with advanced solid tumors (n = 13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma (n = 40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed.Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1,200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were four deaths on study not attributed to andecaliximab treatment. In first-line patients (n = 36), median progression-free survival (PFS) was 9.9 months [95% confidence interval (CI), 5-13.9 months], and the overall response rate (ORR) was 50%. Among all patients (n = 40), median PFS was 7.8 (90% CI, 5.5-13.9) months, and ORR was 48%, with a median duration of response of 8.4 months.Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase III study evaluating mFOLFOX6 ± andecaliximab in this setting is ongoing. Clin Cancer Res; 24(16); 3829-37. ©2018 AACR.",
"affiliations": "Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York. mas9313@med.cornell.edu.;Parkview Comprehensive Cancer Institute/Parkview Health, Fort Wayne, Indiana.;University of Utah Huntsman Cancer Institute, Salt Lake City, Utah.;Vanderbilt University Medical Center, Nashville, Tennessee.;Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida.;Division of Hematology Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, California.;Northwest Medical Specialties PLLC, Tacoma, Washington.;HonorHealth Research Institute, Scottsdale, Arizona.;Alabama Oncology, Birmingham, Alabama.;Gilead Sciences, Inc., Foster City, California.;Gilead Sciences, Inc., Foster City, California.;Gilead Sciences, Inc., Foster City, California.;Gilead Sciences, Inc., Foster City, California.;Gilead Sciences, Inc., Foster City, California.;Gilead Sciences, Inc., Foster City, California.;University of Southern California, Los Angeles, California.;Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.",
"authors": "Shah|Manish A|MA|;Starodub|Alexander|A|;Sharma|Sunil|S|;Berlin|Jordan|J|;Patel|Manish|M|;Wainberg|Zev A|ZA|;Chaves|Jorge|J|;Gordon|Michael|M|;Windsor|Kevin|K|;Brachmann|Carrie Baker|CB|;Huang|Xi|X|;Vosganian|Greg|G|;Maltzman|Julia D|JD|;Smith|Victoria|V|;Silverman|Jeffrey A|JA|;Lenz|Heinz-Josef|HJ|;Bendell|Johanna C|JC|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; C000621903:andecaliximab; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-17-2469",
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"issn_linking": "1078-0432",
"issue": "24(16)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D020780:Matrix Metalloproteinase 9; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077982:Progression-Free Survival; D018719:Receptor, ErbB-2; D013274:Stomach Neoplasms",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "3829-3837",
"pmc": null,
"pmid": "29691300",
"pubdate": "2018-08-15",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "19097774;27697982;20371345;25050215;21487506;12730128;21773953;24901174;21159820;24473089;23547785;15570070;25824764;21089052;27401892;16439202;28235803;9816210;12085177;18989990;25961845;27765757;16026148;18056472",
"title": "Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study.",
"title_normalized": "andecaliximab gs 5745 alone and combined with mfolfox6 in advanced gastric and gastroesophageal junction adenocarcinoma results from a phase i study"
} | [
{
"companynumb": "US-PFIZER INC-2014027222",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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"drugadditional": null,
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{
"abstract": "Gestational primary hyperparathyroidism (GPHPT) is a rare condition with fewer than 200 cases reported. We present the case of a 21-year-old woman who presented at 10 weeks' gestation with severe hypercalcemia. Laboratory investigation was consistent with primary hyperparathyroidism. Neck ultrasound did not reveal any parathyroid enlargement. Due to the persistence of severe hypercalcemia, she was treated with 4 weeks of cinacalcet therapy, which was poorly tolerated due to nausea and vomiting. At 14 weeks' gestation, she underwent neck exploration with right lower, left upper, and partial right upper parathyroid gland excision. Intra- and postoperative parathyroid hormone (PTH) and calcium levels remained elevated. After a thorough discussion of risks/benefits, the patient requested further treatment. A parathyroid sestamibi scan (PSS) revealed an ectopic adenoma in the left mediastinum. The adenoma was removed via video-assisted thorascopic parathyroidectomy with intraoperative PTH declining to nearly undetectable levels. She ultimately delivered a physically and developmentally normal infant at 37 weeks' gestation. Appropriate treatment of severe GPHPT may prevent the maternal and fetal complications of hypercalcemia. This case, in which cinacalcet therapy and PSS were used, adds to the body of literature regarding treatment of severe GPHPT.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22903.;Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22903.;Department of Pathology, University of Virginia Health System, Charlottesville, Virginia 22903.;Division of Nuclear Medicine, Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia 22903.;Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22903.;Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22903.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Virginia Health System, Charlottesville, Virginia 22903.;Division of General Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia 22903.;Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22903.",
"authors": "Horton|William B|WB|;Stumpf|Meaghan M|MM|;Coppock|Joseph D|JD|;Lancaster|Luke|L|;Dalkin|Alan C|AC|;Liu|Zhenqi|Z|;Chisholm|Christian A|CA|;Smith|Philip W|PW|;Kirk|Susan E|SE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/js.2017-00172",
"fulltext": "\n==== Front\nJ Endocr SocJ Endocr SocJSJSJournal of the Endocrine Society2472-1972Endocrine Society Washington, DC JS_20170017210.1210/js.2017-00172Case ReportsParathyroid, Bone, and Mineral MetabolismGestational Primary Hyperparathyroidism Due to Ectopic Parathyroid Adenoma: Case Report and Literature Review Horton William B. 1Stumpf Meaghan M. 1Coppock Joseph D. 2Lancaster Luke 3Dalkin Alan C. 1Liu Zhenqi 1Chisholm Christian A. 4Smith Philip W. 5Kirk Susan E. 11 Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 229032 Department of Pathology, University of Virginia Health System, Charlottesville, Virginia 229033 Division of Nuclear Medicine, Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia 229034 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Virginia Health System, Charlottesville, Virginia 229035 Division of General Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia 22903Address all correspondence to: William B. Horton, MD, 415 Ray C. Hunt Drive, Charlottesville, Virginia 22903. E-mail: WBH2N@hscmail.mcc.virginia.edu.01 9 2017 30 6 2017 30 6 2017 1 9 1150 1155 29 3 2017 26 6 2017 Copyright © 2017 Endocrine SocietyThis article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Gestational primary hyperparathyroidism (GPHPT) is a rare condition with fewer than 200 cases reported. We present the case of a 21-year-old woman who presented at 10 weeks’ gestation with severe hypercalcemia. Laboratory investigation was consistent with primary hyperparathyroidism. Neck ultrasound did not reveal any parathyroid enlargement. Due to the persistence of severe hypercalcemia, she was treated with 4 weeks of cinacalcet therapy, which was poorly tolerated due to nausea and vomiting. At 14 weeks’ gestation, she underwent neck exploration with right lower, left upper, and partial right upper parathyroid gland excision. Intra- and postoperative parathyroid hormone (PTH) and calcium levels remained elevated. After a thorough discussion of risks/benefits, the patient requested further treatment. A parathyroid sestamibi scan (PSS) revealed an ectopic adenoma in the left mediastinum. The adenoma was removed via video-assisted thorascopic parathyroidectomy with intraoperative PTH declining to nearly undetectable levels. She ultimately delivered a physically and developmentally normal infant at 37 weeks’ gestation.\n\nAppropriate treatment of severe GPHPT may prevent the maternal and fetal complications of hypercalcemia. This case, in which cinacalcet therapy and PSS were used, adds to the body of literature regarding treatment of severe GPHPT.\n\nWe present a case of gestational primary hyperparathyroidism due to ectopic parathyroid adenoma that was successfully diagnosed and treated with parathyroid sestamibi scan, cinacalcet, and surgery.\n\nhypercalcemiaprimary hyperparathyroidismpregnancytechnetium Tc 99m sestamibi\n==== Body\nGestational primary hyperparathyroidism (GPHPT) is a rare condition with prevalence of 0.15% to 1.4% [1–3] and fewer than 200 cases reported. Unlike gestational diabetes or thyrotoxicosis, which are pathologic conditions associated with physiologic changes of pregnancy, GPHPT is only incidentally associated with pregnancy due to the fact that women are seeking obstetrical care. It often goes unrecognized, as patients may be asymptomatic or exhibit mild symptoms that are considered normal in pregnancy [4]. Indeed, most women complete pregnancy without biochemical analysis of their calcium levels. GPHPT is a treatable cause of fetal and maternal morbidity and mortality [5]; thus, early diagnosis and appropriate management are vital strategies for avoiding obstetrical complications.\n\n1. Case Presentation\nA 21-year-old female (gravida 2, para 1) presented at 10 weeks’ gestation with headache, intractable vomiting, and polydipsia. Laboratory investigation revealed elevated levels of serum calcium (13.5 mg/dL), ionized calcium (1.69 mmol/L), intact postoperative parathyroid hormone (PTH; 254.3 pg/mL), and 1,25-dihydroxyvitamin D (268 pg/mL), consistent with primary hyperparathyroidism. All other laboratory results were unremarkable (Table 1). She denied any personal or family history of hypercalcemia or endocrine neoplasia. Intravenous fluid (IVF) therapy was initiated, but she continued to experience vomiting and hypercalcemia.\n\nTable 1. Laboratory Values at Time of Initial Presentation\n\nLaboratory Test\tReference Range\tInitial Value\t\nGlucose (mg/dL)\t74–99\t108\t\nSodium (mmol/L)\t136–145\t137\t\nPotassium (mmol/L)\t3.4–4.8\t3.2\t\nChloride (mmol/L)\t98–107\t106\t\nBicarbonate (mmol/L)\t22–29\t21\t\nBlood urea nitrogen (mg/dL)\t7.0–18.7\t5\t\nCreatinine (mg/dL)\t0.6–1.1\t0.5\t\nCalcium (mg/dL)\t8.5–10.7\t13.5\t\nMagnesium (mg/dL)\t1.6–2.6\t1.6\t\nPhosphorus (mg/dL)\t2.3–4.7\t2.3\t\nTotal protein (g/dL)\t6.0–8.3\t6.3\t\nAlbumin (g/dL)\t3.2–5.2\t3.7\t\nTotal bilirubin (mg/dL)\t0.3–1.2\t0.2\t\nPTH (pg/mL)\t9.2–79.5\t254.3\t\nPTH-related peptide (pg/mL)\t14–27\t12\t\n25-Hydroxyvitamin D (ng/mL)\t30–100\t19\t\n1,25-Dihydroxyvitamin D (pg/mL)\t18–78\t268\t\nIonized calcium (mmol/L)\t1.13–1.32\t1.69\t\n24-Hour urine calcium (mg/day)\t100–250\t361\t\nUltrasound confirmed a viable intrauterine pregnancy. Aggressive IVF therapy was continued, but calcium remained elevated (Table 2). She had no palpable neck mass, and neck ultrasound revealed no evidence of parathyroid enlargement. Due to the degree and persistence of hypercalcemia, we planned for neck exploration in the second trimester. As a bridge, the risks/benefits of medical therapy were discussed and cinacalcet was started at 30 mg twice daily. Calcium levels normalized thereafter (Table 2). Once stable, the patient was discharged home.\n\nTable 2. Serum Calcium, Ionized Calcium, and PTH Levels Throughout Treatment Course\n\nLaboratory Test\tReference Range\tDay 0\tDay 1\tDay 3\tDay 4\tDay 5\tDay 6\tDay 11\tDay 13\tDay 16\tDay 33\tDay 34\tDay 35\tDay 38\tDay 50\t\n\t\tIVF Started\t\t\tCinacalcet Started\t\tDischarged\t\t\t\tPES\tVATP\t\tDischarged\t\t\nSerum calcium (mg/dL)\t8.5–10.5\t12.0\t10.8\t11.2\t12.8\t11.0\t10.7\t13.5\t10.4\t10.4\t11.4\t11.3\t9.1\t7.4\t8.6\t\nIonized calcium (mg/dL)\t4.4–5.5\t6.2\t6.2\t6.0\t6.5\t6.1\t6.0\t6.1\t\t\t\t5.6\t4.4\t3.7\t4.9\t\nPTH (pg/mL)\t9–77\t191.0\t\t190.2\t\t\t\t\t217\t\t209.8\t188.7\t1.9\t26.6\t20\t\nAbbreviations: PES, parathyroid exploration surgery; VATP, video-assisted thorascopic parathyroidectomy.\n\nShe continued to experience intractable vomiting leading to sporadic compliance with cinacalcet. At one stage, she was unable to tolerate cinacalcet for 2 days, which led to worsening hypercalcemia and readmission for IVF therapy (day 11 in Table 2).\n\nAt 14 weeks’ gestation, she underwent four-dimensional computed tomography (4DCT) of the neck (with fetal shielding) with and without contrast for preoperative localization, which revealed two normal sized glands (one ∼2 × 1 × 3 mm in the posterior midline and another 2 × 1 × 5 mm just cranial to the left inferior thyroid artery on the left). No candidate parathyroid adenoma in the neck or anterior mediastinum was identified. Endocrine surgery then performed bilateral neck exploration with right lower, left upper, and partial right upper parathyroid gland excision. The left lower parathyroid gland could not be identified. Intraoperative PTH levels steadily increased from 209 to 252 pg/mL over 5 hours. Histologic examination identified normal parathyroid tissue weighing 0.03 g. After extensive discussion of the risks/benefits of additional imaging and a potential second surgery, as well as the option of delaying further tests or treatment until after delivery, the patient opted for and consented to further diagnostic studies. Parathyroid sestamibi scan (PSS) identified an ectopic adenoma low in the left mediastinum [Fig. 1(A) and 1(B)]. The ectopic gland weighed 3.1 g and was removed via video-assisted thorascopic parathyroidectomy. Intraoperative PTH levels were not obtained, as surgery was performed on a weekend, but intact PTH levels decreased from 188.7 pg/mL on day of surgery to 1.9 pg/mL the following morning (Table 2). Histologic examination revealed hypercellular parathyroid tissue, consistent with an adenoma [Fig. 1(C)]. She declined genetic testing for multiple endocrine neoplasia (MEN) syndromes. During the initial postoperative period, she was started on 2 g calcium carbonate daily but developed persistent hypocalcemia with perioral paresthesia, necessitating intravenous calcium gluconate 2 g every 6 hours for approximately 36 hours. PTH and calcium levels slowly normalized (Table 2), and she was transitioned to 0.25 mcg calcitriol twice daily and 2000 mg/400 IU calcium/vitamin D daily. She was discharged home in stable condition and able to discontinue calcium supplementation 4 weeks later. She was later admitted to another facility for pre-eclampsia without severe features at 36 weeks’ gestation with biochemistry showing serum calcium of 7.5 mg/dL with albumin of 2.3 g/dL (corrected calcium within normal limits at 8.9 mg/dL). She ultimately gave birth to a healthy male infant (height 17.5 inches; weight 2.763 kg; Apgar score 8) at 37 weeks via spontaneous vaginal delivery. Calcium levels were not drawn on the infant postpartum, but neither neonatal seizures nor tetany were observed prior to discharge home. At 2-months’ follow-up, he was growing appropriately (height 21.25 inches; weight 4.649 kg; head circumference 15 inches) and met all developmental milestones.\n\nFigure 1. (A) Axial single photon emission computed tomography slice through the mid chest, with tracer activity in orange. The focus of intense activity in the left anterior mediastinum (yellow arrow) corresponds to the ectopic parathyroid adenoma, contiguous with thymus. (B) Maximal intensity projection image of the single photon emission computed tomography data. There is normal uptake of sestamibi in salivary glands, heart, liver, and lactating breasts. The round spot above the heart (black arrow) is abnormal and represents the patient's ectopic parathyroid adenoma. (C) Benign hypercellular parathyroid tissue (red arrow) with adjacent thymic tissue (yellow arrow) at total magnification of ×200.\n\n2. Discussion\nThe physiology of fetal calcium homeostasis is complex. Fetal parathyroid development occurs after the first trimester; therefore, maternal calcium status plays a fundamental role in fetal homeostasis (Fig. 2). Maternal calcium is actively transported across the placenta into the fetal circulation. Placental PTH-related peptide easily enters the fetal circulation as well. In contrast, both maternal PTH and 1,25-dihydroxyvitamin D are prevented from transfer. Maternal 25-hydroxyvitamin D does reach the fetus, but as PTH-related peptide only minimally increases 1-α hydroxylation, its contribution to calcium regulation is limited until fetal PTH production ensues later in gestation.\n\nFigure 2. Regulation of calcium during gestation. Maternal calcium is actively transported across the placenta into the fetal circulation. Placental PTH-related peptide (PTHrP) also rapidly enters the fetal circulation. Conversely, both maternal PTH and 1,25-dihydroxyvitamin D (1,25-diOH D) are prevented from transfer. Maternal 25-hydroxyvitamin D (25-OH D) reaches the fetus via passive diffusion. During the second and third trimester, fetal parathyroid development results in fetal circulation of PTH.