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"abstract": "Recurrent vomiting due to bulimia associated with abuse of furosemide and laxatives causing severe hypokalemia may result in recurrent aborted sudden cardiac death (SCD) and seizures. We report a 25-year-old female with a history of bulimia associated with abuse of furosemide and laxatives since the age of 15 years, migraine since puberty, renal abscesses at age 20 y, and rhabdomyolysis of unknown cause at age 24 y. She experienced aborted SCD due to severe hypokalemia with symptomatic seizures at 21 and 25 years of age. Bulimia patients additionally taking laxatives or furosemide are at particular risk of SCD and rhabdomyolysis and require periodic determination of electrolytes, potassium substitution, and adequate psychiatric therapy and surveillance.",
"affiliations": null,
"authors": "Finsterer|Josef|J|;Stöllberger|Claudia|C|",
"chemical_list": "D004232:Diuretics; D005665:Furosemide",
"country": "Chile",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-9887",
"issue": "142(6)",
"journal": "Revista medica de Chile",
"keywords": null,
"medline_ta": "Rev Med Chil",
"mesh_terms": "D002032:Bulimia; D016757:Death, Sudden, Cardiac; D004232:Diuretics; D005260:Female; D005665:Furosemide; D006801:Humans; D007008:Hypokalemia; D012206:Rhabdomyolysis; D012640:Seizures; D055815:Young Adult",
"nlm_unique_id": "0404312",
"other_id": null,
"pages": "799-802",
"pmc": null,
"pmid": "25327327",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent aborted sudden cardiac death with seizures and rhabdomyolysis due to bulimia-induced hypokalemia: report of one case.",
"title_normalized": "recurrent aborted sudden cardiac death with seizures and rhabdomyolysis due to bulimia induced hypokalemia report of one case"
} | [
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"companynumb": "AT-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-98877",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"druga... |
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"abstract": "Natalizumab is an efficacious disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS), often limited by risk of progressive multifocal leukoencephalopathy. We describe the clinical course of RRMS patients switched from natalizumab to another DMT. We identified all RRMS patients treated with natalizumab ≥3 months with JC virus antibody positivity who switched to another DMT. Overall, 84 individuals switched DMT with 57 (68%) beginning fingolimod. On fingolimod, survival without a relapse was 74% (55.8-85.6%) at 36 months and survival without disease progression was 78% (62.6-87.6%) at 36 months. In conclusion, fingolimod is an effective therapy post-natalizumab.",
"affiliations": "Division of Neurology,Dalhousie University,Halifax,Canada.;Division of Neurology,Dalhousie University,Halifax,Canada.;Department of Community Health and Epidemiology,Dalhousie University,Halifax,Canada.;Division of Neurology,Dalhousie University,Halifax,Canada.",
"authors": "Fiander|Maximillian D J|MDJ|;Bhan|Virender|V|;Stewart|Samuel A|SA|;Parks|Natalie E|NE|",
"chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab; D000068876:Fingolimod Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1017/cjn.2019.42",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0317-1671",
"issue": "46(4)",
"journal": "The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques",
"keywords": "Disease modifying therapy; Fingolimod; Multiple sclerosis; Natalizumab; Survival analysis",
"medline_ta": "Can J Neurol Sci",
"mesh_terms": "D000328:Adult; D057915:Drug Substitution; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D012008:Recurrence; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0415227",
"other_id": null,
"pages": "455-458",
"pmc": null,
"pmid": "31113500",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Course of Relapsing Remitting Multiple Sclerosis Post-Natalizumab.",
"title_normalized": "clinical course of relapsing remitting multiple sclerosis post natalizumab"
} | [
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"companynumb": "CA-BIOGEN-2012BI032895",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
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"activesubstancename": "DALFAMPRIDINE"
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"abstract": "Rarely screened in psychiatric patients, primary and/or secondary Carnitine deficiency could be influencing and/or mimicking the mood symptoms of our patient population. The brain and specifically neurons are highly vulnerable to impairments in oxidative metabolism, which can lead to neuronal cell death and disorders of neurotransmitters causing changes in cognition and behavior. For this reason, identification of this disorder is important since its treatment could result in symptom improvement and better quality of life of our patients. We present a case where exacerbation of mood symptoms was associated to primary and secondary Carnitine deficiency.",
"affiliations": "Ponce School of Medicine/VA Caribbean Healthcare System, Ponce, Puerto Rico. cubitek@hotmail.com",
"authors": "Santos-Cubiñá|Javier|J|;Torres-Rodríguez|Alexis|A|;Castaing-Lespier|Pedro A|PA|;Sabaté|Nuria|N|;Torres-Martin|Ana|A|;Carlo|Simón|S|",
"chemical_list": "D000928:Antidepressive Agents; D018692:Antimanic Agents; D027701:Organic Cation Transport Proteins; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D015283:Citalopram; D001569:Benzodiazepines; D014635:Valproic Acid; D007655:Ketoglutarate Dehydrogenase Complex; D000077152:Olanzapine; D008140:Lorazepam; D002331:Carnitine",
"country": "Puerto Rico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-4849",
"issue": "105(3)",
"journal": "Boletin de la Asociacion Medica de Puerto Rico",
"keywords": null,
"medline_ta": "Bol Asoc Med P R",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D018692:Antimanic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D001569:Benzodiazepines; D002331:Carnitine; D015283:Citalopram; D003866:Depressive Disorder; D007174:Disruptive, Impulse Control, and Conduct Disorders; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D006801:Humans; D022124:Hyperammonemia; D007655:Ketoglutarate Dehydrogenase Complex; D008140:Lorazepam; D008297:Male; D019964:Mood Disorders; D000077152:Olanzapine; D027701:Organic Cation Transport Proteins; D000074058:Solute Carrier Family 22 Member 5; D014635:Valproic Acid",
"nlm_unique_id": "7505267",
"other_id": null,
"pages": "43-4",
"pmc": null,
"pmid": "24282920",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Exacerbation of mood symptoms associated to primary and secondary carnitine deficiency: a case report.",
"title_normalized": "exacerbation of mood symptoms associated to primary and secondary carnitine deficiency a case report"
} | [
{
"companynumb": "PHHY2014US016355",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
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"abstract": "Due to the association between Covid-19 and thromboembolic events, there has been a surge in anticoagulation use during the pandemic based on evolving guidelines for management of hospitalized Covid-19 patients. Spontaneous soft tissue hematoma can be a severe complication of anticoagulation. Herein we present a fatal case of severe spontaneous soft tissue hematoma secondary to anticoagulant therapy in a 67kg 81-year-old female with chronic kidney disease who was admitted to the hospital with Covid-19 pneumonia. There is currently no evidence of mortality benefit among Covid-19 patients on high-dose anticoagulation. In the future we hope that practitioners will consider the bleeding risks of anticoagulation and consider patients' age, weight and renal function when determining prophylactic anticoagulation regimens in Covid-19 patients.",
"affiliations": "Critical Care, Catholic Health, Long Island, New York.;Department of Radiology, Catholic Health, Long Island, New York.",
"authors": "Teta|Michael|M|;Drabkin|Michael J|MJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2021.04.029",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433\nElsevier\n\nS1930-0433(21)00237-5\n10.1016/j.radcr.2021.04.029\nCase Report\nFatal retroperitoneal hematoma associated with Covid-19 prophylactic anticoagulation protocol\nTeta Michael PA a\nDrabkin Michael J MD michaeljdrabkin@gmail.com\n⁎b\na Critical Care, Catholic Health, Long Island, New York\nb Department of Radiology, Catholic Health, Long Island, New York\n⁎ Corresponding author. michaeljdrabkin@gmail.com\n15 4 2021\n7 2021\n15 4 2021\n16 7 16181621\n31 3 2021\n11 4 2021\n11 4 2021\n© 2021 The Authors. Published by Elsevier Inc. on behalf of University of Washington.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nDue to the association between Covid-19 and thromboembolic events, there has been a surge in anticoagulation use during the pandemic based on evolving guidelines for management of hospitalized Covid-19 patients. Spontaneous soft tissue hematoma can be a severe complication of anticoagulation. Herein we present a fatal case of severe spontaneous soft tissue hematoma secondary to anticoagulant therapy in a 67kg 81-year-old female with chronic kidney disease who was admitted to the hospital with Covid-19 pneumonia. There is currently no evidence of mortality benefit among Covid-19 patients on high-dose anticoagulation. In the future we hope that practitioners will consider the bleeding risks of anticoagulation and consider patients’ age, weight and renal function when determining prophylactic anticoagulation regimens in Covid-19 patients.\n\nKeywords\n\nRetroperitoneal Hematoma\nAnticoagulant therapy\nLovenox\nCovid-19\nEmbolization\n==== Body\nIntroduction\n\nSpontaneous soft tissue hematoma (SSTH) can be a severe complication of anticoagulation use [1,2]. Incidence of SSTH is rising with increasing use of anticoagulation [2,3]. SSTHs occur most frequently in the rectus sheath and iliopsoas but can occur in other locations as well [2]. Most cases are self-limited and resolve with cessation of anticoagulation and conservative management [4]. The high-rate of success of conservative management is largely due to the fact that these hematomas occur in contained spaces which allows them to be tamponaded by adjacent structures [4]. In certain cases, particularly when coagulopathy cannot be easily reversed or if there is a delay in diagnosis, the SSTH can grow to the point that it causes tearing of additional vessels. In such cases there is a high rate of mortality [1]. In these cases of persistent bleeding or hemodynamic instability despite conservative management, transcatheter arterial embolization (TAE) is generally the next line of treatment; in rare cases surgical management is pursued [1,2].\n\nDuring the recent pandemic, there have been large numbers of Covid-19 patients affected by thromboembolic events, occurring in 11-70% of ICU patients with Covid-19 [[5], [6], [7], [8]]. In response to this, new and more aggressive anticoagulation guidelines have emerged for management of hospitalized Covid-19 patients [9]. As of the writing of this paper, greater than 100 million people have been diagnosed with Covid-19 [10]. Given the scale of Covid-19, any related treatment guidelines can impact large numbers of patients. Many of the existing prophylactic anticoagulation guidelines recommend 40mg of Lovenox once daily for Covid-19 patients with mild symptoms and 0.5 mg/kg of Lovenox twice daily for patients with more severe symptoms or patients that require ICU admission [9,11]. Initiation of therapeutic anticoagulation of 1mg/kg of Lovenox twice daily has been suggested for high-risk patients who require ventilator support or have a markedly elevated D-dimer [9,11].\n\nAs we prescribe these anticoagulants for our patients, we must understand the associated risks. In the general population 0.9-16.5% of patients experienced a major bleeding episode while on anticoagulation therapy [6,[12], [13], [14]]. Higher doses of Lovenox have been associate with increased rates of bleeding complications in the general population as compared to lower doses [15].\n\nA recent study evaluating anticoagulant use in 42 Covid-19 patients found no clinical benefit to the use of therapeutic anticoagulation in Covid-19 patients, however, the same study also did not find any increased incidence of bleeding in these patients [16]. One recent case report described a major bleeding complication from full dose anticoagulation in a Covid-19 patient which resulted in significant morbidity but not mortality [17]. We present a case which is to the best of our knowledge the first reported mortality occurring secondary to bleeding resulting from anticoagulation use in a Covid-19 patient.\n\nCase presentation\n\nAn 81-year-old female weighing 67kg with a past medical history of hypertension, hyperlipidemia, hypothyroidism, COPD and 40 pack-years of smoking, presented to the emergency room with shortness of breath. She was found to have Covid-19 pneumonia and admitted for management of hypoxic respiratory failure. Biomarkers upon admission included a ferritin of 1,462 ng/mL (reference range 12-150), creatine kinase of 114 U/L (reference range 30-135), procalcitonin of 0.56 ug/L (reference range <0.5), D-dimer of 21 mcg/mL (reference range <0.4), and C-reactive protein of 63 mg/L (reference range 0.3-10). Her platelet count (reference range 150-400 × 10(3)/mcL) and hemoglobin (Hgb) (reference range 11.5-17.3 g/dL) were within normal limits and her creatinine clearance was 29 mL/min (reference range >60). As per hospital Covid-19 protocol, she was started on an elevated prophylactic dose of 40mg of Lovenox twice daily (BID). She took Aspirin 81 mg daily at home and was started on Aspirin 325 mg in the hospital. Her respiratory status was initially stable on nasal cannula oxygen.\n\nOn hospital day 5 she experienced hypoxia which resulted in her transfer to the medical intensive care unit. The patient's Lovenox dose was empirically increased to 60 mg BID out of concern for pulmonary embolism (PE). Subsequent CT angiography (CTA) of the chest was negative for PE, with incidental findings of a small amount of fluid in the LUQ of unclear etiology (seen only on the very last slice of the CTA). Later that day, the patient became obtunded, pale, and hypotensive. She was intubated for airway protection, and developed shock requiring vasopressors. Arterial blood gas demonstrated profound acidosis and Hgb of 3.7 g/dL. This was a large drop from Hgb of 11.5 g/dL just 20 hours prior. Her lactic acid was 19.0 mmol/L (reference range 0.4-2.0). Physical exam, including nasogastric lavage, showed no obvious source of bleeding. Her abdomen was soft, nontender, nondistended. After transfusion of 2 units of packed red blood cells (pRBCs), her Hgb improved to 8.5 g/dL. However, the patient continued to require pressor support and transfusion of additional blood products. All anticoagulants and antiplatelet agents were stopped.\n\nOn day 6 she further destabilized and required greater volume of blood products. The patient developed multi-organ failure secondary to profound hypoperfusion evidenced by derangements on complete metabolic panel and worsening coagulopathy. Non-contrast CT performed late that night demonstrated a large left retroperitoneal hematoma measuring up to 25cm in greatest diameter. CTA performed in the early morning hours of hospital day 7 demonstrated active extravasation of contrast into the expanding left retroperitoneal hematoma, now measuring up to 31cm (Fig. 1). That morning she was then taken to interventional radiology and had technically successful embolization of multiple bleeding lumbar arteries (Figs. 2 and 3). She was briefly stabilized during the day, but that night experienced another large drop in Hgb from 11.5 g/dL to 5.0 g/dL and died in the early hours of hospital day 8.Fig. 1 (A) Coronal CT Angiography image through abdomen demonstrates a very large retroperitoneal hematoma. (B) Axial CT Angiography image through the mid abdomen demonstrates a large blush of active extravasation of contrast as well as several smaller blushes within the hematoma.\n\nFig 1\n\nFig. 2 (A) Aortography demonstrates contrast extravasation from several lumbar arteries. (B) Delayed imaging demonstrates increase and persistence of multiple areas of active extravasation.\n\nFig 2\n\nFig. 3 (A) Selective angiography and embolization of the lumbar arteries. (B) Completion aortography shows stasis of contrast within the 3 embolized lumbar arteries. The active extravasation seen on initial aortography is no longer present.\n\nFig 3\n\nDiscussion\n\nDue to the association between Covid-19 and thromboembolic event, there has been a surge in anticoagulation use during the pandemic based on evolving guidelines for management of hospitalized Covid-19 patients. In the present case we have a severe SSTH which developed secondary to prophylactic and/or empiric anticoagulation in a Covid-19 patient. Despite supportive care and TAE, this hemorrhage ultimately resulted in death.\n\nAs anticoagulant therapy guidelines for Covid-19 patients are evolving, it is important to remember that anticoagulant use is not without risk. Hemorrhagic complications of anticoagulant therapy are relatively common in hospitalized patients, and although most of these are self-limited, morbidity and mortality does occur [[1], [2], [3], [4]]. Furthermore, it is important to keep in mind that Lovenox is renally cleared. The patient in our case had a creatinine clearance of only 29 mL/min; in patients with impaired renal function dose adjustment for Lovenox should be considered and Anti-Xa monitoring should be performed [18]. Aspirin use should also be taken into account as combined use of antiplatelet and anticoagulants can increase bleeding risk.[19]\n\nInitially part of the rationale for empiric high-dose anticoagulation therapy in Covid-19 patients was to avoid CT imaging entirely due to patient instability and concern regarding maintaining isolation precautions. A potential solution would be to screen Covid-19 patients for DVT with lower extremity ultrasound. This can help lead to earlier detection of deep venous thrombosis and more precise use of anticoagulants [20].\n\nAt the present time there is no significant evidence of mortality benefit among Covid-19 patients on high-dose anticoagulation. As we write this case report, anticoagulation trials for Covid-19 patients (REMAP-CAP, ACTIV-4, and ATTACC) have been halted due to futility and safety concerns [21].\n\nWe hope that this case report will serve as a reminder of the inherent risks of anticoagulant therapy and may steer clinicians away from high-dose prophylactic doses or initiation of empiric therapeutic anticoagulation. When a SSTH does occur, anticoagulation should immediately be halted and if necessary reversed. In severe cases interventional radiology should be consulted for TAE.\n\nThis case highlights the continued need to practice evidence-based medicine. Despite the terrible and unusual situation that the Covid-19 pandemic has created, we should adhere as closely as is practical to our guiding principles. There is currently no evidence of mortality benefit among Covid-19 patients on high-dose anticoagulation and literature regarding anticoagulation in the general population has shown that there is increased bleeding risk. Further research is needed to assess the efficacy and safety of various doses of anticoagulant therapy in Covid-19 patients.\n\nDeclaration of interests\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests:\n\nThe authors have no conflicts of interest.\n\nThe authors have not received any outside funding.\n\nThis work has not been previously published or presented in any format.\n==== Refs\nReferences\n\n1 Dohan A Sapoval M Chousterman BG di Primio M Guerot E Pellerin O. Spontaneous soft-tissue hemorrhage in anticoagulated patients: safety and efficacy of embolization Am J Roentgenol 204 6 2015 1303 1310 26001242\n2 Touma L Cohen S Cassinotto C Reinhold C Barkun A Tran VT Transcatheter arterial embolization of spontaneous soft tissue hematomas: a systematic review Cardiovasc Intervent Radiol 42 3 2019 335 343 30327927\n3 Investigators Columbus Büller HR Gent M Gallus AS Ginsberg J Prins MH Low-molecular-weight heparin in the treatment of patients with venous thromboembolism N Engl J Med 337 10 1997 657 662 9280815\n4 Rimola J Perendreu J Falcó J Fortuño JR Massuet A Branera J. Percutaneous arterial embolization in the management of rectus sheath hematoma AJR Am J Roentgenol 188 6 2007 W497 W502 17515337\n5 Middeldorp S Coppens M van Haaps TF Foppen M Vlaar AP Müller MCA Incidence of venous thromboembolism in hospitalized patients with COVID-19 J Thromb Haemost JTH 18 8 2020 1995 2002 32369666\n6 Klok FA Kruip MJHA van der Meer NJM Arbous MS Gommers D a.MPJ Kant KM Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Thromb Res 191 2020 145 147 32291094\n7 Poissy J Goutay J Caplan M Parmentier E Duburcq T Lassalle F Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence Circulation 142 2 2020 184 186 32330083\n8 Llitjos J-F Leclerc M Chochois C Monsallier J-M Ramakers M Auvray M High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients J Thromb Haemost JTH 18 7 2020 1743 1746 32320517\n9 Barnes GD Burnett A Allen A Blumenstein M Clark NP Cuker A Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum J Thromb Thrombolysis 50 1 2020 72 81 32440883\n10 COVID-19 Map [Internet]. Johns Hopkins Coronavirus Resource Center 2021 [cited 2021 Jan 31]. Available from https://coronavirus.jhu.edu/map.html\n11 Atallah B Mallah SI AlMahmeed W. Anticoagulation in COVID-19 Eur Heart J - Cardiovasc Pharmacother 6 4 2020 260 261 32352517\n12 Gerlach AT Pickworth KK Seth SK Tanna SB Barnes JF. Enoxaparin and bleeding complications: a review in patients with and without renal insufficiency Pharmacother J Hum Pharmacol Drug Ther 20 7 2000 771 775\n13 Cohen M Demers C Gurfinkel EP Turpie AGG Fromell GJ Goodman S A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease N Engl J Med 337 7 1997 447 452 9250846\n14 Bergqvist D Benoni G Björgell O Fredin H Hedlundh U Nicolas S Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement N Engl J Med 335 10 1996 696 700 8703168\n15 LaPointe NMA. Enoxaparin dosing and associated risk of in-hospital bleeding and death in patients with non–ST-segment elevation acute coronary syndromes Arch Intern Med 167 14 2007 1539 17646609\n16 Pavoni V Gianesello L Pazzi M Stera C Meconi T Frigieri FC. Venous thromboembolism and bleeding in critically ill COVID-19 patients treated with higher than standard low molecular weight heparin doses and aspirin: a call to action Thromb Res 196 2020 313 317 32977129\n17 Patel I Akoluk A Douedi S Upadhyaya V Mazahir U Costanzo E Life-threatening psoas hematoma due to retroperitoneal hemorrhage in a COVID-19 patient on enoxaparin treated with arterial embolization: a case report J Clin Med Res 12 7 2020 458 461 32655742\n18 Hughes S Szeki I Nash MJ Thachil J. Anticoagulation in chronic kidney disease patients—the practical aspects Clin Kidney J 7 5 2014 442 449 25878775\n19 Flaker GC Gruber M Connolly SJ Goldman S Chaparro S Vahanian A Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials Am Heart J 152 5 2006 967 973 17070169\n20 Thromboembolic Events and Role of Point of Care Ultrasound in Hospitalized Covid-19 Patients Needing Intensive Care Unit Admission - Sumit KapoorChand Sudham Dieiev Vladyslav Fazzari Melissa Tanner Tristan Lewandowski David C. [Internet] 2020 [cited 2021 Jan 31]. Available from https://journals.sagepub.com/doi/full/10.1177/0885066620964392\n21 COVID-19 Anticoagulation Trials “Paused” for Futility. Safety [Internet] 2021 Medscape. [cited 2021 Jan 31]. Available from http://www.medscape.com/viewarticle/943085\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1930-0433",
"issue": "16(7)",
"journal": "Radiology case reports",
"keywords": "Anticoagulant therapy; Covid-19; Embolization; Lovenox; Retroperitoneal Hematoma",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "1618-1621",
"pmc": null,
"pmid": "33880136",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal retroperitoneal hematoma associated with Covid-19 prophylactic anticoagulation protocol.",
"title_normalized": "fatal retroperitoneal hematoma associated with covid 19 prophylactic anticoagulation protocol"
} | [
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"activesubstancename": "ENOXAPARIN SODIUM"
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{
"abstract": "Voriconazole is a second-generation azole widely used for the prevention and treatment of fungal infection in leukemia patients. Voriconazole is considered the primary antifungal agent for invasive aspergillosis. We report a case of 16-year-old girl who developed visual disturbance and visual and auditory hallucinations after intravenous voriconazole treatment for invasive pulmonary aspergillosis. Due to the visual hallucinations and visual disturbance began acutely and shortly after the initiation of voriconazole, and no other cause could be determined, the symptoms were considered to be the side effects of voriconazole. Simultaneous development of visual side effects and hallucinations rarely have been reported before.",
"affiliations": "a Department of Pediatric Infectious Disease and.;b Department of Pediatric Hematology , Dursun Odabas Medical Center, Yuzuncu Yil University , Van , Turkey.;b Department of Pediatric Hematology , Dursun Odabas Medical Center, Yuzuncu Yil University , Van , Turkey.;b Department of Pediatric Hematology , Dursun Odabas Medical Center, Yuzuncu Yil University , Van , Turkey.",
"authors": "Bayhan|Gulsum Iclal|GI|;Garipardic|Mesut|M|;Karaman|Kamuran|K|;Akbayram|Sinan|S|",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2015.1020544",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "35(1)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Color discrimination; hallucinations; visual disturbance; voriconazole",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D001228:Aspergillosis; D005260:Female; D006212:Hallucinations; D006801:Humans; D014786:Vision Disorders; D065819:Voriconazole",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "80-2",
"pmc": null,
"pmid": "25799212",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Voriconazole-associated visual disturbances and hallucinations.",
"title_normalized": "voriconazole associated visual disturbances and hallucinations"
} | [
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"companynumb": "PHHY2016TR019149",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
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"dr... |
{
"abstract": "Untreated microangiopathic hemolytic anemia in pregnancy is associated with adverse maternal and perinatal outcomes. Accurate diagnosis is challenging owing to nonspecific clinical features and pathologic findings. Timely initiation of appropriate management is essential to optimize maternal and perinatal outcomes.\n\n\n\nA 26-year-old primiparous woman presented at 20 weeks of gestation with new-onset microangiopathic hemolytic anemia on a background of poorly controlled type 1 diabetes. She received eculizumab for presumed atypical hemolytic uremic syndrome. At 24 weeks of gestation, she developed superimposed early-onset preeclampsia; she delivered at 27 weeks of gestation after continuing eculizumab.\n\n\n\nEculizumab may prolong pregnancy in early-onset preeclampsia. Additional research is needed to assess short-term and long-term maternal and newborn outcomes.",
"affiliations": "Departments of Obstetrics & Gynecology and Nephrology, Monash Health, Victoria, Australia.",
"authors": "Lu|Angela B|AB|;Lazarus|Benjamin|B|;Rolnik|Daniel L|DL|;Palmer|Kirsten R|KR|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000003570",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "134(6)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D065766:Atypical Hemolytic Uremic Syndrome; D003920:Diabetes Mellitus; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011262:Pregnancy Trimester, Second; D011273:Pregnancy, Prolonged; D011296:Prenatal Diagnosis",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "1215-1218",
"pmc": null,
"pmid": "31764731",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnancy Prolongation After Eculizumab Use in Early-Onset Preeclampsia.",
"title_normalized": "pregnancy prolongation after eculizumab use in early onset preeclampsia"
} | [
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"companynumb": "NVSC2020AU096111",
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"activesubstancename": "PREDNISONE"
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"abstract": "WHO treatment guidelines recommend efavirenz in first-line antiretroviral therapy (ART). Efavirenz commonly causes early transient neuropsychiatric adverse events. We present 20 cases with severe encephalopathy accompanied by ataxia due to efavirenz toxicity.\n\n\n\nConsecutive HIV-infected adults taking efavirenz-containing ART admitted to Tshepong hospital, Klerksdorp, South Africa with ataxia and encephalopathy were included in this case series.\n\n\n\nWe identified 20 women admitted to hospital with severe ataxia. All received efavirenz-based ART for a median of 2 years. All had severe ataxia and none had nystagmus. Eleven had features of encephalopathy. Median weight was 34 kg [interquartile range (IQR): 29.7-35.3]; median CD4 count 299 cells/mm (IQR: 258-300) and most (18 of 19) were virally suppressed. Eight patients had a record of prior weights and 7 of 8 showed significant weight loss with a median weight loss of 10.8 kg (IQR: 8-11.6). All cases had plasma efavirenz assays, 19 were supratherapeutic (more than twice the upper level of therapeutic range), and 15 had concentrations above the upper limit of assay detection. Ataxia resolved after withdrawal of efavirenz at a median time of 2 months (IQR: 1.25-4) and recurred in 2 of 3 patients when rechallenged. Admissions before diagnosis were frequent with 10 cases admitted previously. Three women died.\n\n\n\nEfavirenz toxicity may present with severe reversible ataxia often with encephalopathy years after its initiation, likely in genetic slow metabolizers. We recommend that patients whose weight is <40 kg receive lower doses of efavirenz and that therapeutic drug monitoring be considered, and efavirenz stopped in patients presenting with ataxia. Eight patients had a record of prior subsequent weights and 7 of 8 showed significant weight loss gain; median gain of 10.8 kg (IQR: 8-11.6).",
"affiliations": "*North West Department of Health, Klerksdorp Tshepong Hospital Complex, Matlosana, South Africa; †Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa; ‡Perinatal HIV Research Unit (PHRU), SA MRC Soweto Matlosana Collaborating Centre for HIV/AIDS and TB, University of the Witwatersrand, Johannesburg, South Africa; §Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; ‖Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa; and ¶Center for TB Research, Johns Hopkins University, Baltimore, MD.",
"authors": "Variava|Ebrahim|E|;Sigauke|Farai R|FR|;Norman|Jennifer|J|;Rakgokong|Modiehi|M|;Muchichwa|Petudzai|P|;Mochan|Andre|A|;Maartens|Gary|G|;Martinson|Neil A|NA|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019259:Lamivudine; D000068698:Tenofovir; C098320:efavirenz",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0000000000001451",
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"issn_linking": "1525-4135",
"issue": "75(5)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D001259:Ataxia; D048588:Benzoxazines; D001927:Brain Diseases; D018791:CD4 Lymphocyte Count; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D006801:Humans; D019259:Lamivudine; D013019:South Africa; D000068698:Tenofovir; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "577-579",
"pmc": null,
"pmid": "28520619",
"pubdate": "2017-08-15",
"publication_types": "D016428:Journal Article",