\n\nThis regulatory pathway has clinical implications, as elevated maternal calcium levels transfer directly to the fetus in whom counter-regulatory responses (such as inhibition of PTH) are ineffective or do not exist, especially during the first trimester. Later in gestation, maternal hypercalcemia may cause fetal hypercalcemia with suppression of fetal PTH. At delivery, maternal calcium transfer ceases, which predisposes the baby to postpartum hypocalcemia.\n\nData regarding outcomes of GPHPT are limited to case reports or small case series. One recent study examining pregnancy outcomes in women with primary hyperparathyroidism found that most patients have only mild hypercalcemia, which is generally not associated with obstetrical complications [6]. Conversely, 67% to 80% of pregnancies with severe hypercalcemia may experience poor fetal and maternal outcomes [3], underscoring the need for timely diagnosis and treatment.\n\nTreatment should be individually tailored by gestational age, severity of hypercalcemia, and risk–benefit analysis [7]. Treatment may be challenging, as some therapies are contraindicated (e.g., bisphosphonates) and practitioners may be reluctant to suggest surgery during pregnancy, particularly outside the second trimester [8]. Mild asymptomatic hypercalcemia may be treated conservatively. Patients with severe hypercalcemia (symptomatic and/or ionized serum concentration 5.6 to 8 mg/dL) are appropriate surgical candidates [8]. Failure of medical therapy in symptomatic patients is an indication for surgery regardless of gestational age [8]. As with most surgical procedures during pregnancy, the optimal time for intervention is during the second trimester [8]. Preoperative localization facilitates successful surgical intervention, as up to 2% of patients will have ectopic parathyroid tissue [8]. We could find no epidemiological data regarding the prevalence of MEN syndromes in GPHPT, but one case series demonstrated that two of eight patients (25%) were found to have MEN1 gene mutations [4]. Younger age at diagnosis or parathyroid gland hyperplasia on histologic examination increases the likelihood of a genetic syndrome.\n\nThis case adds to the body of evidence regarding cinacalcet and PSS during pregnancy. To our knowledge, this is only the eighth report of cinacalcet use [9–13] and sixth report of PSS [1, 8, 14] during gestation. Cinacalcet is a calcimimetic agent that binds the calcium-sensing receptor, ultimately leading to decreased PTH secretion [9]. Data on cinacalcet use in human pregnancy are limited to a small number of case reports, in which no teratogenic or other adverse fetal effects were observed and all mothers remained pregnant to term and delivered healthy infants (although two infants experienced transient neonatal hypocalcemia [10, 13] and one pregnancy was terminated prior to delivery for reasons unrelated to cinacalcet use [9]). Although it was unclear whether our patient’s persistent vomiting was worsened by cinacalcet, the health of her infant reinforces these positive reports. It should be noted that our patient received cinacalcet for only 4 weeks and, due to nausea and vomiting, was only able to take ~50% of prescribed doses.\n\nNuclear imaging during pregnancy remains controversial. Radiation risks throughout pregnancy are related to the stage of pregnancy and the absorbed dose. These risks are more substantial during organogenesis and in the early fetal period, somewhat less in the second trimester, and least in the third trimester [15]. Provided there is strong clinical justification and effort to use nonionizing radiation, pregnancy itself is not a contradiction, especially when using short-lived radionuclides [8]. The estimated fetal radiation dose from Tc-99m PSS is 2 to 4 mGy, which is well below the threshold of concern (100 to 200 mGy) for adverse fetal effects from radiation exposure [15]. Precautionary measures should include maternal hydration and frequent voiding after administration of radionuclides to avoid pooling of the radionuclide in the maternal bladder and subsequent fetal exposure. Longer imaging times may also help reduce fetal exposure [8]. All cases referenced in which PSS was used during pregnancy demonstrated no teratogenic effects. The mother also received 4DCT of the neck with fetal shielding for preoperative localization. Computed tomography examinations in areas of the body other than the abdomen and pelvis deliver minimal radiation doses to the fetus [16]. Moreover, fetal radiation doses from computed tomography examinations of the abdomen and pelvis rarely exceed 25 mGy (which would also be below the reported threshold of concern) [16]. In this case, the radiation risk to fetus was low given 4DCT of the neck was performed and fetal shielding was in place before imaging began.\n\n3. Conclusion\nGPHPT due to ectopic parathyroid tissue is rare, and its management can be challenging. This report adds to the literature regarding treatment of this condition, detailing the use of cinacalcet as a bridge to surgery and PSS for localization of ectopic parathyroid tissue.\n\nAbbreviations: 4DCTfour-dimensional computed tomography\n\nGPHPTgestational primary hyperparathyroidism\n\nIVFintravenous fluid\n\nMENmultiple endocrine neoplasia\n\nPSSparathyroid sestamibi scan\n\nPTHparathyroid hormone.\n\n\n\nAcknowledgments\nWe thank the patient for allowing us to share her story with the medical community.\n\nDisclosure Summary: The authors have nothing to disclose.\n==== Refs\nReferences and Notes\n1. McMullen TP , Learoyd DL , Williams DC , Sywak MS , Sidhu SB , Delbridge LW \nHyperparathyroidism in pregnancy: options for localization and surgical therapy . World J Surg . 2010 ;34 (8 ):1811 –1816 .20386905 \n2. Kelly TR \nPrimary hyperparathyroidism during pregnancy . Surgery . 1991 ;110 (6 ):1028 –1033, discussion 1033–1034 .1745971 \n3. Schnatz PF , Curry SL \nPrimary hyperparathyroidism in pregnancy: evidence-based management . Obstet Gynecol Surv . 2002 ;57 (6 ):365 –376 .12140371 \n4. Stringer KM , Gough J , Gough IR \nPrimary hyperparathyroidism during pregnancy: management by minimally invasive surgery based on ultrasound localization . ANZ J Surg (in press). 10.1111/ans.13378.\n5. Gokkaya N , Gungor A , Bilen A , Bilen H , Gviniashvili D , Karadeniz Y \nPrimary hyperparathyroidism in pregnancy: a case series and literature review . Gynecol Endocrinol . 2016 ;32 (10 ):783 –786 .27243597 \n6. Hirsch D , Kopel V , Nadler V , Levy S , Toledano Y , Tsvetov G \nPregnancy outcomes in women with primary hyperparathyroidism . J Clin Endocrinol Metab . 2015 ;100 (5 ):2115 –2122 .25751112 \n7. Kamenický P , Lecoq AL , Chanson P \nPrimary hyperparathyroidism in pregnancy . Ann Endocrinol (Paris) . 2016 ;77 (2 ):169 –171 .27157105 \n8. Saad AF , Pacheco LD , Costantine MM \nManagement of ectopic parathyroid adenoma in pregnancy . Obstet Gynecol . 2014 ;124 (2 Pt 2 , Suppl 1)478 –480 .25004326 \n9. Rey E , Jacob CE , Koolian M , Morin F \nHypercalcemia in pregnancy - a multifaceted challenge: case reports and literature review . Clin Case Rep . 2016 ;4 (10 ):1001 –1008 .27761256 \n10. Nadarasa K , Bailey M , Chahal H , Raja O , Bhat R , Gayle C , Grossman AB , Druce MR \nThe use of cinacalcet in pregnancy to treat a complex case of parathyroid carcinoma . Endocrinol Diabetes Metab Case Rep . 2014 ;2014 :140056 .25298882 \n11. Edling KL , Korenman SG , Janzen C , Sohsman MY , Apple SK , Bhuta S , Yeh MW \nA pregnant dilemma: primary hyperparathyroidism due to parathyromatosis in pregnancy . Endocr Pract . 2014 ;20 (2 ):e14 –e17 .24013984 \n12. Horjus C , Groot I , Telting D , van Setten P , van Sorge A , Kovacs CS , Hermus A , de Boer H \nCinacalcet for hyperparathyroidism in pregnancy and puerperium . J Pediatr Endocrinol Metab . 2009 ;22 (8 ):741 –749 .19845125 \n13. Vera L , Oddo S , Di Iorgi N , Bentivoglio G , Giusti M \nPrimary hyperparathyroidism in pregnancy treated with cinacalcet: a case report and review of the literature . J Med Case Reports . 2016 ;10 (1 ):361 .\n14. Baretić M , Tomić Brzac H , Dobrenić M , Jakovčević A \nParathyroid carcinoma in pregnancy . World J Clin Cases . 2014 ;2 (5 ):151 –156 .24868516 \n15. Shaw P , Duncan A , Vouyouka A , Ozsvath K \nRadiation exposure and pregnancy . J Vasc Surg . 2011 ;53 (1 , Suppl)28S –34S .20869193 \n16. McCollough CH , Schueler BA , Atwell TD , Braun NN , Regner DM , Brown DL , LeRoy AJ \nRadiation exposure and pregnancy: when should we be concerned? \nRadiographics . 2007 ;27 (4 ):909 –917, discussion 917–918 .17620458\n\n",
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"keywords": "hypercalcemia; pregnancy; primary hyperparathyroidism; technetium Tc 99m sestamibi",
"medline_ta": "J Endocr Soc",
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"references": "27243597;25004326;27761256;1745971;24868516;25298882;20869193;27998296;12140371;26631158;19845125;17620458;20386905;24013984;25751112;27157105",
"title": "Gestational Primary Hyperparathyroidism Due to Ectopic Parathyroid Adenoma: Case Report and Literature Review.",
"title_normalized": "gestational primary hyperparathyroidism due to ectopic parathyroid adenoma case report and literature review"
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"abstract": "•High-risk multi-agent drug resistant GTN is a life threatening disease.•Majority of choriocarcinomas show intense PD-L1 immunoreactivity.•Pembrolizumab increases antitumor activity.•Effectiveness of Pembrolizumab in treating patients with high-risk multi-agent drug resistant GTN.",
"affiliations": "Division of Gynecologic Surgery, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.;Division of Gynecologic Surgery, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.;Division of Gynecologic Surgery, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.;Division of Gynecologic Surgery, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Goldfarb|Jennifer A|JA|;Dinoi|Giorgia|G|;Mariani|Andrea|A|;Langstraat|Carrie L|CL|",
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"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 Elsevier \n\nS2352-5789(20)30040-0\n10.1016/j.gore.2020.100574\n100574\nCase Report\nA case of multi-agent drug resistant choriocarcinoma treated with Pembrolizumab\nGoldfarb Jennifer A. jgoldfa1@villanova.edu⁎ Dinoi Giorgia 1 Mariani Andrea Langstraat Carrie L. Division of Gynecologic Surgery, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA\n⁎ Corresponding author. jgoldfa1@villanova.edu1 Present Address: Gynecologic Oncology Unit, Women Wealth Area, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.\n\n\n23 4 2020 \n5 2020 \n23 4 2020 \n32 10057412 3 2020 16 4 2020 18 4 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• High-risk multi-agent drug resistant GTN is a life threatening disease.\n\n• Majority of choriocarcinomas show intense PD-L1 immunoreactivity.\n\n• Pembrolizumab increases antitumor activity.\n\n• Effectiveness of Pembrolizumab in treating patients with high-risk multi-agent drug resistant GTN.\n\n\n\nKeywords\nUterine choriocarcinomaGestational trophoblastic neoplasia (GTN)PD-L1PembrolizumabHigh-risk multidrug resistance\n==== Body\n1 Introduction\nGestational trophoblastic disease (GTD) is a spectrum of benign to malignant lesions following molar or non-molar pregnancies (Angiolo et al., 2019). Risk factors for gestational trophoblastic neoplasia (GTN) include age at the time of pregnancy, with GTN being more common in very young patients and patients over the age of 40, and history of a prior molar pregnancy. The incidence of GTN varies by race and ethnicity, but this is not well understood. In the United States, the incidence of choriocarcinoma following a gestational event, regardless of the patient’s race, is 1 in 41,094 pregnancies (Smith et al., 2003). Incidence also varies by country, with an increased risk of choriocarcinoma reported in Asia (Shanmugaratnam et al., 1971).\n\nThe diagnosis of GTN can occur after evacuation of a partial or complete mole in a patient with persistent elevated β-hCG or with abnormal uterine bleeding after delivery. The work-up of a patient with GTN includes serum β-hCG level, CT scan of the abdomen and pelvis, chest X-ray, and kidney and liver function tests. If imaging reveals liver metastasis, an MRI of the head should also be obtained to assess for brain metastasis. Using this information and a clinical exam, the patient is given a risk score to determine treatment (Table 1) (Figo Oncology Committee, 2002). Patients with high risk scores are more likely to develop drug resistance and are commonly treated with surgery followed by multi-agent chemotherapy with or without adjuvant radiation. The preferred multiagent chemotherapy EMA/CO (etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine) has remission rates reported as high as 91% (Kim, 1998). Yet, there are still 0.5–5% of patients who die from GTNs as a result of multidrug resistance often seen in conjunction with metastasis to the brain or liver (Ghorani, 2017). These patients require a new treatment approach.Table 1 GTN scoring according to risk score criteria developed by the World Health Organization (WHO) as used by FIGO. Low risk is a score < 6. High risk is a score ≥ 7 (Figo Oncology Committee, 2002).\n\nPrognostic Factor Score\t0\t1\t2\t4\t\nMaternal age\tYounger than 40\t40 and/or older\t---\t---\t\nPrevious pregnancy\tHydatidiform mole\tAbortion\tFull-term pregnancy\t---\t\nMonths since last pregnancy\t<4\t4–6\t7–12\t>12\t\nPretreatment hCG (IU/mL)\t<103\t103-104\t>104-105\t≥105\t\nLargest tumor size, including uterus\t<3cm\t3 to < 5 cm\t≥5cm\t---\t\nSite of metastases\tLung\tSpleen or kidney\tGastrointestinal tract\tBrain, liver\t\nNumber of metastases*\t0\t1–4\t5–8\t>8\t\nNumber of drugs used to treat the tumor that have failed\t0\t0\t1\t≥2\t\n* Chest X-ray is used to count number of lung metastases.\n\n\n\nA new class of anti-cancer drugs, called immune checkpoint inhibitors, can be effective in restoring host immunity (Jørgensen, 2019). One way the human body regulates immunity is through the interaction between programmed cell death protein 1 (PD-1) on T-cells and its ligand PD-L1 on tumor cells. Among drugs targeting this interaction is Pembrolizumab. Since the incidence of GTN is rare, not much has been published on the treatment of patients with high-risk multidrug resistant GTN. Here we report on the treatment with Pembrolizumab of a woman with choriocarcinoma who showed consistent disease progression following six previous treatment therapies.\n\n2 Case report\nA 50-year-old Caucasian female (gravida 3, para 2, abortus 1) presented with an intra-uterine mass and hemorrhaged during an office endometrial biopsy requiring an emergent hysterectomy and bilateral salpingo-oopohrectomy. Pathology confirmed uterine choriocarcinoma with full-thickness myometrial involvement. A chest CT showed numerous small bilateral pulmonary nodules and her β-hCG was 28,725.0 mlU/mL. CT of the abdomen was negative for additional metastatic disease.\n\nThe patient was started on multi-agent chemotherapy with EMA/CO of which she completed eleven cycles. Her β-hCG decreased to a negative value as per our lab standard (<7 mlU/mL for post-menopausal women) after four cycles and remained negative for twenty-two weeks. Since the patient’s β-hCG was expected to decrease to ≤ 1 because she was on a high dose oral contraceptive, she was treated with three cycles of EMA/CO past her plateau at 1. Two months after the eleventh cycle, her β-hCG rose to 9.3 mlU/mL, and a chest CT showed persistent pulmonary nodules that were unchanged from three months prior. Consequently, the patient was started on EMA/EP (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine, substituting cyclophosphamide and vincristine for cisplatin and etoposide on Day 8) of which she completed five cycles, showing a decrease to a negative β-hCG following the first cycle.\n\nTwo months from her final cycle of EMA/EP, her β-hCG began to rise again, and in another two months it had reached 220 mlU/mL. Imaging showed a PET positive lesion at the top of the vagina. Although the final histology was negative for recurrence, this warranted an EUA and robotic upper vaginectomy which showed no disease.\n\nAfter surgery her β-hCG initially normalized, but then increased for three months. She was started on TP/TE (paclitaxel, cisplatin/paclitaxel, etoposide) of which she completed seven cycles. Thirty-nine weeks after TP/TE initiation, a chest CT showed that at least three of her pulmonary nodules had increased in size and were amenable to pulmonary metastasectomy. The patient underwent two thoracotomy multiple lung wedge resections with mediastinal lymphadenectomy. Three resections in the right lung were positive for choriocarcinoma with clear margins. The left lung had one upper lobe nodule involved by metastatic choriocarcinoma. The patient’s post-operative β-hCG was elevated at 23 mlU/mL.\n\nA month later, the patient was started on FAEV chemotherapy (floxuridine, dactinomycin, etoposide, vincristine) of which she completed four cycles. Two months after the patient’s fourth cycle, her β-hCG had increased again and continued increasing over the following three months to 385 mlU/mL. She underwent a PET scan which showed multiple enlarged nodules in the left lower lobe and one in the right lung. A new punctate nodule was found in the left lower lobe.\n\nFive months after her fourth cycle of FAEV, the patient was switched to ICE (ifosfamide, carboplatin and etoposide). She completed four cycles, but before her final cycle, a PET-CT showed her left lower lung nodule had enlarged and a new right mediastinal node had appeared.