"references": "23889591;26636156;21045634;16267739;12676886;18090393;15622315;23080225;16287792;19223781;19225447;19124658;25611810;16272958;22509819;18784459",
"title": "Brief Report: Late Efavirenz-Induced Ataxia and Encephalopathy: A Case Series.",
"title_normalized": "brief report late efavirenz induced ataxia and encephalopathy a case series"
} | [
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"abstract": "BACKGROUND\nPercutaneous Endoscopic Gastrostomy (PEG) can involve some complications, despite the good safety of its track record. The Buried Bumper Syndrome (BBS) is a rare, late and dangerous complication that consists in the erosion of the internal bumper through the gastric wall. Case presentation We report the development of BBS in a man with chronic obstructive pulmonary disease (COPD) who had a persistent chronic cough which was prevalently but not solely in the morning and required placement of a PEG tube for continuous infusion of Levodopa/carbidopa intestinal gel for advanced Parkinson's disease.\n\n\nCONCLUSIONS\nWe believe that COPD with chronic cough while not representing an absolute contraindication to PEG placement, may potentially cause BBS and therefore an appropriate regimen of tube care by expert personnel is mandatory in this setting.",
"affiliations": "Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy. antoniettagerarda.gravina@unicampania.it.;Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy.;Department of Woman, Child and General and Specialized Surgery, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy.;Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy.;Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy.;Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy.;Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy.;Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Via Pansini, 5, 80131, Naples, Italy.;Department of Woman, Child and General and Specialized Surgery, University of Campania \"Luigi Vanvitelli\", Naples, Italy.",
"authors": "Gravina|A G|AG|http://orcid.org/0000-0001-8049-0115;Tessitore|A|A|;Ormando|V M|VM|;Nagar|F|F|;Romeo|M|M|;Amato|M R|MR|;Dallio|M|M|;Loguercio|C|C|;Federico|A|A|;Romano|M|M|;Ferraro|F|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12876-021-01603-0",
"fulltext": "\n==== Front\nBMC Gastroenterol\nBMC Gastroenterol\nBMC Gastroenterology\n1471-230X BioMed Central London \n\n1603\n10.1186/s12876-021-01603-0\nCase Report\nMay chronic cough in chronic obstructive pulmonary disease be a contraindication of Percutaneous Endoscopic Gastrostomy placement: a case report\nhttp://orcid.org/0000-0001-8049-0115Gravina A. G. antoniettagerarda.gravina@unicampania.it 1 Tessitore A. 2 Ormando V. M. 1 Nagar F. 3 Romeo M. 1 Amato M. R. 1 Dallio M. 1 Loguercio C. 1 Federico A. 1 Romano M. 1 Ferraro F. 3 1 grid.9841.40000 0001 2200 8888Hepatogastropenterology Unit, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Pansini, 5, 80131 Naples, Italy \n2 grid.9841.40000 0001 2200 8888Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy \n3 grid.9841.40000 0001 2200 8888Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy \n21 1 2021 \n21 1 2021 \n2021 \n21 3130 1 2020 6 1 2021 © The Author(s) 2021Open 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\nPercutaneous Endoscopic Gastrostomy (PEG) can involve some complications, despite the good safety of its track record. The Buried Bumper Syndrome (BBS) is a rare, late and dangerous complication that consists in the erosion of the internal bumper through the gastric wall.\n\nCase presentation\n\nWe report the development of BBS in a man with chronic obstructive pulmonary disease (COPD) who had a persistent chronic cough which was prevalently but not solely in the morning and required placement of a PEG tube for continuous infusion of Levodopa/carbidopa intestinal gel for advanced Parkinson's disease.\n\nConclusion\nWe believe that COPD with chronic cough while not representing an absolute contraindication to PEG placement, may potentially cause BBS and therefore an appropriate regimen of tube care by expert personnel is mandatory in this setting.\n\nKeywords\nPercutaneous endoscopic gastrostomyBuried bumper syndromeChronic obstructive pulmonary diseaseCoughissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nPercutaneous endoscopic gastrostomy (PEG) is considered a safe procedure to provide long term enteral nutrition and enteral access [1]. In addition, the PEG tube can be used to intubate the proximal jejunum with an extension tube (J-PEG) to allow the pharmacological treatment of Advanced Parkinson’s Disease through a continuous delivery of levodopa (L-Dopa)/carbidopa intestinal gel (LCIG). It represents a new approach in patients with Advanced Parkinson’s Disease who respond to oral administration of L-Dopa therapy but with dyskinesias and motor fluctuations which are poorly managed by optimized oral therapy alone [2].\n\nAlthough it has been generally considered safe, PEG tube placement can be associated with many potential complications that can be classified as minor or major. Major complications include aspiration pneumonia, hemorrhage, buried bumper syndrome (BBS), colon perforation during the PEG insertion, necrotizing fasciitis [1, 3–5]. An unusual and late complication could be the BBS that occurs when the internal bumper erodes from the lumen of the stomach into the gastric wall or subcutaneous tissue. BBS is due to excessive tension between the internal and external bumpers that causes ischemic necrosis of the gastric wall. It usually manifests with the signs and symptoms of infection due to leakage of gastric content from around the PEG tube insertion site in the peristomal site. We may observe fixity of the PEG tube, abdominal pain and resistance to water or nutritional solution infusion. Inability to insert PEG tube, loss of patency and leakage around the PEG tube are considered to be a typical symptomatic triad [6]. However, if the tube is not removed as soon as possible, severe complications might happen such as perforation of the stomach, peritonitis and death [7–9].\n\nCase presentation\nA 57 years old man affected by Advanced Parkinson’s Disease was selected for J-PEG placement to allow the continuous administration of LCIG in duodenum (AbbVie PEG polyurethane Tube 20 F). We obtained informed consent. He had a smoking history of 30/40 cigarettes per day for the past 30 years reporting a chronic cough, prevalently but not solely in the morning. On examination he appeared overweight (BMI = 29) with an abdominal fat distribution. Lung clinical examination revealed a barrel chest decreased brief sounds, with moderate inspiratory and expiratory wheezing, he used accessory muscles of respiration. There were signs and symptoms of chronic obstructive pulmonary disease (COPD); spirometry showed a ratio of forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) slightly lower than normal (65%); and low maximum expiratory flow (MEF was 80% at 25% and 50%). There were no absolute contraindication to place PEG tube. A pull-technique was used and a routine post insertion endoscopic confirmation of satisfactory PEG placement (AbbVie PEG polyurethane Tube 20 F) was performed at the end of the procedure. The PEG appeared successfully placed. Thirteen days later the tube was unable to infuse solution, there was a peritubal leak and the patient had abdominal pain with signs of edema and erythema of the tube insertion area. On the clinical examination we observed that during cough attack abdomen of our patient become prominent. Endoscopic evaluation showed that gastric mucosa covering internal gastrostomy site resulted in a complete closure of the orifice with visualization of only the J-tube extension. The internal bumper was not visible on the gastric wall but mucosa was ulcerated at the presumed site (Fig. 1). The patient underwent computed tomography (CT) (Fig. 2) of the abdomen, BBS was recognized and the device was removed by using a needle-knife assisted endoscopic dissection technique. After one week, following a thorough multidisciplinary evaluation due to the patient’s considerable anesthesiological risk, we positioned a new PEG-tube endoscopically in an area at a distance from the one used previously. Unfortunately, however, one month later the BBS presented again..Because the internal bumper was not visible endoscopically due to its dislocation into the abdominal wall, a microinvasive endoscopic needle knife-assisted approach was not feasible, and, therefore, we removed it surgically.Fig. 1 Endoscopic image of BBS, the internal bumper is not visible on the gastric wall\n\nFig. 2 Computed Tomography (CT) image demonstrating a BBS type 3\n\n\n\nDiscussion and conclusion\nBBS is usually a late and rare complication of PEG occurring in 0.3–2.4% of the patients [1]. BBS usually appears no earlier than 4 months after PEG placement. Nevertheless it has been described a case of BBS after three weeks from tube placement [9]. In our patient, BBS occurred thirteen days after PEG insertion and then again after one month. The case of our patient suggests that COPD and chronic cough may represent a potential cause of BBS, even though the association between COPD with chronic cough and BBS as in our case does not necessarily imply a cause-effect relationship. Our case report underlines the important role of the traction performed by the respiratory movements in a patient with COPD with little airway obstruction, as evaluated by spirometry. The persistent cough produced a traction of the PEG tube and a bumper compression which in turn lead to gastric wall erosion. We cannot completely rule out the possibility that too much tension was placed on the bumper during PEG tube insertion or that there had been a lack of appropriate management of the tube. The first time, after thirteen days from the first positioning, there was a displacement corresponding to a type 3 BBS because the internal bumper appeared total visible at mobilization. The second time, after one month from the second PEG placement, a deep type 4 BBS occurred. This is according to Richter-Schraq HJ et al. who described 4 types of BBS: in type 1 the internal bumper is outside the body or in the subcutaneous tissue; in type 2 the internal bumper is partially visible in gastric lumen; in type 3 the internal bumper is not visible in the gastric lumen and is in the most superficial layers of the gastric wall; in type 4 the internal bumper is not visible in the gastric cavity and is in the deeper layers of the gastric wall [7]. BBS is a dangerous major complication of the PEG placement because it may cause infection, necrotizing fasciitis [3, 10], peritonitis and consequently septic shock with a fatal outcome [8]. Absolute contraindication to PEG placement are pharyngeal and esophageal occlusion for pull technique, active serious coagulopathy, hemodynamic instability, sepsis, severe ascites, peritonitis, peritoneal carcinomatosis, portal hypertension with gastric varices, total gastrectomy [1, 11]. Our patient had none of these absolute contraindications. Moreover some studies associated COPD at a higher risk of fatal outcome due to an increased susceptibility of COPD patients to develop gastroesophageal reflux disease that is strictly associated to a higher aspiration pneumonia risk, rather than a higher risk of BBS rising [12]. We believe that COPD with chronic cough may cause the displacement of the internal bumper thus causing BBS. Therefore, in case of a complication such as BBS it is important to have a radiologic evaluation in order to better assess the problem and possibly solving it through a surgical approach.\n\nPEG is a safe for enteral nutrition and J-PEG has a fundamental role in the pharmacological treatment of Advanced Parkinson’s Disease as well as to ability to feed directly into the jejunum. PEG tube placement may have complications and BBS is one of these ones. PEG-related complications are mostly prevented by an appropriate tube care.. It is essential for all patients, but particularly in those who have a chronic cough, that during the daily tube cleaning the PEG is not only rotated, but advanced further into the stomach and then pulled back until set to the correct length and tension. In these patients, the tube needs to have some slack to accommodate the excursion of the abdominal wall during forced expiration while coughing. In order to avoid BBS, some PEG tubes with externally removable internal bumpers were found useful in the treatment of BBS allowing the bumper removal by external traction without any endoscopic or surgical methods [13].\n\nCOPD with chronic cough does not represent a contraindication to placement of PEG tube but in our opinion, by facilitating movements of internal bumper, it may favor erosion of internal bumper from gastric lumen into the gastric wall or subcutaneous tissue thus causing BBS. Therefore, based on this case report, not only much attention should be paid to PEG placement but also an accurate post-procedure tube care should be strongly advised in this particular setting.\n\nAbbreviations\nPEGPercutaneous endoscopic gastrostomy\n\nBBSBuried bumper syndrome\n\nCOPDChronic obstructive pulmonary disease\n\nJ-PEGPEG with jejunal extension tube\n\nL-DopaLevodopa\n\nLCIGLevodopa/carbidopa intestinal gel\n\nBMIBody max index\n\nFEV1Forced expiratory volume in 1s\n\nFVCForced vital capacity\n\nMEFMaximum expiratory flow\n\nCTComputed tomography\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nA. G. Gravina and A. Tessitore have contributed equally to this work.\n\nAcknowledgements\nResearch activity of Dr. Antonietta G. Gravina was supported by the Valere Program.\n\nAuthors’ contributions\nAGG and FF: draft of the manuscript; AT: neurologist who proposed the placement of PEG-J for Parkinson's therapy in this patient; AGG, MRA and VMO: performed upper gastrointestinal endoscopy and PEG placement; FF and FN: anesthesia evaluation and deep sedation during PEG placement; MD: references serch; MR: references serch and revision; AGG, AT, FF, CL, MR, AF: critical review of the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions.\n\nFunding\nNo funding to declare.\n\nAvailability of data and materials\nAll the data supporting our findings can be found in the patient hospital medical report. Unlikely, we don't have an electronic repository at out Institution. All the personal patients' data, including biochemical, endoscopic and radiological exams, are stored on paper at our hospital. Therefore we can't share our data.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nThe patient provided written consent for the publication of identifying information and/or images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Rahnemai-Azar AA Rahnemaiazar AA Naghshizadian R Kurtz A Farkas DT Percutaneous endoscopic gastrostomy: indications, technique, complications and management World J Gastroenterol 2014 20 7739 7751 10.3748/wjg.v20.i24.7739 24976711 \n2. Zibetti M Merola A Artusi CA Rizzi L Angrisano S Reggio D Levodopa/carbidopa intestinal gel infusion in advanced Parkinson's disease: a 7-year experience Eur J Neurol 2014 21 2 312 318 10.1111/ene.12309 24313838 \n3. Artul S Nseir W Assaf V Abboud N Abdominal wall necrotising fasciitis due to dislodged percutaneous endoscopic gastrostomy tube BMJ Case Rep 2014 10.1136/bcr-2013-201346 25326568 \n4. Roveron G Antonini M Barbierato M Calandrino V Canese G Chiurazzi LF Clinical practice guidelines for the nursing management of percutaneous endoscopic gastrostomy and jejunostomy (Peg/PEJ) in adult patients: an executive summary J Wound Ostomy Continence Nurs 2018 45 4 326 334 10.1097/WON.0000000000000442 29994859 \n5. Pars H Çavuşoğlu H A literature review of percutaneous endoscopic gastrostomy: dealing with complications Gastroenterol Nurs 2019 42 4 351 359 10.1097/SGA.0000000000000320 29219857 \n6. Cyrany J Rejchrt S Kopacova M Bures J Buried bumper syndrome: a complication of percutaneous endoscopic gastrostomy World J Gastroenterol 2016 22 2 618 627 10.3748/wjg.v22.i2.618 26811611 \n7. Richter-Schraq HJ Fischer A Buried bumper syndrome: a new classification and therapy algorithm Der Chirurg 2015 86 963 969 10.1007/s00104-014-2973-x \n8. Biswas S Dontukurthy S Rosenzweig MG Kothuru R Abrol S Buried bumper syndrome revisited: a rare but potentially fatal complication of PEG tube placement Case Rep Crit Care 2014 10.1155/2014/634953 24829839 \n9. Geer W Jeanmonod R Early presentation of buried bumper syndrome Western J Emerg Med 2013 14 421 423 10.5811/westjem.2013.2.15843 \n10. Tenembaum D Inayat F Rubin M Necrotizing fasciitis secondary to acute buried bumper syndrome Clin Gastroenterol Hepatol 2015 13 A17 18 10.1016/j.cgh.2014.10.026 \n11. Pih GY Na HK Ahn JY Jung KW Kim DH Lee JH Risk Factors for complications and mortality of percutaneous endoscopic gastrostomy insertion BMC Gastroenterol 2018 18 1 101 10.1186/s12876-018-0825-8 29954339 \n12. Kawano M Anan H Shimizu M Evaluation of percutaneous endoscopic gastrostomy in elderly patients with silicosis and co-morbidities The Kurume Medical Journal 2003 50 81 85 10.2739/kurumemedj.50.81 14768469 \n13. Erdil A Genç H Uygun A Ilica AT Dağalp K The buried bumper syndrome: the usefulness of retrieval PEG tubes in its management Turk J Gastroenterol 2008 19 1 45 48 18386240\n\n",
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"journal": "BMC gastroenterology",
"keywords": "Buried bumper syndrome; Chronic obstructive pulmonary disease; Cough; Percutaneous endoscopic gastrostomy",
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D000075202:Contraindications; D003371:Cough; D004750:Enteral Nutrition; D005774:Gastrostomy; D006801:Humans; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive",
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"title": "May chronic cough in chronic obstructive pulmonary disease be a contraindication of Percutaneous Endoscopic Gastrostomy placement: a case report.",
"title_normalized": "may chronic cough in chronic obstructive pulmonary disease be a contraindication of percutaneous endoscopic gastrostomy placement a case report"
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"abstract": "Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity of potentially curative cancer therapy regimens. Cisplatin is the class of chemotherapy agent that has a broad spectrum of activity against several solid tumors, but it induces sensory neuropathy of upper and lower extremities. Cisplatin-induced peripheral neuropathy is usually in a \"gloves and socks\" distribution that can persist for months or years after completion of chemotherapy treatment. If the pain is severe, it affects the patient's long-term quality of life and can potentially result in chemotherapy dose reduction or treatment discontinuation. The mechanism of CIPN is not well understood, and a number of pathophysiological mechanisms have been proposed to explain the phenomenon. Although many therapies have been investigated for the prevention or treatment of CIPN, there is currently no accepted proven therapy. Here we report a case in which lacosamide alleviated painful CIPN symptoms. Lacosamide is an anticonvulsant drug that blocks the voltage-gated sodium channels in the neurons and may also be a promising novel candidate for the prevention and treatment of chemotherapy-induced peripheral neuropathy. Preclinical data support the role of lacosamide protective effect in a rat model of chemotherapy-induced neuropathy, randomized clinical trial is needed.",
"affiliations": "Division of Hematology and Medical Oncology, Department of Medicine, Indiana University Simon Cancer Center, Indianapolis, Indiana, USA. samibrah@iupui.edu.;Division of Hematology and Medical Oncology, Department of Medicine, Indiana University Simon Cancer Center, Indianapolis, Indiana, USA.;Division of Hematology and Medical Oncology, Department of Medicine, Indiana University Simon Cancer Center, Indianapolis, Indiana, USA.",
"authors": "Ibrahim|Samar A|SA|;Albany|Zhanna|Z|;Albany|Constantine|C|",
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"issue": "13(5)",
"journal": "The Journal of community and supportive oncology",
"keywords": "Chemotherapy-induced peripheral neuropathy; cisplatin; lacosamide; voltage-gated sodium channel 1.7",
"medline_ta": "J Community Support Oncol",
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"nlm_unique_id": "101621609",
"other_id": null,
"pages": "202-4",
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"pmid": "26029937",
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"title": "Significant response to lacosamide in a patient with severe chemotherapy-induced peripheral neuropathy.",
"title_normalized": "significant response to lacosamide in a patient with severe chemotherapy induced peripheral neuropathy"
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"companynumb": "US-UCBSA-2015019853",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTo present our experience of post-transplant infections in allogeneic stem cell transplants at Sheikha Badryia Stem Cell Transplant Centre, Kuwait.\n\n\nMETHODS\nRetrospective analysis of 21 consecutive patients with malignant and non-malignant hematological disorders who received a transplant of an unmanipulated bone marrow graft from an HLAidentical sibling donor from November 2011 to December 2013. Pre-transplant infection surveillance was carried out, and strict prophylaxis against infection was observed. Bone marrow stem cells were used as the stem cell source. Cyclosporin and methotrexate with or without mycophenolate mofetil/methylprednisolone were used as graftversus-host disease (GVHD) prophylaxis. The engraftment was monitored with molecular analysis. Survival was calculated from the date of transplant to death or last follow-up.\n\n\nRESULTS\nTwenty-one patients received allogeneic stem cell transplants from HLA- matched siblings for various hematological disorders. Twelve patients were female. The median age of the patient cohort was 34 years (range 3-41 years). All patients and donors were cytomegalovirus (CMV) IgG-positive. Seventeen patients (80.95%) developed febrile episodes in different phases of post-transplant recovery. Posttransplant infections were confirmed in 20 patients (90.2%) on the basis of clinical assessment and microbiological, virological, and histopathological examination. Mortality related to infections and chronic graft versus host disease was one patient (4.8%).\n\n\nCONCLUSIONS\n90% of our patients developed febrile episodes with relatively low culture yield. The majority of infections were treated effectively.",
"affiliations": "Department of Medicine, Kuwait University Faculty of Medicine, Kuwait.;Department of Medical Oncology, Shaikha Badryia Stem Cell Transplant Center, Kuwait.;Microbiology Department, Ibn Sina Hospital, Kuwait.;Virology Department, Mubarak AlKabeer Hospital, Kuwait.",
"authors": "AlShemmari|S|S|;Refaat|S|S|;Abdullah|A A|AA|;Abul|M A|MA|",
"chemical_list": null,
"country": "Kuwait",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-2101",
"issue": "1(18)",
"journal": "The Gulf journal of oncology",
"keywords": null,
"medline_ta": "Gulf J Oncolog",
"mesh_terms": null,
"nlm_unique_id": "101500911",
"other_id": null,
"pages": "79-86",
"pmc": null,
"pmid": "26003109",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Infectious complications after allogeneic bone marrow transplantation: Sheikha Badryia Center, Kuwait.",
"title_normalized": "infectious complications after allogeneic bone marrow transplantation sheikha badryia center kuwait"
} | [
{
"companynumb": "KW-PFIZER INC-2018262550",
"fulfillexpeditecriteria": "1",
"occurcountry": "KW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "Azathioprine, an immunosuppressant which is widely used in the management of the autoimmune neuromuscular disorder. Myasthenia gravis is known to cause myelotoxicity. A 55-year-old male recently diagnosed with myasthenia gravis and chronic kidney disease was put on azathioprine (100 mg/d) along with pyridostigmine and prednisolone. When the treatment was initiated, the hematological reports revealed normal levels of blood count. However, approximately within 3 weeks of continuing the prescribed drugs, the patient was readmitted for complaints of loose watery stools, weakness, and giddiness. Clinical investigations revealed severe pancytopenia, suspecting to be related to azathioprine. The suspected drug (azathioprine) was withdrawn, and the management for pancytopenia was initiated. However, on the second day of hospitalization, the patient underwent cardiac arrest and septic shock which lead to death. Adverse drug reaction assessment revealed a plausible and causal relationship of azathioprine with pancytopenia and other adverse effects seen in this patient.",
"affiliations": "1 Department of Clinical Pharmacy, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University Erandwane, Pune, Maharashtra, India.;1 Department of Clinical Pharmacy, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University Erandwane, Pune, Maharashtra, India.;2 Department of General Medicine, Bharati Vidyapeeth Deemed University Medical College and Hospital, Pune, Maharashtra, India.",
"authors": "Panda|Bijoy K|BK|;Umarje|Siddhi|S|;Diwan|Arundhati|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190017729521",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "31(5)",
"journal": "Journal of pharmacy practice",
"keywords": "adverse effects; azathioprine; myasthenia gravis; pancytopenia",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D001379:Azathioprine; D017809:Fatal Outcome; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D010198:Pancytopenia; D018805:Sepsis",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "510-513",
"pmc": null,
"pmid": "28874083",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Azathioprine-Induced Pancytopenia and Septic Complications: A Probable Cause of Death.",
"title_normalized": "azathioprine induced pancytopenia and septic complications a probable cause of death"
} | [
{
"companynumb": "IN-IMPAX LABORATORIES, INC-2018-IPXL-03303",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditi... |
{
"abstract": "Second-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer.\n\n\n\nThirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0-5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.\n\n\n\nMedian age (range) was 65 (51-78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort.\n\n\n\nIn patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.",
"affiliations": "Guy's and St Thomas' NHS Foundation Trust, London, UK rebecca.kristeleit@gstt.nhs.uk.;START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain.;START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain.;Hospital Universitario Ramón y Cajal, Madrid, Spain.;PharmaMar SA, Colmenar Viejo, Madrid, Spain.;Instituto Valenciano de Oncología, Valencia, Spain.;START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain.;Hospital Universitari Vall d'Hebron, Barcelona, Spain.;PharmaMar SA, Colmenar Viejo, Madrid, Spain.;PharmaMar SA, Colmenar Viejo, Madrid, Spain.;Clinical Development, PharmaMar SA, Colmenar Viejo, Spain.;PharmaMar SA, Colmenar Viejo, Madrid, Spain.;NIHR UCLH Clinical Research Facility, London, UK.",
"authors": "Kristeleit|Rebecca|R|;Moreno|Victor|V|;Boni|Valentina|V|;Guerra|Eva M|EM|;Kahatt|Carmen|C|;Romero|Ignacio|I|;Calvo|Emiliano|E|;Basté|Neus|N|;López-Vilariño|José A|JA|;Siguero|Mariano|M|;Alfaro|Vicente|V|0000-0002-0150-2390;Zeaiter|Ali|A|;Forster|Martin|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/ijgc-2021-002881",