\n\nA month after completing the ICE regimen, she was put on a compassionate use treatment with TRC105, a monoclonal antibody that binds an angiogenic target called endoglin which is highly expressed on GTN tumor vessels and cells. Despite an initial drop in β-hCG, imaging showed signs of disease progression only eight weeks after initiating this treatment. Avastin was added to cycles three and four, but her β-hCG continued to increase to 283 mlU/mL by the fourth cycle.\n\nAfter a team discussion of chemotherapy options following disease progression after her sixth treatment regimen, the patient was started on Pembrolizumab. Her tumor was 100% PD-L1 positive, and she underwent six cycles of Pembrolizumab. After three cycles, her β-hCG became negative (Fig. 1). One month after initiating Pembrolizumab, the patient’s chest CT showed a slight decrease in her left lower lobe nodule and no signs of disease progression. After cycle six, a chest CT showed continual decrease of disease. The Pembrolizumab regimen was complicated by peripheral grade 3 neuropathy requiring discontinuance after cycle six.Fig. 1 Patient’s β-hCG level from the first (Cycle 1 initiation = Day 0) through final cycle (Cycle 6 initiation = Day 131) of Pembrolizumab treatment. The β-hCG level decreased to a negative value as per our lab standard (<7 mlU/mL for post-menopausal women) after 3 cycles (Cycle 3 initiation = Day 43) of Pembrolizumab.\n\n\n\nStarting eight months after her final cycle, the patient’s β-hCG level began to increase from a negative value to 46 mlU/mL over the next seven months. Sixteen months after her final cycle, a PET-CT showed no evidence of new disease. At twenty-two months from her final cycle, disease progression was detected from a PET scan showing a new hilar lymphadenopathy and a chest CT showed multiple pulmonary nodules suspicious for disease recurrence. The patient recently reinitiated Pembrolizumab.\n\n3 Discussion\nHigh-risk multi-agent drug resistant GTN is a life threatening disease, and PD-1 immunotherapy has the potential to be an effective treatment. When PD-1 and PD-L1 interact there is an inhibitory signal which reduces T-cell proliferation (Alsaab et al., 2017). The antibodies in Pembrolizumab block PD-1 from interacting with PD-L1 which increases T-cell proliferation thereby increasing antitumor activity (Jørgensen, 2019). The majority of choriocarcinomas show intense PD-L1 immunoreactivity (Veras et al., 2017).\n\nOur case presents a patient diagnosed with choriocarcinoma who was resistant to six prior treatment regimens, and achieved her longest period of remission following six cycles of Pembrolizumab treatment (Table 2). The patient’s β-hCG remained negative for eight months after her final Pembrolizumab cycle before a subsequent increase, and no new nodularity had been detected until twenty-two months after her final cycle. This case is also unique because it is one of the first published compassionate uses of Pembrolizumab to treat GTN in the United States.Table 2 Summarizes patient’s treatment regimens.\n\nName of treatment regimen\tNumber of cycles\tβ-hCG level (mlU/mL) *\tβ-hCG level (mlU/mL) **\tPersistent disease detected by imaging\t\nEMA/CO\t11\t28,725.0\t1.1\t• persistent pulmonary nodules\n\n\t\nEMA/EP\t5\t22\t<0.6\t• suspicious lesion at the top of the vagina\n\n• persistent pulmonary disease\n\n\t\nTP/TE\t6\t799\t<0.6\t• enlarged pulmonary nodules\n\n\t\nFAEV\t4\t23\t<0.6\t• persistent, enlarged, and new multiple pulmonary nodules in both lobes\n\n\t\nICE\t4\t385\t70\t• new right mediastinal node\n\n\t\nTRC105\t4\t70\t354\t• hilar lymphadenopathy enlarged\n\n\t\nPembrolizumab\t6\t480\t2.6\t• hilar lymphadenopathy***\n\n• pulmonary nodules***\n\n\t\nEMA/CO etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine, EMA/EP etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine, substituting cyclophosphamide and vincristine for cisplatin and etoposide on Day 8, TP/TE paclitaxel, cisplatin/paclitaxel, etoposide, FAEV floxuridine, dactinomycin, etoposide and vincristine, ICE ifosfamide, carboplatin and etoposide.\n\n* Upon initiation of treatment [results from first treatment day or prior lab test].\n\n** Upon when treatment was ended [results from the final treatment day or subsequent lab test].\n\n*** Detected twenty-two months from final Pembrolizumab cycle.\n\n\n\nAnother article published specifically on treatment of GTN with Pembrolizumab, a multicenter study conducted in the United Kingdom and Sweden by Ghorani et al. in 2017, reported on four patients between the ages of 37–47 when diagnosed. Three out of the four patients with metastatic drug-resistant GTN to the lung, liver, and or brain achieved remission with Pembrolizumab after recurrence of the disease following prior chemotherapy regimens (Ghorani, 2017).\n\nImmune checkpoint inhibitors have the possibility to be a useful treatment for women showing multidrug resistance and may even be an alternative to high dose chemotherapy considering its favorable low toxicity.\n\nBased on this rationale, a French group started an ongoing phase II trial (NCT03135769) investigating Avelumab in Chemo-resistant GTN. At the end of the study (estimated February 2023) they plan to demonstrate the clinical efficacy of Avelumab evaluated by the rate of patients with successful normalization of hCG assays and the oncologic outcomes (You, 2020).\n\nIn conclusion, our patient showed 100% PD-L1 tumor expression which is consistent with the literature that suggests choriocarcinomas express high PD-L1 immunoreactivity (Veras et al., 2017). Our treatment of this patient adds to the current scarcity of literature regarding the effectiveness of Pembrolizumab in treating patients with high-risk multi-agent drug resistant GTN, as we managed to show that Pembrolizumab can be an effective therapy in a case of a patient with this disease. This treatment approach should be further investigated in wider studies to be considered as a valid treatment for patients with high-risk multi-agent drug resistant GTN.\n\nCRediT authorship contribution statement\nJennifer A. Goldfarb: Writing - original draft, Methodology, Formal analysis, Visualization. Giorgia Dinoi: Writing - review & editing, Methodology. Andrea Mariani: Conceptualization, Writing - review & editing. Carrie L. Langstraat: Conceptualization.\n\nDeclaration of Competing Interest\nDr. Langstraat reports grants from Medtronic, grants from Eight Medical, grants from ConMed, outside the submitted work. The other three authors have nothing to disclose.\n==== Refs\nReferences\nAngiolo G. Silvestro C. Guerrieri M.E. Damiano A.G. Placental site trophoblastic tumor and epithelioid trophoblastic tumor: Clinical and pathological features, prognostic variables and treatment strategy Gynecol. Oncol. 153 3 2019 684 693 10.1016/j.ygyno.2019.03.011 31047719 \nSmith H.O. Qualls C.R. Prairie B.A. Padilla L.A. Rayburn W.F. Key C.R. Trends in gestational choriocarcinoma: A 27-year perspective Obstet. Gynecol. 102 5 2003 978 987 10.1016/s0029-7844(03)00669-0 14672473 \nShanmugaratnam K. Muir C.S. Tow S.H. Cheng W.C. Christine B. Pedersen E. Rates per 100,000 births and incidence of choriocarcinoma and malignant mole in Singapore Chinese and Malays. Comparison with connecticut, Norway and Sweden Int. J. Cancer 8 1 1971 165 175 10.1002/ijc.2910080120 5118207 \nFigo Oncology Committee FIGO staging for gestational trophoblastic neoplasia 2000 Int. J. Gynecol. Obstet. 77 3 2002 285 287 10.1016/S0020-7292(02)00063-2 \nKim S.J. Effects of multiagent chemotherapy and independent risk factors in the treatment of high-risk GTT - 25 years experiences of KRI-TRD pp. 1, pp. 85–96 Int. J. Gynecol. Obstet. 60 SUPPL 1998 10.1016/S0020-7292(98)80010-6 \nGhorani E. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia Lancet 390 10110 2017 2343 2345 10.1016/S0140-6736(17)32894-5 29185430 \nJørgensen J.T. A paradigm shift in biomarker guided oncology drug development 148–148 Ann. Transl. Med. 7 7 2019 10.21037/atm.2019.03.36 \nAlsaab Hashem O. Sau Samaresh Alzhrani Rami Tatiparti Katyayani Bhise Ketki Kashaw Sushil K. Iyer Arun K. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome Front. Pharmacol. 8 2017 10.3389/fphar.2017.00561 \nVeras Emanuela Kurman Robert J. Wang Tian-Li Shih Ie-Ming PD-L1 Expression in Human Placentas and Gestational Trophoblastic Diseases: Int. J. Gynecol. Pathol. 36 2 2017 146 153 10.1097/PGP.0000000000000305 27362903 \nB. You, “Trial record 1 of 1 for : Saved Studies Avelumab in Chemo-resistant Gestational Trophoblastic Neoplasias (TROPHIMMUN),” NIH U.S. National Library of Medicine Clinical Trials, 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT03135769?id=NCT03135769&draw=2&rank=1&load=cart.\n\n",
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"journal": "Gynecologic oncology reports",
"keywords": "Gestational trophoblastic neoplasia (GTN); High-risk multidrug resistance; PD-L1; Pembrolizumab; Uterine choriocarcinoma",
"medline_ta": "Gynecol Oncol Rep",
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"pubdate": "2020-05",
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"title": "A case of multi-agent drug resistant choriocarcinoma treated with Pembrolizumab.",
"title_normalized": "a case of multi agent drug resistant choriocarcinoma treated with pembrolizumab"
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"abstract": "The coronavirus disease 2019 (COVID-19) has caused a global pandemic with an unprecedented burden on health and the economy worldwide. Although it primarily involves the respiratory tract system, cardiovascular complications, particularly arterial and venous thrombosis, are frequently reported and are associated with adverse outcomes.\nWe describe the case of a 57-year-old female who presented with acute hypoxic respiratory failure and shock. She was found to have left lower extremity deep vein thrombosis and a suspected pulmonary embolism. A large mobile right atrial mass was found on echocardiogram. Given the large thrombus burden that portended an extremely high risk for embolization to the pulmonary arteries, emergent percutaneous aspiration of an organized thrombus (rather than thrombolysis) was performed using the AngioVac system (Angiodynamics Inc., Latham, NY, USA) complicated by haemodynamic collapse due to acute right ventricular failure. An Impella RP (Abiomed, Danvers, MA, USA) was then placed, with rapid stabilization of haemodynamics. The patient tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). She was treated with antimicrobial and systemic anticoagulation therapy. She was successfully weaned off the Impella RP on post-operative day 4 and was extubated on day 5. She was discharged on day 16 in a stable condition.\nIncident venous thrombo-embolism is frequently encountered in COVID-19 patients. We report the first case of a large intracardiac thrombus associated with SARS-CoV-2 infection managed successfully with percutaneous thrombectomy and right ventricular mechanical circulatory support.",
"affiliations": "Division of Cardiology, Department of Internal Medicine, Ascension St John Hospital and Medical Center, Detroit, MI, USA.;Division of Cardiology, Department of Internal Medicine, Ascension St John Hospital and Medical Center, Detroit, MI, USA.;Division of Cardiology, Department of Internal Medicine, Ascension St John Hospital and Medical Center, Detroit, MI, USA.;Division of Cardiology, Department of Internal Medicine, Ascension St John Hospital and Medical Center, Detroit, MI, USA.",
"authors": "Kaki|Amir|A|;Singh|Hemindermeet|H|0000-0002-1301-3471;Cohen|Gerald|G|0000-0001-8261-0395;Schreiber|Theodore|T|",
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"doi": "10.1093/ehjcr/ytaa308",
"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/ytaa308\nytaa308\nCase Reports\nOther\nAcademicSubjects/MED00200\nA case report of a large intracardiac thrombus in a COVID-19 patient managed with percutaneous thrombectomy and right ventricular mechanical circulatory support\nKaki Amir\nhttp://orcid.org/0000-0002-1301-3471\nSingh Hemindermeet\nhttp://orcid.org/0000-0001-8261-0395\nCohen Gerald\nSchreiber Theodore\nDivision of Cardiology, Department of Internal Medicine, Ascension St John Hospital and Medical Center, Detroit, MI, USA\nCameli Matteo Handling Editor\nNistor Dan Octavian Editor\nBin Abdulhak Aref Editor\nMukherjee Rahul Editor\nThomson Ross Editor\nCorresponding author. 22101 Moross Road, VEP, 2nd floor Cath Lab, Detroit, MI 48236, USA. Tel: +1 586 612 3886, Email: drhemindermeet.94@gmail.com, Twitter: @singh_heminder\n12 2020\n05 11 2020\n05 11 2020\n4 6 15\n31 5 2020\n03 7 2020\n11 8 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 journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nThe coronavirus disease 2019 (COVID-19) has caused a global pandemic with an unprecedented burden on health and the economy worldwide. Although it primarily involves the respiratory tract system, cardiovascular complications, particularly arterial and venous thrombosis, are frequently reported and are associated with adverse outcomes.\n\nCase summary\n\nWe describe the case of a 57-year-old female who presented with acute hypoxic respiratory failure and shock. She was found to have left lower extremity deep vein thrombosis and a suspected pulmonary embolism. A large mobile right atrial mass was found on echocardiogram. Given the large thrombus burden that portended an extremely high risk for embolization to the pulmonary arteries, emergent percutaneous aspiration of an organized thrombus (rather than thrombolysis) was performed using the AngioVac system (Angiodynamics Inc., Latham, NY, USA) complicated by haemodynamic collapse due to acute right ventricular failure. An Impella RP (Abiomed, Danvers, MA, USA) was then placed, with rapid stabilization of haemodynamics. The patient tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). She was treated with antimicrobial and systemic anticoagulation therapy. She was successfully weaned off the Impella RP on post-operative day 4 and was extubated on day 5. She was discharged on day 16 in a stable condition.\n\nDiscussion\n\nIncident venous thrombo-embolism is frequently encountered in COVID-19 patients. We report the first case of a large intracardiac thrombus associated with SARS-CoV-2 infection managed successfully with percutaneous thrombectomy and right ventricular mechanical circulatory support.\n\nCase report\nCOVID-19\nThrombus\nAspiration thrombectomy\nPercutaneous\nImpella\n==== Body\nLearning points\n\nCardiovascular complications, particularly venous and arterial thrombosis, are frequently reported in coronavirus disease 2019 (COVID-19).\n\nThis is the first unusual case of a large intracardiac in situ thrombus in a COVID-19 patient.\n\nPercutaneous mechanical thrombectomy has a potential role in emergent aspiration of large right heart thrombus.\n\nRight ventricular mechanical circulatory support can be beneficial in management of acute decompensated right heart failure with cardiogenic shock.\n\nIntroduction\n\nCoronavirus disease 2019 (COVID-19) is a systemic infectious disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has caused a global pandemic, with >6 million infected and 360 000 deaths worldwide as of 30 May 2020.1,2 Although SARS-CoV-2 infection primarily affects the lower respiratory tract system, emerging reports suggest direct and indirect cardiovascular complications including acute myocardial injury, cardiomyopathy, arrhythmias, and acute coronary syndrome.3,4 Furthermore, severe inflammatory state, hypoxia, and immobilization in COVID-19 patients impose a high risk of venous thrombo-embolism (VTE).5–7 We report a case of a large right heart thrombus leading to right ventricular (RV) failure in a 57-year-old female with SARS-CoV-2 infection, that was successfully managed with percutaneous aspiration thrombectomy and RV mechanical circulatory support.\n\nTimeline\n\nDay 0\tPatient admitted with acute hypoxic respiratory failure and shock.\t\nDay 1\tTransthoracic echocardiogram showed a large mobile mass in the right atrium. Given the state of shock and the large thrombus burden, emergent aspiration of an organized thrombus was performed using an AngioVac cannula. An Impella RP was placed due to decompensated right ventricular (RV) failure post-thrombectomy.\t\nDay 2\tSignificant improvement in patient’s haemodynamics and mixed venous oxygen, with successful weaning of vasopressors. PCR for SARS-CoV2 infection came back positive and the patient started on antimicrobial therapy.\t\nDay 3\tRepeat echocardiogram consistent with improvement in RV systolic function.\t\nDay 4\tPatient was weaned off the Impella RP and it was removed at the bedside.\t\nDay 5\tRenal parameters deteriorated with anuria. A temporary haemodialysis catheter was inserted for initiation of renal replacement therapy.\t\nDay 6\tPatient was weaned off mechanical ventilation and extubated. Intermittent haemodialysis was started.\t\nDay 14\tImprovement in urine output with return of renal functions to baseline. No further requirement for haemodialysis.\t\nDay 23\tPatient discharged home in stable condition with home health services.