"fulltext": "\n==== Front\nInt J Gynecol Cancer\nInt J Gynecol Cancer\nijgc\nijgc\nInternational Journal of Gynecological Cancer\n1048-891X\n1525-1438\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34610971\nijgc-2021-002881\n10.1136/ijgc-2021-002881\nOriginal Research\n1506\nDoxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study\nKristeleit Rebecca 1\nMoreno Victor 2\nBoni Valentina 3\nGuerra Eva M 4\nKahatt Carmen 5\nRomero Ignacio 6\nCalvo Emiliano 3\nBasté Neus 7\nLópez-Vilariño José A 5\nSiguero Mariano 5\nhttp://orcid.org/0000-0002-0150-2390\nAlfaro Vicente 8\nZeaiter Ali 5\nForster Martin 9\n1 Guy’s and St Thomas’ NHS Foundation Trust, London, UK\n2 START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain\n3 START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain\n4 Hospital Universitario Ramón y Cajal, Madrid, Spain\n5 PharmaMar SA, Colmenar Viejo, Madrid, Spain\n6 Instituto Valenciano de Oncología, Valencia, Spain\n7 Hospital Universitari Vall d'Hebron, Barcelona, Spain\n8 Clinical Development, PharmaMar SA, Colmenar Viejo, Spain\n9 NIHR UCLH Clinical Research Facility, London, UK\nCorrespondence to Dr Rebecca Kristeleit, Department of Oncology, Guy's and ST Thomas' NHS Foundation Trust, London SE1 9RT, UK; rebecca.kristeleit@gstt.nhs.uk\n11 2021\n5 10 2021\n31 11 14281436\n21 6 2021\n03 9 2021\n© IGCS and ESGO 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nObjective\n\nSecond-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer.\n\nMethods\n\nThirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0–5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.\n\nResults\n\nMedian age (range) was 65 (51–78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort.\n\nConclusions\n\nIn patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.\n\nendometrial neoplasms\nendometrium\nUCL/UCLH NIHR Biomedical Research Centre Pharma Mar S.A. Centro para el Desarrollo Tecnológico Industrial (CDTI) special-featureunlocked\n==== Body\npmcHIGHLIGHTS\n\nThis phase I trial suggests a synergistic effect for lurbinectedin and doxorubicin.\n\nIn the expansion phase, response rate was 42.1% and duration of response was 7.5 months for the combination of doxorubicin plus lurbinectedin.\n\nMedian progression-free survival was 7.7 months and median overall survival was 14.2 months.\n\nIntroduction\n\nRelapsed endometrial cancer has a poor prognosis with a median survival of 12–15 months. This patient population has a significant unmet clinical need and optimal treatment is yet to be established.1 2 There are promising signs of clinical efficacy with anti-programmed death-1 targeting drugs for mismatch repair deficient relapsed endometrial cancer and combination treatment with pembrolizumab plus lenvatinib in microsatellite stable recurrent endometrial cancer. Recently, dostarlimab was approved for second-line treatment of adult patients with advanced or recurrent mismatch repair deficient disease. Biomarkers such as overexpression of polymerase epsilon, proto-oncogene Neu, and microsatellite instability or mismatch repair deficiency are increasingly being used in the setting of recurrent disease.3 4 However, single agent chemotherapy remains the most frequent treatment for relapsed endometrial cancer.2\n\nLurbinectedin is a minor groove targeting DNA binder that interacts with specific factors involved in DNA repair and transcription pathways, thereby inhibiting trans-activated transcription in tumor cells, and also transcription and secretion of selected cytokines by tumor-associated macrophages. In June 2020, the United States Food and Drug Administration (FDA) granted accelerated approval to lurbinectedin for adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy.5 Lurbinectedin plus doxorubicin showed synergistic antitumor effect in small cell lung cancer xenografted tumors. Improved activity with this combination and activity observed for lurbinectedin in a study of humans6 prompted a phase I trial to evaluate this combination in advanced solid tumors.7 During the dose escalation, activity was promising in two tumor types—small cell lung cancer and endometrial cancer—and expansion cohorts were evaluated. We show the results observed in advanced endometrial cancer during dose escalation and cohort expansion, exploring a modified regimen to reduce myelosuppression.\n\nMethods\n\nPatients were enrolled in sites from Spain and the United Kingdom. The study followed the International Conference on Harmonization Good Clinical Practice guidelines, and was approved by the respective Research Ethics Committees for each country. Written informed consent was obtained from all patients. The trial is registered in the European Clinical Trials Register database (EudraCT 2010-024291-25) and at ClinicalTrials.gov (NCT01970540).\n\nEligibility Criteria\n\nEligible patients were aged 18 years and older with endometrial cancer treated with one or two prior lines of cytotoxic chemotherapy for advanced disease and were anthracycline naïve; had documented disease progression during or immediately after their last therapy in those treated in the expansion cohort; had recovered from previous toxicities (at least 3 weeks since last anticancer therapy); had life expectancy of 3 months or more; had Eastern Cooperative Oncology Group performance status of 2 or lower; had normal left ventricular ejection fraction; and had adequate bone marrow, hepatic and renal function, including albumin ≥3.0 g/dL. Prior endocrine therapy was allowed (not considered a line of treatment).\n\nPatients were excluded if they had symptomatic progressive or corticosteroid-requiring brain metastases or leptomeningeal involvement; had prior bone marrow/stem cell transplantation, cardiac disease, uncontrolled alcohol consumption or cirrhosis, active uncontrolled infection, or any disease potentially interfering with the study outcome.\n\nStudy Design and Treatment\n\nStudy design is summarized in Figure 1. Dose escalation has been described elsewhere.7 Briefly, 74 patients with advanced solid tumors (15 patients with endometrial cancer) were included using a 3+3 cohort design. Four dose levels were evaluated: fixed doxorubicin 50 mg/m2 as an intravenous bolus with escalating flat doses of lurbinectedin (3.0, 3.5, 4.0 and 5.0 mg) intravenously over 1 hour on day 1 every 3 weeks. The recommended dose was doxorubicin 50 mg/m2 plus lurbinectedin 4.0 mg.\n\nFigure 1 Study design. DLT, dose-limiting toxicity; FD, flat dose; MTD, maximum tolerated dose; q3wk, every 3 weeks; RD, recommended dose.\n\nAfter identification of the recommended dose and encouraging antitumor activity, expansion cohorts were started in small cell lung cancer and advanced endometrial cancer. Results for the expanded small cell lung cancer cohort are described elsewhere.7 This report focuses on the endometrial cohort. In this expanded cohort, patients were treated with a new recommended dose, doxorubicin 40 mg/m2 intravenous bolus plus lurbinectedin 2.0 mg/m2 1 hour intravenous infusion, using the same schedule (day 1 every 3 weeks) as the dose escalation phase. Doxorubicin dose was lowered to 40 mg/m2 and lurbinectedin dose was transformed to a body surface area based dose to reduce severe myelosuppression. This change was introduced in a protocol amendment because dose-limiting toxicities were found in several patients with small cell lung cancer and endometrial cancer at the initial recommended dose (doxorubicin 50 mg/m2 plus lurbinectedin 4.0 mg.). All dose-limiting toxicities reported in patients with endometrial cancer were neutropenia related and 86.4% of patients with small cell lung cancer had grade 4 neutropenia. These findings suggested that the initial recommended dose might not be feasible in these patient populations. Both doxorubicin and lurbinectedin doses were capped at a body surface area of 2.0 m2. Furthermore, to prevent cardiomyopathy,8 patients who received 10 cycles of the combination (before a cumulative dose of 450 mg/m2 was reached), or discontinued doxorubicin due to a cardiac adverse event, continued treatment with lurbinectedin alone (4.0 mg/m2 on day 1 every 3 weeks).\n\nAll patients received standard antiemetic prophylaxis before each infusion.9 Treatment was given until disease progression, unacceptable toxicity, intercurrent illness precluding study continuation, patient refusal and/or non-compliance with study requirements, treatment delay greater than 15 days (except if clear clinical benefit), and requirement of more than two dose reductions.\n\nStudy Assessments\n\nAntitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1 (responses confirmed at least 4 weeks later). Overall response rate was the percentage of patients with confirmed complete or partial response. Time-to-event parameters were duration of response and progression-free survival. Progression-free survival was defined as the time from the date of first infusion of study treatment to the date of progression or death (due to any cause).10 Overall survival was reported only in the dose expansion phase as an exploratory assessment. Overall survival was defined as the time from the date of first infusion of study treatment to the date of death (due to any cause).10\n\nAdverse events were coded with the Medical Dictionary for Regulatory Activities version 14.1 and graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4. Laboratory abnormalities (hematological and biochemical) were measured weekly in the first cycle, and on day 1 and day 10 in further cycles, and graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.\n\nStatistical Analysis\n\nContinuous variables were presented with summary statistics and categorical variables in frequency tables. Time-to-event variables were calculated using the Kaplan-Meier approach. Binomial exact distribution was used to calculate 95% CI intervals for categorical variables.\n\nResults\n\nDose Feasibility for the New Recommended Dose\n\nForty-seven patients were treated with doxorubicin 40 mg/m2 plus lurbinectedin 2.0 mg/m2 every 3 weeks in the expansion cohort: 28 patients with small cell lung cancer and 19 patients with endometrial cancer. Dose-limiting toxicities occurred in four of 46 evaluable patients (9%); this percentage was lower than the threshold (one third) established by the study protocol to define the recommended dose, thereby confirming dose feasibility. All dose-limiting toxicities occurred in small cell lung cancer patients, and comprised grade 3/4 febrile neutropenia (n=2), grade four thrombocytopenia, and grade three decreased appetite (n=1 each).11\n\nCharacteristics of Patients With Endometrial Cancer\n\nThirty-four patients with advanced endometrial cancer were treated in this phase I study: 15 patients during the escalation phase and 19 patients in the expansion cohort (Table 1). Median age was 64 (range 51–78) years in the escalation phase and 66 (55–73) years in the expansion cohort, and most patients (23/34; 67.6%) had Eastern Cooperative Oncology performance status score of 1. The most common histological type was endometrioid (26 patients; 76.5%). The median number of prior lines for advanced disease was one (range zero to two), with platinum and taxanes as the most common agents. Median platinum-free interval was 4.5 (range 0.3–17.1) months in the escalation phase and 4.3 (0.3–16.5) months in the expansion cohort.\n\nTable 1 Baseline characteristics of patients with endometrial cancer\n\n\tDose escalation phase (n=15)*\tExpanded cohort\n(n=19)†\t\nN\t%\tN\t%\t\nMedian age (range) (years)\t64 (51–78)\t66 (55–73)\t\nECOG performance status\t\n0\t4\t26.7\t6\t31.6\t\n1\t11\t73.3\t12\t63.2\t\n2\t–\t–\t1\t5.3\t\nMedian BSA (range) (m2 )\t1.7 (1.4–2.1)\t1.8 (1.6–2.3)\t\nBulky disease (lesion >50 mm)\t5\t38.5\t4\t21.1\t\nVisceral disease\t7\t46.7\t7\t36.8\t\nHistology\t\nEndometrioid\t11\t73.3\t15\t78.9\t\nCarcinosarcoma\t3\t20.0\t3\t15.8\t\nClear cell\t1\t6.7\t–\t–\t\nSerous/papillary\t–\t–\t1\t5.3\t\nMedian No of sites (range)\t2 (1–5)\t2 (1–3)\t\nMost common metastatic sites\t\nLymph nodes\t9\t60.0\t10\t52.6\t\nLung\t6\t40.0\t5\t26.3\t\nPeritoneum\t2\t13.3\t8\t42.1\t\nPelvis\t2\t13.3\t3\t15.8\t\nLiver\t2\t13.3\t2\t10.5\t\nPrior therapy\t\t\t\t\t\nChemotherapy\t15\t100.0\t19\t100.0\t\nSurgery\t10\t66.7\t15\t78.9\t\nRadiotherapy\t6\t40.0\t12\t63.2\t\nHormonal therapy\t4\t26.7\t4\t21.1\t\nBiological therapy\t1\t6.7\t2\t10.5\t\nPrior chemotherapy lines\t\t\t\nMedian (range)\t1 (1–2)\t1 (1–2)\t\n1\t11\t73.3\t15\t78.9\t\n2\t4\t26.7\t4\t21.1\t\nLines for advanced disease, median (range)\t1 (0–2)\t1 (0–2)\t\nMost common prior anticancer agents\t\nPlatinum compounds\t9\t60.0\t16\t84.2\t\nTaxanes\t8\t53.3\t15\t78.9\t\nPlatinum-free interval\t4.5 (0.3–17.1)\t4.3 (0.3–16.5)\t\n*Patients treated at fixed doxorubicin dose (50 mg/m2) and escalating lurbinectedin doses (ranging from 3.0 to 5.0 mg flat dose) on day 1 every 3 weeks.\n\n†Patients treated at the recommended dose of doxorubicin 40 mg/m2 plus lurbinectedin 2.0 mg/m2 on day 1 every 3 weeks.\n\nBSA, body surface area; ECOG, Eastern Cooperative Oncology Group.;\n\nTreatment Exposure\n\nIn the escalation phase, the median number of cycles per patient was 8 (range 1–52). Median relative dose intensity for doxorubicin and lurbinectedin was 95.0% and 83.7%, respectively. Treatment-related cycle delays, dose reductions and discontinuations were observed in 79%, 71% and 13% of patients, mainly because of hematological toxicity. In the expansion cohort, the median number of cycles per patient was 9 (range 1–28). Median relative dose intensity for doxorubicin and lurbinectedin was 95.0% and 90.3%, respectively. Treatment-related cycle delays, dose reductions and discontinuations were observed in 65%, 47% and 11% of patients, also mainly because of hematological toxicity.\n\nEfficacy\n\nIn the escalation phase, four (26.7%) of 15 patients had confirmed responses: two complete responses and two partial responses (95% CI 7.8% to 55.1%). The two patients with complete response were treated with lurbinectedin 4.0 and 5.0 mg/m2; the two patients with partial response were treated with lurbinectedin 3.0 and 4.0 mg/m2. Median duration of response was 19.5 (8.2 to not reached) months and median progression-free survival was 7.3 (2.5 to 10.1) months (Table 2).\n\nTable 2 Efficacy results with lurbinectedin plus doxorubicin in patients with endometrial cancer\n\n\tDose escalation phase (n=15)*\tExpanded cohort (n=19)†\t\nObjective response per RECIST v1.1.\t\n CR, n (%)\t2 (13.3)\t–\t\n PR, n (%)\t2 (13.3)\t8 (42.1)\t\n SD ≥4 months, n (%)\t5 (33.3)\t4 (21.1)\t\n SD <4 months, n (%)\t3 (20.0)\t3 (15.8)\t\n PD, n (%)\t3 (20.0)\t4 (21.1)\t\n ORR, % (95% CI)\t26.7 (7.8 to 55.1)\t42.1 (20.3 to 66.5)\t\nDisease control rate (95% CI) ‡\t80.0 (51.9 to 95.7)\t78.9 (54.4 to 93.9)\t\nClinical benefit rate (95% CI) §\t60.0 (32.3 to 83.7)\t63.2 (38.4 to 83.7)\t\nMedian DoR (months) (95% CI)\t19.5 (8.2 to NR)\t7.5 (6.4 to NR)\t\nMedian PFS (months) (95% CI)\t7.3 (2.5 to 10.1)\t7.7 (2.0 to 16.7)\t\nMedian OS (months) (95% CI)\tNA\t14.2 (4.5 to NR)\t\n*Patients treated at fixed doxorubicin dose (50 mg/m2) and escalating lurbinectedin doses (ranging from 3.0 to 5.0 mg flat dose) on day 1 every 3 weeks.\n\n†Patients treated at the recommended dose of doxorubicin 40 mg/m2 plus lurbinectedin 2.0 mg/m2 on day 1 every 3 weeks.\n\n‡Objective response plus stable disease.\n\n§Objective response plus stable disease ≥4 months.\n\nCR, complete response; DoR, duration of response; NA, not available; NR, not reached; ORR, overall response rate; OS, overall survival; PD, disease progression; PFS, progression-free survival; PR, partial response; SD, stable disease.\n\nIn the expansion cohort, 8 (42.1%) of 19 patients had confirmed partial responses (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months (Table 2). Overall, 69% of patients had reduction in tumor sized as based on imaging assessment, with activity mostly observed in the endometrioid type (Figure 2). Of note, the overall response rate in patients with endometrioid carcinoma (n=26) was 36.4% (95% CI 10.9% to 69.2%) in the escalation phase and 46.7% (21.3% to 73.4%) in the expansion cohort. The overall response rate in patients with non-endometrioid types (n=8) was 0% in the escalation phase and 25% (0.6% to 80.6%) in the expansion cohort. Duration of response in each responder patient is shown in Figure 3.\n\nFigure 2 Waterfall plot showing maximum variation of target lesions size. Endom, endometrioid; PD, disease progression; PR, partial response; S/P, serous/papillary.\n\nFigure 3 Swimmer plot showing duration of response. Each bar represents one patient with endometrial cancer (n=34). Data shown on the left of each bar are the histological type and the duration of response. AE, adverse event; CR, complete response; PD, disease progression; PR, partial response; SD, stable disease.\n\nSafety\n\nThe most frequent treatment-related (or with unknown relationship) adverse events reported in the escalation phase were fatigue (80.0%), nausea (80.0%), decreased appetite (60.0%), mucositis (46.7%) and vomiting (46.7%). Grade 3 and higher adverse events consisted of febrile neutropenia (40%), fatigue (20%), and diarrhea, nausea and vomiting (7% each). However, patients received different doses, some being lower or higher than the recommended dose. Hence, the safety results are more focused on the patients treated in the expansion cohort (Table 3). The most frequent adverse events were fatigue (78.9%), nausea (68.4%), alopecia (52.6%), constipation (42.1%), and diarrhea, mucositis and vomiting (26.3% each). No cardiac toxicities related to left ventricular ejection fraction occurred. Grade 3 and higher adverse events consisted of fatigue (26.3%), febrile neutropenia (21.1%), and diarrhea, lower respiratory tract infection, neutropenic infection and renal failure acute (5.3% each).\n\nTable 3 Treatment-related adverse events (>10% of patients or grade >3) and laboratory abnormalities regardless of relationship, in patients with advanced endometrial cancer treated at the recommended dose: doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2 on day one every 3 weeks\n\n\tExpansion cohort (n=19 patients)\t\nNCI-CTCAE grade\t\n1/2\t3\t4\tTotal*†\t\nN\t%\tN\t%\tN\t%\tN\t%\t\nTreatment-related adverse events ‡\t\nFatigue\t10\t52.6\t5\t26.3\t–\t–\t15\t78.9\t\nNausea\t13\t68.4\t–\t–\t–\t–\t13\t68.4\t\nAlopecia\t10\t52.6\t–\t–\t–\t–\t10\t52.6\t\nConstipation\t8\t42.1\t–\t–\t–\t–\t8\t42.1\t\nDiarrhea\t4\t21.1\t1\t5.3\t–\t–\t5\t26.3\t\nMucositis\t5\t26.3\t–\t–\t–\t–\t5\t26.3\t\nVomiting\t5\t26.3\t–\t–\t–\t–\t5\t26.3\t\nDecreased appetite\t4\t21.1\t–\t–\t–\t–\t4\t21.1\t\nDysgeusia\t4\t21.1\t–\t–\t–\t–\t4\t21.1\t\nFebrile neutropenia\t–\t–\t2\t10.5\t2\t10.5\t4\t21.1\t\nMyalgia\t3\t15.8\t–\t–\t–\t–\t3\t15.8\t\nDyspepsia\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\nEpistaxis\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\nPain in extremity\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\nPalmar-plantar erythrodysesthesia syndrome\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\nPalpitations\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\nPeripheral edema\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\nPeripheral sensory neuropathy\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\nAcute renal failure\t–\t–\t1\t5.3\t–\t–\t1\t5.3\t\nLower respiratory tract infection\t–\t–\t1\t5.3\t–\t–\t1\t5.3\t\nNeutropenic infection\t–\t–\t1\t5.3\t–\t–\t1\t5.3\t\nLaboratory abnormalities\t\nAnemia\t13\t68.4\t6\t31.6\t–\t–\t19\t100.0\t\nNeutropenia\t4\t21.1\t3\t15.8\t12\t63.2\t19\t100.0\t\nCreatinine increased\t15\t78.9\t–\t–\t1\t5.3\t16\t84.2\t\nThrombocytopenia\t11\t57.9\t1\t5.3\t2\t10.5\t14\t73.7\t\nAP increased\t10\t52.6\t1\t5.3\t–\t–\t11\t57.9\t\nALT increased\t8\t42.1\t2\t10.5\t–\t–\t10\t52.6\t\nAST increased\t8\t42.1\t–\t–\t–\t–\t8\t42.1\t\nBilirubin increased\t2\t10.5\t–\t–\t–\t–\t2\t10.5\t\n*Adverse events and laboratory abnormalities ordered by incidence from higher to lower.\n\n†No grade 5 adverse events were reported.\n\n‡Including adverse events with unknown relationship.\n\nAP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events, v4.\n\nIn the escalation phase, grade 3 and higher hematological laboratory abnormalities consisted of anemia (80.0%), neutropenia (93.3%; grade 4, 86.7%), and thrombocytopenia (46.6%; grade 4, 33.3%). In the expansion cohort, grade 3 and higher hematological laboratory abnormalities consisted of anemia (31.6%), neutropenia (78.9%; grade 4, 63.2%), and thrombocytopenia (15.8%; grade 4, 10.5%) (Table 3). Grade 4 neutropenia was transient with a median duration of 2 days (range 1–6 days). Most biochemical laboratory abnormalities were grade 1 or 2 with no effects on the study treatment.\n\nOne patient died due to a doxorubicin-related adverse event, acute monocytic leukemia, which was detected 129 days after the last study treatment infusion (during follow-up for survival). This patient had previously received pelvic radiotherapy and brachytherapy as well as carboplatin and paclitaxel.\n\nDiscussion\n\nSummary of Main Results\n\nThe overall response rate was 42.1%, median duration of response was 7.5 months, median progression-free survival was 7.7 months and median overall survival was 14.2 months in patients with recurrent advanced endometrial cancer treated with doxorubicin (40 mg/m2) and lurbinectedin (2.0 mg/m2) on day 1 every 3 weeks.\n\nResults in the Context of Published Literature\n\nBased on the results from KEYNOTE-146/Study 111, the US FDA granted accelerated approval to pembrolizumab/lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high or mismatch repair deficient with disease progression following prior systemic therapy and in candidates for curative surgery or radiation.12 In this phase I/II study, the final primary efficacy analysis results in a group of 94 patients with microsatellite stable-H/mismatch repair proficient disease showed an overall response rate of 37.2%, disease control rate ofs 84.0% and clinical benefit rate of 58.5%.13 Time-to-event data were not available, and two confirmatory phase III trials (ClinicalTrials.gov identifier NCT03884101 and NCT03517449) are currently underway. Despite promising clinical efficacy, this study reported treatment-related adverse events leading to dose interruptions in 74% of patients and dose reductions in 53% of patients, with a high discontinuation rate (9%). Doxorubicin 40 mg/m2 plus lurbinectedin 2.0 mg/m2 every 3 weeks in combination showed similar antitumor activity than pembrolizumab/lenvatinib: overall response rate of 42.1% versus 37.2%; disease control rate of 78.9% versus 84.0%, and clinical benefit rate of 63.2% versus 58.5%; and activity was seen across both endometrioid and non-endometrioid histologies.\n\nFurthermore, the results observed for the doxorubicin plus lurbinectedin combination compare favorably with those previously observed in advanced or relapsed endometrial cancer with several agents tested in the second-line setting. Overall, antitumor activity in these previous studies was modest, with response rate ranging between 0% and 27%, paclitaxel being the most active (Table 4).\n\nTable 4 Clinical trials evaluating chemotherapy in second-line treatment of relapsed endometrial cancer\n\nDrugs\tNo of patients\tORR (%)\tReference (year)\t\nCisplatin\t25\t4\tThigpen et al. (1984)19\t\nCyclophosphamide\t15\t0\tPawinski et al.(1999)20\t\nDactinomycin\t27\t12\tMoore et al. (1999)21\t\nDocetaxel (weekly)\t27\t8\tGarcia et al. (2008)22\t\nDoxorubicin\t18\n255\t0\n14\tDi Legge et al. (2011)\nMiller et al. (2018)17 23\t\nDoxorubicin (pegylated)\t42\n19\t10\n11*\tMuggia et al. (2002)\nEscobar et al. (2003)24 25\t\nEtoposide\t22\t0\tRose et al.(1996)26\t\nGemcitabine\t23\t4\tTait et al. (2011) 27\t\nIfosfamide\t40\t15\tSutton et al. (1994)28\t\nIxabepilone\t52\t12\tDizon et al. (2009)29\t\nIxabepilone vs paclitaxel or doxorubicin†\t223/223\t15/16\tMcMeekin et al. (2015)14\t\nOxaliplatin\t54\t14\tFracasso et al. (2006)30\t\nPaclitaxel‡\t44\t27\tLincoln et al. (2003)31\t\nTopotecan\t22\t9\tMiller et al. (2002)32\t\nZoptarelin (AEZ108)§\t256\t12\tMiller et al. (2018)17\t\nLurbinectedin\t40\t13\tForster et al. (2017) 16\t\nPaclitaxel plus lurbinectedin\t11\t27\tForster et al. (2017) 16\t\nDoxorubicin plus lurbinectedin\t15¶\n19 **\t27\n44\tCurrent phase I trial\n(NCT01970540)\t\n*21% response: RECIST (two patients; 11%) and CA-125 response (defined as major symptomatic improvement associated with >50% decline in CA-125 value) (other two patients).\n\n†Phase III randomized trial.\n\n‡Patients had no prior paclitaxel.\n\n§Top-line results from a phase III trial (NCT01767155) evaluating zoptarelin compared with doxorubicin showed no significant difference in the primary endpoint (overall survival), but also in secondary endpoints like progression-free survival.\n\n¶Doxorubicin 50 mg/m2 plus lurbinectedin 3–5 mg flat dose.\n\n**Doxorubicin 40 mg/m2 plus lurbinectedin 2.0 mg/m2.\n\nORR, overall response rate; RECIST, Response Evaluation Criteria in Solid Tumors.\n\nThe median progression-free survival (7.7 months) and median overall survival (14.2 months) observed with doxorubicin plus lurbinectedin can be considered promising. The median progression-free survival was similar to the 7.4 months reported with pembrolizumab/lenvatinib.13 Shorter median progression-free survival (3.4–4.2 months) and overall survival (10.5–12.3 months) have been found with palliative chemotherapy14 and antiangiogenic therapies15 in recurrent endometrial cancer.\n\nActivity with lurbinectedin has been found in other studies conducted in advanced endometrial cancer. In a phase II basket study, 40 patients with endometrial cancer treated with lurbinectedin 3.2 mg/m2 every 3 weeks showed an overall response rate of 12.5% (one complete and four partial responses), median duration of response of ≥4.3 months and median progression-free survival of ≥2.5 months.16 Another trial evaluating lurbinectedin/paclitaxel showed an overall response rate of 27% (three partial responses), median duration of response of 6.1 months and median progression-free survival of 1.9 months in a small cohort of 11 patients.16 However, the most remarkable antitumor activity in terms of overall response rate and progression-free survival has been found in the current trial with lurbinectedin/doxorubicin.\n\nDoxorubicin has shown low antitumor activity in second-line endometrial cancer. A phase III trial compared ixabepilone with paclitaxel or doxorubicin as the control arm: the overall response rate was 16% and the median overall survival was 12.3 months in the control arm.14 Another phase III trial compared zoptarelin with doxorubicin alone: the overall response rate in the doxorubicin arm was 14%, the clinical benefit rate was 52%, and the median overall survival was 10.8 months.17 Therefore, the results from the current phase I trial suggest a synergistic effect of both lurbinectedin and doxorubicin when given in combination, concordant with observations in preclinical studies.\n\nTo date, most chemotherapeutic options for advanced endometrial cancer have been associated with limited efficacy, and some with significant toxicity. Subsequent efforts are focused on exploiting the molecular biology of this disease for target-specific and immunotherapeutic approaches. However, patients with endometrial cancer are often older than 65 years and have comorbidities, and tolerability of treatment is an important consideration, especially with targeted therapy combinations. Pembrolizumab/lenvatinib is associated with substantial toxicity, with treatment-related and grade 3 or 4 adverse events observed in 97% and 67% of patients in the KEYNOTE-146/Study 111.13 The safety analysis supporting the accelerated approval included Study 111 and monotherapy trials that evaluated the contribution of each drug to the safety profile of the combination. Fatal adverse reactions occurred in 3% of patients receiving the combination, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome with intraventricular hemorrhage, and intracranial hemorrhage. Treatment discontinuation due to adverse reactions occurred in 21% and serious adverse events in 52% of patients.12 Hypothyroidism was the most frequent adverse event occurring in a greater proportion of patients (48%).13 Immune-mediated adverse events or infusion-related reactions with pembrolizumab occurred in 57.4% of patients.12 In contrast, doxorubicin/lurbinectedin was generally well tolerated, and associated with manageable and predictable myelotoxicity. Patients received a median of nine cycles and relative dose intensity for lurbinectedin and doxorubicin was 90.3% and 95.0%, respectively. Of note, the absence of cardiac events related to changes in left ventricular ejection fraction either during dose escalation or in the expansion cohort suggest that lurbinectedin does not increase ventricular dysfunction over doxorubicin.18 Due to the incidence of febrile neutropenia, the use of growth colony-stimulating factors is mandatory for further studies.\n\nStrengths and Weaknesses\n\nA strength of this study was the inclusion of an expanded cohort to evaluate a new recommended dose. A limitation of this analysis is that data came from a phase I study with overall response rate assessed by the investigators and a small cohort of patients, which limits the conclusions that can be drawn. Furthermore, no molecular tests were done to check biomarkers in the population evaluated; so, for instance, no comparison with agents in advanced/recurrent mismatch repair deficient disease can be done.\n\nImplications for Practice and Future Research\n\nBecause second-line treatment of advanced endometrial cancer is an unmet medical need, based on the preliminary efficacy results observed, further clinical development of the doxorubicin plus lurbinectedin combination is warranted in relapsed endometrial cancer. This combination may provide a further option for patients with disease unlikely to be cross resistant with newer therapeutic paradigms such as single agent immunotherapy and pembrolizumab/lenvatinib.\n\nConclusions\n\nPromising antitumor activity and a tolerable safety profile have been found for the combination of doxorubicin 40 mg/m2 plus lurbinectedin 2.0 mg/m2 on day 1 every 3 weeks in patients with advanced endometrial cancer. The combination was generally well tolerated, with manageable and predictable myelotoxicity as the main toxicity.\n\nWe gratefully acknowledge the patients, their families and investigator teams.\n\nData availability statement\n\nAll data relevant to the study are included in the article or uploaded as supplementary information. Individual participant data are not publicly available since this requirement was not anticipated in the study protocol considering that this trial started patient enrolment in 2014. Clinical trial summary results were uploaded to the European Clinical Trials Database (EudraCT; https://eudract.ema.europa.eu) and ClinicalTrials.gov (identifier: NCT01970540).\n\nEthics statements\n\nPatient consent for publication\n\nNot applicable.\n\nPresented at: Preliminary results of this study have been presented at the American Society of Clinical Oncology 53rd Annual Meeting. ‘Forster et al. Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer. J Clin Oncol 2017, 35: Abstract 5586’.\n\nContributors: RK: conceptualization, investigation, resources, writing—original draft, writing—review and editing. VM: investigation, resources, writing—review and editing. VB: investigation, resources, writing—review and editing. EMG: investigation, resources, writing—review and editing. CK: conceptualization, methodology, writing—review and editing, supervision. IR: investigation, resources, writing—review and editing. EC: investigation, resources, writing—review and editing. NB: investigation, resources, writing—review and editing. JAL-V: methodology, writing—review and editing, supervision. MS: methodology, formal analysis, writing—review and editing. VA: methodology, writing—original draft, writing—review and editing. AZ: methodology, writing—review and editing, supervision. MF: investigation, resources, writing—review and editing.\n\nFunding: This work was supported by Pharma Mar, S.A. Grants from the Centro para el Desarrollo Tecnológico Industrial (CDTI) were obtained. Rebecca Kristeleit and Martin Forster were supported by the UCL/UCLH NIHR Biomedical Research Center and run early phase studies in the NIHR UCLH Clinical Research Facility supported by the UCL ECMC.\n\nCompeting interests: RK reports personal fees from Eisai. GSK, Clovis, Basilea, AstraZeneca, Roche, InCyte, and PharmaMar; non-financial support from GSK, Clovis, Basilea, AstraZeneca and Roche; and a grant from Clovis, outside the submitted work. VM reports personal fees and other (travelling support, speaker’s bureau) from Bayer, BMS, Pieris, Roche, Janssen, Regeneron/Sanofi and Nanobiotix, and a grant from Medscape/Bayer, outside the submitted work. VB reports personal fees from Oncoart, Guidepoint, PUMA, Cytomx, Loxo Therapeutics, and institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, AstraZeneca, BMS Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics; Mersana; GSK; Daiichi; Nektar; Astellas; ORCA; Boston Therapeutics; Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, and Zenith, outside the submitted work. EMG reports advisory/consultancy honorariums from AstraZeneca-MSD, Clovis Oncology, GSK-Tesaro, PharmaMar and Roche; she has received speaker bureau/expert testimony honorariums from AstraZeneca, PharmaMar, Roche and GSK; and has received travel/accommodation/expenses from Roche, Tesaro: A GSK Company and Baxter. IR reports personal fees and non-financial support from Pharmamar; grants, personal fees and non-financial support from Roche; personal fees from Clovis; personal fees from GSK; and grants, personal fees and non-financial support from AstraZeneca, outside the submitted work. EC reports grants and personal fees from Astellas, Novartis, Nanobiotix, Pfizer, Janssen-Cilag, PsiOxus Therapeutics, Merck, BMS, Seattle Genetics, Boehringer Ingelheim, AstraZeneca, Roche/Genentech, Servier, Celgene, Abbvie, Amcure, Alkermes, PharmaMar, BeiGene and GLG; personal fees from Medscape, Gilead, Pierre Fabre, Cerulean Pharma, EUSA, Gerhmann Consulting, Guidepoint, OncoDNA; and grants from ACEO, Adaptaimmune, AMGEN, Cytomx, GSK, H3, Incyte, Kura, Lilly, Nektar, Loxo, Macrogenics, Menarini, Merus, Principia, PUMA, Sanofi, Taiho, Tesaro, Transgene, Takeda, Innovio, MSD, Mersana, Daiichi, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Regeneron, Millenium, Synthon, Spectrum and Rigontec, outside the submitted work. NB reports personal fees and non-financial support from BMS and Merck Serono, and personal fees from AstraZeneca, BioNTech, Eisai and MSD, outside the submitted work. CK, JAL-V, MS, VA and AZ report grants from the Centro para el Desarrollo Tecnológico Industrial (CDTI) during the conduct of the study; and personal fees for salary as full time employee and stock ownership from Pharma Mar, outside the submitted work. MF reports grants from Merck Educational Grant for EACH study, grants from MSD Educational Grant for POPPY study, grants from Boehringer Ingelheim Educational Grant for DARWIN1 study, grants from AstraZeneca Educational Grant for ORCA2 study, personal fees from Achilles Advisory and Consultancy Work, personal fees from AstraZeneca Advisory and Consultancy Work, personal fees from BMS Advisory and Consultancy Work, personal fees from Merck Advisory and Consultancy Work, personal fees from MSD Advisory and Consultancy Work, personal fees from Nanobiotix Advisory and Consultancy Work, personal fees from Novartis Advisory and Consultancy Work, personal fees from Pfizer Advisory and Consultancy Work, personal fees from Pharmamar Advisory and Consultancy Work, personal fees from Roche Advisory and Consultancy Work, personal fees from Takeda Advisory and Consultancy Work, personal fees from Bayer Advisory and Consultancy Work, outside the submitted work.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Makker V , Hensley ML , Zhou Q , et al . 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Clinical endpoints in oncology - a primer. Am J Cancer Res 2021;11 :1121–31. 33948349\n11 Olmedo ME , Forster M , Moreno V , et al . Efficacy and safety of lurbinectedin and doxorubicin in relapsed small cell lung cancer. results from an expansion cohort of a phase I study. Invest New Drugs 2021;39 :1275–83. 