\t\n\nCase presentation\n\nA 57-year-old female with bronchial asthma presented to the emergency department (ED) with a 1-week history of worsening shortness of breath, fever, and intermittent nausea. She also reported left lower extremity pain and swelling. Her husband had similar symptoms. On initial evaluation, she was hypoxic and tachycardic. Her blood pressure was 90/67 mmHg, heart rate 111 b.p.m., and saturation 96% on 4 L of oxygen through a nasal cannula. Physical examination was significant for clear breath sounds and left leg oedema. ECG showed sinus tachycardia, incomplete right bundle branch block, and Q waves in lead III (Figure 1). Laboratory work-up was pertinent for leukocytosis of 27.35 × 109/μL, absolute lymphocyte count of 0.27 × 109/μL, creatinine 2.2 mg/dL, lactic acid 6.8 mmol/L, troponin-T 0.21 ng/mL, probrain natriuretic peptide (pro-BNP) 8969 pg/mL, C-reactive protein (CRP) 266.9 mg/L, and ferritin 3233 ng/mL. Chest X-ray did not show any acute cardiopulmonary pathology. A rapid COVID test in the ED was negative. A venous duplex scan of the left leg revealed a large occlusive thrombus in the left femoral and popliteal veins. Transthoracic echocardiogram showed a large mobile filling defect in the right atrium (RA) partially prolapsing into a dysfunctional right ventricle with positive McConnell’s sign (Figure 2; Supplementary material online, Video S1). Left ventricular ejection fraction was preserved. The patient was started on levophed infusion. Given that the patient was in shock with an imminent risk of a catastrophic event in the case of embolization of the right heart mass, the decision was made to proceed with emergent percutaneous aspiration with the Angio-Vac system (Angiodynamics Inc., Latham, NY, USA) rather than intravenous or catheter- directed thrombolysis which would have minimal effect on a large thrombus.\n\nFigure 1 12-lead ECG showing sinus tachycardia, incomplete right bundle branch block, and Q waves in lead III.\n\nFigure 2 Apical four-chamber view of the trans-thoracic echocardiogram showing a large mobile mass (red arrow) in the right atrium partially prolapsing into the right ventricle (A). Short-axis view of the intraoperative transoesophageal echocardiogram confirmed the mass (yellow arrow) (B). Cine-angiogram showing aspiration of the mass with the Angiovac cannula (C). An organized thrombus (green arrow) extracted from the right heart (D).\n\nThe patient was intubated prior to the procedure. Intra-operative transoesophageal echocardiogram (TOE) confirmed a large mobile mass in the RA (Figure 2). The right internal jugular (IJ) vein and common femoral vein (CFV) were cannulated under ultrasound guidance. After performing right heart catheterization and pulmonary angiography (Supplementary material online, Video S2), a 24 Fr dry-seal sheath was advanced into the RA through the right IJ vein for introduction of a suction cannula. A 19 Fr extracorporeal membrane oxygenation (ECMO) cannula was placed in the upper inferior vena cava through the right CFV for reinfusion of blood. The AngioVac catheter was then advanced through the right IJ sheath and multiple runs of aspiration were performed with extraction of a large organized thrombus (Figure 2; Supplementary material online, Video S3). TOE showed resolution of the thrombus; however, embolization of small thrombi was noted in the right ventricle and pulmonary artery. Post-thrombectomy, the patient further decompensated, with systolic blood pressure dropping to 50 mmHg and heart rate to ∼40 b.p.m. CPR was initiated and maintained for 5 min with the standard ACLS protocol. Repeat haemodynamics showed elevated RA pressures of 20 mmHg (baseline 12 mmHg) and mixed venous oxygen (MVO2) of 42% along with an akinetic right ventricle on TOE, findings consistent with acute RV failure. At this time, the 19 Fr cannula in the right CFV was upgraded to a 24 Fr sheath, and an Impella RP (Abiomed, Danvers, MA, USA) was inserted in the pulmonary artery for RV support (Figure 2). The arterial blood pressure waveform showed an immediate increase in systolic blood pressure from <50 mmHg to >120 mmHg after Impella placement, as demonstrated in Supplementary material online, Video S4. Also, there was significant improvement in MVO2. The right IJ cannula was removed and the patient was transferred to the intensive care unit (ICU) in stable condition.\n\nCOVID PCR was reported positive the following day, and the patient was started on hydroxychloroquine and azithromycin. She was anticoagulated with intravenous heparin. Further hypercoagulability and malignancy work-up was planned. She remained haemodynamically stable with consistent improvement in her MVO2 and RV function on post-operative days 1 and 2. Repeat echocardiogram showed resolution of the thrombus and improvement in RV contractility (Figure 3). Her further ICU course was essentially uncomplicated besides acute renal failure requiring temporary haemodialysis. She was successfully weaned off the Impella and it was subsequently removed on post-operative day 4. The patient was extubated on day 5 and transferred to a routine ward. She was eventually discharged in a stable condition with home care on day 23 of hospitalization.\n\nFigure 3 Apical five-chamber view of the post-operative transthoracic echocardiogram showing resolution of the thrombus in the right atrium.\n\nDiscussion\n\nPatients with COVID-19 and cardiovascular complications have been shown to have worse outcomes.8,9 Incident VTE is frequently encountered in these patients. In a multicentre study from the Netherlands, the incidence of VTE was reported to be in 31% of COVID-19 patients admitted to the ICU.6 In another study conducted in Wuhan, China, VTE was reported in 25%.10 The proposed mechanism of accelerated thrombosis is hypercoagulability induced by severe inflammation, endothelial dysfunction, and stasis.11,12 Several laboratory parameters support this hypothesis characterized by elevations in fibrinogen and D-dimer.13 Some patients with severe COVID-19 infection can develop thrombosis from disseminated intravascular coagulation (DIC). Interleukin-6 (IL-6) levels may also correlate with disease severity and a procoagulant profile.14\n\nLarge vessel and intracardiac thrombus have not yet been reported in a COVID-19 patient. Our patient had a large occlusive deep vein thrombosis (DVT) and right atrial thrombosis. She was in clinical shock with acute respiratory failure; thus, CT angiography of the chest could not be performed. Intra-operative TOE and pulmonary angiogram did show evidence of small thrombi in the main pulmonary artery. We decided to proceed with percutaneous thrombectomy as there was imminent risk of a catastrophic outcome without any intervention. The Angiovac system which was used is a vacuum-based device, FDA-approved in 2014 for percutaneous drainage of undesirable material such as fresh thrombi or emboli. It is composed of a venous drainage and a reinfusion cannula connected to an extracorporeal circuit and bypass pump. When the pump is started, suction force is created, facilitating aspiration of thrombotic material. Our patient had profound hypotension and bradycardia post-aspiration thrombectomy. Distal embolization of the thrombus to the pulmonary vasculature causing acute RV failure is a likely explanation. Similarly, intra-operative TOE confirmed severely reduced RV systolic function. Although there is a paucity of data regarding use of the Impella RP in cardiogenic shock and acute RV failure from pulmonary thrombo-embolism, we decided to place RV mechanical support due to acute decompensation post-thrombectomy. The early initiation of support helped in rapid stabilization of the haemodynamics as well as in preventing irreversible RV damage.\n\nHerein, we report the first case of a large intracardiac in situ thrombus associated with SARS-CoV-2 infection. Our case illustrated not only the potential value of the Angiovac device in the management of this case, but also the potential of mechanical RV support in the management of associated right heart decompensation and cardiogenic shock.\n\nLead author biography\n\nAmir Kaki, MD is an Interventional Cardiologist and Director of Mechanical Circulatory Support/High risk coronary interventions at Ascension St John Hospital and Medical Center in Detroit, Michigan, USA. His areas of interest include cardiogenic shock and large bore vascular access management.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal – Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary 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: A.K. is a speaker and proctor for Abiomed. The other authors have no financial or proprietary interest in the subject matter of this article.\n\nSupplementary Material\n\nytaa308_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 The Center for Systems Science and Engineering (CSSE) at John Hopkins University. https://coronavirus.jhu.edu/map.html\n2 COVID-19 information dashboard from World Health Organization (WHO). www.who.int/news-room/feature-stories/detail/who-updates-covid-19-dashboard-with-better-data-visualization\n3 Huang C , Wang Y , Li X , Ren L , Zhao J , Hu Y , Zhang L , Fan G , Xu J , Gu X , Cheng Z , Yu T , Xia J , Wei Y , Wu W , Xie X , Yin W , Li H , Liu M , Xiao Y , Gao H , Guo L , Xie J , Wang G , Jiang R , Gao Z , Jin Q , Wang J , Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395 :497–506.31986264\n4 Li B , Yang J , Zhao F , Zhi L , Wang X , Liu L , Bi Z , Zhao Y. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol 2020;109 :531–538.32161990\n5 ,Terpos E , Ntanasis-Stathopoulos I , Elalamy I , Kastritis E , Sergentanis T , Politou M , Psaltopoulou T , Gerotziafas G , Dimopoulos MA. Hematological findings and complications of COVID-19. Am J Hematol 2020;95 :834–847.32282949\n6 Klok F , Kruip M , van der Meer N , Arbous M , Gommers D , Kant K , Kaptein FHJ , van Paassen J , Stals MAM , Huisman MV , Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191 :145–147.32291094\n7 Panigada M , Bottino N , Tagliabue P , Grasselli G , Novembrino C , Chantarangkul V , Pesenti A , Peyvandi F , Tripodi A. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020;18 :1738–1742.32302438\n8 Zheng YY , Ma YT , Zhang JY , Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17 :259–260.32139904\n9 Driggin E , Madhavan M , Bikdeli B , Chuich T , Laracy J , Biondi-Zoccai G , Brown TS , Der Nigoghossian C , Zidar DA , Haythe J , Brodie D , Beckman JA , Kirtane AJ , Stone GW , Krumholz HM , Parikh SA. Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic. J Am Coll Cardiol 2020;75 :2352–2371.32201335\n10 Cui S , Chen S , Li X , Liu S , Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020;18 :1421–1424.32271988\n11 Marongiu F , Mameli A , Grandone E , Barcellona D. Pulmonary thrombosis: a clinical pathological entity distinct from pulmonary thrombosis? Semin Thromb Hemost 2019;45 :778–783.31537029\n12 Libby P , Simon DI. Inflammation and thrombosis: the clot thickens. Circulation 2001;103 :1718–1720.11282900\n13 Lippi G , Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med 2020;58 :1131–1134.32119647\n14 Han H , Yang L , Liu R , Liu F , Wu K , Li J , Liu XH , Zhu CL. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med 2020;58 :1116–1120.32172226\n15 Starck C , Dreizler T , Falk V. The AngioVac system as a bail-out option in infective valve endocarditis. Ann Cardiothorac Surg 2019;8 :675–677.31832358\n\n",
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"title": "A case report of a large intracardiac thrombus in a COVID-19 patient managed with percutaneous thrombectomy and right ventricular mechanical circulatory support.",
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"abstract": "We present a rare case of post-antiretroviral therapy (ART) paradoxically worsening of radiological findings in a patient with advanced HIV-infection on treatment for Rhodococcus pneumonia who was misdiagnosed with pulmonary tuberculosis. Despite clinical improvement, serial chest radiographs showed deteriorations a month after starting ART. This was attributed to Immune Reconstitution Inflammatory Syndrome (IRIS) which spontaneously resolved without any treatment.",
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"title": "Paradoxical worsening of chest radiographs secondary to immune reconstitution syndrome (IRIS) in a patient with advanced HIV infection and Rhodococcus pneumonia.",
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"abstract": "We report a case of non-alcoholic steatohepatitis with cirrhosis in a woman receiving tamoxifen as adjuvant treatment for breast cancer. Despite the presence of other risk factors for non-alcoholic steatohepatitis (such as diabetes, obesity and hyperlipidemia), the patient developed non-alcoholic steatohepatitis and cirrhosis only after tamoxifen was started. We suggest that patients receiving tamoxifen, especially patients with predisposing metabolic disorders, should be evaluated for non-alcoholic steatohepatitis, because progression to cirrhosis may occur.",
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"abstract": "Thromboembolism is a known phenomenon in patients with Coronavirus disease 2019 (COVID-19). Recent investigations have revealed that a significant proportion of those hospitalized with severe COVID-19 demonstrate clinical and laboratory markers compatible with hypercoagulability, which is differentiated from disseminated intravascular coagulation (DIC), termed COVID-associated coagulopathy. Additionally, there is increasing concern for development of acute ischemic stroke because of this hypercoagulable state. We present a patient with COVID-19 pneumonia who was managed with unfractionated heparin (UFH) infusion and developed a large ischemic infarct shortly after cessation of the infusion. In retrospect, the patient's coagulation parameters were consistent with overt DIC, although some of these parameters are easily masked by the effects of UFH. These findings emphasize the importance of anticoagulation as well as its careful discontinuation, as failure to do so may result in a significant thromboembolic event.",
"affiliations": "Department of Diagnostic Radiology, State University of New York (SUNY) Downstate Medical Center, University Hospital Brooklyn, Brooklyn, NY, United States.;Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.;Department of Diagnostic Radiology, State University of New York (SUNY) Downstate Medical Center, University Hospital Brooklyn, Brooklyn, NY, United States.;Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada.",
"authors": "Efendizade|Aslan|A|;Dmytriw|Adam A|AA|;Hewitt|Kevin|K|;Davies|Gwynivere A|GA|",
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"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.573356\nNeurology\nCase Report\nUnfractionated Heparin in SARS-CoV-2 Pneumonia: Ischemic Stroke Case Report\nEfendizade Aslan 1* Dmytriw Adam A. 23 Hewitt Kevin 1 Davies Gwynivere A. 4 1Department of Diagnostic Radiology, State University of New York (SUNY) Downstate Medical Center, University Hospital Brooklyn, Brooklyn, NY, United States\n2Department of Medical Imaging, University of Toronto, Toronto, ON, Canada\n3Department of Neuroradiology & Neurointervention, Brigham and Women's Hospital, Boston, MA, United States\n4Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada\nEdited by: Tomohisa Nezu, Hiroshima University, Japan\n\nReviewed by: Siyuan Fan, Peking Union Medical College Hospital (CAMS), China; David García-Azorín, Hospital Clínico Universitario de Valladolid, Spain; Sean Ruland, Loyola University Medical Center, United States\n\n*Correspondence: Aslan Efendizade Aslan.efendizade@downstate.eduThis article was submitted to Stroke, a section of the journal Frontiers in Neurology\n\n\n25 9 2020 \n2020 \n25 9 2020 \n11 57335616 6 2020 20 8 2020 Copyright © 2020 Efendizade, Dmytriw, Hewitt and Davies.2020Efendizade, Dmytriw, Hewitt and DaviesThis 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.Thromboembolism is a known phenomenon in patients with Coronavirus disease 2019 (COVID-19). Recent investigations have revealed that a significant proportion of those hospitalized with severe COVID-19 demonstrate clinical and laboratory markers compatible with hypercoagulability, which is differentiated from disseminated intravascular coagulation (DIC), termed COVID-associated coagulopathy. Additionally, there is increasing concern for development of acute ischemic stroke because of this hypercoagulable state. We present a patient with COVID-19 pneumonia who was managed with unfractionated heparin (UFH) infusion and developed a large ischemic infarct shortly after cessation of the infusion. In retrospect, the patient's coagulation parameters were consistent with overt DIC, although some of these parameters are easily masked by the effects of UFH. These findings emphasize the importance of anticoagulation as well as its careful discontinuation, as failure to do so may result in a significant thromboembolic event.\n\nCOVID-19strokeanticoagulationheparinthromboembolism\n==== Body\nIntroduction\nPreliminary observations of Coronavirus disease 2019 (COVID-19) were consistent with hypoxemic respiratory failure from acute respiratory distress syndrome (ARDS) (1, 2). However, recent investigations have led researchers to question whether the predominant cause of respiratory failure is vascular, with development of microthrombi and pulmonary vasodilatation (3). This is especially relevant given the incidence of venous thromboembolism (VTE) and risk of disseminated intravascular coagulation (DIC) in patients with COVID-19 (2, 4, 5).