10.1007/s10637-020-01025-x 33704620\n12 Arora S , Balasubramaniam S , Zhang W , et al . FDA approval summary: pembrolizumab plus lenvatinib for endometrial carcinoma, a collaborative international review under project Orbis. Clin Cancer Res 2020;26 :5062–7. 10.1158/1078-0432.CCR-19-3979 32295834\n13 Makker V , Taylor MH , Aghajanian C , et al . Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol 2020;38 :2981–92. 10.1200/JCO.19.02627 32167863\n14 McMeekin S , Dizon D , Barter J , et al . Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol 2015;138 :18–23. 10.1016/j.ygyno.2015.04.026 25925990\n15 Aghajanian C , Sill MW , Darcy KM , et al . Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a gynecologic Oncology Group study. J Clin Oncol 2011;29 :2259–65. 10.1200/JCO.2010.32.6397 21537039\n16 Forster MD , Moreno V , Boni V , et al . Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer. JCO 2017;35 :5586. 10.1200/JCO.2017.35.15_suppl.5586\n17 Miller DS , Scambia G , Bondarenko I , et al . ZoptEC: phase III randomized controlled study comparing zoptarelin with doxorubicin as second line therapy for locally advanced, recurrent, or metastatic endometrial cancer (NCT01767155). JCO 2018;36 :5503. 10.1200/JCO.2018.36.15_suppl.5503\n18 Stone JR , Kanneganti R , Abbasi M , et al . Monitoring for chemotherapy-related cardiotoxicity in the form of left ventricular systolic dysfunction: a review of current recommendations. JCO Oncol Pract 2021;17 :228–36. 10.1200/OP.20.00924 33689453\n19 Thigpen JT , Blessing JA , Lagasse LD , et al . Phase II trial of cisplatin as second-line chemotherapy in patients with advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group study. Am J Clin Oncol 1984;7 :253–6. 10.1097/00000421-198406000-00010 6539565\n20 Pawinski A , Tumolo S , Hoesel G , et al . Cyclophosphamide or ifosfamide in patients with advanced and/or recurrent endometrial carcinoma: a randomized phase II study of the EORTC Gynecological Cancer Cooperative Group. Eur J Obstet Gynecol Reprod Biol 1999;86 :179–83. 10.1016/S0301-2115(99)00066-4 10509788\n21 Moore DH , Blessing JA , Dunton C , et al . Dactinomycin in the treatment of recurrent or persistent endometrial carcinoma: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 1999;75 :473–5. 10.1006/gyno.1999.5652 10600310\n22 Garcia AA , Blessing JA , Nolte S , et al . A phase II evaluation of Weekly docetaxel in the treatment of recurrent or persistent endometrial carcinoma: a study by the gynecologic Oncology Group. Gynecol Oncol 2008;111 :22–6. 10.1016/j.ygyno.2008.06.013 18675446\n23 Di Legge A , Trivellizzi IN , Moruzzi MC , et al . Phase 2 trial of nonpegylated doxorubicin (Myocet) as second-line treatment in advanced or recurrent endometrial cancer. Int J Gynecol Cancer 2011;21 :1446–51. 10.1097/IGC.0b013e31822d754e 22027749\n24 Muggia FM , Blessing JA , Sorosky J , et al . Phase II trial of the pegylated liposomal doxorubicin in previously treated metastatic endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol 2002;20 :2360–4. 10.1200/JCO.2002.08.171 11981008\n25 Escobar PF , Markman M , Zanotti K , et al . Phase 2 trial of pegylated liposomal doxorubicin in advanced endometrial cancer. J Cancer Res Clin Oncol 2003;129 :651–4. 10.1007/s00432-003-0497-8 14505047\n26 Rose PG , Blessing JA , Lewandowski GS , et al . A phase II trial of prolonged oral etoposide (VP-16) as second-line therapy for advanced and recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 1996;63 :101–4. 10.1006/gyno.1996.0286 8898177\n27 Tait DL , Blessing JA , Hoffman JS , et al . A phase II study of gemcitabine (gemzar, LY188011) in the treatment of recurrent or persistent endometrial carcinoma: a gynecologic oncology group study. Gynecol Oncol 2011;121 :118–21. 10.1016/j.ygyno.2010.11.027 21159366\n28 Sutton GP , Blessing JA , Homesley HD , et al . Phase II study of ifosfamide and mesna in refractory adenocarcinoma of the endometrium. A Gynecologic Oncology Group study. Cancer 1994;73 :1453–5. 10.1002/1097-0142(19940301)73:5<1453::aid-cncr2820730521>3.0.co;2-x 8111713\n29 Dizon DS , Blessing JA , McMeekin DS , et al . Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: Gynecologic Oncology Group trial 129-P. J Clin Oncol 2009;27 :3104–8. 10.1200/JCO.2008.20.6995 19451430\n30 Fracasso PM , Blessing JA , Molpus KL , et al . Phase II study of oxaliplatin as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2006;103 :523–6. 10.1016/j.ygyno.2006.03.043 16712905\n31 Lincoln S , Blessing JA , Lee RB , et al . Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a gynecologic Oncology Group study. Gynecol Oncol 2003;88 :277–81. 10.1016/S0090-8258(02)00068-9 12648575\n32 Miller DS , Blessing JA , Lentz SS , et al . A phase II trial of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2002;87 :247–51. 10.1006/gyno.2002.6804 12468321\n\n",
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"title": "Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study.",
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"abstract": "We present a 23-year-old Nepalese migrant with mycobacterial tuberculosis (TB) pericarditis manifesting as effusive constrictive disease and subsequent rapid progression to constrictive pericarditis resulting from bulky granulomatous disease.\nFollowing initial presumptive diagnosis of TB pericarditis based on presence of moderate pericardial effusion and positive polymerase chain reaction on concurrent pleural aspirate, the patient was managed with standard empiric therapy. Despite treatment, he developed progressive heart failure with New York Heart Association (NYHA) class III symptoms and had confirmation of constrictive physiology on simultaneous left and right heart catheterization. He underwent pericardiectomy 4 months after his initial diagnosis, with debridement of large necrotizing granulomas and an associated immediate improvement clinical improvement. He remains well at 6-month follow-up with no residual heart failure symptoms off diuretic therapy.\nTuberculous pericarditis accounts for 1-2% of presentations with TB infection, with progression to constrictive pericarditis in between 17 and 40% of cases. To date, pericardiectomy remains mainstay of treatment for constriction, albeit with high perioperative risk. In combination with anti-tuberculous therapy, prednisone and pericardiocentesis may reduce risk of progression to constriction, however, neither have shown mortality benefit. Our patient continued to progress, despite medical therapy and proceeded to pericardiectomy only 4 months after his initial diagnosis, with rapid improvement in symptoms, demonstrating the importance of close monitoring and revision of management strategy in these patients.",
"affiliations": "Department of Cardiology, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia.;Department of Cardiology, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia.;Department of Cardiothoracics, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia.;Department of Cardiology, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia.",
"authors": "Barua|Sumita|S|0000-0001-9091-6773;Phua|Bernadette|B|0000-0003-1140-1726;Orr|Yishay|Y|;Skinner|Michael|M|",
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"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytaa208\nytaa208\nCase Reports\nHeart Failure\nAcademicSubjects/MED00200\nBulky granulomatous disease resulting in constrictive tuberculous pericarditis requiring pericardiectomy: a case report\nhttp://orcid.org/0000-0001-9091-6773Barua Sumita \nDepartment of Cardiology, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia\n\nFaculty of Medicine, University of New South Wales, UNSW Sydney, NSW 2052, Australia\n http://orcid.org/0000-0003-1140-1726Phua Bernadette \nDepartment of Cardiology, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia\n Orr Yishay \nDepartment of Cardiothoracics, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia\n Skinner Michael \nDepartment of Cardiology, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145, Australia\n Holy Erik Editor Bakogiannis Constantinos Editor Green Peregrine Editor D’Amario Domenico Handling Editor Simovic Stefan Editor Corresponding author. Tel: +61451667247, Email: sbarua88@gmail.com\n10 2020 \n27 9 2020 \n27 9 2020 \n4 5 1 6\n20 2 2020 17 3 2020 05 6 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.2020This 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 \nWe present a 23-year-old Nepalese migrant with mycobacterial tuberculosis (TB) pericarditis manifesting as effusive constrictive disease and subsequent rapid progression to constrictive pericarditis resulting from bulky granulomatous disease.\n\nCase summary \nFollowing initial presumptive diagnosis of TB pericarditis based on presence of moderate pericardial effusion and positive polymerase chain reaction on concurrent pleural aspirate, the patient was managed with standard empiric therapy. Despite treatment, he developed progressive heart failure with New York Heart Association (NYHA) class III symptoms and had confirmation of constrictive physiology on simultaneous left and right heart catheterization. He underwent pericardiectomy 4 months after his initial diagnosis, with debridement of large necrotizing granulomas and an associated immediate improvement clinical improvement. He remains well at 6-month follow-up with no residual heart failure symptoms off diuretic therapy. \n\nDiscussion \nTuberculous pericarditis accounts for 1–2% of presentations with TB infection, with progression to constrictive pericarditis in between 17 and 40% of cases. To date, pericardiectomy remains mainstay of treatment for constriction, albeit with high perioperative risk. In combination with anti-tuberculous therapy, prednisone and pericardiocentesis may reduce risk of progression to constriction, however, neither have shown mortality benefit. Our patient continued to progress, despite medical therapy and proceeded to pericardiectomy only 4 months after his initial diagnosis, with rapid improvement in symptoms, demonstrating the importance of close monitoring and revision of management strategy in these patients.\n\nCase reportTuberculous pericarditisConstrictive pericarditisPericardiectomyGranulomatous disease\n==== Body\nLearning points\nMultidisciplinary involvement is required for patients with tuberculous pericarditis to monitor response to therapy and assess for interval development of constriction.\n\nMultiple diagnostic modalities, both non-invasive and invasive, with serial evaluation may be required to identify progression to constrictive pericarditis in this setting.\n\nConstrictive pericarditis, particularly with bulky granulomatous disease and symptoms of heart failure, requires pericardiectomy for treatment.\n\n\n\n\nIntroduction\nMycobacterial tuberculosis (TB) infection remains rare in the Australian population, with an estimated incidence of 6.8 per 100 000 population.1 Tuberculous pericarditis accounts for 1–2% of presentations with TB infection,2 progressing to constrictive pericarditis in between 17% and 40% of cases.3 We present a case of effusive constrictive TB pericarditis as the first manifestation of TB infection in a 23-year-old Nepalese migrant, with rapid progression to constrictive pericarditis due to bulky granulomas requiring pericardiectomy.\n\nTimeline\nSeptember 2018\tFirst presentation. Newly diagnosed moderate pericardial and pleural effusion. Transthoracic echocardiogram is suggestive of effusive constrictive disease. Pleural aspirate Mycobacterial tuberculosis (TB) polymerase chain reaction (PCR) positive. Commenced on standard anti-TB therapy and prednisone.\t\nOctober 2018\tDischarged from hospital, however, rapid progression to New York Heart Association class III symptoms.\t\nNovember 2018–January 2019\tReadmission with bilateral pleural effusions. Pleural biopsy TB PCR positive. Refractory pleural effusions with prolonged drain requirements.\t\nJanuary 2019\tSimultaneous left and right heart catheterization consistent with constriction. Pericardial thickening without calcification on computed-tomography chest. Proceeded to pericardiectomy.\t\nFebruary 2019\tAll diuretics ceased. Discharged from hospital.\t\nMay 2019\tAnti-TB therapy ceased following completion of 36-week course.\t\nJune 2019\tNo residual heart failure symptoms at follow-up\t\nCase presentation \nThe patient is a 23-year-old university student, recently emigrated from Nepal, with no known medical history. His sister was treated for presumed TB lymphadenitis 10 years prior. He initially presented in September 2018 with a 1-month history of pleuritic chest pain, dry cough, fevers, and night sweats. On clinical examination, he was found to be tachycardic, with reduced air entry at both lung bases. There were no other clinical signs of tamponade.\n\nElectrocardiogram demonstrated sinus tachycardia with no electrical alternans. Serology showed an elevated C-reactive protein (52 mg/L), and D-dimer (>10 mg/L). All other laboratory values were within normal range. Computed tomography (CT) chest imaging demonstrated pleural and pericardial effusions and subsequent targeted transthoracic echocardiogram (TTE) confirmed a moderate-to-large global pericardial effusion up to 20 mm in maximal dimension. The lateral left ventricular wall appeared tethered to the visceral pericardium with echodense fibrinous material throughout the pericardial space (Figure 1). Respiratory inflow variations were significant at 42% for mitral and 67% for tricuspid valves, respectively. There was paradoxical interventricular septal motion despite absence of right atrial and right ventricular collapse (Video 1). The inferior vena cava (IVC) was dilated with only 30% variation on inspiration. There was expiratory hepatic vein flow reversal and tissue annulus reversus with septal mitral annular E’ 11 cm compared with lateral mitral annular E’ 7 cm, suggestive effusive constriction (Figure 2). Overall left ventricular function was normal, and high sensitivity troponins were negative, suggesting no myocardial involvement. Induced sputum aspirates were negative, however, diagnostic pleurocentesis demonstrated an exudative effusion (pleural to serum protein ratio 0.6) with a positive TB polymerase chain reaction (PCR) result.\n\n\nFigure 1 Parasternal long axis and apical four chamber images on transthoracic echocardiogram demonstrating moderate-to-large pericardial effusion, with basal lateral wall left ventricular wall adherent to visceral pericardium. Scale 23.11 cm × 8.57 cm.\n\nFigure 2 Mitral annulus reversus of tissue Doppler velocities (A and B). Hepatic vein flow reversal with expiration (C and D). Scale 16.58 cm × 12.24 cm.\n\nHe was commenced on empiric therapy for effusive constrictive TB pericarditis, with once daily Rifampicin 600 mg, Isoniazid 300 mg, Ethambutol 800 mg, Pyrazinamide 1.5 g, and weaning course of Prednisone. He was additionally noted to have a CD4 lymphopaenia (CD4 count 137 cells/mm3) despite negative Human Immunodeficiency Virus (HIV) serology and commenced on Sulfamethoxazole/Trimethoprim 400/80 mg daily prophylaxis.\n\nOver the subsequent 1 month, he developed New York Heart Association (NYHA) class III symptoms with an exertional tolerance of 5 m, despite continuing to work as a cleaner 6 days per week prompting re-admission in November 2018. Prednisone was ceased and TB treatment rationalized as per current guidelines. He underwent left-sided video-assisted thoracoscopic surgery. Inspected pleura showed small nodularities throughout, with positive biopsy for TB on PCR. He had continuously high pleural drain outputs bilaterally for almost 2 months prior to both drains being removed. Unfortunately, he was readmitted 3 days following discharge in January 2019 with reaccumulation of pleural effusions and dependent lower limb oedema refractory to escalating doses of frusemide and spironolactone (40 mg BD intravenous and 25 mg oral daily, respectively).\n\nRepeat TTE showed marked degradation of acoustic windows, presumed due to pericardial thickening. The pericardial effusion had resolved, replaced by heterogenous echodense material within the pericardial space. The entire left ventricular mass appeared adherent to the pericardium (Figure 3). Marked septal bounce was seen, and the IVC remained dilated without respiratory variation. CT chest showed gross pericardial thickening without calcification. Interestingly, there were air-filled cavities present within the pericardial space, which in conjunction with the heterogenous echodense material seen on TTE suggests possible necrotic granulomas (Figure 3).\n\n\nFigure 3 Progress transthoracic echocardiogram showing resolution of pericardial fluid and replacement with heterogenous echodense material, degradation of imaging quality due to pericardial thickening, and increased adherence of ventricular cavities to visceral pericardium (A and B). Computed tomographic images showing air-filled cavities within pericardial space and pericardial thickening ( C–E). Scale 38.63 cm × 21.98 cm.\n\nThe patient proceeded to simultaneous left and right heart catheterization, which demonstrated diastolic equalization of pressures with diastolic ‘dip-and-plateau’, and discordance of ventricular pressures during the respiratory cycle confirming presence of constrictive physiology (Figure 4).\n\n\nFigure 4 (A) Diastolic equalization of right and left ventricular pressures with ‘dip-and-plateau’ morphology. (B) Discordance in ventricular pressures with respiration. Scale 19.05 cm × 10.23 cm.\n\nFollowing multidisciplinary discussion of his progression despite corticosteroids and anti-tuberculous treatment, he proceeded to pericardiectomy. There was clear constriction of the heart, with ventricular cavities much more filled once the pericardium was excised. The pericardium was grossly thickened. Additionally, there were several caseating abscess cavities, the largest measuring 4 cm in its maximal dimension (Figure 5). These were all debrided and all involved pericardium excised with instantaneous improvement in central venous pressures from 30 cm at the beginning to 16 cm at the end of the case. The patient was extubated that evening and subsequently discharged 2 weeks later off all diuretic therapy. He has now completed his 36-week course of anti-tuberculous therapy and remains well at follow-up to 6 months. He has no residual heart failure symptoms, has resumed his studies, and is seeking employment as a nursing assistant.\n\n\nFigure 5 (A) Photo taken at the time of surgery demonstrating high vascular pericardium with arrowheads showing unroofed caseating granuloma. (B) Haematoxylin and Eosin (H&E) stain (100×) Granuloma with dirty necrosis (bottom left) and palisading histiocytes. (C) H&E (200×) Well formed epitheloid granuloma. Scale 23.6 cm × 5.89 cm. Haematoxylin and Eosin (H&E) stain\n\nDiscussion\nFor established TB constrictive pericarditis, pericardiectomy remains the mainstay of treatment, albeit with high perioperative risk. In a case series of 110 patients with presumed or confirmed TB constriction, 22% of cases had myocardial wall or major vessel injury, 66% had low-output cardiac failure in the post-operative period, and 14% did not survive.4 Conversely, in those who did survive, there was significant improvement in NYHA class symptoms, with most patients shifting from Class II–III symptoms pre-operatively to Class I symptoms post-operatively.4\n\nIn view of the high perioperative morbidity and mortality associated with pericardiectomy, less invasive therapies have been sought to reduce the risk of progression to constrictive pericarditis in these patients. Prednisone, combined with anti-tuberculous therapy, is the most commonly used first line therapy for tuberculous pericarditis. The largest trial of its use to date, the IMPI trial, showed no significant difference in the primary outcome, a composite of death, cardiac tamponade, and constriction, with prednisone use compared to placebo. There was however a significant difference in progression to constriction, with 7.8% following prednisone compared with 4.4% following placebo, as well as repeat hospitalization with 20.7% following prednisone and 25.2% following placebo.5\n\nIntradermal injection of Mycobacterium indicus pranii, also evaluated in the IMPI trial, did not show reduction in the composite of death, cardiac tamponade, and constriction, nor a reduction in progression to constriction.5 The use of colchicine in a subset of patients with concomitant HIV infection and TB pericarditis did not show improvement in development of constriction.6 Interestingly, pericardiocentesis appeared to reduce the risk of progression to constriction in this small group. This finding was supported by a series of 162 patients undergoing pericardiocentesis for pericardial TB, of whom 11 went onto to further pericardial surgery, although only 1 was suspected to have pericardial constriction.7\n\nContemporary observational studies have shown best results with anti-tuberculous and prednisone combined with pericardiocentesis in terms of progression to constriction, with 93% in one series showing no effusion or thickening, or <1 cm effusion with some pericardial thickening on CT following this treatment regime.8\n\nOur patient had progressive heart failure related to constrictive pericarditis, despite medical therapy and proceeded to pericardiectomy 4 months after his initial diagnosis. This was associated with rapid improvement in symptoms, demonstrating the importance of close monitoring and revision of management strategy in these patients. This case was unique given large necrotizing granulomas, which were difficult to appreciate on imaging, as TTE image quality is often degraded due to pericardial thickening, with limited pericardial tissue characterization on CT imaging. These granulomas were unlikely to resolve with medical therapy alone and in themselves contributed to constrictive physiology due to their mechanical compression on the cardiac chambers, again highlighting the importance of multimodality assessment of the patient with concerns of TB-related constrictive pericarditis.\n\nLead author biography\nDr. Sumita Barua is a cardiologist having recently completed cardiology advanced training at Westmead Hospital. Her interests include coronary intervention and advanced heart failure therapies.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSupplementary Material\nytaa208_Supplementary_Data Click here for additional data file.\n\n Acknowledgements\nThe authors would like to express their appreciation to Dr Jen Kok for giving permission to present this case and his ongoing care of the patient, as well as to Dr Winny Varikatt for assistance with the histopathology slides. \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 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\n\nConflict of interest: none declared.\n==== Refs\nReferences\n1 World Health Organisation. TB burden estimates and country-reported TB data. https://worldhealthorg.shinyapps.io/tb_profiles/?_inputs_&lan=%22EN%22&iso2=%22AU%22&main_tabs=%22est_tab%22 (30 June 2020).\n2 \nMayosi BM , Burgess LJ , Doubell AF. \nTuberculous pericarditis\n. Circulation 2005 ;112 :3608 –3616\n.16330703 \n3 \nSyed FF , Mayosi BM. \nA modern approach to tuberculous pericarditis\n. Prog Cardiovasc Dis 2007 ;50 :218 –236\n.17976506 \n4 \nMutyaba AK , Balkaran S , Cloete R , Du Plessis N , Badri M , Brink J \net al\nConstrictive pericarditis requiring pericardiectomy at Groote Schuur Hospital, Cape Town, South Africa: causes and perioperative outcomes in the HIV era (1990-2012\n). J Thorac Cardiovasc Surg 2014 ;148 :3058 –3065.e1\n.25175954 \n5 \nMayosi BM , Ntsekhe M , Bosch J , Pandie S , Jung H , Gumedze F \net al\nPrednisolone and Mycobacterium indicus pranii in tuberculous pericarditis\n. N Engl J Med 2014 ;371 :1121 –1130\n.25178809 \n6 \nLiebenberg JJ , Dold CJ , Olivier LR. \nA prospective investigation into the effect of colchicine on tuberculous pericarditis\n. Cardiovasc J S Afr 2016 ;27 :350 –355\n.\n7 \nReuter H , Burgess LJ , Louw VJ , Doubell AF. \nThe management of tuberculous pericardial effusion: experience in 233 consecutive patients\n. Cardiovasc J S Afr 2007 ;18 :20 –25\n.17392991 \n8 \nLi H , Liu FY , Li XL , Zhu L , Zhou H. \nClinical observation on pericardiocentesis and glucocorticoid in the treatment of tuberculous pericarditis\n. Eur Rev Med Pharmacol 2016 ;20 :1130 –1134\n.\n\n",
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"keywords": "Case report; Constrictive pericarditis; Granulomatous disease; Pericardiectomy; Tuberculous pericarditis",
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"abstract": "AMR is a risk factor for graft failure after SBTx. We studied impact of DSAs and AMR in 22 children transplanted between 2008 and 2012 (11 isolated SBTx, 10 liver inclusive Tx, and one modified multivisceral Tx). Three patients never developed DSA, but DSAs were found in seven in the pre-Tx period and de novo post-Tx in 19 children. Pathology revealed cellular rejection (15/19), with vascular changes and C4d+. Patients were treated with IV immunoglobulins, plasmapheresis, and steroids. Rescue therapy included antithymocyte globulins, rituximab, eculizumab, and bortezomib. Pathology and graft function normalized in 13 patients, graft loss occurred in two, and death in seven. At the end of the follow-up, 15 children were alive (68%), 13 with functioning graft (59%). Prognosis factors for poor outcome after Tx were the presence of symptoms at AMR suspicion (P +.033). DSAs were often found following SBTx, mostly de novo. Resistant ACR or severe AMR is still difficult to differentiate, with a high need for immunosuppression in both. DSAs may precede development of severe disease and pathology features on the graft: relationship and correlation need to be better investigated with larger groups before and after Tx.",
"affiliations": "Unité d'Hépato-Gastroentérologie et Nutrition Pédiatriques, Hôpitaux Universitaires de Genève, Geneve, Switzerland.;Service d'Anatomopathologie, Hôpital Necker Enfants Malades, Paris, France.;Service d'Anatomopathologie, Hôpital Necker Enfants Malades, Paris, France.;Laboratoire d'Histocompatibilité, Hôpital Saint Louis, Paris, France.;Service d'Hépato-Gastroentérologie et Nutrition Pédiatriques, Hôpital Necker Enfants Malades, Paris, France.;Service de Chirurgie Viscérale Pédiatrique, Hôpital Necker Enfants Malades, Paris, France.;Service d'Hépato-Gastroentérologie et Nutrition Pédiatriques, Hôpital Necker Enfants Malades, Paris, France.",
"authors": "Petit|L-M|LM|;Rabant|M|M|;Canioni|D|D|;Suberbielle-Boissel|C|C|;Goulet|O|O|;Chardot|C|C|;Lacaille|F|F|",
"chemical_list": "D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D006680:HLA Antigens; D016756:Immunoglobulins, Intravenous; D007518:Isoantibodies; D010446:Peptide Fragments; D013256:Steroids; D000069283:Rituximab; D000069286:Bortezomib; D015935:Complement C4b; C032261:complement C4d; C481642:eculizumab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12847",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(2)",
"journal": "Pediatric transplantation",
"keywords": "antibody-mediated rejection; donor-specific antibodies; intestinal transplantation; long-term graft survival; steroid-resistant rejection",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D015935:Complement C4b; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006680:HLA Antigens; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007165:Immunosuppression Therapy; D007223:Infant; D007422:Intestines; D007518:Isoantibodies; D008297:Male; D010446:Peptide Fragments; D010956:Plasmapheresis; D011379:Prognosis; D000069283:Rituximab; D013256:Steroids; D014019:Tissue Donors; D014180:Transplantation; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28084679",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impacts of donor-specific anti-HLA antibodies and antibody-mediated rejection on outcomes after intestinal transplantation in children.",
"title_normalized": "impacts of donor specific anti hla antibodies and antibody mediated rejection on outcomes after intestinal transplantation in children"
} | [
{
"companynumb": "CH-TAKEDA-2017MPI001598",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nUterine rupture is a tear in the uterine wall involving its full thickness, resulting in the formation of a defect in the uterine wall. The major risk factor is the presence of uterine scarring (specifically from Caesarean section), but it can also occur in an unscarred uterus. Although rare, this has been shown to result in more severe complications.\n\n\nMETHODS\nA 31-year-old woman, gravida 6 para 6, without prior uterine incision or manipulation developed significant postpartum bleeding. She was found to have a uterine rupture with retroperitoneal extension, and surgical management was required.\n\n\nCONCLUSIONS\nEarly diagnosis of uterine rupture with rapid initiation of supportive and surgical care may significantly improve prognosis. It is imperative to consider uterine rupture in any obstetrical patient with hemodynamic instability or hemorrhage, regardless of whether risk factors (including a previous uterine scar) are present.",
"affiliations": "Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba, Winnipeg MB.;Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba, Winnipeg MB.;Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba, Winnipeg MB.;Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba, Winnipeg MB; Division of Gynecologic Oncology, University of Manitoba, Winnipeg MB.",
"authors": "Haakman|Olga|O|;Ambrose|Devon|D|;Katopodis|Christina|C|;Altman|Alon D|AD|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/s1701-2163(16)30052-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1701-2163",
"issue": "37(11)",
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": "Caesarean section; hysterectomy; postpartum hemorrhage; postpartum period; uterine rupture",
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": "D000328:Adult; D036861:Delivery, Obstetric; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007044:Hysterectomy; D007231:Infant, Newborn; D010298:Parity; D006473:Postpartum Hemorrhage; D011247:Pregnancy; D011256:Pregnancy Outcome; D012422:Rupture, Spontaneous; D058994:Salpingectomy; D014599:Uterus",
"nlm_unique_id": "101126664",
"other_id": null,
"pages": "1021-4",
"pmc": null,
"pmid": "26629723",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous Rupture of an Unscarred Uterus Diagnosed Postpartum: A Case Report.",
"title_normalized": "spontaneous rupture of an unscarred uterus diagnosed postpartum a case report"
} | [
{
"companynumb": "PHHY2016CA087060",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GLYCOPYRRONIUM"
},
"drugadditional": null,
... |
{