\n\nAn analysis of 1,026 admitted Chinese patients demonstrated that 40% were considered high risk of developing VTE, with many at high risk for bleeding and death, suggesting the need for careful prophylaxis (6). Cui et al. (7) reported a single-center experience of 81 patients in ICU with severe COVID-19 infection who demonstrated a 25% VTE rate [though these patients did not receive prophylactic anticoagulation (7)]. Patients with VTE were older, had significantly lower lymphocyte counts, higher D-dimer values, and prolonged activated partial thromboplastin times (aPTT).\n\nMany patients with sepsis demonstrate deranged coagulation factors. DIC is characterized by dysregulation of coagulation and fibrinolysis, resulting in widespread thrombosis and hemorrhage. Several societies have formulated diagnostic criteria for DIC, such as the International Society of Thrombosis and Hemostasis (ISTH), which tends to classify cases into overt or non-overt DIC. The classification system assigns points (0–3) based on values associated with each parameter—platelet count, fibrin-related markers, prothrombin time (PT), and fibrinogen—and a score ≥5 is compatible with overt DIC (8). One study of 183 hospitalized patients with COVID-19 found that 71.4% of non-survivors (and 0.6% of survivors) met the criteria for overt DIC according to ISTH criteria (9). Subgroup analysis of 99 patients (with high sepsis-induced coagulopathy scores or D-dimer values) who received prophylactic anticoagulation demonstrated significantly reduced mortality, which led some institutions to adopt intermediate or therapeutic anticoagulation for severe cases of COVID-19. How best to dose, time, and discontinue anticoagulation remains to be determined.\n\nCase Description\nA 56-year-old Haitian man with past medical history significant for hypertension, diabetes mellitus, seizure disorder, and prior cerebrovascular accident (CVA) (Figure 1) of unknown etiology with residual dysarthria and gait abnormality presented with worsening dry cough and dyspnea on exertion. He denied other respiratory symptoms, fevers, myalgia, sick contacts, and recent travel, as well as novel neurological symptoms. Home medications included amlodipine, aspirin, clopidogrel, atorvastatin, metformin, and levetiracetam.\n\nFigure 1 Prior infarct. Rostral to caudal (A–D) non-contrast computed tomographic axial slices of the head performed 2 years prior to current admission demonstrates hypoattenuation and parenchymal volume loss in the right parasagittal occipital lobe compatible with an old posterior cerebral artery territory infarct, as well as acute infarct in the territory of the bilateral superior cerebellar arteries.\n\nIn the emergency department, the patient was afebrile with an oxygen saturation of 50% on room air, improving to 91% on bilevel positive airway pressure. Physical examination revealed crackles within the lung bases, and the patient was unable to speak in full sentences. Additionally, it was noted that he was not oriented to time or person, nor was he cooperative with a neurological exam, although novel focal neurological deficits were not observed. Relevant admission laboratory markers are summarized (Table 1). Electrocardiogram was unremarkable, and chest radiography revealed bilateral multifocal airspace opacities. SARS-CoV-2 polymerase chain reaction by nasopharyngeal sampling was positive, and the patient was started on hydroxychloroquine, ceftriaxone, and azithromycin in addition to standard supportive care.\n\nTable 1 Relevant admission laboratory markers.\n\nMarker\tValue\tReference range\t\nLymphocyte count ( ×103/μl)\t0.5\t0.9–2.9\t\nCreatinine (mg/dl)\t2.0\t0.7–1.3\t\nAST (U/L)\t153\t13–19\t\nALT (U/L)\t81\t7–52\t\nCRP (mg/L)\t304\t0–8\t\nFerritin (μg/L)\t2,495\t16–294\t\nLDH (U/L)\t1,046\t140–271\t\nProcalcitonin (ng/ml)\t0.58\t0.00–0.10\t\nAdditional labs seen in “Day 1” of Table 2. AST, aspartate transaminase; ALT, alanine transaminase; CRP, C-reactive protein; LDH, lactate dehydrogenase.\n\nOn the second day of admission, the patient's hypoxemia worsened, requiring intubation and mechanical ventilation with a fraction of inspired oxygen of 0.50. Further D-Dimer elevation (>4,000 ng/ml FEU) led to initiation of therapeutic unfractionated heparin (UFH). Based on management criteria (10), UFH was selected for concomitant acute renal failure (ARF).\n\nOn day 5, UFH was held secondary to elevation of aPTT (Table 2). Approximately 2 h after, the patient developed a non-reactive left pupil followed by myoclonic head movements 6 h after that. Given that the patient was intubated and under sedation, neurological examination was limited, and this was initially managed as seizure activity given the patient's history. However, he was non-responsive to antiseizure medications. Subsequent neurological evaluation revealed a left fixed pupil (4 mm), absent corneal and vestibulo-ocular reflexes, and no response to painful stimulation. The patient then underwent computed tomography (CT) of the head, which revealed infarcts within the parasagittal left occipital lobe and brainstem (Figure 2). Although advanced imaging was not performed, on coronal and sagittal reconstructions of the non-contrast head CT, a dense vessel sign was observed extending from the mid basilar into the left posterior cerebral artery. It should be noted that on the day prior, a bedside transthoracic echocardiogram was unremarkable, and electrocardiogram did not reveal an arrhythmia. Unfortunately, despite supportive care, the patient passed away.\n\nTable 2 Timeline of coagulation parameters.\n\nMarker\tDay 1\tDay 2\tDay 3\tDay 4\tDay 5\tDay 6\tDay 7\t\nAnticoagulation\tSubQ heparin\tSubQ heparin\tHeparin drip\tHeparin drip\tDrip held <8 A.M\t–\t–\t\nD-Dimera (ng/ml FEU)\t1,704\t–\t>4,000\t–\t–\t–\t–\t\nPT (s)\t–\t–\t13.7\t–\t–\t13.5\t16.3\t\naPTT (s)\t40\t–\t–\t90.3\t86.9\t27.8\t37.5\t\nPlatelets ( ×103/μl)\t169\t200\t219\t238\t220—Large\t248—Large\t219—Large\t\nOn days 1 to 3, the patient received prophylactic subcutaneous heparin 5,000 units every 8 h. On day 3, the patient was transitioned to heparin drip at 1,000 units/h with target aPTT of 60–80 s. On the night of day 4, the patient had equal and reactive pupils. Heparin drip was held before 8 A.M on day 5, and (at 10 A.M) the patient's left pupil became non-reactive and at ~4 P.M displayed myoclonic head movements. PT, prothrombin time; aPTT, activated partial thromboplastin time; Large, large platelets seen on smear.\n\na D-Dimer reference level 500 ng/ml or less of fibrinogen equivalent units (FEU).\n\nFigure 2 Acute ischemic infarct. Rostral to caudal (A–D) non-contrast computed tomographic axial slices of the head performed on this admission demonstrates loss of gray–white differentiation in the parasagittal left occipital lobe and sulcal effacement compatible with recent ischemia, as well as diffuse brainstem edema. Additional surrounding punctate foci of hyperattenuation suggest petechial hemorrhage.\n\nDiscussion\nDisseminated Intravascular Coagulation\nSuggested management of COVID-19 involves monitoring D-Dimer, prothrombin time (PT), international normalized ratio, aPTT, fibrinogen, and platelet counts (11), consistent with sepsis guidelines. The incidence of DIC in COVID-19 patients varies widely by severity of presentation but can be seen in >2/3 of patients who die from severe disease (5). Non-survivors also had significantly higher fibrin degradation product levels and prolonged PT and aPTT values at admission. Interestingly, a meta-analysis of nine studies investigating COVID-19 demonstrated significantly higher values of PT and D-dimer for severe vs. mild cases, but no difference in aPTT or platelet count was observed (12). Relatively mild thrombocytopenia and the disproportionate increase in PT vs. aPTT has led to adoption of the term COVID-associated coagulopathy (CAC).\n\nTypical management strategy for sepsis-associated DIC involves treatment of the underlying infection. Unfortunately, there is no known effective treatment for COVID-19 infection. In DIC with a thrombotic phenotype, therapeutic doses of heparin have been suggested with one randomized controlled trial (RCT) demonstrating superior efficacy of LMWH compared to UFH (13). However, prophylaxis using LMWH, UFH, or mechanical thromboprophylaxis remains the standard of care in most patients with DIC.\n\nAnticoagulation\nSeveral medical centers have published guidelines on prophylactic or therapeutic anticoagulation for COVID-19 patients based on D-Dimer levels and VTE occurrence (10, 11). At our Brooklyn center, both prophylactic and therapeutic anticoagulation is often achieved with apixaban or enoxaparin. UFH infusion is reserved for those with ARF. The Journal of the American College of Cardiology released guidelines addressing the management of COVID-19 associated thromboembolic events (4), identifying additional risk factors including critical illness, prolonged hospitalization and intubation, immobility, and use of investigational therapies. Troponin elevations in COVID-19 patients may therefore not be a direct result of infection but rather inflammation leading to plaque rupture or microthrombi from cytokine storm. For anticoagulation, they recommend prophylactic dosing, with an emphasis on LMWH to reduce health care worker exposure from blood draws or medication management.\n\nPotential Role of UFH in DIC and COVID-19\nIf the decision is made to initiate UFH, the subsequent diagnosis of DIC may be delayed for various reasons including reduced platelet consumption, attribution of PT elevation to UFH (14), reduced D-Dimer, and fibrinogen variability (an acute phase reactant). Therefore, use of UFH may lead to delayed recognition of progressive coagulopathy, potentially increasing their risk for adverse consequences. Utilizing the ISTH criteria for DIC, we can retrospectively calculate a score of 5 based on PT and D-Dimer values on the third day of admission (Table 2), which is compatible with overt DIC.\n\nAdditionally, precautions must be used for timing of medications as previous studies have shown rebound coagulopathy with discontinuation of both UFH and LMWH. In one RCT of patients with acute coronary syndrome, plasma prothrombin fragment and thrombin–antithrombin levels post-discontinuation exceeded levels both during and prior to treatment (15). While this change occurred faster in UFH, the peak levels after LMWH discontinuation were higher, suggesting that both can result in reactivation of the coagulation system, causing thrombus growth, and platelet recruitment. Given the long clinical course of COVID-19 and lack of definitive treatment, patients are thus at higher risk of thrombosis with sudden discontinuation of anticoagulation, which should be discouraged except in the case of clinically relevant bleeding. UFH nomograms should be re-evaluated considering this specific CAC phenotype, whereby preserved platelet counts may predispose to thrombotic events. In contrast, though a study of 221 patients with COVID-19 demonstrated 13 cases of cerebrovascular events, none of these are reported to have occurred in the setting of anticoagulation discontinuation or adjustment (16).\n\nOnce a thrombus has formed, the use of thrombolytics, such as tissue plasminogen activator (tPA), may be warranted if timely revascularization would relay a mortality benefit (with massive pulmonary embolism or ischemic stroke). Addressing this, a case series from Poor et al. in which five critically ill COVID-19 patients with ventilator-dependent respiratory failure demonstrated improvement with systemic tPA (3), suggested the presence of microvascular thrombi that did not respond to prophylactic or therapeutic anticoagulation. In our case, given the delay in symptom recognition and diagnosis of ischemic infarct, the patient was not a candidate for administration of thrombolytics. Furthermore, the extent of edema seen on non-contrast head CT suggests that the majority (if not entirety) of the involved vascular territory was infarcted, precluding endovascular thrombectomy.\n\nThe relationship between COVID-19 and ischemic stroke is still under investigation. Recently, two multi-center studies have been conducted to investigate the incidence and shed light on the possible etiology. In one study comparing the incidence of stroke in hospitalized or emergency department visits, the authors report an incidence of 1.6% in COVID-19 vs. 0.2% in patients with influenza (17). Another study performed in close geographic proximity to our institution demonstrated 0.9% incidence of imaging proven stroke in patients hospitalized with COVID-19 (18). Of those cases, the authors report that a majority (65.6%) were cryptogenic in etiology and that the observed cases were more likely to be in younger men as compared to historical controls.\n\nLimitations\nGiven the tumultuous and resource-strained context during this incident case, there are several limitations. No advanced neuroimaging or Doppler studies were performed as part of the stroke workup. Given the territory of involved brain parenchyma, the location of prior CVA, and the dense vessel seen on head CT, thromboembolism is a possible etiology. However, it should be noted that prior imaging (Figure 1) demonstrates the presence of a remote and acute infarct, suggesting that the new infarct (Figure 2) likely occurred in the setting of vertebrobasilar disease. With respect to underlying vertebrobasilar disease, blood pressure monitoring in the days leading up to the stroke suggests that a hypotensive episode in the setting of vertebrobasilar disease is less likely as the patient's lowest recorded mean arterial pressure was 78 mmHg.\n\nThe period during this admission was quite worrisome for our hospital, such that presence in the patients' rooms and high-risk interactions were limited and may have contributed to a delay in timely and thorough neurological investigation. Furthermore, in the days leading up to the stroke, the patient was intubated and under sedation such that typical manifestations of an acute stroke were not displayed. Thus, it may be the case that the ischemic event occurred before interruption of UFH. Furthermore, additional laboratory investigations were not performed to exclude other etiologies of coagulopathy, such as antiphospholipid antibodies. Finally, venous duplex studies of the extremities or CT pulmonary angiography were not performed to suggest concomitant thromboembolic events.\n\nConclusion\nIn conclusion, we present a patient with COVID-19 pneumonia who was initiated on UFH for elevated coagulation parameters and subsequently developed neurological symptoms after 2-h UFH interruption, which may have been a sequela of acute ischemic infarct. Additionally, the patient's retrospective ISTH score was compatible with overt DIC, although diagnosis may have been delayed due to UFH effects. This supports the finding of increasing thrombotic risk with COVID-19 that can occur concurrently with an unusual DIC phenotype, outlining the importance of prophylaxis and careful discontinuation of therapeutic anticoagulation.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/Supplementary Material.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by SUNY Downstate School of Medicine Institutional Review Board. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAE: case investigation, manuscript draft, and manuscript revisions. AD and KH: case discussion and manuscript revisions. GD: case discussion manuscript draft and manuscript revisions. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2020.573356/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Chen N Zhou M Dong X Qu J Gong F Han Y . Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study\n. Lancet. (2020 ) 395 :507 –13\n. 10.1016/S0140-6736(20)30211-7 32007143 \n2. Wu Z McGoogan JM . Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention\n. JAMA. (2020 ) 323 :1239 –42\n. 10.1001/jama.2020.2648 32091533 \n3. Poor HD Ventetuolo CE Tolbert T Chun G Serrao G Zeidman A . COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis\n. Clin Transl Med. (2020 ) 10 :e44 . 10.1002/ctm2.44 32508062 \n4. Bikdeli B Madhavan MV Jimenez D Chuich T Dreyfus I Driggin E \nCOVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up\n. J Am Coll Cardiol . (2020 ) 75 :2950 –73\n. 10.1016/j.jacc.2020.04.031 32311448 \n5. Tang N Li D Wang X Sun Z . Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia\n. J Thromb Haemost. (2020 ) 18 :844 –7\n. 10.1111/jth.14768 32073213 \n6. Wang T Chen R Liu C Liang W Guan W Tang R . Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19\n. Lancet Haematol . (2020 ) 7 :e362 –3\n. 10.1016/S2352-3026(20)30109-5 32278361 \n7. Cui S Chen S Li X Liu S Wang F . Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia\n. J Thromb Haemost . (2020 ) 18 :1421 –4\n. 10.1111/jth.14830 32271988 \n8. Taylor FB JrToh CH Hoots WK Wada H Levi M . Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation\n. J Thromb Haemost . (2001 ) 86 :1327 –30\n. 10.1055/s-0037-1616068 11816725 \n9. Tang N Bai H Chen X Gong J Li D Sun Z \nAnticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy\n. J Thromb Haemost . (2020 ) 18 :1094 –9\n. 10.1111/jth.14817 32220112 \n10. Yale \nCOVID-19 Treatment Adult Algorithm . (2020 ). Available online at: https://medicine.yale.edu/intmed/COVID-19%20TREATMENT%20ADULT%20Algorithm%2004272020_382832_5_v4.pdf (accessed April 29, 2020).\n11. MGH \nCOVID-19 Treatment Guidance . (2020 ). Available online at: https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf (accessed April 29, 2020)\n12. Xiong M Liang X Wei YD . Changes in blood coagulation in patients with severe coronavirus disease 2019. (COVID-19): a meta-analysis\n. Br J Haematol. (2020 ) 189 :1050 –2\n. 10.1111/bjh.16725 32304581 \n13. Wada H Matsumoto T Yamashita Y . Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines\n. J Intensive Care. (2014 ) 2 :15 . 10.1186/2052-0492-2-15 25520831 \n14. Schultz NJ Slaker RA Rosborough TK . The influence of heparin on the prothrombin time\n. Pharmacotherapy. (1991 ) 11 :312 –6\n. 1923913 \n15. Bijsterveld NR Moons AH Meijers JC Tijssen JG Buller HR Levi M . Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison between unfractionated and low-molecular-weight heparin\n. J Am Coll Cardiol. (2002 ) 39 :811 –7\n. 10.1016/S0735-1097(01)01825-3 11869846 \n16. Li Y Wang M Zhou Y Chang J Xian Y Mao L . Acute cerebrovascular disease following covid-19: a single center, retrospective, observational study\n. Stroke Vasc Neurol. (2020 ) 2020 . 10.2139/ssrn.3550025 . [Epub ahead of print]. 32616524 \n17. Merkler AE Parikh NS Mir S Gupta A Kamel H Lin E . Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza\n. JAMA Neurol . (2020 ) 2020 :e202730 . 10.1001/jamaneurol.2020.2730 32614385 \n18. Yaghi S Ishida K Torres J Grory BM Raz E Humbert K \nSARS-CoV-2 and stroke in a new york healthcare system\n. Stroke. (2020 ) 51 :2002 –11\n. 10.1161/STROKEAHA.120.030335 32432996\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "11()",