"abstract": "Thalamic haemorrhage is usually considered a single entity although the thalamus is composed of anatomically as well as functionally discrete subregions receiving blood from different arteries. The clinical features vary according to the intrathalamic location of the haematomas and the bleeding artery. We investigated the impact of haematoma location and vascular territory on the clinical symptoms and signs, neuro-imaging findings and clinical courses of patients with thalamic haemorrhages by a retrospective analysis of 175 consecutive patients with thalamic haemorrhage. Based on the neuro-imaging findings we classified thalamic haematomas into four regional types and one global type according to the primary bleeding sites: (i) anterior type occurring in the territory of the tuberothalamic arteries, (ii) posteromedial type occurring in the territory of the thalamic-subthalamic paramedian arteries, (iii) posterolateral type occurring in the territory of the thalamogeniculate arteries. (iv) dorsal type occurring in the territory of the posterior choroidal arteries and (v) global type occupying the entire area of the thalamus. We studied the clinical and neuroimaging characteristics of each type. Eleven patients (7%) had the anterior type: these were the smallest haematomas and often ruptured into the anterior horn of the lateral ventricle. The major clinical signs were acute behavioural abnormalities: the clinical course was usually benign. Twenty-four patients (14%) had the posteromedial type in which haematomas often ruptured into the third ventricle, causing marked hydrocephalus, and often extended mediocaudally, involving the mesencephalon. The prognoses of this type depended on the presence of mesencephalic involvement which was associated with the worst outcome among the types even if the size of the haematoma itself was not large. The posterolateral type was most frequent (77 patients, 44%) and was characterized by large haematomas, rupture into the posterior horn of the lateral ventricle and frequent extension into the posterior limb of the internal capsule. Clinical signs included marked sensory and motor signs, hemineglect in right-side haematomas and language abnormalities with left-side haematomas. The case fatality with this type was relatively high (35%) and permanent neurologic sequelae frequently resulted. In the dorsal type (32 patients, 18%) haematomas were best visualized at the level of the body of the lateral ventricle on CT scans. The size was moderate and haematomas often extended posterolaterally into the adjacent subcortical white matter. Sensory and motor signs were common and about one third of the patients were first misdiagnosed as having lacunar infarcts. The prognoses were excellent. The global type (31 patients, 18%) of thalamic haemorrhage was clinically and radiologically very similar to the posterolateral type except that the haematomas were too large to define the bleeding focus. Severe sensory and motor signs were almost always present. In this type 25 patients died (the case fatality was 81%).",
"affiliations": "Department of Neurology, Samsung Medical Center, Seoul, Korea.",
"authors": "Chung|C S|CS|;Caplan|L R|LR|;Han|W|W|;Pessin|M S|MS|;Lee|K H|KH|;Kim|J M|JM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/brain/119.6.1873",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-8950",
"issue": "119 ( Pt 6)()",
"journal": "Brain : a journal of neurology",
"keywords": null,
"medline_ta": "Brain",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002543:Cerebral Hemorrhage; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011859:Radiography; D013786:Thalamic Diseases",
"nlm_unique_id": "0372537",
"other_id": null,
"pages": "1873-86",
"pmc": null,
"pmid": "9009994",
"pubdate": "1996-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thalamic haemorrhage.",
"title_normalized": "thalamic haemorrhage"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-NB-006791",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
}... |
{
"abstract": "BACKGROUND\nThe most recent findings show a histopathological, genetic and clinical uniformity in cases of tumors called embryonal tumors with multilayer rosettes. This group is composed of medulloepithelioma, ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes. Amplification of locus 19q13.42, which includes C19MC cluster containing genes for microRNA, and also LIN28A positivity are present in all three entities. Dysregulation of epigenetic modifiers is very important in pathogenesis of the disease. These tumors manifest in little children (median less than 3 years of age); overall survival is 5-10%.\n\n\nMETHODS\nAlmost three year-old boy diagnosed with brainstem tumor: meduloepithelioma, WHO grade IV confirmed by histological investigation. He presented with dysarthria, bulbar syndrome, central lesion of the facial nerve, quadriparesis with right-side dominancy. He received three induction cycles of chemotherapy from March to May 2014 (according to protocol COG ACNS0334). Only partial improvement of his clinical state was reached. Signs of an intracranial hypertension appeared resulting in VP shunt insertion; impairment of consciousness developed after the induction cycles and before any other treatment could be initiated. He underwent radiotherapy due to vital indication. After application of two fractions (boost in the center of the tumor), the patient became quickly comatose. Spinal cord metastasis was demarked by MRI scan (in the level of 3rd cervical vertebra). A bilateral infiltration in pulmonary parenchyma, according to a radiologist metastasis-wise, was detected by CT scan (histologisation of infiltration was not implemented). The patient died in August 2014--six months after manifestation of first symptoms.\n\n\nCONCLUSIONS\nWe reported our first documented case of a patient with tumor from embryonal tumors with multilayer rosettes group in Slovakia. Nowadays, there is no effective treatment of these tumors. Research of molecules targeting to epigenetic modifiers would be one of the possible promises for future therapy.",
"affiliations": null,
"authors": "Pleško|M|M|;Husáková|K|K|;Kaiserová|E|E|;Tichý|M|M|;Zámečník|J|J|",
"chemical_list": null,
"country": "Czech Republic",
"delete": false,
"doi": "10.14735/amko2015288",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0862-495X",
"issue": "28(4)",
"journal": "Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti",
"keywords": null,
"medline_ta": "Klin Onkol",
"mesh_terms": "D001932:Brain Neoplasms; D002675:Child, Preschool; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018242:Neuroectodermal Tumors, Primitive; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9425213",
"other_id": null,
"pages": "288-92",
"pmc": null,
"pmid": "26299744",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Embryonal Tumors with Multilayer Rosettes--Rare Central Nervous System Tumors in Infants.",
"title_normalized": "embryonal tumors with multilayer rosettes rare central nervous system tumors in infants"
} | [
{
"companynumb": "SK-ACCORD-034415",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "A 49-year-old man was diagnosed with small cell lung cancer in May 2005. Chemotherapy was started with 60 mg/day cisplatin iv drip (from days one to three), 2 mg topotecan (TP) hydrochloride iv drip (from days one to four), and traditional Chinese medicine (TCM) AiDi injection for anti-tumor. After four cycles, he underwent conformal radiotherapy with 56Gy/28 fractions in October 2005. In April 2006, a mass on the right supraclavicular area was found. Therefore, he underwent another course of radiotherapy. The fields included the right supraclavicular area and the radiation dose was 50Gy/25 fractions. After completion of chemoradiotherapy, the patient achieved complete remission. Subsequently, the patient received prophylactic cranial irradiation (PCI). Until April of 2012, he had been followed up regularly. Since the SCLC diagnosis, he had received TCM for seven years. In April 2012, the patient complained of coughing again. Subsequently, the patient was given five cycles of an etoposide carboplatin regimen. A computed tomography (CT) scan was performed for review, which showed no obvious change. The patient underwent a second-line chemotherapy irinotecan cisplatin three times. However, the symptoms and CT of this patient showed no significant improvement. We changed the chemotherapy regimen to TP (topotecan 1.2 mg iv drip, days one to five; carboplatin 100 mg iv drip, days one to five). After two TP regimens, the patient died in his sleep on 3 March 2013. In this case, the standardized sequential chemotherapy and radiotherapy treatment, PCI, TCM, and good compliance may have contributed to the patient's longer survival.",
"affiliations": "Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.;Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.;Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.;Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.;Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.;Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.;Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.;Department of Respiratory Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University Xi'an, China.",
"authors": "Zhong|Yujie|Y|;Zhang|Qiuhong|Q|;Deng|Wenjing|W|;Zhang|Yuping|Y|;Ming|Zongjuan|Z|;Hou|Yanli|Y|;Niu|Zequn|Z|;Yang|Shuanying|S|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.12088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-7706",
"issue": "5(4)",
"journal": "Thoracic cancer",
"keywords": "Chemotherapy; long-term survival; prophylactic cranial irradiation; radiotherapy; small cell lung cancer",
"medline_ta": "Thorac Cancer",
"mesh_terms": null,
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "349-53",
"pmc": null,
"pmid": "26767023",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": "16117878;22622031;22855039;23231806;23426938;23673987;23692812;23731740;23760544;23760883;24137362;24137376;28920194;28920219",
"title": "Long-term survival for 93 months of limited-stage small cell lung cancer: A case report and literature review.",
"title_normalized": "long term survival for 93 months of limited stage small cell lung cancer a case report and literature review"
} | [
{
"companynumb": "PHHY2014CN092010",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nRisankizumab is a humanized IgG monoclonal antibody that selectively inhibits interleukin-23 through binding the p19 subunit. In Phase 3 trials, risankizumab demonstrated superior efficacy compared with adalimumab and ustekinumab in patients with moderate-to-severe plaque psoriasis. Here, we evaluated the impact of baseline characteristics on efficacy of risankizumab compared with ustekinumab in patients with moderate-to-severe plaque psoriasis.\n\n\nMETHODS\nThis analysis included all patients initially randomized to risankizumab or ustekinumab from the replicate, double-blinded, randomized, placebo-controlled phase 3 trials, UltIMMa-1 (NCT02684370) and UltIMMa-2 (NCT02684357). Patients received either risankizumab (150 mg) or ustekinumab (weight-based; 45 or 90 mg per label) at weeks 0, 4, 16, 28 and 40. Efficacy was assessed as the proportion of patients achieving ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at weeks 16 and 52 by baseline patient demographics, disease characteristics and prior biologic exposure. Mean per cent improvement in PASI was calculated by body weight and body mass index at week 52. Missing efficacy data were imputed as non-responders for categorical variables and last observation carried forward for continuous variables. Logistic regression analyses assessed for interactions between treatment and five independent variables (age, sex, weight, baseline PASI score and presence of psoriatic arthritis) at both weeks 16 and 52.\n\n\nRESULTS\nBaseline patient demographics, disease characteristics and prior biologic exposure were similar between patients randomized to risankizumab (n = 598) and ustekinumab (n = 199). At weeks 16 and 52, risankizumab demonstrated superior efficacy compared with ustekinumab across these patient characteristics (P < 0.01). Logistic regression analyses demonstrated that risankizumab was superior to ustekinumab at weeks 16 and 52 in all models tested (P < 0.0001 for all).\n\n\nCONCLUSIONS\nRisankizumab demonstrated consistent and superior efficacy compared with ustekinumab regardless of patient demographics, disease characteristics or prior biologic exposure.",
"affiliations": "Yale University, New Haven, CT, USA.;Baylor Scott and White, Dallas, TX, USA.;Central Dermatology, Richmond Heights, MO, USA.;Medical College of Wisconsin, Milwaukee, WI, USA.;Ghent University, Ghent, Belgium.;Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.;AbbVie, Inc., North Chicago, IL, USA.;AbbVie, Inc., North Chicago, IL, USA.;AbbVie, Inc., North Chicago, IL, USA.;St. Vincent's Hospital Melbourne, Probity Medical Research, Skin Health Institute, The University of Melbourne, Melbourne, VIC, Australia.",
"authors": "Strober|B|B|https://orcid.org/0000-0002-8394-2057;Menter|A|A|;Leonardi|C|C|;Gordon|K|K|;Lambert|J|J|;Puig|L|L|https://orcid.org/0000-0001-6083-0952;Photowala|H|H|;Longcore|M|M|;Zhan|T|T|;Foley|P|P|",
"chemical_list": "D000911:Antibodies, Monoclonal; C000601773:risankizumab; D000069549:Ustekinumab",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.16521",
"fulltext": "\n==== Front\nJ Eur Acad Dermatol Venereol\nJ Eur Acad Dermatol Venereol\n10.1111/(ISSN)1468-3083\nJDV\nJournal of the European Academy of Dermatology and Venereology\n0926-9959 1468-3083 John Wiley and Sons Inc. Hoboken \n\n32320088\n10.1111/jdv.16521\nJDV16521\nOriginal Article\nPsoriasis\nEfficacy of risankizumab in patients with moderate‐to‐severe plaque psoriasis by baseline demographics, disease characteristics and prior biologic therapy: an integrated analysis of the phase III UltIMMa‐1 and UltIMMa‐2 studies\nRZB efficacy in patient subgroupsStrober et al.Strober B. https://orcid.org/0000-0002-8394-2057\n1\n\n2\nbrucestrober30@me.com Menter A. \n3\n Leonardi C. \n4\n Gordon K. \n5\n Lambert J. \n6\n Puig L. https://orcid.org/0000-0001-6083-0952\n7\n Photowala H. \n8\n Longcore M. \n8\n Zhan T. \n8\n Foley P. \n9\n \n1 \nYale University\nNew Haven\nCT\nUSA\n\n\n2 \nCentral Connecticut Dermatology Research\nCromwell\nCT\nUSA\n\n\n3 \nBaylor Scott and White\nDallas\nTX\nUSA\n\n\n4 \nCentral Dermatology\nRichmond Heights\nMO\nUSA\n\n\n5 \nMedical College of Wisconsin\nMilwaukee\nWI\nUSA\n\n\n6 \nGhent University\nGhent\nBelgium\n\n\n7 \nHospital de la Santa Creu i Sant Pau\nBarcelona\nSpain\n\n\n8 \nAbbVie, Inc.\nNorth Chicago\nIL\nUSA\n\n\n9 \nSt. Vincent’s Hospital Melbourne\nProbity Medical Research\nSkin Health Institute\nThe University of Melbourne\nMelbourne\nVIC\nAustralia\n\n* \nCorrespondence: B. Strober. E‐mail: brucestrober30@me.com\n\n03 7 2020 \n12 2020 \n34 12 10.1111/jdv.v34.122830 2838\n21 1 2020 31 3 2020 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and VenereologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nBackground\nRisankizumab is a humanized IgG monoclonal antibody that selectively inhibits interleukin‐23 through binding the p19 subunit. In Phase 3 trials, risankizumab demonstrated superior efficacy compared with adalimumab and ustekinumab in patients with moderate‐to‐severe plaque psoriasis. Here, we evaluated the impact of baseline characteristics on efficacy of risankizumab compared with ustekinumab in patients with moderate‐to‐severe plaque psoriasis.\n\nMethods\nThis analysis included all patients initially randomized to risankizumab or ustekinumab from the replicate, double‐blinded, randomized, placebo‐controlled phase 3 trials, UltIMMa‐1 (NCT02684370) and UltIMMa‐2 (NCT02684357). Patients received either risankizumab (150 mg) or ustekinumab (weight‐based; 45 or 90 mg per label) at weeks 0, 4, 16, 28 and 40. Efficacy was assessed as the proportion of patients achieving ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at weeks 16 and 52 by baseline patient demographics, disease characteristics and prior biologic exposure. Mean per cent improvement in PASI was calculated by body weight and body mass index at week 52. Missing efficacy data were imputed as non‐responders for categorical variables and last observation carried forward for continuous variables. Logistic regression analyses assessed for interactions between treatment and five independent variables (age, sex, weight, baseline PASI score and presence of psoriatic arthritis) at both weeks 16 and 52.\n\nResults\nBaseline patient demographics, disease characteristics and prior biologic exposure were similar between patients randomized to risankizumab (n = 598) and ustekinumab (n = 199). At weeks 16 and 52, risankizumab demonstrated superior efficacy compared with ustekinumab across these patient characteristics (P < 0.01). Logistic regression analyses demonstrated that risankizumab was superior to ustekinumab at weeks 16 and 52 in all models tested (P < 0.0001 for all).\n\nConclusions\nRisankizumab demonstrated consistent and superior efficacy compared with ustekinumab regardless of patient demographics, disease characteristics or prior biologic exposure.\n\nAbbVie 10.13039/100006483 source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.01.2021Conflict of interest\n\nBruce Strober has served as an investigator (no direct payments made to Bruce Strober, MD, PhD) for Dermavant, AbbVie, the CORRONA Psoriasis Registry, and Dermira; has served as Scientific Director (consulting fee) for the CORRONA Psoriasis Registry; has served as a consultant (honoraria) for AbbVie, Almirall, Amgen, Arena, Aristea, Boehringer Ingelheim, Bristol‐MyersSquibb, Celgene, Dermavant, Dermira, Janssen, Leo, Eli Lilly, Kyowa Hakko Kirin, Meiji Seika Pharma, Novartis, Pfizer, GlaxoSmithKline, UCB Pharma, Sun Pharma, Ortho Dermatologics, Regeneron, and Sanofi‐Genzyme; and has served as a speaker for AbbVie, Lilly, Janssen, and Ortho Dermatologics. Alan Menter has received grant support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Janssen Biotech, Inc., LEO Pharma, Merck, and Sienna; honoraria from AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Janssen Biotech, Inc., LEO Pharma, Novartis, Sienna, and UCB; has served as an investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen Biotech, Inc., LEO Pharma, Merck, Novartis, Sienna, and UCB; has served on the advisory board of AbbVie, Amgen, Boehringer Ingelheim, Janssen Biotech, Inc., LEO Pharma, and Sienna; has served as a consultant for AbbVie, Amgen, Eli Lilly, Janssen Biotech, Inc., LEO Pharma, Novartis, Sienna, and UCB; and has served as a speaker for AbbVie, Amgen, Janssen Biotech, Inc., LEO Pharma, Sienna, and UCB. Craig L. Leonardi, MD, FAAD, served as a consultant/advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, Dermira, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Leo Pharma A/S, Ortho Dermatologics, Pfizer, Inc., Sandoz (a Novartis Company), UCB and Vitae receiving honoraria; as a speaker for AbbVie, Amgen, Celgene Corporation, Eli Lilly and Company, Novartis, Sun Pharmaceuticals, Ltd and UCB receiving honoraria; as a principal investigator for Actavis, Amgen, Boehringer Ingelheim, Celgene Corporation, Cellceutix, Coherus Biosciences, Corrona, Dermira, Eli Lilly and Company, Galderma Laboratories, L.P., Glenmark Generics, Inc., Janssen Pharmaceuticals, Inc., Leo Pharma, Inc., Merck, Novartis, Novella, Pfizer, Inc., Sandoz (a Novartis Company), Sienna Biopharmaceuticals, Stiefel a GSK company, UCB, and Warner Chillcott receiving other financial benefits (fee for service). Kenneth Gordon has received research grants from AbbVie, Bristol‐Myers Squibb, Celgene, Janssen, and Novartis, and has served as a consultant for AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Dermira, Eli Lilly, Janssen, Novartis, Pfizer, Sun, and UCB Pharma. Jo Lambert has received research grants from and has been an advisor/speaker for AbbVie, Celgene, Janssen, LEO Pharma, Eli Lilly, and Novartis. Lluís Puig has received grants/research support (paid to the institution) from or participated in clinical trials for AbbVie, Amgen, Boehringer Ingelheim, Janssen, Leo Pharma, Lilly, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB; received honoraria or consultation fees from AbbVie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen, Leo Pharma, Lilly, Merck‐Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB; and has participated in company‐sponsored speakers' bureaus for Celgene, Janssen, Lilly, MSD, Novartis, and Pfizer. Huzefa Photowala, Michelle Longcore, and Tianyu Zhan are employees of AbbVie, Inc. and may hold stock or stock options. Peter Foley has received grant support from AbbVie, Amgen, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, and Sun Pharma. He has served as an investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, UCB Pharma, Valeant, BMS, Celtaxsys, CSL, Cutanea, Dermira, Galderma, Genentech, GSK, Leo Pharma, Regeneron Pharmaceuticals Inc, Roche, and Sanofi. He has also served on advisory boards for AbbVie, Amgen, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, UCB Pharma, Valeant, Galderma, GSK, Leo Pharma, and Sanofi. He has served as a consultant for Janssen, Lilly, Novartis, Pfizer, UCB Pharma, BMS, Galderma, Leo Pharma, and Roche. He has received travel grants from AbbVie, Janssen, Lilly, Merck, Novartis, Pfizer, Galderma, Leo Pharma, Roche, Sun Pharma, and Sanofi, and has served as a speaker for or received honoraria from AbbVie, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Valeant, Galderma, GSK, Leo Pharma, and Roche.\n\nFunding source\n\nAbbVie sponsored the study, contributed to its design, data collection, analysis, and interpretation of the data, and participated in the writing, review, and approval of the manuscript. All authors had access to relevant data.\n==== Body\nIntroduction\nPsoriasis is a chronic immune‐mediated disease that affects an estimated 100 million people worldwide.\n1\n, \n2\n Patients with moderate‐to‐severe psoriasis are at increased risk of comorbidities, including obesity.\n3\n, \n4\n Although recent scientific advances have led to highly efficacious treatments for moderate‐to‐severe psoriasis, lower efficacy has been reported with biologic treatments in patients with comorbid obesity or in those with prior biologic exposure and/or failure.\n5\n, \n6\n, \n7\n, \n8\n, \n9\n, \n10\n, \n11\n, \n12\n, \n13\n, \n14\n, \n15\n, \n16\n Thus, there is a need for psoriasis treatments to demonstrate consistently high efficacy regardless of patient demographics or prior biologic therapy.\n\nRecent preclinical and clinical findings demonstrated that interleukin‐23 (IL‐23) is a regulatory cytokine critical for the development and maintenance of psoriatic inflammation.\n17\n Preclinical research established that IL‐23 activates T helper and other cells to produce key cytokines and drive psoriatic inflammation. In clinical trials of patients with moderate‐to‐severe plaque psoriasis, efficacy has been demonstrated by an IL‐12/IL‐23 inhibitor, ustekinumab and, more recently, by the selective IL‐23p19 inhibitors, guselkumab, tildrakizumab and risankizumab, further supporting the role of IL‐23 in psoriasis.\n18\n, \n19\n, \n20\n, \n21\n, \n22\n, \n23\n\n\n\nRisankizumab is a humanized IgG monoclonal antibody that binds with high affinity and specificity to the p19 subunit and selectively inhibits IL‐23.\n24\n, \n25\n Exposure‐response analyses of Phase 2 and 3 trials demonstrated that, following initial doses at weeks 0 and 4, the every 12‐week dosing of risankizumab (150 mg) led to maximal efficacy at weeks 16 and 52.\n26\n In phase 3 trials (IMMhance, UltIMMa‐1, UltIMMa‐2, and IMMvent), risankizumab demonstrated superior efficacy compared with placebo, ustekinumab and adalimumab at week 16 that was sustained compared with adalimumab and ustekinumab at weeks 44 and 52, respectively.\n22\n, \n23\n, \n27\n Overall, risankizumab has demonstrated early and sustained high skin clearance with 12‐week dosing in patients with moderate‐to‐severe psoriasis.\n22\n, \n23\n To date, however, the association of baseline disease or prior treatment variables on risankizumab’s efficacy has not been reported.\n\nHere, using integrated data from UltIMMa‐1 and UltIMMa‐2, we assessed the impact of baseline patient demographics, disease characteristics and prior biologic exposure on the efficacy of risankizumab compared with ustekinumab in patients with moderate‐to‐severe plaque psoriasis.\n\nMethods\nPatients\nThis integrated analysis included all patients initially randomized to risankizumab or ustekinumab in UltIMMa‐1 or UltIMMa‐2. In both trials, adult patients (≥18 years of age) were eligible if they had stable moderate‐to‐severe chronic plaque psoriasis for the preceding ≥6 months (with or without psoriatic arthritis) with body surface area (BSA) involvement of 10% or greater, Psoriasis Area and Severity Index (PASI) 12 or greater, and static Physician’s Global Assessment (sPGA) score 3 or greater. Patients were required to be candidates for systemic therapy, phototherapy and treatment with ustekinumab (according to local label). Prior treatment exposure to IL‐17 and tumour necrosis factor (TNF) inhibitors was allowed depending on timing prior to randomization; prior treatment exposure to ustekinumab or other IL‐23 inhibitors was not permitted. Prior biologic exposure was self‐reported; prior biologic failure was defined as any patient with prior biologic exposure who failed to respond to biologic treatment (primary failure) or failed due to loss of response or lack of tolerability (secondary failures). A complete list of inclusion and exclusion criteria is included in Table S1, Supporting Information).\n\nThe trials were conducted in accord with the Good Clinical Practice Guideline, as defined by the International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Declaration of Helsinki and applicable local regulations. All study‐related documents (including the study protocol) were approved by an institutional review board or institutional ethics committee at each trial site, and all patients provided written informed consent before participation.\n\nStudy design\nDetailed methodology has been reported previously for the replicate, multi‐part phase 3, multinational, multicenter, randomized, double‐blinded, placebo‐ and active comparator‐controlled trials, UltIMMa‐1 and UltIMMa‐2.\n22\n Here, we report on patients with moderate‐to‐severe plaque psoriasis who were initially randomized to either risankizumab (150 mg) or ustekinumab (weight‐based; 45 or 90 mg) in Part A (Fig. 1). Randomization was stratified by baseline weight (≤100 kg vs. >100 kg) and prior exposure to TNF inhibitor (yes vs. no). Patients initially randomized to receive risankizumab or ustekinumab received 150 mg risankizumab or weight‐based ustekinumab (45 mg for patients with body weight ≤100 kg or 90 mg for patients with body weight >100 kg) subcutaneously at weeks 0, 4, 16, 28 and 40.\n\nFigure 1 Study design for UltIMMa‐1 and UltIMMa‐2. OLE, open‐label extension; PASI, Psoriasis Area and Severity Index; sPGA, static Physician’s Global Assessment.\n\nAssessments\nEfficacy was analysed using pooled data from UltIMMa‐1 and UltIMMa‐2 in all patients initially randomized to either risankizumab or ustekinumab using an intention‐to‐treat analysis. Efficacy was assessed by demographics and baseline characteristics [age, sex, body mass index (BMI), weight, baseline PASI score, baseline sPGA score and presence of psoriatic arthritis] as well as prior treatment experience (prior biologic exposure, TNF inhibitor exposure, IL‐17 inhibitor exposure and prior biologic failure, including failure of 1 or ≥2 biologics and primary or secondary failure). Efficacy outcomes included the proportion of patients achieving ≥90% improvement in PASI compared to baseline (PASI 90) at weeks 16 and 52. Additional efficacy outcomes were the proportion of patients achieving sPGA score of clear or almost clear (sPGA 0 or 1), or sPGA score of clear (sPGA 0), and PASI 100.\n\nFurther efficacy analyses were conducted in subgroups at week 52 using the categories of BMI (<25, 25–<30, ≥30), weight (≤100 kg and >100 kg), weight quartiles, and weight deciles in order to fully explore the effect of weight on efficacy. Mean per cent improvement in PASI score from baseline to week 52 was analysed for risankizumab and ustekinumab using last observation carried forward.\n\nStatistical analysis\nPatients with missing efficacy data for categorical variables were handled by non‐responder imputation and for continuous variables with last observation carried forward. Categorical variables were tested using the Cochran‐Mantel‐Haenszel risk difference estimate. Per cent change in PASI scores were compared between risankizumab and ustekinumab using analysis of covariance with study, stratum, baseline value and treatment in the model. Logistic regression analyses were conducted for each efficacy endpoint at weeks 16 and 52 to assess the impact on risankizumab efficacy compared with ustekinumab of five independent variables (age, sex, baseline weight, baseline PASI and presence of psoriatic arthritis) and potential interactions between these five independent variables (Table S2, Supporting Information). The Bonferroni correction was used to adjust the critical value of 0.05 for statistical significance in order to account for the multiple comparisons. All statistical analyses were conducted using SAS® version 9.4 (SAS Institute, Inc., Cary, NC, USA) or higher using the UNIX operating system.\n\nResults\nPatient demographics and baseline disease characteristics\nOverall, 797 patients were randomized to receive either 150 mg risankizumab (n = 598) or 45/90 mg ustekinumab (n = 199) at the start of UltIMMa‐1 or UltIMMa‐2, and were included in this integrated analysis. Demographics and baseline disease characteristics were similar between groups (Table 1). Overall, most were male (69.1%); mean age was 47.3 years [standard deviation (SD): 13.7 years] and mean weight was 90.1 kg (SD: 22.3 kg). Mean PASI score was 20.2 (SD: 7.5) and mean BSA involvement was 25.4% (SD: 15.2%). Prior systemic non‐biologic and biologic therapy exposure was reported in 398 (49.9%) and 295 (37.0%) patients, respectively.\n\nTable 1 Baseline demographics and disease characteristics of the intention‐to‐treat population\n\nBaseline characteristics\t\nRisankizumab\n\n\n(N = 598)\n\n\n\t\nUstekinumab†\n\n\n\n(N = 199)\n\n\n\t\nAge, years, mean (SD)\t47.2 (13.6)\t47.5 (14.1)\t\nMale, n (%)\t415 (69.4%)\t136 (68.3%)\t\nRace, white, n (%)\t455 (76.1%)\t165 (82.9%)\t\nWeight, kg, mean (SD)\t90.0 (22.4)\t90.4 (22.2)\t\nWeight >100 kg, n (%)†\n\t169 (28.3%)\t56 (28.1%)\t\nBMI, kg/m2, mean (SD)\t30.5 (7.0)\t30.4 (6.8)\t\nPASI, mean (SD)\t20.6 (7.7)\t19.2 (6.4)\t\nsPGA of severe, n (%)\t114 (19.1%)\t33 (16.6%)\t\nBSA involvement, %, mean (SD)\t26.2 (15.6)\t23.0 (13.6)\t\nPsoriatic arthritis status, n (%)‡\n\t159 (26.6%)\t50 (25.1%)\t\nAny prior biologic therapy, n (%)\t222 (37.1%)\t73 (36.7%)\t\nPrior TNFi exposure, n (%)\n§\n\n\t134 (22.4%)\t43 (21.6%)\t\nPrior IL‐17i exposure, n (%)\t111 (18.6%)\t35 (17.6%)\t\nBMI, body mass index; BSA, body surface area; IL‐17i, interleukin‐17 inhibitor; PASI, Psoriasis Area Severity Index; SD, standard deviation; sPGA, static Physician’s Global Assessment; TNFi, tumour necrosis factor inhibitor.\n\n† Weight‐based dose per label.\n\n‡ Stratification factors at randomization.\n\n§ Diagnosed or suspected.\n\nJohn Wiley & Sons, LtdEfficacy outcomes\nRisankizumab demonstrated superior efficacy compared with ustekinumab regardless of patient subgroup (baseline demographics, disease characteristics or prior biologic exposure). Across all patient subgroups analysed, a significantly greater proportion of patients receiving risankizumab achieved PASI 90 responses at week 16 (70.3–82.2%) and week 52 (77.6–85.9%) compared with those receiving ustekinumab (34.6–55.6% and 30.8–56.3%, respectively, all P < 0.01; Fig. 2). Similar results were observed with sPGA 0 or 1, sPGA 0 (data not shown) and PASI 100 responses at week 16 and 52 (Figs S1 and S2, Supporting Information). The per cent improvement in PASI for individual patients taking risankizumab overall and subgroups of patients with PASI of 18 or above at baseline, BMI of 30 or higher, weight of 100 kg or greater, and who failed one or more biologics can be observed in time‐lapse videos provided as Videos [Link], [Link], [Link], [Link], [Link] (Supporting Information).\n\nFigure 2 Proportion of patients (non‐responder imputation) achieving PASI 90 responses at week 16 (a) and week 52 (b) by baseline patient demographics, disease characteristics and prior biologic therapy (NRI). BL, baseline; NRI, non‐responder imputation; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; RZB, risankizumab; sPGA, static Physician’s Global Assessment; UST, ustekinumab. **P < 0.01, ***P < 0.001 compared with ustekinumab.