"journal": "Frontiers in neurology",
"keywords": "COVID-19; anticoagulation; heparin; stroke; thromboembolism",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "573356",
"pmc": null,
"pmid": "33101181",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "Unfractionated Heparin in SARS-CoV-2 Pneumonia: Ischemic Stroke Case Report.",
"title_normalized": "unfractionated heparin in sars cov 2 pneumonia ischemic stroke case report"
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-52456",
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"activesubstancename": "HEPARIN SODIUM"
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"abstract": "Loss-of-function mutations in the POMC gene are associated with a syndrome with the characteristics of adrenal insufficiency, obesity, and red hair. We describe here a case of pro-opiomelanocortin (POMC) deficiency in which adrenal insufficiency was not treated until the fourth year of life. One of the disease-causative POMC mutations was characterized in vitro using a unique approach.\n\n\n\nA boy presented in the first year of life with red hair, growth acceleration, moderate obesity, and recurrent cholestasis, which was followed by 2 episodes of hypoglycemia at the ages of 1.5 and 3 years. The diagnosis was suspected at the age of 3.6 years after documentation of undetectable levels of plasma adrenocorticotropic hormone and serum cortisol, after which replacement with hydrocortisone was initiated. Sequencing of the POMC gene revealed compound heterozygosity for c.-11C>A/p.W84X mutations. The p.W84X mutation is predicted to result in a marked truncation of preprohormone. Using a messenger RNA transfection approach followed by an in vitro translation assay, we could directly demonstrate that the transcript with c.-11C>A substitution is predominantly translated within a new open reading frame; however, translation of the POMC main reading frame is preserved, with translation efficiency being ∼17% of the wild-type transcript.\n\n\n\nThe current report provides important information on the natural course of POMC deficiency. In vitro translation studies demonstrated residual translation of the main coding region from an allele with the c.-11C>A mutation, which at least partially explains a relatively late presentation of adrenal insufficiency in the patient.",
"affiliations": "School of Bioengineering and Bioinformatics, and.;Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 117977, Russian Federation.;School of Bioengineering and Bioinformatics, and.;Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russian Federation.;Federal State Budgetary Institution Scientific Centre of Children's Health, Moscow 119991, Russian Federation; and.;Endocrinology Research Centre, Moscow, 117036, Russian Federation.",
"authors": "Anisimova|Aleksandra S|AS|;Rubtsov|Petr M|PM|;Akulich|Kseniya A|KA|;Dmitriev|Sergey E|SE|;Frolova|Elena|E|;Tiulpakov|Anatoly|A|",
"chemical_list": "D011333:Pro-Opiomelanocortin",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2016-3318",
"fulltext": null,
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"issn_linking": "0021-972X",
"issue": "102(2)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000309:Adrenal Insufficiency; D000483:Alleles; D004252:DNA Mutational Analysis; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009765:Obesity; D011333:Pro-Opiomelanocortin; D014176:Protein Biosynthesis",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "359-362",
"pmc": null,
"pmid": "27906547",
"pubdate": "2017-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Late Diagnosis of POMC Deficiency and In Vitro Evidence of Residual Translation From Allele With c.-11C>A Mutation.",
"title_normalized": "late diagnosis of pomc deficiency and in vitro evidence of residual translation from allele with c 11c a mutation"
} | [
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"companynumb": "RU-PFIZER INC-2017090307",
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"activesubstancename": "HYDROCORTISONE"
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... |
{
"abstract": "A patient taking regular flecainide for paroxysmal atrial fibrillation presented with broad complex tachycardia and circulatory compromise. With no history of pacemaker insertion and no pacing spikes visible on the ECG, this was presumed to be ventricular tachycardia and treated with electrical cardioversion, leading to p-wave asystole. An indwelling pacemaker was now recognised and ventricular capture was eventually attained by significantly increasing ventricular lead output. Invasive haemodynamic support was required due to new ventricular systolic dysfunction. Pacing thresholds and ventricular function normalised within 72 h consistent with flecainide toxicity; levels were shown to be toxic. Pacemaker interrogation revealed evidence of an undiagnosed atrial flutter, at presentation this was likely slowed by flecainide toxicity to a rate below the pacemaker mode switch, such that it was tracked in the ventricle at the upper tracking rate (120 bpm). Cardioversion terminated the arrhythmia but raised the capture threshold of the ventricle above the maximum lead output.",
"affiliations": "Department of Cardiology, Buckinghamshire Healthcare NHS Trust, High Wycombe, Bucks, UK.;Department of Infectious Diseases, Oxford University Healthcare Trust, Oxford, UK.;Department of Cardiology, Buckinghamshire Healthcare NHS Trust, High Wycombe, Bucks, UK.;Department of Cardiology, John Radcliffe Hospital, Oxford, UK.",
"authors": "Apps|Andrew|A|;Miller|Charles Philip|CP|;Fellows|Sarah|S|;Jones|Michael|M|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D001282:Atrial Flutter; D004554:Electric Countershock; D004562:Electrocardiography; D005424:Flecainide; D006325:Heart Atria; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D010138:Pacemaker, Artificial; D013610:Tachycardia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26286909",
"pubdate": "2015-08-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11373489;21138930;6195608;8901682;8425300;20062654;8246130;3107447;15018877;8131440",
"title": "Cardiac devices with class 1C antiarrhythmics: a potentially toxic combination.",
"title_normalized": "cardiac devices with class 1c antiarrhythmics a potentially toxic combination"
} | [
{
"companynumb": "GB-ALVOGEN-2017-ALVOGEN-092552",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RAMIPRIL"
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{
"abstract": "Clinicians have limited experience with assessment and treatment of overdose from newer anticonvulsant medications. The aim of this investigation was to evaluate clinical effects of newer anticonvulsant overdose, determine if a relationship exists between dose and clinical effect, and if a particular agent appears more toxic in overdose. This was a retrospective study using electronic poison center data, evaluating clinical outcomes from newer anticonvulsant overdose. The Toxicall™ database from January 1, 2002 to December 31, 2011 was queried using key words: \"gabapentin,\" \"lamotrigine,\" \"levetiracetam,\" \"tiagabine,\" \"topiramate,\" \"zonisamide,\" \"pregabalin,\" and \"oxcarbazine.\" Polypharmacy overdose and children less than 15 years of age were excluded. Charts were reviewed by two abstractors for pharmaceutical, self-reported dose, clinical effect score, and clinical signs, symptoms, and vital signs recorded in the chart. Ordinal logistic regression was used to evaluate the relationship between drug type, dose, age, and sex to clinical effect score. Out of 501 cases identified, 347 met the final inclusion criteria. There were 116 gabapentin, 67 lamotrigine, 15 levetiracetam, 15 tiagabine, 56 topiramate, 23 pregabalin, and 55 oxcarbazepine cases. Overdose of newer anticonvulsants frequently results in altered mental status. Seizures may be more common with tiagabine, lamotrigine, and oxcarbazepine. There was one death reported from intentional overdose of topiramate. An information index was created to rank drug toxicity based on reported signs and symptoms for each overdose. There was no significant effect of dose on severity of outcome (β = 0.12, p = 0.23). However, the risk of a more severe outcome score was significantly increased with tiagabine relative to other drugs (β = 2.8, p = 0.001). Lamotrigine ranked highest in terms of toxicity (HT = 1.66) and number of interventions performed (HI = 1.17), and levetiracetam the lowest (HT = 0.98; HI = 0.88). We could not identify a dose-effect in these data which likely reflects the limitations of self-reported doses. Despite limitations of these data, the risk of more severe outcome scores appear to be higher with tiagabine overdose while lamotrigine overdose appears to result in more reported signs, symptoms, and interventions.",
"affiliations": "Division of Clinical Toxicology, VCU Medical Center, Richmond, VA, USA, bwills@mcvh-vcu.edu.",
"authors": "Wills|Brandon|B|;Reynolds|Penny|P|;Chu|Eileen|E|;Murphy|Christine|C|;Cumpston|Kirk|K|;Stromberg|Paul|P|;Rose|Rutherfoord|R|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-014-0384-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "10(3)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011039:Poison Control Centers; D015203:Reproducibility of Results; D012189:Retrospective Studies",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "254-60",
"pmc": null,
"pmid": "24515527",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "12102683;21956161;16323576;22311670;17846277;19043517;12093261;18762404;18072153;17692573;18043485;12645962;17060592;12507057;17364644;15353576;16496496;16034273;17898663;11185974;10604821;7902920;15292499;17448068;9806147;21328633;19514879;23272763;17338851",
"title": "Clinical outcomes in newer anticonvulsant overdose: a poison center observational study.",
"title_normalized": "clinical outcomes in newer anticonvulsant overdose a poison center observational study"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01961",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nInduction chemotherapy incorporating docetaxel, cisplatin and 5- fluorouracil before radiotherapy may improve the outcome of patients with advanced head and neck cancer. Nevertheless, the addition of docetaxel increases hematological toxicity and infectious complications. Therefore, genetic markers predicting toxicity and efficacy of this treatment regimen may help to identify patients, who would have the most benefit from this intensive treatment.\n\n\nMETHODS\nA cohort of 78 patients with advanced head and neck cancer treated with induction chemotherapy was assessed for clinical outcome and toxicity during treatment with curative intention. Genetic polymorphisms primary associated with treatment efficacy (ERCC2-rs13181, rs1799793, ERCC1-rs3212986, rs11615, XRCC1-rs25487) or with docetaxel caused toxicity (CYP39A1-rs7761731, SLCO1B3-rs11045585) were evaluated in all patients. The results of these analyses were correlated with the clinical outcome of the patients (loco regional control, progression free survival, overall survival) and treatment related toxicity during induction chemotherapy.\n\n\nRESULTS\nMedian progression free survival and overall survival was 20 and 31 months in an intention to treat analysis, respectively. Overall response rate to induction chemotherapy was high with 78.1 % of all patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. Genotype A of the CYP39A1 rs7761731 polymorphism was associated with a higher incidence of leucopenia and infections or death during induction chemotherapy.\n\n\nCONCLUSIONS\nIntensive induction chemotherapy results in a high response rate in the majority of patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. The CYP39A1 polymorphism rs7761731 may help to identify patients at high risk for treatment related toxicity.",
"affiliations": "Department of Internal Medicine III, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. t.melchardt@salk.at.;Department of Internal Medicine III, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. cl.hufnagl@salk.at.;Department of Internal Medicine III, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. t.magnes@salk.at.;Department of Internal Medicine III, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. lu.weiss@salk.at.;Institute of Pathology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. g.hutarew@salk.at.;Institute of Pathology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. d.neureiter@salk.at.;Institute of Radiology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. a.schlattau@salk.at.;Department of Otorhinolaryngology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. g.moser@salk.at.;Department of Oral and Maxillofacial Surgery, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. a.gaggl@salk.at.;Institute of Pathology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. w.traenkenschuh@salk.at.;Department of Internal Medicine III, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. r.greil@salk.at.;Department of Internal Medicine III, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria. a.egle@salk.at.",
"authors": "Melchardt|Thomas|T|;Hufnagl|Clemens|C|;Magnes|Teresa|T|;Weiss|Lukas|L|;Hutarew|Georg|G|;Neureiter|Daniel|D|;Schlattau|Alexander|A|;Moser|Gerhard|G|;Gaggl|Alexander|A|;Tränkenschuh|Wolfgang|W|;Greil|Richard|R|;Egle|Alexander|A|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D013250:Steroid Hydroxylases; C499573:CYP39A1 protein, human; D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-015-1776-x",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 26475344177610.1186/s12885-015-1776-xResearch ArticleCYP39A1 polymorphism is associated with toxicity during intensive induction chemotherapy in patients with advanced head and neck cancer Melchardt Thomas t.melchardt@salk.at 123Hufnagl Clemens cl.hufnagl@salk.at 123Magnes Teresa t.magnes@salk.at 123Weiss Lukas lu.weiss@salk.at 123Hutarew Georg g.hutarew@salk.at 4Neureiter Daniel d.neureiter@salk.at 4Schlattau Alexander a.schlattau@salk.at 5Moser Gerhard g.moser@salk.at 6Gaggl Alexander a.gaggl@salk.at 7Tränkenschuh Wolfgang w.traenkenschuh@salk.at 4Greil Richard r.greil@salk.at 123Egle Alexander +43 662 4482 5770a.egle@salk.at 1231 Department of Internal Medicine III, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria 2 Salzburg Cancer Research Institute (SCRI), Müllner-Hauptstrasse 48-5020, Salzburg, Austria 3 Cancer Cluster Salzburg (CCS), Müllner-Hauptstrasse 48-5020, Salzburg, Austria 4 Institute of Pathology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria 5 Institute of Radiology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria 6 Department of Otorhinolaryngology, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria 7 Department of Oral and Maxillofacial Surgery, Paracelsus Medical University Salzburg, Müllner-Hauptstrasse 48-5020, Salzburg, Austria 16 10 2015 16 10 2015 2015 15 72511 6 2015 10 10 2015 © Melchardt et al. 2015Open 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\nInduction chemotherapy incorporating docetaxel, cisplatin and 5- fluorouracil before radiotherapy may improve the outcome of patients with advanced head and neck cancer. Nevertheless, the addition of docetaxel increases hematological toxicity and infectious complications. Therefore, genetic markers predicting toxicity and efficacy of this treatment regimen may help to identify patients, who would have the most benefit from this intensive treatment.\n\nMethods\nA cohort of 78 patients with advanced head and neck cancer treated with induction chemotherapy was assessed for clinical outcome and toxicity during treatment with curative intention. Genetic polymorphisms primary associated with treatment efficacy (ERCC2-rs13181, rs1799793, ERCC1-rs3212986, rs11615, XRCC1-rs25487) or with docetaxel caused toxicity (CYP39A1-rs7761731, SLCO1B3-rs11045585) were evaluated in all patients. The results of these analyses were correlated with the clinical outcome of the patients (loco regional control, progression free survival, overall survival) and treatment related toxicity during induction chemotherapy.\n\nResults\nMedian progression free survival and overall survival was 20 and 31 months in an intention to treat analysis, respectively. Overall response rate to induction chemotherapy was high with 78.1 % of all patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. Genotype A of the CYP39A1 rs7761731 polymorphism was associated with a higher incidence of leucopenia and infections or death during induction chemotherapy.\n\nConclusions\nIntensive induction chemotherapy results in a high response rate in the majority of patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. The CYP39A1 polymorphism rs7761731 may help to identify patients at high risk for treatment related toxicity.\n\nKeywords\nSNPDocetaxelHead and neck cancerInduction chemotherapyToxicityissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nThe management of patients with advanced head and neck cancer is a complex process requiring a multidisciplinary approach including effective cytotoxic regimens, radical surgery and radiotherapy (RT) [1]. It has been shown that patients with locally advanced disease not suitable for surgery can be cured with induction chemotherapy followed by definitive radiochemotherapy (RCTX) [2]. Two randomized controlled phase III trials showed an overall survival (OS) benefit for the addition of docetaxel to induction chemotherapy with a platinum compound and 5-fluorouracil (TPF) followed by RT with or without low-dose carboplatin [3, 4]. Therefore, this approach can be used in patients with locally advanced disease not suitable for surgery although two recently published trials doubt the clinical value of induction treatment in comparison to primary RCTX [5, 6]. Furthermore, the specific value of radio-sensitizing therapy in addition to RT after TPF is unclear.\n\nThis intensive treatment strategy is also associated with significant toxicity. Furthermore, some patients with advanced age and severe comorbidities often caused by substance abuse do not qualify for this treatment. Besides such clinical risk factors, single nucleotide polymorphisms (SNPs) of genes influencing the mode of action or the metabolism of cytotoxic drugs may identify patients, who on the one hand have more benefit from intensive treatment or on the other hand are at higher risk for toxicity. Three SNPs of the DNA repair genes ERCC1, ERCC2 and XRCC1 influencing the efficacy of cisplatin have been described to predict better outcome in a heterogeneous cohort of 103 patients with head and neck cancer treated with cisplatin during induction chemotherapy or RT [7]. Nevertheless, this report included only 40 patients treated with modern induction chemotherapy with cisplatin, fluoropyrimidine and taxanes. Furthermore, data on the influence of genetic polymorphisms on the incidence of treatment related toxicities are still missing. Docetaxel-induced toxicity, especially bone marrow suppression, is reported to be influenced by such polymorphisms [8–11].\n\nTo test the value of these polymorphisms for predicting the efficacy and toxicity of the TPF regimen we assessed the clinical outcome and the genetic signature of 6 genes in all patients treated with TPF therapy for advanced head and neck cancer since 2006 at our cancer center.\n\nMethods\nPatients\nAll patients included for this analysis were diagnosed with advanced head and neck cancer between January 2006 and December 2013 and consecutively treated with TPF chemotherapy as first line therapy treatment at the 3rd Medical Department of the Paracelsus Medical University Salzburg. Follow-up data were available for all patients at the last update of the database on the 28th of February 2014. Clinical data were also obtained by telephone interviews of the general practitioners or relatives if needed. Three cycles of induction treatment including docetaxel (75 mg/m2), cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2 continously for 5 days) were planned in all patients in analogy to the TAX 323 trial [4] as our local standard. Primary use of granulocyte-colony stimulating factor support was mandatory and all patients were hospitalized at least for the first cycle of treatment until bone marrow recovery. Prophylactic antibiotic treatment using a fluoroquinolone was also an institutional practice. Response to induction chemotherapy was clinically assessed before each cycle and radiologic response was assessed after 2 or 3 cylces with the method, which was used for primary staging (magnetic resonance imaging in 82 % of all cases).\n\nAfter completion of induction chemotherapy all patients were referred for concomitant radiotherapy in combination systemic treatment (cisplatin, carboplatin cetuximab). Patients without response to induction chemotherapy after two cycles were referred for salvage surgery or immediate radiotherapy if unresectable.\n\nThis retrospective study was approved by the Ethics Committee of the provincial government of Salzburg, Austria (415-EP/73/340-2014) and written informed consent was obtained from all patients. Clinical data including the stage of disease, loco regional control (LRC), OS and progression free survival (PFS) were analyzed by chart based review. PFS was calculated from start of therapy until disease progression, diagnosis of another tumor or death from any cause. Common toxicity criteria for adverse events version 4.0 (CTCAE 4.0) were used to assess treatment related toxicity.\n\nStatistical analyses were performed using IBM® SPSS® statistics software, version 20. Mann–Whitney-U-test and Pearson’s chi-squared test were used for univariate analyses, where appropriate. Survival was estimated using Kaplan-Meier curve analysis, with statistical comparison using the log-rank statistic. A two-tailed significance-level of 0.05 was considered statistically significant. Only statistically significant factors were included into multivariate Cox-regression analyses. Due to the exploratory and hypothesis generating design of the present SNP data study no adjustment for multiple testing was applied [12].\n\nSNP genotyping\nSNPs influencing the pharmacodynamics of cytotoxic agents were chosen for analysis after extensive review of the available literature dealing with the metabolism of drugs within the TPF regimen. The following SNPs were selected because of reported effect on drug efficacy: ERCC2-rs13181 and rs1799793, ERCC1-rs3212986 and rs11615, XRCC1-rs25487 [7, 13]. The CYP39A1-rs7761731 and SLCO1B3 rs11045585 polymorphisms are reported to be associated with treatment related toxicity caused by docetaxel, which is the major component of hematological toxicity in the used induction chemotherapy regimen [8–11].\n\nGerm line DNA was extracted from frozen peripheral blood cells in 65 % of the patients. In the other patients without frozen peripheral blood cells we used extracted germ line DNA from diagnostic formalin fixed tissue samples with no histologically observed tumor infiltration. This procedure was performed using the Maxwell 16 FFPE Plus LEV or Maxwell Blood DNA Purification KIT. Extracted DNA was amplified using the Genotyping Master Mix and SNP Genotyping assay from TaqMan®. Afterwards allelic discrimination was performed using the software of the Applied Bio System 7500 system (Thermo Fischer). The assessed genotypes were correlated and then subjected to correlative analyses with the clinical outcome of the patients (LCR, PFS, OS) and treatment related toxicity during induction chemotherapy.\n\nResults\nPatient characteristics\nAll 78 patients recruited in the study were consecutively treated with TPF induction chemotherapy for advanced head and neck cancer between 2006 and 2013 (see Table 1). In detail, all patients were Caucasians with a median age of 56.0 years and 88.5 % of the patients were male. As expected, the majority of the patients (80.7 %) had a primary tumor of the pharynx, 15.4 % were diagnosed with a tumor of the oral cavity. Squamous cell carcinoma was diagnosed in 98.7 % of the patients and all except for one were HIV negative. Median follow-up for alive patients was 56 months.Table 1 Patients characteristics treated with first line induction TPF chemotherapy\n\n\tOverall\t\n\t\nn = 78\n\t\nAge (years)\t\t\n Median\t56\t\n Range\t40–72\t\n>60 years (%)\t28.2\t\nSex\t\t\n Male\tn = 69 (88.5 %)\t\n Female\tn = 9 (11.5 %)\t\nTreatment after TPF (%)\t\t\n RT\tn = 69 (88.5 %)\t\n OP\tn = 4 (5.1 %)\t\n no further treatment due to toxicity\tn = 5 (6.4 %)\t\nNodal stage cN2c or cN3\t\t\n Yes\tn = 24 (30.8 %)\t\n No\tn = 54 (69.2 %)\t\ncT4 stage (%)\t\t\n Yes\tn = 53 (67.9 %)\t\n No\tn = 25 (32.1)\t\nStage of disease\t\t\n AJCC Stage 4\tn = 73 (93.4 %)\t\n AJCC Stage 3\tn = 5 (6.4 %)\t\nLocalisation of primary tumor (%)\t\t\n Oral cavity\tn = 12 (15.4 %)\t\n Pharynx\tn = 63 (80.7 %)\t\n Paranasal sinus\tn = 2 (2.6 %)\t\n Not available\tn = 1 (1.3 %)\t\nTPF docetaxel, 5-flurouracil, cisplatin\n\nCUP carcinoma of unknown primary\n\nRT radiotherapy\n\nn number\n\nAJCC American Joint Committee on Cancer\n\n\n\nClinical outcome in patients treated with TPF\nThe median PFS and OS of all patients treated with at least 1 cycle of TPF were 20 and 31 months, respectively (see Fig. 1). Overall response rate (ORR) after chemotherapy was 78.1 % including partial remission (PR) in 63 % and complete response (CR) in 15 % of the patients; 13.7 % had stable disease and 8.2 % of the 73 evaluable patients had refractory disease following induction chemotherapy. The therapy following TPF was RT in 88.5 %, surgery of the primary tumor in 5.1 and 6.4 % of the patients received no further treatment due to toxicity or progression (see Table 1). As expected, the presence of AJCC stage 4 disease or a cT4 primary tumor had negative influence on the clinical outcome of the patients (median PFS not reached vs. 17 months p = 0.026; 50 vs. 13 months p = 0.045), respectively. Nevertheless, multivariate analyses failed to show an independent value of one of these factors, respectively (p = 0.263; p = 0.116).Fig. 1 Clinical outcome in patients treated with induction chemotherapy. PFS (median 20 months a) and OS (median 31 months b) in all patients treated with first line TPF induction chemotherapy\n\n\n\nSixty-eight of these 69 patients receiving RT after TPF were treated with a concomitant regimen during RT. As concomitant therapy for RCTX, high dose cisplatin, carboplatin and cetuximab were used in 67.7, 14.7 and 17.6 % of the patients.\n\nConcomitant cisplatin treatment during RT was associated with better LRC (49 vs 11 months p < 0.001), PFS (36 vs 9 months p < 0.001) and OS (60 vs 19 months p = 0.005) than treatment with another drug regimen. To evaluate a possible influence of the previous response to induction therapy on the choice of concomitant treatment we also evaluated only patients with a response to TPF. Concomitant cisplatin treatment was also associated with a better LRC (59 vs 18 months p = 0.022) and better PFS (49 vs 14 months p = 0.024) in these patients, but OS did not reach statistical significance (60 vs 27 months p = 0.094).\n\nSNP analysis in patients treated with induction chemotherapy\nGerm line DNA for analysis of the 6 SNPs rs13181, rs1799793, rs3212986, rs11615, rs25487, rs7761731 were available for all patients treated with TPF chemotherapy. Despite the limited size of the cohort all SNPs were present at the predicted Hardy-Weinberg equilibrium and the allele frequencies were in line with the published databases (see Table 2). None of the SNPs especially those, who were previously described to be relevant for treatment efficacy, had a significant influence on LRC, PFS or OS in our cohort. We also could not observe any difference in the ORR.Table 2 Allele frequency\n\nSNP\tn\tGenotype frequency\tHWE (p)\t\nrs13181 ERCC2\t78\t19 GG (24.4 %)\t35 GT (44.9 %)\t24 TT (30.8 %)\t0.53\t\nrs3212986 ERCC1\t78\t10 AA (12.8 %)\t24 AC (30.8 %)\t44 CC (56.4 %)\t0.72\t\nrs 11615 ERCC1\t78\t27 AA (34.6 %)\t36 AG (46.2 %)\t15 GG (19.2 %)\t0.58\t\nrs 1799793 ERCC2\t78\t25 CC (32.1 %)\t40 AG CT (51.3 %)\t13 TT (16.7 %)\t0.58\t\nrs 7761731 CYP39A1\t77\t33 AA (42.9 %)\t36 AT (46.8 %)\t8 TT (10.4 %)\t0.66\t\nrs 25487 XRCC1\t78\t36 CC (46.2 %)\t36 CT (46.2 %)\t6 TT (7.7 %)\t0.69\t\nrs11045585 SLCO1B3\t77\t49 AA (63.8 %)\t26 AG (33.3 %)\t2 GG (2.6 %)\t0.50\t\n\n\nToxicity in patients treated with induction chemotherapy\nOverall, 204 cycles of TPF were administered in 78 patients with 73.1 % of patients receiving all of the three planned cycles of therapy. Nevertheless, due to excessive toxicity 11.5 % of the patients received only one cycle of therapy. Therapy related complications (myocardial infarction, 2 septic complications) resulted in 3 deaths during induction chemotherapy (treatment related mortality: 3.8 %). Furthermore, one patient committed suicide after the first cycle of therapy and one patient developed a progressive confusional state after the first cycle of treatment and successful bone marrow recovery without infectious complication and died 2 months later (see Tables 3 and 4). A grade 3 or 4 leucopenia after the first cycle of treatment was observed in 44.7 % of the 76 evaluable patients, but none of them experienced grade 3 or 4 thrombopenia. Grade 3 or 4 infection was observed after 28 of 202 (13.8 %) evaluable cycles of induction therapy and in 22 of 76 (28.9 %) evaluable patients. Renal toxicity higher than grade 1 was documented in 9 out of 202 (4.4 %) cycles in 9 different patients (see also Tables 3 and 4).Table 3 Toxicity during first cycle of induction chemotherapy according to CTCAE 4.0 (76 evaluable patients) by genotype (% per group)\n\n\tGenotype rs7761731\tTotal population (n = 76)\t\nAA (n = 33\tAT (n = 36)\tTT (n = 8)\t\nLeucopenia G3/4 (%)\t62.5 %\t37.1 %\t12.5 %\t44.7 %\t\nInfection G3/4 (%)\t28.1 %\t20.0 %\t25.0 %\t23.1 %\t\nRenal Toxicity > G1 (%)\t3.1 %\t11.4 %\t12.5 %\t9.2 %\t\nThrombopenia G3 (%)\tna.\tna.\tna.\t0 %\t\nTable 4 Toxicity during induction chemotherapy according to CTCAE 4.0 (76 evaluable patients) by genotype (% per group)\n\n\tGenotype rs7761731\tTotal population (n = 76)\t\nAA (n = 33\tAT (n = 36)\tTT (n = 8)\t\nLeucopenia G3/4 (%)\t65.6 %\t45.7 %\t37.5 %\t52.6 %\t\nInfection G3/4 (%)\t40.6 %\t20.0 %\t25.0 %\t28.9 %\t\nRenal Toxicity > G1 (%)\t6.3 %\t14.3 %\t12.5 %\t11.8 %\t\nThrombopenia G3 (%)\tna.\t2.8\tna.\t1.3 %\t\nna. not available\n\n\n\nBeside the tested polymorphisms associated with drug efficacy described above we also tested two polymorphisms related to docetaxel related toxicity.\n\nThe rs7761731 SNP of the CYP39A1 gene is reported to be associated with a higher rate of leucopenia in patients treated with docetaxel [8]. Therefore, we evaluated its influence on the frequency of leucopenia in our patients. Homozygosity of allele A, T and heterozygosity were observed in 42.9, 10.4 and 46.8 % of the patients, respectively (see Table 2). As expected, this polymorphism had no influence on the clinical outcome of patients, Patients with homozygosity for allele A had a significantly higher rate of grade 3 or 4 leucopenia during the first cycle compared to patients with genotype AT and TT (62.5 % vs 32.5 % p = 0.01). This negative effects of allele A also persists comparing the frequency of leucopenia during the first cycle with patients with genotype AA and AT to patients with genotype TT (49.2 % vs 12.5 % p = 0.048). We also observed a higher rate of a combined endpoint of infections or death during induction chemotherapy in patients with homozygosity for allele A compared to patients with genotype AT and TT (45.4 % vs 22.7 % p = 0.035).\n\nFurthermore, we evaluated the influence of the SLCO1B3 rs11045585 polymorphism. This gene encodes a solute carrier organic anion transporter member, which is expressed specifically in the basolateral membrane of hepatocytes and was previously reported to affect toxicity caused by docetaxel [9, 14]. Homozygosity of allele A, G and heterozygosity were observed in 63.6, 2.6 and 33.8 % of the patients, respectively (see Table 2). No influence of the rs11045585 polymorphism on the frequency of leucopenia after the first or entire induction chemotherapy (p = 0.925; p = 0.99) or grade 3 or 4 infection (p = 0.77) was observed.\n\nDiscussion\nDespite improvements of supportive care in medical oncology treatment related toxicity remains a major obstacle in patients with advanced head and neck cancer. Therefore, a more precise clarification of the benefits of intensive induction chemotherapy and concomitant drug regimens during RT is needed.\n\nOur cohort of consecutively treated patients represents one of the largest cohorts treated outside a clinical trial with TPF. The clinical data with a median PFS of 20 months, a median OS of 31 months and a treatment related mortality of 3.8 % related to TPF are in line with the published data from clinical trials and retrospective analyses [3, 4, 15–18]. The ORR to induction chemotherapy was high and the vast majority of patients were referred for further RT as planned.