\n\nPatients taking risankizumab achieved statistically greater mean improvement in PASI scores (per cent change from baseline) at week 52 compared with patients receiving ustekinumab by BMI (<25, 25–<30, ≥30), weight (≤100 kg or >100 kg) and weight quartiles (Fig. 3). Mean PASI improvement (per cent change from baseline) among patients receiving risankizumab remained high (88–98%) across all weight deciles at week 52 (Fig. S3, Supporting Information). Representative images of heavier patients with different baseline disease severity (PASI 15, PASI 26 and PASI 33) show substantial PASI improvement in patients treated with risankizumab from baseline to week 52 (Fig. S4, Supporting Information).\n\nFigure 3 Mean PASI improvement (%) from baseline to week 52 for patients treated with risankizumab and/or ustekinumab by BMI and body weight quartiles (LOCF)†. BMI, body mass index; LOCF, last observation carried forward; PASI, Psoriasis Area and Severity Index; RZB, risankizumab; UST, ustekinumab. **P < 0.01, ***P < 0.001 compared with ustekinumab. Data expressed as mean per cent PASI improvement ± standard error (SE). †Weight quartiles (minimum – maximum) were defined in kg as follows: 1st (43.5–74.0), 2nd (74.2–86.8), 3rd (87.0–103.0) and 4th (103.2–170.0).\n\nA significantly greater proportion of patients receiving risankizumab achieved PASI 90 response at week 16 (73.1–80.2%) and week 52 (78.4–81.6%) compared with those receiving ustekinumab (41.9–46.0% and 32.6–53.2%, respectively, all P < 0.001) regardless of the prior biologic exposure (Fig. 4). For patients with prior biologic failure, a numerically greater proportion of patients receiving risankizumab achieved PASI 90 response at week 16 (70.0–77.6%) and week 52 (70.0–84.5%) compared with those receiving ustekinumab (31.6–37.5% and 15.8–50.0%, respectively) regardless of the number or type of prior failures (Fig. 4). Similar results were observed with sPGA 0 or 1, sPGA 0 (data not shown) and PASI 100 responses (Figs S5 and S6, Supporting Information).\n\nFigure 4 Proportion of patients (non‐responder imputation) achieving PASI 90 responses at week 16 (a) and week 52 (b) by prior biologic treatment experience (NRI). IL‐17i, interleukin‐17 inhibitors; NRI, non‐responder imputation; PASI, Psoriasis Area and Severity Index; RZB, risankizumab; TNFi, tumour necrosis factor inhibitor; UST, ustekinumab. Data expressed as per cent of patients with 95% confidence intervals (upper bounds shown). *P < 0.05, ***P < 0.001 compared with ustekinumab.\n\nMultivariate logistic regression analyses\nLogistic regression analyses were conducted in order to assess whether risankizumab demonstrated superior efficacy compared with ustekinumab at either week 16 or 52 regardless of patient characteristics (age, sex, weight, baseline PASI score and presence of psoriatic arthritis). All logistic regression models at week 16 and week 52 demonstrated that risankizumab treatment led to and maintained superior efficacy, respectively (all P < 0.001), compared with ustekinumab for PASI 90, PASI 100 and sPGA 0 or 1 (Table S3, Supporting Information); this analysis yielded similar results for sPGA 0 (data not shown) as for PASI 100.\n\nDiscussion\nIn this integrated analysis, risankizumab treatment resulted in statistically greater proportions of patients achieving high skin clearance compared with ustekinumab at both weeks 16 and 52, regardless of baseline patient demographics, disease characteristics, or prior biologic therapy exposure. Response rates with risankizumab treatment were consistently high across all subgroups analysed at both weeks 16 and 52. The proportion achieving PASI 90 or sPGA 0 or 1 on risankizumab treatment remained relatively stable across subgroups from week 16 to week 52, while risankizumab treatment showed an increase in the proportion of patients achieving complete clearance (PASI 100) from week 16 to week 52 across subgroups analysed. Logistic regression analyses revealed that risankizumab demonstrated superior efficacy compared with ustekinumab at weeks 16 and 52 even when accounting for effects of five independent covariates typically associated with reduced efficacy responses with other commonly used biologics.\n\nDespite the availability of multiple classes of biologics with different treatment targets, psoriasis remains undertreated partially due to inadequate efficacy or loss of efficacy over time with current therapies.\n28\n In clinical practice, this has resulted in dose optimization in order to increase or maintain clinical responses.\n29\n, \n30\n, \n31\n In particular, patients with higher BMI or body weight have demonstrated lower response rates with many fixed‐dose biologic treatments,\n5\n, \n6\n, \n8\n, \n9\n, \n10\n, \n11\n, \n12\n leading some biologics to be used with weight‐based dosing or more frequent dosing schedules in order to achieve comparable efficacy in these patients.\n7\n, \n32\n, \n33\n Another factor that adversely affects efficacy with some biologics is prior exposure to or failure on a biologic.\n13\n, \n14\n, \n15\n, \n16\n In this analysis, risankizumab achieved superior efficacy compared with ustekinumab in patients with higher BMI or body weight and any prior biologic exposure or failure. Thus, these data support the use of risankizumab without dose adjustment to treat all patients, including those with higher BMI or body weight and in patients with prior biologic exposure or failure.\n\nThere are limitations to this study inherent to its design. This was a post hoc subgroup analysis of two replicate phase 3 trials. The self‐report of prior biologic exposure could be subject to recall errors and biases. Another limitation is the lack of information on disease duration for patients enrolled in these trials. Psoriasis disease duration has been shown to negatively impact efficacy of other biologic treatments for psoriasis.\n18\n Further clinical or real‐world studies are warranted to assess the impact of psoriasis disease duration on the efficacy of risankizumab. Some strengths are the inclusion of an active comparator through 52 weeks, inclusion of a high percentage of historically difficult‐to‐treat patients (prior biologic therapy exposure, high disease severity and high average BMI), and the inclusion of patients across the globe allowing for generalizability of the findings. An additional strength is the inclusion of the logistic regression analyses to control for the effect of five independent covariates (age, sex, weight, baseline PASI score and presence of psoriatic arthritis) and their potential interactions on the efficacy of risankizumab compared with ustekinumab. These multivariate analyses aimed to better represent patients routinely seen in clinical practice where the presence of multiple factors could affect efficacy. Risankizumab demonstrated superior efficacy compared with ustekinumab in all models tested, which included the covariate of weight (>100 kg) known to adversely affect efficacy of other biologic treatments.\n5\n, \n6\n, \n7\n, \n8\n, \n9\n, \n10\n, \n11\n, \n12\n\n\n\nIn summary, risankizumab demonstrated superior efficacy compared with ustekinumab through 52 weeks of treatment regardless of patient baseline demographics, disease characteristics or prior biologic therapy exposure. These results support risankizumab as a psoriasis treatment suitable for a wide variety of patients given its high and durable skin clearance across all subgroups analysed.\n\nSupporting information\n\nFigure S1. Proportion of patients (non‐responder imputation) achieving sPGA 0/1 (a) and PASI 100 (b) responses at week 16 by baseline patient demographics, disease characteristics and prior biologic therapy.\n\n\nFigure S2. Proportion of patients (non‐responder imputation) achieving sPGA 0/1 (a) and PASI 100 (b) responses at week 52 by baseline patient demographics, disease characteristics and prior biologic therapy.\n\n\nFigure S3. Mean PASI improvement from baseline to week 52 by weight deciles in patients treated with risankizumab (LOCF)*.\n\n\nFigure S4. Representative images from 3 patients (a–c) treated with risankizumab at baseline, week 4, week 16, and week 52.\n\n\nFigure S5. Proportion of patients (non‐responder imputation) achieving sPGA 0/1 (a) and PASI 100 (b) responses at week 16 by prior treatment experience.\n\n\nFigure S6. Proportion of patients (non‐responder imputation) achieving sPGA 0/1 (a) and sPGA 0 (b) responses at week 52 by prior treatment experience.\n\n\nTable S1. Inclusion and exclusion criteria.\n\n\nTable S2. Independent variables and their interactions analyzed for their effects on risankizumab compared with ustekinumab using logistic regression.\n\n\nTable S3. Logistic regression models tested comparing proportion of patients achieving efficacy thresholds on risankizumab compared with ustekinumab at weeks 16 and 52.\n\nClick here for additional data file.\n\n \nVideo S1. Time‐lapse of individual patients’ percent improvement in PASI through 52 weeks of risankizumab treatment.\n\nClick here for additional data file.\n\n \nVideo S2. Time‐lapse of individual patients’ percent improvement in PASI through 52 weeks of risankizumab treatment: subgroup of patients with PASI 18 or above.\n\nClick here for additional data file.\n\n \nVideo S3. Time‐lapse of individual patients’ percent improvement in PASI through 52 weeks of risankizumab treatment: subgroup of patients with body mass index of 30 or more.\n\nClick here for additional data file.\n\n \nVideo S4. Time‐lapse of individual patients’ percent improvement in PASI through 52 weeks of risankizumab treatment: subgroup of patients with weight of 100 kg and above.\n\nClick here for additional data file.\n\n \nVideo S5. Time‐lapse of individual patients’ percent improvement in PASI through 52 weeks of risankizumab treatment: subgroup of patients who failed 1 or more biologics.\n\nClick here for additional data file.\n\n Acknowledgements\nMedical writing support was provided by Daniel O’Brien, Ph.D., of AbbVie. Writing support was also provided by Janet Matsuura, Ph.D., of Complete Publication Solutions, LLC; this support was funded by AbbVie.\n==== Refs\nReferences\n1 \n\nHarden \nJL \n, \nKrueger \nJG \n, \nBowcock \nAM \n. The immunogenetics of psoriasis: a comprehensive review\n. J Autoimmun \n2015 ; 64 : 66 –73\n.26215033 \n2 \nWorld Health Organization \n. Global Report on Psoriasis . 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Dermatology \n2008 ; 217 : 365 –373\n.18810241 \n10 \n\nPapp \nKA \n, \nReich \nK \n, \nBlauvelt \nA \n\net al\nEfficacy of tildrakizumab for moderate‐to‐severe plaque psoriasis: pooled analysis of three randomized controlled trials at weeks 12 and 28\n. J Eur Acad Dermatol Venereol \n2019 ; 33 : 1098 –1106\n.30838709 \n11 \n\nPrussick \nR \n, \nUnnebrink \nK \n, \nValdecantos \nWC \n. Efficacy of adalimumab compared with methotrexate or placebo stratified by baseline BMI in a randomized placebo‐controlled trial in patients with psoriasis\n. J Drugs Dermatol \n2015 ; 14 : 864 –868\n.26267731 \n12 \n\nReich \nK \n, \nPuig \nL \n, \nMallbris \nL \n, \nZhang \nL \n, \nOsuntokun \nO \n, \nLeonardi \nC \n. The effect of bodyweight on the efficacy and safety of ixekizumab: results from an integrated database of three randomised, controlled Phase 3 studies of patients with moderate‐to‐severe plaque psoriasis\n. J Eur Acad Dermatol Venereol \n2017 ; 31 : 1196 –1207\n.28370467 \n13 \n\nMazzotta \nA \n, \nEsposito \nM \n, \nCostanzo \nA \n, \nChimenti \nS \n. Efficacy and safety of etanercept in psoriasis after switching from other treatments: an observational study\n. Am J Clin Dermatol \n2009 ; 10 : 319 –324\n.19658444 \n14 \n\nPapp \nKA \n, \nGordon \nKB \n, \nLangley \nRG \n\net al\nImpact of previous biologic use on the efficacy and safety of brodalumab and ustekinumab in patients with moderate‐to‐severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE‐2 and AMAGINE‐3\n. Br J Dermatol \n2018 ; 179 : 320 –328\n.29488226 \n15 \n\nCassano \nN \n, \nGalluccio \nA \n, \nDe Simone \nC \n\net al\nInfluence of body mass index, comorbidities and prior systemic therapies on the response of psoriasis to adalimumab: an exploratory analysis from the APHRODITE data\n. J Biol Regul Homeost Agents \n2008 ; 22 : 233 –237\n.19036225 \n16 \n\nGottlieb \nAB \n, \nLacour \nJP \n, \nKorman \nN \n\net al\nTreatment outcomes with ixekizumab in patients with moderate‐to‐severe psoriasis who have or have not received prior biological therapies: an integrated analysis of two Phase III randomized studies\n. J Eur Acad Dermatol Venereol \n2017 ; 31 : 679 –685\n.27696577 \n17 \n\nHawkes \nJE \n, \nYan \nBY \n, \nChan \nTC \n, \nKrueger \nJG \n. Discovery of the IL‐23/IL‐17 signaling pathway and the treatment of psoriasis\n. J Immunol \n2018 ; 201 : 1605 –1613\n.30181299 \n18 \n\nPapp \nKA \n, \nLangley \nRG \n, \nLebwohl \nM \n\net al\nEfficacy and safety of ustekinumab, a human interleukin‐12/23 monoclonal antibody, in patients with psoriasis: 52‐week results from a randomised, double‐blind, placebo‐controlled trial (PHOENIX 2)\n. Lancet \n2008 ; 371 : 1675 –1684\n.18486740 \n19 \n\nReich \nK \n, \nPapp \nKA \n, \nBlauvelt \nA \n\net al\nTildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials\n. Lancet \n2017 ; 390 : 276 –288\n.28596043 \n20 \n\nBlauvelt \nA \n, \nPapp \nKA \n, \nGriffiths \nCE \n\net al\nEfficacy and safety of guselkumab, an anti‐interleukin‐23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double‐blinded, placebo‐ and active comparator‐controlled VOYAGE 1 trial\n. J Am Acad Dermatol \n2017 ; 76 : 405 –417\n.28057360 \n21 \n\nReich \nK \n, \nArmstrong \nAW \n, \nFoley \nP \n\net al\nEfficacy and safety of guselkumab, an anti‐interleukin‐23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double‐blind, placebo‐ and active comparator‐controlled VOYAGE 2 trial\n. J Am Acad Dermatol \n2017 ; 76 : 418 –431\n.28057361 \n22 \n\nGordon \nKB \n, \nStrober \nB \n, \nLebwohl \nM \n\net al\nEfficacy and safety of risankizumab in moderate‐to‐severe plaque psoriasis (UltIMMa‐1 and UltIMMa‐2): results from two double‐blind, randomised, placebo‐controlled and ustekinumab‐controlled phase 3 trials\n. Lancet \n2018 ; 392 : 650 –661\n.30097359 \n23 \n\nReich \nK \n, \nGooderham \nM \n, \nThaci \nD \n\net al\nRisankizumab compared with adalimumab in patients with moderate‐to‐severe plaque psoriasis (IMMvent): a randomised, double‐blind, active‐comparator‐controlled phase 3 trial\n. Lancet \n2019 ; 394 : 576 –586\n.31280967 \n24 \n\nKrueger \nJG \n, \nFerris \nLK \n, \nMenter \nA \n\net al\nAnti‐IL‐23A mAb BI 655066 for treatment of moderate‐to‐severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single‐rising‐dose, randomized, double‐blind, placebo‐controlled trial\n. J Allergy Clin Immunol \n2015 ; 136 : 116 –124\n.e7.25769911 \n25 \n\nMcKeage \nK \n, \nDuggan \nS \n. Risankizumab: first global approval\n. Drugs \n2019 ; 79 : 893 –900\n.31098898 \n26 \n\nKhatri \nA \n, \nSuleiman \nAA \n, \nPolepally \nAR \n, \nOthman \nAA \n. Exposure‐response Relationship for Efficacy and Safety of Risankizumab in Patients with Moderate‐to‐severe Plaque Psoriasis: Integrated Analyses of Phase 2 and 3 Clinical Trials . Presented at the American Academy of Dermatology (AAD) meeting , Washington, DC , 2019 .\n27 \n\nBlauvelt \nA \n, \nPapp \nKA \n, \nGooderham \nM \n\net al\nEfficacy and safety of risankizumab, an interleukin‐23 inhibitor, in patients with moderate‐to‐severe chronic plaque psoriasis: 16‐week results from the phase III IMMhance trial. Psoriasis Gene to Clinic, 8th International Congress; December 2\n, London, UK , 2017 .\n28 \n\nMenter \nA \n, \nStrober \nBE \n, \nKaplan \nDH \n\net al\nJoint AAD‐NPF guidelines of care for the management and treatment of psoriasis with biologics\n. J Am Acad Dermatol \n2019 ; 80 : 1029 –1072\n.30772098 \n29 \n\nBrezinski \nEA \n, \nArmstrong \nAW \n. Off‐label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy\n. PLoS ONE \n2012 ; 7 : e33486.22509259 \n30 \n\nCarrascosa \nJM \n, \nGarcia‐Doval \nI \n, \nPerez‐Zafrilla \nB \n\net al\nUse of off‐label doses is frequent in biologic therapy for moderate to severe psoriasis: a cross‐sectional study in clinical practice\n. J Dermatolog Treat \n2015 ; 26 : 502 –506\n.25886087 \n31 \n\nEsposito \nM \n, \nGisondi \nP \n, \nConti \nA \n\net al\nDose adjustment of biologic therapies for psoriasis in dermatological practice: a retrospective study\n. J Eur Acad Dermatol Venereol \n2017 ; 31 : 863 –869\n.28146329 \n32 \n\nReich \nK \n, \nPuig \nL \n, \nSzepietowski \nJC \n\net al\nSecukinumab dosing optimization in patients with moderate to severe plaque psoriasis: results from the randomised, open‐label OPTIMISE study\n. Br J Dermatol \n2020 182 : 304 –315\n.31102257 \n33 \n\nLangley \nRG \n, \nLebwohl \nM \n, \nKrueger \nGG \n\net al\nLong‐term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate‐to‐severe psoriasis: results from the PHOENIX 2 study through 5 years of follow‐up\n. Br J Dermatol \n2015 ; 172 : 1371 –1383\n.25307931\n\n",
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"title": "Efficacy of risankizumab in patients with moderate-to-severe plaque psoriasis by baseline demographics, disease characteristics and prior biologic therapy: an integrated analysis of the phase III UltIMMa-1 and UltIMMa-2 studies.",
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"abstract": "OBJECTIVE\nTo determine the adequacy of seizure control and the adverse effects of administering an IV loading dose of phenytoin by constant infusion pump.\n\n\nMETHODS\nA prospective study of patients presenting with acute onset of seizures. Patients were divided into two groups. Group 1 comprised all patients 50 years of age or younger without a history of atherosclerotic cardiovascular disease (ASCVD). Group 2 comprised all patients older than 50 years or with a history of ASCVD.\n\n\nMETHODS\nA rural community hospital emergency department.\n\n\nMETHODS\nForty-two adult patients.\n\n\nMETHODS\nBoth groups received an IV loading dose of phenytoin at 15 mg/kg. Infusion rates were 50 mg/min and 25 mg/min for groups 1 and 2, respectively. Cardiac rhythm and vital signs were monitored throughout and after infusion.\n\n\nRESULTS\nGroup 2 demonstrated significantly more cardiovascular side effects (hypotension and bradycardia) than did group 1 (Fisher's exact test, P less than .05).\n\n\nCONCLUSIONS\nPhenytoin provided adequate seizure control in both groups. For individuals with ASCVD, IV phenytoin administration rates should not exceed 25 mg/min. For individuals without ASCVD, phenytoin administration at 50 mg/min appears safe and without significant cardiovascular side effects.",
"affiliations": "Department of Emergency Service, North Adams Regional Hospital, Massachusetts 01247.",
"authors": "Donovan|P J|PJ|;Cline|D|D|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001161:Arteriosclerosis; D001794:Blood Pressure; D002318:Cardiovascular Diseases; D005260:Female; D006339:Heart Rate; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010672:Phenytoin; D011446:Prospective Studies; D012640:Seizures; D013226:Status Epilepticus",
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"title": "Phenytoin administration by constant intravenous infusion: selective rates of administration.",
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"abstract": "Adenomyosis is a common disease that affects many premenopausal women. Two patients with adenomyosis, aged 51 and 42 years, presented with dysmenorrhea and increased menstrual volume. They refused laparoscopy or laparotomy surgery and were not eligible for the levonorgestrel-releasing intrauterine system (LNG-IUS). The first patient underwent endometrial ablation and subcutaneous etonogestrel (ENG)-releasing implant placement at the same time. Her symptoms of dysmenorrhea and heavy menstruation improved significantly. When serum follicle-stimulating hormone (FSH) and estradiol (E2) levels suggested menopause, the ENG-releasing implant was removed. However, her abdominal pain recurred and was relieved by medication. For the second patient, an ENG-releasing implant was placed first, and her dysmenorrhea and heavy menstrual volume were relieved. However, the bleeding pattern changed from regular bleeding to prolonged bleeding, which troubled the patient. Endometrial ablation was performed 4 months later to solve the problem. Both patients had improved symptoms and were satisfied with the treatment. For patients with adenomyosis who refuse surgery and are not candidates for the use of LNG-IUS, an ENG-releasing implant combined with endometrial ablation may be an effective alternative.",
"affiliations": "Department of Gynecology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, P. R. China.;Department of Gynecology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, P. R. China.;Department of Gynecology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, P. R. China.;Department of Gynecology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, P. R. China.",
"authors": "Nie|Le-Kai|LK|https://orcid.org/0000-0001-8650-1866;Zou|Hong-Li|HL|;Cheng|Lei|L|;Zhang|Pei-Hai|PH|https://orcid.org/0000-0002-1080-4497",
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"keywords": "adenomyosis; case report; endometrial ablation; subcutaneous etonogestrel-releasing implant",
"medline_ta": "J Obstet Gynaecol Res",
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"title": "Subcutaneous etonogestrel implant combined with endometrial ablation for the treatment of adenomyosis: two case reports.",
"title_normalized": "subcutaneous etonogestrel implant combined with endometrial ablation for the treatment of adenomyosis two case reports"
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"abstract": "Efficacy of levetiracetam (LEV) combined with sodium valproate (SV) on pediatric epilepsy and its effect on serum miR-106b in children were investigated. One hundred and twenty children with epilepsy in Xuzhou Children's Hospital from July 2015 to July 2017 were enrolled, and divided into control group (n=60) and observation group (n=60) according to random sampling. Additionally, 100 children undergoing normal physical examination were collected as normal group. Patients in the control group were treated with SV, and patients in the observation group were treated with SV and LEV. RT-qPCR was used for detecting the relative expression of serum miR-106b in children. The clinical efficacy was evaluated. After treatment, the relative expression of serum miR-106b in the control group was significantly higher than that in the observation group (P<0.05). The difference in the control group was smaller than that in the observation group (P<0.05). According to the ROC curve analysis, when the cut-off value was 1.442, the sensitivity, specificity and area under curve (AUC) of miR-106b in the diagnosis of pediatric epilepsy were 94.00, 64.17 and 0.833 respectively. The clinical efficacy in the observation group was significantly better than that in the control group (P<0.05). Spearman's test showed that the expression of miR-106b gradually decreased with the continuous improvement of the clinical efficacy (P<0.05). The AUC of miR-106b was 0.833, 95% CI: 0.779 to 0.887, the cut-off was 1.442. LEV combined with SV is effective in the treatment of children with epilepsy, and does not increase the clinical ADR. The expression of serum miR-106b in children can be used as a clinical prognostic indicator and a potential diagnostic indicator.",
"affiliations": "Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. China.;Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. China.;Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. China.;Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. China.;Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. China.;Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. China.",
"authors": "Zhao|Jiaqiang|J|;Sang|Yan|Y|;Zhang|Yuan|Y|;Zhang|Dongli|D|;Chen|Jiao|J|;Liu|Xiaoming|X|",
"chemical_list": null,
"country": "Greece",
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"doi": "10.3892/etm.2019.8098",
"fulltext": "\n==== Front\nExp Ther MedExp Ther MedETMExperimental and Therapeutic Medicine1792-09811792-1015D.A. Spandidos 10.3892/etm.2019.8098ETM-0-0-8098ArticlesEfficacy of levetiracetam combined with sodium valproate on pediatric epilepsy and its effect on serum miR-106b in children Zhao Jiaqiang Sang Yan Zhang Yuan Zhang Dongli Chen Jiao Liu Xiaoming Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. ChinaCorrespondence to: Dr Xiaoming Liu, Department of Neurology, Xuzhou Children's Hospital, Xuzhou Medical University, 18 Sudi North Road, Xuzhou, Jiangsu 221006, P.R. China, E-mail: minglx@yeah.net12 2019 14 10 2019 14 10 2019 18 6 4436 4442 29 11 2018 21 8 2019 Copyright: © Zhao et al.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Efficacy of levetiracetam (LEV) combined with sodium valproate (SV) on pediatric epilepsy and its effect on serum miR-106b in children were investigated. One hundred and twenty children with epilepsy in Xuzhou Children's Hospital from July 2015 to July 2017 were enrolled, and divided into control group (n=60) and observation group (n=60) according to random sampling. Additionally, 100 children undergoing normal physical examination were collected as normal group. Patients in the control group were treated with SV, and patients in the observation group were treated with SV and LEV. RT-qPCR was used for detecting the relative expression of serum miR-106b in children. The clinical efficacy was evaluated. After treatment, the relative expression of serum miR-106b in the control group was significantly higher than that in the observation group (P<0.05). The difference in the control group was smaller than that in the observation group (P<0.05). According to the ROC curve analysis, when the cut-off value was 1.442, the sensitivity, specificity and area under curve (AUC) of miR-106b in the diagnosis of pediatric epilepsy were 94.00, 64.17 and 0.833 respectively. The clinical efficacy in the observation group was significantly better than that in the control group (P<0.05). Spearman's test showed that the expression of miR-106b gradually decreased with the continuous improvement of the clinical efficacy (P<0.05). The AUC of miR-106b was 0.833, 95% CI: 0.779 to 0.887, the cut-off was 1.442. LEV combined with SV is effective in the treatment of children with epilepsy, and does not increase the clinical ADR. The expression of serum miR-106b in children can be used as a clinical prognostic indicator and a potential diagnostic indicator.\n\nlevetiracetamsodium valproatepediatric epilepsymiR-106befficacy\n==== Body\nIntroduction\nEpilepsy is a chronic brain dysfunction syndrome caused by highly synchronous abnormal discharge of neurons in the brain (1). This common disorder in clinical neurology has sudden onset. Patients with epilepsy, mainly the elderly or children, are often accompanied by varying degrees of transient disturbance of consciousness, and patients with more severe epilepsy may have a general convulsion (2). It has been reported that (3) there are 50 patients diagnosed with epilepsy in 100,000 people in North America each year. Another study shows that (4) more than half of the 50 million patients with epilepsy in the world are in Asia. Childhood is a critical period for the development of human brain function, and the long-term abnormal discharge in the brain has a very adverse effect on the development of the brain function (5). The treatment of epilepsy in children needs to completely control the onset of the disease and eliminate the cause, as well as ensure the learning and daily living ability of children as much as possible. Therefore, how to actively and effectively treat children with epilepsy has become one of the problems that clinicians need to solve now.\n\nNew anti-epileptic drugs have emerged, bringing new hope for the treatment of epilepsy. The main component of levetiracetam (LEV) is a derivative of pyrrolidone. By binding to SV2A in the brain, synaptic vesicle protein 2A, LEV effectively inhibits the high-voltage-activated N-type Ca ion channel in the vertebral neurons of the hippocampus CA1 region, and thereby plays an anti-epileptic role (6). By improving the activity of glutamic acid decarboxylase, sodium valproate (SV) as a conventional therapeutic drug for epilepsy promotes the synthesis of γ-aminobutyric acid in the brain, inhibits γ-aminobutyrate transaminase and prevents the degradation of γ-aminobutyric acid, thereby improving the epileptic symptoms in patients (7).\n\nMicroRNA (miR), a hot research topic in recent years, is a small (19–22 nucleotides) non-coding single-stranded RNA molecule. It causes the translational inhibition of target mRNA or the cleavage of mRNA by regulating gene expression (8). Studies in recent years have shown that miR is differentially expressed in tumor, cardiovascular and nervous system diseases (9–11). In the study by Sun et al (12), the expression of miR-106b is significantly increased in the serum of adult patients with epilepsy. However, there is no study showing the expression of miR-106b in pediatric epilepsy. Whether it can be a potential prognostic indicator has not been reported previously.\n\nTherefore, the efficacy of LEV combined with SV in the treatment of pediatric epilepsy was analyzed in this study, and whether miR-106b could be used as a potential prognostic indicator for the treatment of children with epilepsy was also analyzed, in order to provide a reference for clinicians.\n\nPatients and methods\nA total of 120 children with epilepsy treated in Xuzhou Children's Hospital (Xuzhou, China) from July 2015 to July 2017 were enrolled, and divided into the control group (n=60) and the observation group (n=60) according to random sampling. The control group consisted of 31 males and 29 females, and the observation group consisted of 35 males and 25 females. Additionally, 100 children undergoing normal physical examination were collected as the normal group for this study.\n\nThis study was approved by the Ethics Committee of Xuzhou Children's Hospital, Xuzhou Medical University. Patients who participated in this research had complete clinical data. The family members of the children were informed of this study and signed an informed consent form.\n\n\nInclusion and exclusion criteria\nInclusion criteria: All children met the diagnostic criteria for pediatric epilepsy developed by The Basic and Clinical Aspects of Pediatric Neurological Diseases (13). Children had normal blood routine indicators, coagulation function and liver and kidney function.\n\nExclusion criteria: Children with a history of encephalitis, brain trauma and meningitis; children with immunodeficiency; children complicated with other malignant tumors; children treated with anti-epileptic drugs 1 month before enrollment; children with abnormalities in CT and MRI detection and children with an allergy to therapeutic drugs or a corresponding contraindication.\n\nDrugs and source of kits\nSV (Hangzhou Sanofi Pharmaceutical Co., Ltd., SFDA approval number: H20010595), LEV (UCB Pharma S.A., approval number: H20160251), TransScript miRNA first-strand cDNA synthesis superMix and easypure miRNA kit (TransGen Biotech, AT351-01, ER601-01), PCR instrument (Applied Biosystems; Thermo Fisher Scientific, Inc., 7500). The primers were designed and synthesized by Sangon Biotech (Shanghai) Co., Ltd.\n\nTreatment programs\nPatients in the control group were treated with SV, and the specific treatment was as follows: the initial dose was 5–10 mg/(kg × day). If epilepsy was not controlled 1 week after medication, the dose would be added with 5–10 mg/(kg × day) per week based on the initial dose, until the seizure did not occur [the maximum dose was controlled at 30–40 mg/(kg × day)].\n\nPatients in the observation group were treated with LEV and SV, and the specific treatment was as follows: the initial dose was 10 mg/(kg × day), which was added once a week. The target dose was controlled at 20–60 mg/(kg × day) on the 3rd to 4th week, the daily dose was divided into 2 doses.