\n\nDespite this multimodality treatment is a standard option in patients with advanced head and neck cancer, the role of the concomitant cytotoxic agents after induction chemotherapy is less clear. In combination with postoperative and definitive RT high dose cisplatin therapy is considered as gold standard in feasible patients [19, 20], but a recent phase 2 trial doubted its role in comparison to cetuximab after induction chemotherapy [21]. Because of suggested higher efficacy concomitant cisplatin therapy is considered as treatment standard after induction chemotherapy in our cancer center in fit patients without contraindications for or severe toxicities during induction chemotherapy. This intensive management was associated with a better clinical outcome than treatment with carboplatin or cetuximab. To exclude a bias of patients, who were switched to cetuximab because of a lack of response to cytotoxic induction therapy we also analyzed only the subgroup of patients, who achieved at least a PR after induction therapy. Cisplatin was also associated with a better LRC and PFS than non-intensive therapy, but OS did not reach statistical significance in these patients. Therefore, we continue to use cisplatin as concomitant regimen after induction chemotherapy in patients without contraindications. Nevertheless, we want to point out a selection bias in this analysis due to the fact that only patients in good clinical condition were considered for this intensive treatment with high dose cisplatin during RT.\n\nBesides clinical risk factors such as age or comorbidites, the tolerance and efficacy of cytotoxic drugs may be influenced by SNPs of genes involved in drug metabolism. Polymorphism of the ERCC2 and XPD gene have been described to associated with a better OS in patients treated with various cisplatin based chemotherapy regimens, but only 40 patients were treated with modern induction chemotherapy including taxanes [7]. We tested these SNPS together with polymorphisms of the ERCC1 gene, which are also associated with a better outcome with cisplatin based treatment [13], in our cohort of 78 uniformly treated patients with TPF, but we could not reproduce any association of a certain polymorphism with the clinical outcome.\n\nWe further tested the influence of the CYP39A1-rs7761731 and SLCO1B3-rs11045585 polymorphisms on adverse effects during TPF chemotherapy. The addition of docetaxel to cisplatin and 5-fluorouracil nearly doubled the rate of leucopenia in two randomized trials and therefore a genomic marker to identify patients at high risk for leucopenia would be useful. CYP39A1 is a microsomal cytochrome P450 enzyme and is expressed in the liver, where docetaxel is mainly metabolized. It is involved in the conversion of cholesterol to bile acids. There is one report so far published that genotype A of this gene was associated with neutropenia after docetaxel treatment in Japanese patients with gynecological malignancies [8]. We could show now for the first time that Caucasian patients with both genotypes AA and AT are more prone to severe leucopenia in the first cycle of TPF treatment in comparison to patients with TT genotype despite prophylactic growth factor use in all patients. We also observed a higher rate of infections or death during TPF in patients with the genotype AA despite antibiotic prophylaxis. Nevertheless, we could not reproduce the effect of the SLCO1B3 rs11045585 polymorphism on docetaxel-induced leucopenia reported in previous literature [9–11]. It remains unclear, if this effect was diminished by the use of prophylactic growth factor or the combined effect of 3 cytotoxic drugs.\n\nOur work has several limitations. Despite the fact that we provided a detailed follow-up of all consecutively treated patients this analysis may imply an operative selection bias. The size of our cohort is larger than most of the published retrospective cohorts of patients treated with TPF [15–18], but of course cannot be compared with large phase 3 trials [3, 4]. Absolute neutrophil counts in addition to leukocytes counts would have been desirable, but were not available for the majority of patients, because the total leukocyte count is often completely sufficient in clinical practice. Nevertheless, documentation of toxicity was precise, especially in the first cycle of treatment because of hospitalization of all patients until bone marrow recovery with routine blood count testing at least every other day. Assessment of the HPV status was not available in this analysis, but this has no proven value for the choice of induction chemotherapy during clinical routine.\n\nFurthermore, our results suggest a superiority of the use of concomitant cisplatin in patients already treated with TPF for subsequent radiochemotherapy. Although we could show this effect also in patients with a radiological response to TPF, these results may be biased due to less comorbdities and better performance status in patients further treated with cisplatin. Therefore, we think this question will only be clarified in a prospective randomized clinical trial.\n\nConclusion\nIn summary, we could show the feasibility of intensive induction chemotherapy using the TPF regimen in a large single center cohort, but significant toxicity despite growth factor and antibiotic support remains a major concern in these patients. This is the first report of a gene polymorphism associated with treatment related toxicity during induction chemotherapy in patients with head and neck cancer. This finding is hypothesis-generating and further evaluation in other larger cohorts is needed to confirm this observation.\n\nAbbreviations\nRTRadiotherapy\n\nRCTXRadiochemotherapy\n\nOSOverall survival\n\nTPFChemotherapy with a platinum compound, docetaxel and 5-fluorouracill\n\nLCRLoco regional control\n\nOSOverall survival\n\nPFSProgression free survival\n\nSNPSingle nucleotide polymorphism\n\nHIVHuman immunodeficiency virus\n\nAJCCAmerican Joint Committee on Cancer\n\nORROverall response rate\n\nThomas Melchardt and Clemens Hufnagl contributed equally to this work.\n\nCompeting interests\n\nThe authors declare that they have no competing interests with regard to the content discussed in the manuscript. This work was supported by the Paracelsus Medical University (PMU Grant: E13/04/053-MEL).\n\nAuthors’ contributions\n\nTM, CH and AE are primarily responsible for writing of the manuscript. CH and TM were responsible for the SNP data and statistical analyses of the data. TM, TM, LW, GM, AG and RG treated the patients and participated in the collection of the clinical data. AS was responsible for the radiological response assessment. GH, DN and WT took care of the tissue samples of the patients. All authors critically revised and approved the final manuscript.\n\nAcknowledgment\nWe thank our patients for their consent for publication.\n==== Refs\nReferences\n1. Argiris A Karamouzis MV Raben D Ferris RL Head and neck cancer Lancet 2008 371 1695 709 10.1016/S0140-6736(08)60728-X 18486742 \n2. Pignon JP le Maitre A Maillard E Bourhis J Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients Radiother Oncol 2009 92 4 14 10.1016/j.radonc.2009.04.014 19446902 \n3. Posner MR Hershock DM Blajman CR Mickiewicz E Winquist E Gorbounova V Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer N Engl J Med 2007 357 1705 15 10.1056/NEJMoa070956 17960013 \n4. Vermorken JB Remenar E van Herpen C Gorlia T Mesia R Degardin M Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer N Engl J Med 2007 357 1695 704 10.1056/NEJMoa071028 17960012 \n5. Haddad R O’Neill A Rabinowits G Tishler R Khuri F Adkins D Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial Lancet Oncol 2013 14 257 64 10.1016/S1470-2045(13)70011-1 23414589 \n6. Zhong LP Zhang CP Ren GX Guo W William WN Jr Sun J Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma J Clin Oncol 2013 31 744 51 10.1200/JCO.2012.43.8820 23129742 \n7. Quintela-Fandino M Hitt R Medina PP Gamarra S Manso L Cortes-Funes H DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy J Clin Oncol 2006 24 4333 9 10.1200/JCO.2006.05.8768 16896002 \n8. Uchiyama T Kanno H Ishitani K Fujii H Ohta H Matsui H An SNP in CYP39A1 is associated with severe neutropenia induced by docetaxel Cancer Chemother Pharmacol 2012 69 1617 24 10.1007/s00280-012-1872-4 22562553 \n9. Choi JR Kim JO Kang DR Shin JY Zhang XH Oh JE Genetic Variations of Drug Transporters Can Influence on Drug Response in Patients Treated with Docetaxel Chemotherapy Cancer Res Treat 2015 47 509 17 10.4143/crt.2014.012 25648089 \n10. Chew SC Singh O Chen X Ramasamy RD Kulkarni T Lee EJ The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients Cancer Chemother Pharmacol 2011 67 1471 8 10.1007/s00280-011-1625-9 21468756 \n11. Kiyotani K Mushiroda T Kubo M Zembutsu H Sugiyama Y Nakamura Y Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia Cancer Sci 2008 99 967 72 10.1111/j.1349-7006.2008.00765.x 18294295 \n12. Bender R Lange S Adjusting for multiple testing--when and how? J Clin Epidemiol 2001 54 343 9 10.1016/S0895-4356(00)00314-0 11297884 \n13. Isla D Sarries C Rosell R Alonso G Domine M Taron M Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer Ann Oncol 2004 15 1194 203 10.1093/annonc/mdh319 15277258 \n14. Konig J Cui Y Nies AT Keppler D Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide J Biol Chem 2000 275 23161 8 10.1074/jbc.M001448200 10779507 \n15. Billan S Kaidar-Person O Atrash F Doweck I Haim N Kuten A Toxicity of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil for advanced head and neck cancer Isr Med Assoc J 2013 15 231 5 23841243 \n16. Rampino M Bacigalupo A Russi E Schena M Lastrucci L Iotti C Efficacy and feasibility of induction chemotherapy and radiotherapy plus cetuximab in head and neck cancer Anticancer Res 2012 32 195 9 22213307 \n17. Ko EC Genden EM Misiukiewicz K Som PM Kostakoglu L Chen CT Toxicity profile and clinical outcomes in locally advanced head and neck cancer patients treated with induction chemotherapy prior to concurrent chemoradiation Oncol Rep 2012 27 467 74 22020564 \n18. Kim B Dillman RO Chen P Hafer R Cox C Barth N A retrospective study of induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiotherapy with cetuximab in locally advanced head and neck cancer Am J Otolaryngol 2012 33 93 7 10.1016/j.amjoto.2011.02.004 21524816 \n19. Cooper JS Pajak TF Forastiere AA Jacobs J Campbell BH Saxman SB Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck N Engl J Med 2004 350 1937 44 10.1056/NEJMoa032646 15128893 \n20. Bernier J Domenge C Ozsahin M Matuszewska K Lefebvre JL Greiner RH Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer N Engl J Med 2004 350 1945 52 10.1056/NEJMoa032641 15128894 \n21. Lefebvre JL Pointreau Y Rolland F Alfonsi M Baudoux A Sire C Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study J Clin Oncol 2013 31 853 9 10.1200/JCO.2012.42.3988 23341517\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "15()",
"journal": "BMC cancer",
"keywords": null,
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil; D005838:Genotype; D006258:Head and Neck Neoplasms; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013250:Steroid Hydroxylases; D043823:Taxoids",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "725",
"pmc": null,
"pmid": "26475344",
"pubdate": "2015-10-16",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23414589;15277258;23841243;19446902;25648089;17960012;17960013;15128893;22020564;22562553;21468756;10779507;22213307;18294295;16896002;15128894;18486742;23341517;23129742;11297884;21524816",
"title": "CYP39A1 polymorphism is associated with toxicity during intensive induction chemotherapy in patients with advanced head and neck cancer.",
"title_normalized": "cyp39a1 polymorphism is associated with toxicity during intensive induction chemotherapy in patients with advanced head and neck cancer"
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"abstract": "Here we present a patient with rheumatoid arthritis (RA), who was suspected to have developed malignant lymphoma during immunosuppressive therapy 5 years earlier. She temporarily achieved remission after discontinuing therapy; however, her disease worsened with remittent fever and splenomegaly. Splenic biopsy demonstrated infiltration by abnormal cells, which were positive for CD56 and T cell intracytoplasmic antigen, but negative for CD3 and Epstein-Barr virus (EBV) -encoded RNA. Cytogenetic analysis of bone marrow and lumbar spine tumor revealed common complex karyotype abnormalities. Thus, she was diagnosed with chronic natural killer cell lymphoproliferative disorder (NK-LPD) and finally died of disease progression. The most common type of LPD in methotrexate-related patients with RA is B-lymphoid LPD, whereas NK-LPD is extremely rare. Furthermore, almost all cases of NK-LPD have been reported to be positive for EBV. This is the first case report on a patient with EBV-negative NK-LPD developed during immunosuppressive therapy for RA.",
"affiliations": "Department of Hematology, Eiju General Hospital.;Department of Hematology, Eiju General Hospital.;Department of Hematology, Eiju General Hospital.;Department of Pathology, Eiju General Hospital.;Department of Pathology, The University of Teikyo.;Department of Hematology, Eiju General Hospital.",
"authors": "Uchida|Tomoyuki|T|;Inoue|Morihiro|M|;Hua|Jian|J|;Tajima|Shogo|S|;Ota|Yasunori|Y|;Hagihara|Masao|M|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.624",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(6)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Chronic natural killer lymphoproliferative disorder; Epstein-Barr virus; Iatrogenic immunodeficiency-associated lymphoproliferative disorders; Rheumatoid arthritis",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001172:Arthritis, Rheumatoid; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007694:Killer Cells, Natural; D008232:Lymphoproliferative Disorders; D011241:Prednisone; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "624-629",
"pmc": null,
"pmid": "28679993",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Iatrogenic immunodeficiency-associated Epstein-Barr virus (EBV) -negative natural killer cell lymphoproliferative disorder in a patient undergoing rheumatoid arthritis therapy.",
"title_normalized": "iatrogenic immunodeficiency associated epstein barr virus ebv negative natural killer cell lymphoproliferative disorder in a patient undergoing rheumatoid arthritis therapy"
} | [
{
"companynumb": "JP-TEVA-2017-JP-831329",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nShort-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a rare form of primary headache, classified as trigeminal autonomic cephalalgia. Since the underlying mechanism of the pathogenesis has not yet been determined, a standardized therapeutic strategy for SUNCT is unavailable. We present a case of SUNCT syndrome with successful pain relief by intravenous administration of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist.\n\n\nMETHODS\nA 56-year-old male patient reported severe throbbing and shooting pain in forehead, temporal and periorbital region. We confirmed conjunctival injection, lacrimation, blepharoptosis, and miosis as symptoms related to autonomic activity, and made a diagnosis of SUNCT based on ICHD-3 beta. Numerous treatments were attempted, including pregabalin, gabapentine, nonsteroidal antiinflammatory drugs, acetaminophen, steroids, antidepressants, triptans, nerve blocks, and intravenous lidocaine with unsatisfactory results. Intravenous administration of ketamine (0.4 mg/kg) for one hour, was found to relieve the severe pain.\n\n\nCONCLUSIONS\nIntravenous ketamine can effectively treat SUNCT syndrome. This case demonstrated that involvement of NMDAR could be one of the mechanisms of SUNCT syndrome pathogenesis and establish a therapeutic strategy for this pain syndrome.",
"affiliations": "Division of Dental Anesthesiology, Department of Control of Physical Function, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.;Division of Dental Anesthesiology, Department of Control of Physical Function, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.;Division of Dental Anesthesiology, Department of Control of Physical Function, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.",
"authors": "Shiiba|Shunji|S|;Sago|Teppei|T|;Kawabata|Kazune|K|",
"chemical_list": "D007649:Ketamine",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-768X",
"issue": "30(1)()",
"journal": "Acta neurologica Taiwanica",
"keywords": "SUNCT; Ketamine; NMDA receptor Trigeminal neuralgia; neuropathic pain.",
"medline_ta": "Acta Neurol Taiwan",
"mesh_terms": "D061605:Administration, Intravenous; D001763:Blepharoptosis; D006261:Headache; D006801:Humans; D007649:Ketamine; D008297:Male; D008875:Middle Aged; D050798:SUNCT Syndrome",
"nlm_unique_id": "9815355",
"other_id": null,
"pages": "35-38",
"pmc": null,
"pmid": "34549399",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pain Relief in Short-Lasting Unilateral Neuralgiform Headache with Conjunctival inJection and Tearing Syndrome with Intravenous Ketamine: A Case Report.",
"title_normalized": "pain relief in short lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome with intravenous ketamine a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1044871",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "3",
... |
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