\n\nRT-qPCR detection\nVenous blood (5 ml) was collected from the child in the morning, allowed to stand at room temperature for 15–30 min, and centrifuged at 3,000 × g for 10 min at 4°C. Serum was collected and centrifuged at 10,080 × g for 10 min using an ultra-speed centrifuge at 4°C to remove the cell debris. A portion of the serum was taken for subsequent experiments, and the rest was stored at −80°C. The EasyPure miRNA kit was used for the extraction of total RNA from the serum, UV spectrophotometer and agarose gel electrophoresis for detecting the purity, concentration and integrity of the total RNA extracted, TransScript® miRNA RT Enzyme mix and 2X TS miRNA reaction mix (belonging to the PCR kit) for the reverse transcription of cDNA. The reverse transcription was carried out in strict accordance with the instructions, and cDNA was taken for subsequent experiments. PCR system was as follows: 1 µl of cDNA, each of 0.4 µl of upstream and downstream primers, 10 µl of 2X TransStart® Top/Tip green qPCR supermix, passive reference dye (50X) (optional), and finally nuclease-free water supplemented to 20 µl. A two-step method was used for detection. PCR reaction conditions were: pre-denaturation at 94°C for 30 sec, denaturation at 94°C for 5 sec, annealing and extension at 60°C for 30 sec, for a total of 40 cycles. U6 was used as an internal reference gene in this experiment, and 2−ΔCq was used to express the relative expression of miR-106b. The primer sequences are shown in Table I (14).\n\nOutcome measures\nMain outcome measures: The clinical efficacy in the children was evaluated according to The Diagnosis and Curing Criteria of Clinical Diseases in 2002 (Table II). The difference in the expression of serum miR-106b was observed in children in the control group and the observation group before treatment and subjects in the normal group. The relative expression of serum miR-106b in children was observed before and 12 weeks after treatment, and that of serum miR-106b in children with different efficacy was observed.\n\nSecondary outcome measures: The clinical data of children in the groups were observed. The ROC curve was plotted according to the expression of serum miR-106b in control, observation and normal group. The incidence of adverse drug reaction (ADR) was compared between the two groups.\n\nStatistical analysis\nIn this study, SPSS20.0 software package was used for the statistical analysis of the data, GraphPad Prism 7 for plotting the figures. Count data were expressed as rate (%), tested by Chi-square and denoted by χ2. Measurement data were expressed as mean ± standard deviation (means ± SD). Independent sample t-test was used for comparison between the groups, paired t-test for comparison in the group before and after treatment and denoted by t. Grade data were tested by rank sum test and denoted by Z. Analysis of variance was used for comparison between multiple groups, LSD t-test for pairwise comparison in the group. The ROC curve was plotted according to the expression of serum miR-106b in the control, the observation and the normal group. The Spearman's test was used to analyze the relationship between the expression of miR-106b and the clinical efficacy. P<0.05 was considered to indicate a statistically significant difference.\n\nResults\n\nClinical data of children\nThe clinical data of children in the three groups were analyzed. There were no statistically significant differences in sex, age, BMI and place of residence between the three groups (P>0.05). The children in the control group and the observation group were compared. In the control group, the average course of disease was 1.25 years and the seizure frequency was 2.48 times/year; there were 23 children with simple partial seizure, 11 children with complex partial seizure, 10 children with tonic-clonic seizure, 7 children with tonic seizure and 9 children with Lennox-Gastaut syndrome. In the observation group, the average course of disease was 1.28 years and the seizure frequency was 2.52 times/year; there were 25 children with simple partial seizure, 9 children with complex partial seizure, 11 children with tonic-clonic seizure, 9 children with tonic seizure and 6 children with Lennox-Gastaut syndrome. There were no statistically significant differences in other data between the two groups (P>0.05) (Table III).\n\nRelative expression of serum miR-106b in three groups of children\nThe expression of serum miR-106b in children before treatment was detected. Before treatment, the expression of serum miR-106b in the control group and the observation group was significantly higher than that in the normal group, with a significant difference (P<0.05); there was no statistically significant difference between the control group and the observation group (P>0.05) (Fig. 1). The expression of serum miR-106b in the two groups after treatment was significantly lower than that before treatment (P<0.05); after treatment, the relative expression of serum miR-106b in the control group was significantly higher than that in the observation group, with a statistically significant difference (P<0.05). The difference of miR-106b during the treatment was compared. The difference in the control group was smaller than that in the observation group, with a statistically significant difference (P<0.05) (Tables IV and V).\n\nDiagnostic value of miR-106b in children with epilepsy\nThe serum miR-106b before treatment was detected in healthy children and in children with epilepsy. The area under curve (AUC) of miR-106b was 0.833, 95% CI: 0.779 to 0.887 the cut-off: 1.442. The sensitivity, the specificity and the Youden index were 94.00, 64.17, and 58.17%, respectively (Fig. 2).\n\nRelationship between clinical efficacy and miR-106b in two groups of children\nThe clinical efficacy in the two groups of children was compared. In the control group, there were 8 children cured, 20 children with marked effect, 18 children with effect and 14 children with invalidity. In the observation group, there were 15 children cured, 27 children with marked effect, 10 children with effect and 8 children with invalidity. The results of comparison showed that the clinical efficacy in the observation group was significantly better than that in the control group, with a statistically significant difference (P<0.05) (Table VI). The relationship between miR-106b and different clinical efficacy was analyzed. Spearman test showed that the expression of miR-106b gradually decreased with the continuous improvement of the clinical efficacy (P<0.05) (Table VII).\n\nADR statistics\nAccording to the ADR statistics, in the control group, there were 3 children with nausea, 4 children with vomiting, 2 children with hypersomnia, 5 children with anorexia, 3 children with dizziness and 3 children with liver function damage. In the observation group, there were 2 children with nausea, 3 children with vomiting, 2 children with hypersomnia, 3 children with anorexia, 2 children with dizziness and 2 children with liver function damage. The results of comparison showed that there was no statistically significant difference in the ADR between the two groups (P>0.05) (Table VIII).\n\nDiscussion\nEpilepsy is a common syndrome in neurology (15). It has been reported that approximately 9 million people are affected by epilepsy in China, the population of which is mainly children and the elderly (16,17). Compared with the elderly, the child's brain is at the developmental stage. Recurrent and transient tonic and clonic seizures for a long time easily cause hypoxia in the brain. Without timely intervention, the neurons of the child are damaged as the disease progresses, seriously affecting the intelligence and the daily life of the child. Therefore, the treatment of pediatric epilepsy is increasingly valued (18).\n\nIn this study, LEV and SV were used to treat children with epilepsy, and their clinical efficacy was observed. SV is the most commonly used broad-spectrum antiepileptic drug for the clinical treatment of epilepsy in clinical practice (19). Although the drug is effective, it is metabolized by the liver and may cause liver function damage in children. Besides, the anti-epileptic treatment process is long and prone to various adverse reactions, which increases the treatment pain and reduces the treatment compliance of the child, resulting in unsatisfactory expected effect (20). Guo et al (21), reported that the long-term use of SV has a serious impact on growth and osteopenia in children with epilepsy. LEV is a new broad-spectrum antiepileptic drug for the treatment of epilepsy (22). There is a study showing that it has a lower effect on liver enzymes and creatine kinase in children (23). The clinical efficacy in the two groups of children after treatment was first observed. The improvement of the disease condition in the observation group was significantly better than that in the control group. In the study by Tan and Appleton (24), 26 children with epilepsy aged under 10 years were treated with LEV alone, and 61% of them had a good response to LEV, with the seizure frequency reduced by at least 50%. In addition, 2 children with refractory epilepsy had no seizure after medication. In this study, the effective rate of LEV combined with SV for the treatment of children was 93.64%, and the efficacy was significantly better than that of single medication. This suggests that the combined medication can effectively improve the condition of the child. Then, the adverse events during the treatment were compared between the two groups. There was no difference in the ADR between the two groups. This suggests that LEV and SV have good efficacy in the treatment of children with epilepsy, and have small adverse reactions.\n\nmiR-106b is an important member of the miR-17 family and differentially expressed in tumor and cardiovascular diseases (25,26). According to Cava et al (27), highly expressed in the serum of patients with epilepsy, miR-106b is expected to become a new diagnostic indicator. However, there is no relevant research on whether it can be a prognostic indicator in the treatment of epilepsy. Therefore, in this study, whether miR-106b can be used as a prognostic indicator in the treatment of children with epilepsy was investigated. The expression of serum miR-106b in children with epilepsy was first detected. The expression of serum miR-106b in the control group and the observation group was significantly higher than that in the normal group, consistent with the results of Pitkänen et al (28). Subsequently, the ROC curve was plotted. In the study by An et al (29), the AUC of miR-106b was 0.786, 95% CI: 0.693–0.824, while the AUC was 0.882, 95% CI: 0.839–0.926 in the study by Wang et al (30), consistent with the results of this study. In the present study, the AUC of miR-106b was 0.833, 95% CI: 0.779–0.887. These findings suggest that miR-106b can be used as a potential diagnostic indicator for children with epilepsy. Finally, the correlation analysis between the clinical efficacy and the expression of miR-106b in children was performed. The expression of miR-106b in children after treatment gradually decreased with the improvement of the disease, suggesting that miR-106b is expected to be a potential prognostic indicator for children with epilepsy after treatment.\n\nThis study showed the clinical efficacy of LEV combined with SV in children with epilepsy. The combination of the two drugs effectively improves the condition of the child, and does not increase the clinical ADR. The expression of serum miR-106b in children was detected. miR-106b was highly expressed in children with epilepsy. The expression of serum miR-106b in children can be used as a prognostic indicator. However, there are still limitations in this study. First, the children were not followed up for a long time, and the specific improvement of them remains unclear. Secondly, the specific mechanism of LEV combined with SV on improving of the expression of miR-106b in children needs further investigation.\n\nIn summary, LEV combined with SV is effective in the treatment of children with epilepsy, and does not increase the clinical ADR. The expression of serum miR-106b in children can be used as a clinical prognostic indicator and a potential diagnostic indicator.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nJZ wrote the manuscript. JZ and YS were responsible for PCR. YZ and DZ assisted with the clinical efficacy analysis. JC and XL were responsible for the statistical analysis. All the authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe study was approved by the Ethics Committee of Xuzhou Children's Hospital, Xuzhou Medical University (Xuzhou, China). Patients who participated in this research, had complete clinical data. The family members of the children were informed of this study and signed an informed consent form.\n\nPatient consent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. Relative expression of serum miR-106b in groups of children. RT-qPCR showed that there was a difference in the expression of serum miR-106b in children between the groups. The expression of serum miR-106b in the normal group was significantly lower than that in the control group and the observation group (P<0.05). There was no significant difference between the control group and the observation group (P>0.05). ***P<0.001 indicates that the two groups were compared.\n\nFigure 2. Diagnostic value of miR-106b in children with epilepsy. The ROC curve showed that the AUC of miR-106b was 0.833, 95% CI: 0.779–0.887. The maximum sensitivity and specificity obtained at 1.442 were 94.00% and 64.17%, respectively. The Youden index was 58.17%. AUC, area under curve.\n\nTable I. Primer sequences.\n\nGenes\tUpstream primer\tDownstream primer\t\nmiR-106b\t5′-TGCCTCCTCATTGTCTTCA-3′\t5′-GCCATCTCAAATACCTCCC-3′\t\nU6\t5′-CTCGCTTCGGCAGCACA-3′\t5′-AACGCTTCACGAATTTGCGT-3′\t\nTable II. Clinical efficacy grading.\n\nEfficacy grade\tPerformance\t\nCured\tNo epileptic seizure in children\t\nMarkedly effective\tNo epileptic seizure or seizure frequency reduced by >75%\t\nEffective\tSeizure frequency reduced by 25–75%\t\nInvalid\tSeizure frequency reduced by <25%, or no significant reduction, or increase in seizure\t\nTable III. Clinical data of children.\n\nFactor\tControl group (n=60)\tObservation group (n=60)\tNormal group (n=100)\tt/χ2/F value\tP-value\t\nSex\t\n Male\t31 (51.67)\t35 (58.33)\t58 (58.00)\t0.742\t0.690\t\n Female\t29 (48.33)\t25 (41.67)\t42 (42.00)\t\t\t\nAge (years)\t 7.2±1.8\t 7.5±1.9\t 7.0±1.5\t1.624\t0.200\t\nBMI (kg/m2)\t15.12±1.25\t14.82±1.42\t14.98±1.62\t0.623\t0.537\t\nAverage course of disease (years)\t 1.25±0.35\t 1.28±0.29\t\t0.511\t0.610\t\nSeizure frequency (times/years)\t 2.48±1.22\t 2.52±1.35\t\t0.170\t0.865\t\nEpileptic seizure type\t\n Simple partial seizure\t23 (38.33)\t25 (41.67)\t\t1.110\t0.893\t\n Complex partial seizure\t11 (18.33)\t 9 (15.00)\t\t\t\t\n Tonic-clonic seizure\t10 (16.67)\t11 (18.33)\t\t\t\t\n Tonic seizure\t 7 (11.67)\t 9 (15.00)\t\t\t\t\n Lennox-Gastaut syndrome\t 9 (15.00)\t 6 (10.00)\t\t\t\t\nPlace of residence\t\n Urban\t35 (58.33)\t30 (50.00)\t58 (58.00)\t1.170\t0.557\t\n Rural\t25 (41.67)\t30 (50.00)\t42 (42.00)\t\t\t\nTable IV. Relative expression of miR-106b in two groups of children before and after treatment.\n\n\tRelative expression of miR-106b\t\t\t\n\t\t\t\t\nGroup\tBefore treatment\tAfter treatment\tt value\tP-value\t\nControl group (n=60)\t1.627±0.456\t1.454±0.302\t 7.508\t<0.001\t\nObservation group (n=60)\t1.586±0.466\t1.244±0.256\t12.205\t<0.001\t\nt value\t0.487\t4.109\t\t\t\nP-value\t0.627\t<0.001\t\t\t\nTable V. Comparison of difference in relative expression of miR-106b between the two groups before and after treatment.\n\nScore\tControl group (n=110)\tObservation group (n=110)\tt value\tP-value\t\nDifference in relative expression of miR-106b\t0.172±0.128\t0.342±0.217\t5.227\t<0.001\t\nTable VI. Clinical efficacy in two groups of children.\n\nGroups\tCured\tMarkedly effective\tEffective\tInvalid\tZ value\tP-value\t\nControl (n=60)\t 8 (13.33)\t20 (33.33)\t18 (30.00)\t14 (23.33)\t−2.525\t0.012\t\nObservation (n=60)\t15 (25.00)\t27 (45.00)\t10 (16.67)\t 8 (13.33)\t\t\t\nTable VII. Relationship between clinical efficacy and miR-106b.\n\nEfficacy grade\tn\tRelative expression of miR-106b\tr value\tP-value\t\nCured\t23\t1.124±0.394\t\t\t\nMarkedly effective\t47\t1.319±0.284\t0.784\t<0.001\t\nEffective\t28\t1.239±0.298\t\t\t\nInvalid\t22\t1.658±0.207\t\t\t\nTable VIII. ADR statistics.\n\nGroups\tNausea\tVomiting\tHypersomnia\tAnorexia\tDizziness\tLiver function damage\t\nControl (n=60)\t3 (5.00)\t4 (6.67)\t2 (3.33)\t5 (8.33)\t3 (5.00)\t3 (5.00)\t\nObservation (n=60)\t2 (3.33)\t3 (5.00)\t2 (3.33)\t3 (5.00)\t2 (3.33)\t2 (3.33)\t\nχ2 value\t0.209\t0.152\t0\t0.536\t0.209\t0.209\t\nP-value\t0.648\t0.697\t1\t0.464\t0.648\t0.648\n==== Refs\nReferences\n1 Berg AT Scheffer IE New concepts in classification of the epilepsies: Entering the 21st century Epilepsia 52 1058 1062 2011 10.1111/j.1528-1167.2011.03101.x 21635233 \n2 Russ SA Larson K Halfon N A national profile of childhood epilepsy and seizure disorder Pediatrics 129 256 264 2012 10.1542/peds.2010-1371 22271699 \n3 Theodore WH Spencer SS Wiebe S Langfitt JT Ali A Shafer PO Berg AT Vickrey BG Epilepsy in North America: A report prepared under the auspices of the global campaign against epilepsy, the International Bureau for Epilepsy, the International League Against Epilepsy, and the World Health Organization Epilepsia 47 1700 1722 2006 10.1111/j.1528-1167.2006.00633.x 17054693 \n4 Mac TL Tran DS Quet F Odermatt P Preux PM Tan CT Epidemiology, aetiology, and clinical management of epilepsy in Asia: A systematic review Lancet Neurol 6 533 543 2007 10.1016/S1474-4422(07)70127-8 17509488 \n5 Glennon JM Weiss-Croft L Harrison S Cross JH Boyd SG Baldeweg T Interictal epileptiform discharges have an independent association with cognitive impairment in children with lesional epilepsy Epilepsia 57 1436 1442 2016 10.1111/epi.13479 27503785 \n6 Belcastro V Costa C Galletti F Autuori A Pierguidi L Pisani F Calabresi P Parnetti L Levetiracetam in newly diagnosed late-onset post-stroke seizures: A prospective observational study Epilepsy Res 82 223 226 2008 10.1016/j.eplepsyres.2008.08.008 18829259 \n7 Chen L Feng P Wang J Liu L Zhou D Intravenous sodium valproate in mainland China for the treatment of diazepam refractory convulsive status epilepticus J Clin Neurosci 16 524 526 2009 10.1016/j.jocn.2008.06.007 19243950 \n8 Ha M Kim VN Regulation of microRNA biogenesis Nat Rev Mol Cell Biol 15 509 524 2014 10.1038/nrm3838 25027649 \n9 Condorelli G Latronico MV Cavarretta E microRNAs in cardiovascular diseases: Current knowledge and the road ahead J Am Coll Cardiol 63 2177 2187 2014 10.1016/j.jacc.2014.01.050 24583309 \n10 Lin S Gregory RI MicroRNA biogenesis pathways in cancer Nat Rev Cancer 15 321 333 2015 10.1038/nrc3932 25998712 \n11 Sun Y Luo ZM Guo XM Su DF Liu X An updated role of microRNA-124 in central nervous system disorders: A review Front Cell Neurosci 9 193 2015 10.3389/fncel.2015.00193 26041995 \n12 Sun J Cheng W Liu L Tao S Xia Z Qi L Huang M Identification of serum miRNAs differentially expressed in human epilepsy at seizure onset and post-seizure Mol Med Rep 14 5318 5324 2016 10.3892/mmr.2016.5906 27840934 \n13 Healy F Panitch HB Pulmonary complications of pediatric neurological diseases Pediatr Ann 39 216 224 2010 10.3928/00904481-20100318-06 20411899 \n14 Livak KJ Schmittgen TD Analysis of relative geneexpression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method Methods 25 402 408 2001 10.1006/meth.2001.1262 11846609 \n15 Fisher RS Acevedo C Arzimanoglou A Bogacz A Cross JH Elger CE Engel J Jr Forsgren L French JA Glynn M ILAE official report: A practical clinical definition of epilepsy Epilepsia 55 475 482 2014 10.1111/epi.12550 24730690 \n16 Singh A Trevick S The epidemiology of global epilepsy Neurol Clin 34 837 847 2016 10.1016/j.ncl.2016.06.015 27719996 \n17 Ollenberger GP Byrne AJ Berlangieri SU Rowe CC Pathmaraj K Reutens DC Berkovic SF Scheffer IE Scott AM Assessment of the role of FDG PET in the diagnosis and management of children with refractory epilepsy Eur J Nucl Med Mol Imaging 32 1311 1316 2005 10.1007/s00259-005-1844-6 16078061 \n18 Lagunju IA Oyinlade AO Babatunde OD Seizure-related injuries in children and adolescents with epilepsy Epilepsy Behav 54 131 134 2016 10.1016/j.yebeh.2015.11.019 26708062 \n19 Stephen LJ Kwan P Shapiro D Dominiczak M Brodie MJ Hormone profiles in young adults with epilepsy treated with sodium valproate or lamotrigine monotherapy Epilepsia 42 1002 1006 2001 10.1046/j.1528-1157.2001.0420081002.x 11554885 \n20 Fisher K Vuppalanchi R Saxena R Drug-induced liver injury Arch Pathol Lab Med 139 876 887 2015 10.5858/arpa.2014-0214-RA 26125428 \n21 Guo CY Ronen GM Atkinson SA Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy Epilepsia 42 1141 1147 2001 10.1046/j.1528-1157.2001.416800.x 11580761 \n22 Weijenberg A Brouwer OF Callenbach PM Levetiracetam monotherapy in children with epilepsy: A systematic review CNS Drugs 29 371 382 2015 10.1007/s40263-015-0248-9 26013703 \n23 Attilakos A Dinopoulos A Paschalidou M Tsirouda M Prasouli A Siafakas N Garoufi A Effect of levetiracetam monotherapy on liver enzymes and creatine kinase concentrations in children with epilepsy: A prospective study J Clin Neurol 14 594 595 2018 10.3988/jcn.2018.14.4.594 30284772 \n24 Tan MJ Appleton RE Efficacy and tolerability of levetiracetam in children aged 10 years and younger: A clinical experience Seizure 13 142 145 2004 10.1016/S1059-1311(03)00193-6 15010050 \n25 Moshiri F Salvi A Gramantieri L Sangiovanni A Guerriero P De Petro G Bassi C Lupini L Sattari A Cheung D Circulating miR-106b-3p, miR-101-3p and miR-1246 as diagnostic biomarkers of hepatocellular carcinoma Oncotarget 9 15350 15364 2018 10.18632/oncotarget.24601 29632649 \n26 Wronska A Kurkowska-Jastrzebska I Santulli G Application of microRNAs in diagnosis and treatment of cardiovascular disease Acta Physiol (Oxf) 213 60 83 2015 10.1111/apha.12416 25362848 \n27 Cava C Manna I Gambardella A Bertoli G Castiglioni I Potential role of miRNAs as theranostic biomarkers of epilepsy Mol Ther Nucleic Acids 13 275 290 2018 10.1016/j.omtn.2018.09.008 30321815 \n28 Pitkänen A Löscher W Vezzani A Becker AJ Simonato M Lukasiuk K Gröhn O Bankstahl JP Friedman A Aronica E Advances in the development of biomarkers for epilepsy Lancet Neurol 15 843 856 2016 10.1016/S1474-4422(16)00112-5 27302363 \n29 An N Zhao W Liu Y Yang X Chen P Elevated serum miR-106b and miR-146a in patients with focal and generalized epilepsy Epilepsy Res 127 311 316 2016 10.1016/j.eplepsyres.2016.09.019 27694013 \n30 Wang J Yu JT Tan L Tian Y Ma J Tan CC Wang HF Liu Y Tan MS Jiang T Genome-wide circulating microRNA expression profiling indicates biomarkers for epilepsy Sci Rep 5 9522 2015 10.1038/srep09522 25825351\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-0981",
"issue": "18(6)",
"journal": "Experimental and therapeutic medicine",
"keywords": "efficacy; levetiracetam; miR-106b; pediatric epilepsy; sodium valproate",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "4436-4442",
"pmc": null,
"pmid": "31777547",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "17054693;30284772;15010050;19243950;17509488;25825351;30321815;11580761;21635233;16078061;26013703;26041995;22271699;27503785;11554885;18829259;27694013;25027649;11846609;29632649;24583309;26708062;27840934;25998712;27719996;24730690;26125428;27302363;20411899;25362848",
"title": "Efficacy of levetiracetam combined with sodium valproate on pediatric epilepsy and its effect on serum miR-106b in children.",
"title_normalized": "efficacy of levetiracetam combined with sodium valproate on pediatric epilepsy and its effect on serum mir 106b in children"
} | [
{
"companynumb": "CN-UCBSA-2019052455",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Presenting the first clinical case of Wickerhamomyces myanmarensis.\n\n\n\nYeast cells were isolated from blood and central venous catheter of a 5.5-year-old male subject. API 20C AUX, MALDI-TOF MS, ITS and LSU rDNA sequencing, and our qPCR assay were used for identification and the MIC values were determined by CLSI M27-A3.\n\n\n\nITS and LSU rDNA sequencing identified both isolates as W. myanmarensis, while API 20C AUX and MALDI-TOF MS did not identify them correctly. Our qPCR specifically distinguished W. myanmarensis from W. anomalus. Isolate obtained from blood showed a higher MIC value for fluconazole, voriconazole and posaconazole.\n\n\n\nUtilization of reliable identification tools might reveal the genuine spectrum of opportunistic yeast species.",
"affiliations": "Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.;Basic Sciences in Infectious Diseases Research Center, & Department of Medical Mycology & Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.;Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.;Department of Dermatology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.;Basic Sciences in Infectious Diseases Research Center, & Department of Medical Mycology & Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.;Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.;Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.;Biology Department, Faculty of Science, Sahid Bahonar University of Kerman, Kerman, Iran.;Department of Dermatology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.;Department of Dermatology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.;Basic Sciences in Infectious Diseases Research Center, & Department of Medical Mycology & Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.;Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.;Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands.",
"authors": "Arastehfar|Amir|A|;Bakhtiari|Mina|M|;Daneshnia|Farnaz|F|;Fang|Wenjie|W|;Sadati|Sara Khanjari|SK|;Al-Hatmi|Abdullah Ms|AM|;Groenewald|Marizeth|M|;Sharifi-Mehr|Hamid|H|;Liao|Wanqing|W|;Pan|Weihua|W|;Zomorodian|Kamiar|K|;Hagen|Ferry|F|;Boekhout|Teun|T|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D015725:Fluconazole; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.2217/fmb-2018-0253",
"fulltext": "\n==== Front\nFuture MicrobiolFuture MicrobiolFMBFuture Microbiology1746-09131746-0921Future Medicine Ltd London, UK 3085986010.2217/fmb-2018-0253Case SeriesFirst fungemia case due to environmental yeast Wickerhamomyces myanmarensis: detection by multiplex qPCR and antifungal susceptibility Arastehfar, Bakhtiari, Daneshnia et al.Fungemia due to Wickerhamomyces myanmarensis & its identificationArastehfar Amir \n‡\n\n1\nBakhtiari Mina \n2\nDaneshnia Farnaz \n1\nFang Wenjie \n3\n\n5\nSadati Sara Khanjari \n2\nAl-Hatmi Abdullah MS \n1\n\n4\nGroenewald Marizeth \n1\nSharifi-Mehr Hamid \n6\nLiao Wanqing \n3\n\n5\nPan Weihua *\n3\n\n5\nZomorodian Kamiar **\n2\nHagen Ferry \n1\nBoekhout Teun \n1\n\n2\n\n7\n\n1 Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands\n2 Basic Sciences in Infectious Diseases Research Center, & Department of Medical Mycology & Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran\n3 Department of Dermatology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China\n4 Ministry of Health, Directorate General of Health Services, Ibri, Oman\n5 Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai Institute of Medical Mycology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China\n6 Biology Department, Faculty of Science, Sahid Bahonar University of Kerman, Kerman, Iran\n7 Institute of Biodiversity & Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands*Author for correspondence: Tel.: +860 2181 885 494; Fax: +860 2181 885 493; panweihua@smmu.edu.cn**Author for correspondence: Tel.: +98 9177 144 094; Fax: +98 7132 349 411; zomorodian2@yahoo.com\n‡Present address: Westerdijk Fungal Biodiversity Institute, Utrecht, The Netherlands\n\n3 2019 12 3 2019 12 3 2019 14 4 267 274 07 9 2018 09 1 2019 12 3 2019 © 2019 Weihua Pan2019This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported LicenseAim:\nPresenting the first clinical case of Wickerhamomyces myanmarensis.\n\nPatients & methods:\nYeast cells were isolated from blood and central venous catheter of a 5.5-year-old male subject. API 20C AUX, MALDI-TOF MS, ITS and LSU rDNA sequencing, and our qPCR assay were used for identification and the MIC values were determined by CLSI M27-A3.\n\nResults:\nITS and LSU rDNA sequencing identified both isolates as W. myanmarensis, while API 20C AUX and MALDI-TOF MS did not identify them correctly. Our qPCR specifically distinguished W. myanmarensis from W. anomalus. Isolate obtained from blood showed a higher MIC value for fluconazole, voriconazole and posaconazole.\n\nConclusion:\nUtilization of reliable identification tools might reveal the genuine spectrum of opportunistic yeast species.\n\nKeywords: \nantifungal susceptibility testingbloodcentral venous catheterspecific multiplex qPCRWickerhamomyces myanmarensis\n==== Body\nNumber of patients who are at risk for candidemia continues to escalate [1]. Moreover, misuse of antifungals including fluconazole, and the emergence of rare yeast species posed a challenge for treatment of bloodstream infections [2]. For instance, nowadays Candida auris due to it being a multidrug resistant, a persistent colonizer in ICU wards, and causing a high mortality rate of 30–60% created a challenge for public health agencies [3].\n\n\nWickerhamomyces (Pichia) myanmarensis for the first time was isolated from sugar palm in 2005 [4]. Due to its high level of similarity at LSU rDNA with W. anomalus, it was thought to be either W. anomalus or its sister species [4]. However, its ability to grow at 37 and 40°C, assimilation of D-arabinose, detection by specific DNA hybridization probes, the production of hat-shaped ascospores, and presence of Q7-ubiquinone convinced investigators to consider it as a new species, Pichia myanmarensis [4]. Recent study considered P. myanmarensis as W. myanmarensis [5]. Herein, we reported W. myanmarensis as a novel opportunist yeast species that for the first time has been isolated from blood and central venous catheter samples.\n\nCase\nA 5.5-year-old boy who presented with recurrent GI tract bleeding and abnormal liver function was admitted to the pediatric surgery ward at Namazi Hospital, Shiraz, Iran on 26 October 2017. The patient lived in a rural area in the Northern part of Iran in a middle-class family (Babol, Mazandaran, Iran). The clinical history of the patient showed that he experienced esophageal and gastric fundal varices and splenectomy. Endoscopic documentation suggested diffuse erosion and convulsion in the stomach. His international normalized ratio test (INR) of 3.9 and prothrombin time (PT) of 45 along with sudden hemoglobin drop suggested portal hypertension and gastrointestinal hemorrhage. In order to compensate blood loss, the patient was supplied with several blood transfusions. Sonography examination revealed small-sized liver with mild coarse parenchymal echogenicity. One day after admission (27 October 2017), in order to control gastroesophageal reflux disorder, the patient was treated orally with omeprazole twice a day. On 1 November 2017, patient underwent laparotomy and distal splenorenal shunt and he was intravenously (RT jugular triple lumen) prescribed with prophylactic treatment of 200 mg of vancomycin once a day, 400 mg of meropenem, and 40 mg of cefazolin three-times a day. From 1 to 17 November 2017, the patient manifested several fever episodes, hence, frequent blood, urine and abdominal fluid samples were taken, which all yielded negative results. However, one blood sample taken on 17 November 2017 and one double-lumen catheter sample on 18 November yielded positive growth after 48 h of incubation in BD Bactec Bacton device (MD, USA). Streaking 100 μl of positive blood bottles on blood agar, EMB, Sabouraud dextrose agar and CHROMagar (24–48 h, 37°C) yielded yeast colonies. Presence of yeast cells in the blood sample (positive blood bottle) was confirmed by direct smear testing and germ tube testing was negative. On 2 December 2017, patient was discharged with omeprazole treatment, while he did not receive any antifungal treatments. According to the latest follow-up of the patient (18 November 2018) on 24 January 2018 due to gastrointestinal bleeding, he was referred to the same hospital and on 16 February 2018 a distal splenectomy shunt was inserted to control his hematemesis (vomiting blood). His family members mentioned that, since then, he was not re-referred to the hospital and his general health condition was satisfactory.\n\nMicrobiology\nTransferring single colonies obtained from CVC and blood samples on CHROMagar (24–48 h at 37°C) yielded small pink colonies. Presence of yeast cells was confirmed by direct smear testing (Figure 1) of the positive blood bottle and the germ tube test was negative. As the first line of identification, colonies were subjected to API 20C AUX (Biomeriux, France) and the API strips were read after incubation of 72 h at 30°C. API 20C AUX identified both isolates as Wickerhamomyces anomalus.\n\nFigure 1. \nDirect microscopy revealed presence of yeast cells in positive blood bottle sample.\n\nPictures were taken with 40× lens. Arrows clearly indicate yeast cells.\n\nUsing full extraction method [6], the proteins of clinical strains were extracted, and 1 μl of supernatants were evaluated by MALDI-TOF MS using a Bruker device (MicroFlex LT, Bruker Daltonics, Bremen, Germany). Bruker MALDI-TOF MS device failed to identify these two isolates and categorized them as not reliable identification with red scores (<1.6) matching with Kytococcus sedentarius. Repeated full extraction method and identification by MALDI-TOF MS showed the same results. Consequently, DNA sequencing of large subunit (LSU) using LROR and LR5 primers and internal transcribed sequence (ITS) domains of ribosomal DNA (rDNA) using ITS1 and ITS4 primers were performed as gold standard technique [7]. Obtained sequences were searched by BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) and LSU showed 100% similarity with W. myanmarensis, 99% with W. anomalus and 98% with W. edaphicus, while ITS showed 100% similarity with W. myanmarensis and 98% with W. anomalus. For further confirmation, using concatenated sequences of LSU and ITS, a phylogenetic tree was constructed (Figure 2). Subsequently, relevant sequences of the other closely related yeast species were retrieved from NCBI and aligned using MEGA v7.0. Phylogenetic trees using neighbor-joining method and 1000 bootstraps with MEGA clustered our clinical isolates of W. myanmarensis with the environmental isolate of W. myanmarensis (CBS 9786 and BCRC 23287) and both isolates (one from CVC and the other one from blood) were placed in the same clade. Obtained sequences of LSU and ITS rDNA for both strains were deposited in the GenBank database (https://www.ncbi.nlm.nih.gov/genbank/) and they were designated with the following accession numbers, MH236218, MH236219, MH236220 and MH236221. Due to a high degree of similarity on the rDNA gene with W. anomalus and the fact that there is no specific and rapid molecular test for identification of W. myanmarensis, a SYBR-Green I-based qPCR was developed (Table 1). Our multiplex PCR based on melting temperature of PCR products unequivocally distinguished W. myanmarensis (74.91 ± 0.31°C) from W. anomalus (73.04 ± 0.23°C) (Figure 3B & C). When subjected to our multiplex qPCR, W. edaphicus yielded high Ct values (Ct = 39) for (Figure 3A), which further confirmed that our isolates were W. myanmarensis. Specificity testing with 27 various opportunistic yeast species (Table 2) resulted in 100% specificity (Figure 3A). Yeast species that were the most common cause of yeast infections or those that were both clinically important and had a close genetic background to the target species were included in the specificity testing. Obtaining average R2 value of 0.99 indicated a high degree of reproducibility of our qPCR assay (Figure 3D). CBS-type strains of W. myanmarensis (CBS 9786; n = 1), W. edaphicus (CBS 10408; n = 1) and W. anomalus (n = 13 CBS reference strains mentioned in Table 2) were subjected to API 20C AUX, MALDI-TOF MS, ITS and LSU rDNA sequencing, and our real-time PCR assay.\n\nFigure 2. \nPhylogenetic tree based on concatenated sequences of ITS and LSU D1/D2 domains of rDNA.\n\nThe tree was constructed using neighbor-joining method and 1000 bootstraps. Bar shows one nucleotide substitution in 100 nucleotides. Phylogenetic tree obviously placed our clinical isolates within the cluster of environmental strains of Pichia myanmarensis (CBS 9786 and BCRC 23287).\n\nTable 1. \nList of primers utilized in this study.\n\nPrimer name\tPrimer sequence\tTarget loci\tTarget species\tMelting temperature\tPCR product size\t\nPF-Universal\tGAAATAATGTATTAGGTTCTTCCAAC\tITS\tW. anomalus/W. myanmarensis\tNA\tNA\t\n\t\nPR-Anomala\tGCCGAGCCTAAAATACTTCT\tITS\tW. anomalus\t73.04 ± 0.23\t71 bps\t\n\t\nPR-myanmar\tACTTTGTGTATATGTTATTGGGC\tITS\tW. myanmarensis\t74.91 ± 0.31\t93 bps\t\nFigure 3. \nProperties of designed qPCR are depicted.\n\n\n(A) Ct values for target species and nontarget species, (B) Tm distribution for W. myanmarensis and W. anomalus, (C) Individual melting curve for W. anomalus and W. myanmarensis, and (D) obtained standard curves for target species.\n\nTable 2. \nReference strains of various opportunistic yeast species were used for specificity testing.\n\nSpecies\tOrigin\t\nCandida albicans\tCBS 2704\t\n\t\nCandida tropicalis\tCBS 2313\t\n\t\nCandida parapsilosis\tCBS 11045\t\n\t\nCandida glabrata\tCBS 138\t\n\t\nPichia kudriavzevii\tCBS 5147\t\n\t\nPichia norvegensis\tCBS 6564\t\n\t\nClavispora lusitaniae\tCBS 6936\t\n\t\nDebaromyces hansenii\tCBS 767\t\n\t\nCandida dubliniensis\tCLF 10\t\n\t\nPichia guilliermondii\tCBS 7099\t\n\t\nKluyvermyces marxianus\tSTA 63\t\n\t\nCandida rugosa\tCBS 613\t\n\t\nYarrowia lipolytica\tCBS 6124\t\n\t\nPichia fermentans\tCBS 187\t\n\t\nPichia kluyveri\tCBS 188\t\n\t\nPichia membranifaciens\tCBS 107\t\n\t\nKluyveromyces marxianus\tCBS 712\t\n\t\nLodderomyces elongisporus\tCBS 2605\t\n\t\nMagnusiomyces capitatus\tCBS 162.8\t\n\t\nMeyerozyma caribbica\tCBS 9966\t\n\t\nCryptococcus neoformans\tCBS 8710\t\n\t\nCryptococcus gattii\tCBS 7229\t\n\t\nRhodotorula mucilaginosa\tCBS 316\t\n\t\nSaccharomyces cerevisiae\tCBS 1171\t\n\t\nTrichosporon asahii\tCBS 2479\t\n\t\nTrichosporon inkin\tCBS 5585\t\n\t\nWickerhamomyces edaphicus\tCBS 10408\t\n\t\nWickerhamomyces myanmarensis\tCBS 9786\t\n\t\nWickerhamomyces anomalus\tCBS 5759; CBS 6417; CBS 110; CBS 2870; CBS 7338; CBS 2871; CBS 260; CBS 5702; CBS 262; CBS 263; CBS 257; CBS 605; CBS 6407\t\nRegarding antifungal susceptibility testing, five antifungal drugs, including posaconazole (Sigma–Aldrich, Switzerland), itraconazole (Janssen Research Foundation, Beerse, Belgium), voriconazole (Pfizer, Central Research, UK), fluconazole (Pfizer, CT, USA), and amphotericin B (AMB, Sigma–Aldrich, MO, USA) were utilized. Broth microdilution method as instructed by CLSI M27-A3 was performed [8]. The strain isolated from CVC showed a high MIC value for AMB (MIC = 2), while it was susceptible to ITC (MIC = 0.06), FLU (MIC = 0.5), PSC (MIC = 0.125) and VRC (MIC = 0.06). Surprisingly, strain isolated from blood showed only low MIC value for ITC (MIC = 0.06), while high MIC values were exhibited for FLU (MIC = 16), PSC (MIC = 0.5), VRC (MIC = 1) and AMB (MIC = 2). Unfortunately, due to financial constraints and unavailability, the main echinocandin agents, namely micafungin and anidulafungin, were not included for antifungal susceptibility testing. In addition, interlaboratory variability shown by caspofungin convinced us not to use this agent in our antifungal susceptibility testing [9].\n\nDiscussion\nAdvances in the medicine and therapeutic options such as surgeries and utilization of a diverse range of immunosuppressant drugs aided in increase in frequency and spectrum of isolation of yeast species in clinical settings [10]. In this study, for the first time we have recovered two isolates of W. myanmarensis from blood and CVC samples. W. anomalus (also known as Candida pelliculosa), is one of the most prominent species in this genus that can constitute up to 4.4% of total clinical isolates of non-Candida albicans Candida species [11] and even can cause fungemia outbreaks [12].\n\nOur patient was a 5.5-year-old boy with several underlying conditions, including surgery, CVC placement, parenteral nutrition, broad-spectrum antibiotic therapy, thymic hyperplasia, mucosal erosion of GI tract and liver abnormalities. In agreement with previous studies, surgery, broad-spectrum antibiotic therapy and utilization of CVC that are associated with the development of candidemia [1]. Besides, our patient underwent splenectomy operation and spleen as an important lymphoid tissue homes for macrophages and is involved in clearance of infection [13].\n\nAs both CVC and blood samples yielded the same species, it could be transmitted through the hands of healthcare workers, but no samples were taken from the hands of healthcare workers and environmental sampling was not performed to prove this speculation. Moreover, studies have shown that W. anomalus as a close relative of W. myanmarensis is a member of human gut microbiota [14] and revealed that inflamed epithelial tissues are positively correlated with the proportion of W. anomalus in the gut of patients suffering from ulcerative colitis [14]. As a result, probably W. myanmarensis could be either among the human microbiota or transient inhabitants delivered by food components and inflamed mucosa has encouraged its colonization and outgrowth followed by invasion. Hence, we investigated the daily diet of the patient and his parents acknowledged that he did not consume dates (as the main biological niches of this species primarily was found to be sugar palm). However, he regularly ate honey, from which the causative agent has never been isolated. Additionally, patient was treated with omeprazole (proton pump inhibitor) for a long period of time, which decreases the acidity of the stomach providing a more favorable environment for growth and colonization of microorganisms in GI tract [15,16]. Consequently, utilization of omeprazole, in combination with erosions of mucosal barriers of GI tract and the possibility of taking foods contained W. myanmarensis [4,17], may have allowed the fungus to find its way from the GI tract into the bloodstream. As there is scarcity in global isolation of this yeast and there is no evidence supporting the fact that it was isolated from environmental samples in Iran, we speculate that considering these isolates as environmental contaminant is less unlikely. Despite of antibiotic therapy and lack of isolation of any other etiological agents, patient presented with persistent fever, which is one of the possible signs of infection [18].\n\n\nW. myanmarensis did not form germ tube and, like W. anomalus, yielded colonies with pink coloration on CHROMagar. Application of API 20C AUX identified both isolates as W. anomalus. Repeated experimentation of MALDI-TOF MS even using full extraction method resulted in failed identification, which is due to the lack of reference spectrum of this species in the MALDI-TOF MS library. However, DNA sequencing of ITS and LSU D1/D2 rDNA and the subsequent constructed phylogenetic tree, definitively clustered our clinical strains with the environmentally obtained isolates of W. myanmarensis and differentiated them from W. anomalus and W. edaphicus. In addition, as MALDI-TOF MS failed in identification of this species, biochemical and phenotypic assays wrongly identified both isolates as W. anomalus and due to close genetic background between W. myanmarensis and W. anomalus, we developed a rapid multiplex qPCR that reliably and specifically can distinguish these two species in less than 4 h (including DNA extraction step). Although, the application of our multiplex PCR can be restricted to rare cases, it could be a rapid and reliable alternative to time-consuming and inaccurate phenotypic and biochemical assays, where they have identified an isolate as W. anomalus. There is only one study that using DNA hybridization probe could distinguish W. myanmarensis from W. anomalus [4].\n\nAntifungal susceptibility testing of isolate of W. myanmarensis obtained from blood showed high MIC values for fluconazole, voriconazole, posaconazole and AMB, while it was susceptible to itraconazole. However, isolate obtained from CVC showed high MIC value only for AMB. The observed difference in antifungal susceptibility patterns of the two isolates might be due to the fact that they belonged to two distinctive clones. Although, the patient was not treated with antifungal, the follow-up of blood samples remained negative and this infection was manifested as a self-limiting and transient one. We suppose that this phenomenon could be linked to a combination of multiple factors, including active immune system, low virulence attributes of W. myanmarensis as a not fully established and adapted opportunistic yeast species, and low sensitivity of culture to capture low quantity of fungal cells. There are studies that showed that blood samples of 50% of patients suffering from candidemia contain 1 CFU/ml and the rest of the 50% harbor less than or equal to 1 CFU/ml [19]. As a result, we estimated that the active immune system has thwarted the multiplication of the low virulent W. myanmarensis strains and the low sensitivity of culture showed false-negative results. Secondary to insufficient sensitivity of the culture as the gold standard method, unlucky timing of blood withdrawal is another factor playing role in transient candidemia cases [20].\n\nUnfortunately, we could not trace the source of infection whether if the etiologic agent was acquired from the hands of healthcare workers or it was acquired through ingestion of specific fermented foods. However, as shown in other studies, conducting environmental screening does not always guarantee solving the source of infection [21] and in some cases finding source of infection requires huge efforts and is quite time consuming [22]. Moreover, due to the lack of authority for offering intervention and the research-based nature of the study, the patient was left untreated with antifungal drugs. As a result, we were deprived from observing the efficacy of appropriate antifungal for clearance of infection.\n\nConclusion\nAs the number of yeast species causing infection in human is on the rise and the majority of the rare and emerging yeast species are less susceptible to routinely prescribed antifungal drugs, this is highly important to create species-specific breakpoints to acquire a clear idea about their susceptibility patterns. Unfortunately, clinical breakpoints and epidemiological cut-off values are just restricted to a handful number of Candida species. Moreover, MALDI-TOF MS should accommodate the spectra of emerging and rare yeast species to identify them correctly. Advances in nucleic acid-based technologies such as real-time PCR and utilization of appropriate pan fungal, pan yeasts and pan filamentous fungi will aid in timely prescription of appropriate antifungal drugs, and hence, reducing mortality rate associated with fungal infections. Utilization of metagenomics technologies could revolutionize our understanding about the human microbiome, which is followed by ease of tacking of the sources of newly emerged infectious yeast species.\n\nSummary points\nIsolation of first case of candidemia caused by Wickerhamomyces myanmarensis from both central venous catheter and blood of a 5.5-year-old boy.\n\nOur patient was an immunocompetent with severe background conditions.\n\nMisidentification of this yeast by using API 20C AUX, as a widely used biochemical assay in routine laboratories.\n\nLack of identification using MALDI-TOF MS, which is due to the lack of reference spectra of this yeast in the reference library.\n\nConcatenated sequences of ITS and LSU rDNA followed by construction of phylogenetic tree placed our isolate in the same cluster as the environmental strains of Wickerhamomyces myanmarensis.\n\nDevelopment of a specific melt curve-based multiplex PCR assay that could unequivocally distinguish Wickerhamomyces myanmarensis from its close relative Wickerhamomyces anomalus.\n\nAntifungal susceptibility testing showed higher MIC values for blood isolate.\n\nAs this yeast for the first time was isolated from sugar palm and the patient was suffering from ulceration in the gut, this infection could be transferred through ingesting some dietary products contaminated with this yeast.\n\n\nWickerhamomyces anomalus, the close relative of Wickerhamomyces myanmarensis, was found in the microbiome of a human, hence, this yeast might live within the human gut and have somehow found its way to the bloodstream.\n\nAs this infection was transiently observed, we speculate that there was lack of adaptability to the host environment and low virulence attribute of this yeast, along with immunocompetent status of the host has eradicated this yeast, hence, this infection was manifested as a self-limiting one.\n\n\nFinancial & competing interests disclosure\n\n\nThis work was supported by the Major National R&D Projects of the National Health Department (2018ZX10101003), European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 642095, National Natural Science Foundation of China (31770161 and 81720108026), Shanghai Science and Technology Committee (grant numbers 17DZ2270900, 19YF1448000 and 2017ZZ01024). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nOpen access\n\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\nPapers of special note have been highlighted as: • of interest; •• of considerable interest\n\n1 Cristabol L Luis OZ Mindy S What is new in the clinical and diagnostic management of invasive candidiasis in critically ill patients Intensive Care Med. 40 6 808 819 2014 24718642 \n2 Frederic L Shawn L Elizabeth LB Thierry C Changes in the epidemiological landscape of invasive candidiasis J. Antimicrob. 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Dis. 2015 630816 2015 26618013 \n18 \nCandida Infection of the Bloodstream – Candidemia Am. Thorac. Soc. 185 3 4 2013 \n19 Christopher DP Gregory PS Wiley AS Barth R Jhon RP Barbara DA Quantitation of Candida CFU in initial positive blood cultures J. Clin. Microbiol. 49 8 2879 2883 2011 21677065 \n20 Bradford H New molecular method for detection of candidemia, but don't forget the blood cultures Clin. Infect. Dis. 66 11 1687 1688 2018 29438497 \n21 Noura AS Suhail A Seema K Leena J Mohammad A Ziauddin K \nCyberlindnera fabianii fungemia outbreak in preterm neonates in Kuwait and letrature review Mycoses 62 1 51 61 2019 30184277 \n22 David WE Anna ES Hilary M A Candida auris outbreak and its control in an intensive care setting N. Engl. J. Med. 379 14 1322 1331 2018 30281988\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1746-0913",
"issue": "14()",
"journal": "Future microbiology",
"keywords": " ; antifungal susceptibility testing; blood; central venous catheter; specific multiplex qPCR",
"medline_ta": "Future Microbiol",
"mesh_terms": "D000935:Antifungal Agents; D002648:Child; D025141:Drug Resistance, Fungal; D015725:Fluconazole; D016469:Fungemia; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D060888:Real-Time Polymerase Chain Reaction; D004718:Saccharomycetales; D014230:Triazoles; D065819:Voriconazole",
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"other_id": null,
"pages": "267-274",
"pmc": null,
"pmid": "30859860",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30281988;19571014;30184277;21677065;26823635;30030072;26618013;24108614;24018263;15713612;19786155;25463041;24718642;29438497;23050985;29296188;24453230;15879285;17033535",
"title": "First fungemia case due to environmental yeast Wickerhamomyces myanmarensis: detection by multiplex qPCR and antifungal susceptibility.",
"title_normalized": "first fungemia case due to environmental yeast wickerhamomyces myanmarensis detection by multiplex qpcr and antifungal susceptibility"
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"abstract": "Food-dependent exercise-induced anaphylaxis (FDEIA) is a severe systemic syndrome induced by physical exercise after ingesting causative food. Aspirin is a well-known trigger for anaphylaxis in patients with FDEIA. Possible mechanisms by which symptoms are aggravated by aspirin include enhanced antigen absorption and mast cell activation. The aim of this study was to determine whether aspirin intake has an influence on mast cell/basophil activation in patients with FDEIA. Provocation tests revealed that adding aspirin to the causative food challenge in 7 of 9 (77.8%) patients with FDEIA provoked symptoms. In most cases, pretreatment with aspirin did not enhance skin tests (71.4%) or histamine release tests (88.9%) with food allergen challenges. The study confirms that histamine release and skin prick tests can be adjunctive tools for diagnosing FDEIA. In addition, our results suggest that exacerbation of FDEIA symptoms by aspirin is not mediated by direct effects of aspirin on mast cell/basophil activation.",
"affiliations": "Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kusunoki-cho, Chuo-ku, Japan. atsushi@med.kobe-u.ac.jp",
"authors": "Fukunaga|Atsushi|A|;Shimizu|Hideki|H|;Tanaka|Mami|M|;Kikuzawa|Ayuko|A|;Tsujimoto|Mariko|M|;Sekimukai|Akiko|A|;Yamashita|Junji|J|;Horikawa|Tatsuya|T|;Nishigori|Chikako|C|",
"chemical_list": "D001241:Aspirin",
"country": "Sweden",
"delete": false,
"doi": "10.2340/00015555-1210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5555",
"issue": "92(5)",
"journal": "Acta dermato-venereologica",
"keywords": null,
"medline_ta": "Acta Derm Venereol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000707:Anaphylaxis; D001241:Aspirin; D001491:Basophils; D004797:Enzyme-Linked Immunosorbent Assay; D015444:Exercise; D005080:Exercise Test; D005260:Female; D005512:Food Hypersensitivity; D006636:Histamine Release; D006801:Humans; D008297:Male; D008407:Mast Cells; D008875:Middle Aged; D011237:Predictive Value of Tests; D012307:Risk Factors; D012882:Skin Tests",
"nlm_unique_id": "0370310",
"other_id": null,
"pages": "480-3",
"pmc": null,
"pmid": "22068206",
"pubdate": "2012-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Limited influence of aspirin intake on mast cell activation in patients with food-dependent exercise-induced anaphylaxis: comparison using skin prick and histamine release tests.",
"title_normalized": "limited influence of aspirin intake on mast cell activation in patients with food dependent exercise induced anaphylaxis comparison using skin prick and histamine release tests"
} | [
{
"companynumb": "PHHY2014JP168711",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "OBJECTIVE\nLung cancer is one of the most common malignant tumors in China. The aim of this study is to observe the efficacy and safety of recombinant human vascular endostatin (endostar) durative transfusion combined with window period arterial infusion chemotherapy in the treatment of advanced lung squamous carcinoma.\n\n\nMETHODS\nFrom February 2014 to January 2015, 10 cases of the cytological or histological pathology diagnosed stage IIIb - stage IV lung squamous carcinoma were treated with recombinant human vascular endostatin (30 mg/d) durative transfusion combined with window period arterial infusion chemotherapy. Over the same period of 10 cases stage IIIb - stage IV lung squamous carcinoma patients for pure arterial perfusion chemotherapy were compared. Recombinant human vascular endostatin was durative transfused every 24 hours for 7 days in combination group, and in the 4th day of window period, the 10 patients were received artery infusion chemotherapy, using docetaxel combined with cisplatin. Pure treatment group received the same arterial perfusion chemotherapy regimen. 4 weeks was a cycle. 4 weeks after 2 cycles, to evaluate the short-term effects and the adverse drug reactions.\n\n\nRESULTS\n2 groups of patients were received 2 cycles treatments. The response rate (RR) was 70.0%, and the disease control rate (DCR) was 90.0% in the combination group; In the pure treatment group were 50.0%, 70.0% respectively, there were no statistically significant difference (P=0.650, 0.582). The adverse reactions of the treatment were mild, including level 1-2 of gastrointestinal reaction and blood toxicity, there were no statistically significant difference (P=0.999, P=0.628). In the combination group, 1 patient occurred level 1 of cardiac toxicity.\n\n\nCONCLUSIONS\nRecombinant human vascular endostatin durative transfusion combined with window period arterial infusion chemotherapy in the treatment of advanced lung squamous carcinoma could take a significant curative effect, and the patients were well tolerated by the mild adverse reactions.",
"affiliations": "Department of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China.;Department of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China.;Department of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China.;Department of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China.;Department of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China.;Department of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China.;Department of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China.",
"authors": "Lv|Yuan|Y|;Jiang|Rong|R|;Ma|Chunhua|C|;Li|Jinduo|J|;Wang|Bin|B|;Sun|Liwei|L|;Mu|Ning|N|",
"chemical_list": "D000970:Antineoplastic Agents; D043169:Endostatins; D011994:Recombinant Proteins",
"country": "China",
"delete": false,
"doi": "10.3779/j.issn.1009-3419.2015.08.05",
"fulltext": "\n==== Front\nZhongguo Fei Ai Za Zhi\nZhongguo Fei Ai Za Zhi\nZGFAZZ\nChinese Journal of Lung Cancer\n1009-3419 1999-6187 中国肺癌杂志编辑部 天津市和平区南京路228号300020 \n\n26302347\nzgfazz-18-8-500\n10.3779/j.issn.1009-3419.2015.08.05\n临床研究\nClinical Research\n重组人血管内皮抑制素静脉持续泵入联合窗口期动脉灌注化疗治疗晚期肺鳞癌的临床观察\nClinical Observation of Recombinant Human Vascular Endostatin Durative Transfusion Combined with Window Period Arterial Infusion Chemotherapy in the Treatment of Advanced Lung Squamous Carcinoma 吕 远 LV Yuan 姜 镕 JIANG Rong jiangrong1989@sina.com* 马 春华 MA Chunhua 李 金铎 LI Jinduo 王 斌 WANG Bin 孙 立伟 SUN Liwei 穆 宁 MU Ning \n \n300060 天津，天津市环湖医院肿瘤介入科，天津市脑血管与神经变性重点实验室\nDepartment of Intervention, Tianjin HuanHu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Disease, Tianjin 300060, China\n\n姜镕, Rong JIANG, E-mail: jiangrong1989@sina.com\n20 8 2015 \n18 8 500 504\n3 4 2015 23 4 2015 版权所有©《中国肺癌杂志》编辑部2015Copyright ©2015 Chinese Journal of Lung Cancer. All rights reserved.2015This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) License. See: https://creativecommons.org/licenses/by/3.0/背景与目的\n肺癌是我国最常见的恶性肿瘤之一，本研究旨在观察重组人血管内皮抑制素（恩度）静脉持续泵入联合窗口期动脉灌注化疗治疗晚期肺鳞癌患者的有效性及安全性。\n\n方法\n2014年2月-2015年1月10例经细胞学或组织学病理确诊的Ⅲb期-Ⅳ期的肺鳞癌患者采用持续静脉泵入重组人血管内皮抑制素联合窗口期动脉灌注化疗与10例同期住院接受单纯动脉灌注化疗的Ⅲb期-Ⅳ期的肺鳞癌患者比较，联合治疗组重组人血管内皮抑制素剂量均为30 mg/d，持续静脉泵入，d1-d7，在第4天血管正常化窗口期接受动脉灌注化疗，灌注化疗采用多西他赛联合顺铂化疗方案，单纯治疗组动脉灌注化疗方案同联合治疗组。每4周为1周期，连续治疗2个周期后4周行近期疗效评价及药物不良反应评价。\n\n结果\n两组患者均完成2次以上治疗，联合治疗组有效率（response rate, RR）为70.0%，疾病控制率（disease control rate, DCR）为90.0%，单纯治疗组RR为50.0%，DCR为70.0%，差异无统计学意义（P=0.650, P=0.582）。两组的药物不良反应轻微，主要为1级-2级胃肠道反应和血液毒性，差异无统计学意义（P=0.999, P=0.628）。联合治疗组1例患者发生1级心脏毒性。两组患者未发生3级以上药物不良反应。\n\n结论\n重组人血管内皮抑制素静脉持续泵入联合窗口期动脉灌注化疗治疗晚期肺鳞癌近期疗效明显，患者耐受性良好，且不良反应轻微。\n\nBackground and objective\nLung cancer is one of the most common malignant tumors in China. The aim of this study is to observe the efficacy and safety of recombinant human vascular endostatin (endostar) durative transfusion combined with window period arterial infusion chemotherapy in the treatment of advanced lung squamous carcinoma.\n\nMethods\nFrom February 2014 to January 2015, 10 cases of the cytological or histological pathology diagnosed stage Ⅲb -stage Ⅳ lung squamous carcinoma were treated with recombinant human vascular endostatin (30 mg/d) durative transfusion combined with window period arterial infusion chemotherapy. Over the same period of 10 cases stage Ⅲb -stage Ⅳ lung squamous carcinoma patients for pure arterial perfusion chemotherapy were compared. Recombinant human vascular endostatin was durative transfused every 24 hours for 7 days in combination group, and in the 4th day of window period, the 10 patients were received artery infusion chemotherapy, using docetaxel combined with cisplatin. Pure treatment group received the same arterial perfusion chemotherapy regimen. 4 weeks was a cycle. 4 weeks after 2 cycles, to evaluate the short-term effects and the adverse drug reactions.\n\nResults\n2 groups of patients were received 2 cycles treatments. The response rate (RR) was 70.0%, and the disease control rate (DCR) was 90.0% in the combination group; In the pure treatment group were 50.0%, 70.0% respectively, there were no statistically significant difference (P=0.650, 0.582). The adverse reactions of the treatment were mild, including level 1-2 of gastrointestinal reaction and blood toxicity, there were no statistically significant difference (P=0.999, P=0.628). In the combination group, 1 patient occurred level 1 of cardiac toxicity.\n\nConclusion\nRecombinant human vascular endostatin durative transfusion combined with window period arterial infusion chemotherapy in the treatment of advanced lung squamous carcinoma could take a significant curative effect, and the patients were well tolerated by the mild adverse reactions.\n\n肺肿瘤重组人血管内皮抑制素动脉灌注化疗不良反应Lung neoplasmsRecombinant human vascular endostatinArterial infusion chemotherapyAdverse reactions天津市卫生局科技基金项目2014KZ042the grant from Health Bureau Funded Projects of Science and Technology of Tianjin2014kz042本研究受天津市卫生局科技基金项目（No.2014KZ042）资助This study was supported by the grant from Health Bureau Funded Projects of Science and Technology of Tianjin (No.2014kz042)(to Rong JIANG)\n==== Body\n肺癌是我国最常见的恶性肿瘤之一，非小细胞肺癌（non-small cell lung cancer, NSCLC）约占所有肺癌的80%，肺鳞癌约占NSCLC的30%。以三代化疗药物联合铂类的两药化疗方案虽然提高了晚期肺鳞癌的疗效，但有效率仅为20%-30%，疗效进入了平台期[1]。随着分子靶向药物的出现，该类药物逐渐成为杀伤肿瘤的一个重要武器。重组人血管内皮抑制素注射液（恩度）是我国上市的多靶点血管内皮抑制剂，其通过抑制内皮细胞增殖及迁移，发挥抗血管生成的作用，从而促进肿瘤细胞凋亡。重组人血管内皮抑制素本身无细胞毒性作用，与化疗联合可达到疗效协同作用[2]。重组人血管内皮抑制素联合静脉化疗已经成为了NSCLC的一线治疗方案[3, 4]。\n\n动脉灌注化疗是治疗晚期肺癌的一个非常有效的治疗方式，在提高疗效的同时减少了化疗药物带来的副反应[5, 6]。研究[7]报道，重组人血管内皮抑制素持续泵点联合窗口期（第4天）静脉化疗取得较好的临床效果。现通过观察天津市环湖医院肿瘤介入科自2014年2月-2015年1月应用重组人血管内皮抑制素持续静脉泵入联合窗口期（第4天）动脉灌注化疗治疗晚期肺鳞癌10例与单纯动脉灌注化疗治疗的晚期肺鳞癌10例比较，观察联合方案的有效性及安全性，现将结果报告如下。\n\n1 资料与方法\n1.1 病例资料\n自2014年2月-2015年1月我科住院患者中共20例进入本研究，联合治疗组10例，男性8例，女性2例；中位年龄65岁（63岁-81岁）；ECOG功能状态评分为0分-1分3例，2分-3分7例；Ⅲb期5例，Ⅳ期5例，Ⅳ期患者以颅内、骨及肝转移多见。单纯治疗组10例，男性8例，女性2例；中位年龄68岁（60岁-83岁）；ECOG功能状态评分为0分-1分5例，2分-3分5例；Ⅲb期4例，Ⅳ期6例，Ⅳ期患者以颅内、骨及肝转移多见。两组患者的基线特征无统计学差异（均P > 0.05），具有可比性（表 1）。\n\n1 20例晚期鳞癌患者基线情况比较\n\nThe baseline comparison of 20 cases with adanced squamous carcinoma\n\nClinical features\tCombined treatment group (cases) \n\tSimple treatment group (cases) \n\t\nχ2\n\t\nP\n\t\nPS: performance status. \n\t\nGender\t\n\t\n\t0.001\t0.999\t\n Male\t8\t8\t\n\t\n\t\n Female\t2\t2\t\nStage\t\n\t\n\t0.202\t0.999\t\n Ⅲb\t5\t4\t\n\t\n\t\n Ⅳ \n\t5\t6\t\nPS score\t\n\t\n\t0.833\t0.650\t\n 0-1\t3\t5\t\n\t\n\t\n 2-3\t7\t5\t\n1.2 病例选择\n纳入标准：①经组织病理学或细胞学确诊的Ⅲb期-Ⅳ期肺鳞癌患者；②肺部病灶经胸部计算机断层扫描（computed tomography, CT）诊断及评价，至少有1个可测量的病灶；③既往未接受过抗肿瘤治疗的，且拒绝接受外科手术、静脉化疗、放射治疗者；④东部肿瘤协作组（Eastern Cooperative Oncology Group, ECOG）功能状态评分为0分-3分；⑤预计生存期≥12周；⑥血常规及肝肾功能等化验指标和心功能基本正常，无重要器官出血、功能障碍；⑦能够耐受动脉灌注化疗；⑧签署知情同意书。排除标准：①有出血倾向、血栓病史或服用抗凝药物；②脏器功能异常，无法耐受重组人血管内皮抑制素及化疗副作用。\n\n1.3 治疗方法\n联合治疗组患者在治疗前均置入深静脉置管，使用百特输液泵静脉持续输注重组人血管内皮抑制素，剂量为30 mg/d，d1-d7。在第4天血管正常化窗口期接受动脉灌注化疗。本组患者灌注化疗均采用多西他赛60 mg-80 mg联合顺铂60 mg-80 mg动脉灌注化疗方案。动脉灌注化疗采用Seldinger穿刺技术，经一侧股动脉穿刺，用导管分别选择性插入支气管动脉及其他转移灶供血动脉内，经数字剪影血管造影（digital subtraction angiography, DSA）确定为肿瘤供血动脉，经导管依次灌注经0.9%生理盐水20 mL-40 mL稀释的化疗药物。单纯动脉灌注化疗组患者仅接受动脉灌注化疗治疗，动脉灌注化疗过程同联合治疗组。每4周为1个周期，连续治疗2个周期后行评价有效性及安全性。\n\n1.4 近期疗效评价\n根据实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors, RECIST）1.1版标准对患者进行疗效评价，分为完全缓解（complete response, CR）、部分缓解（partial response, PR）、疾病稳定（stable disease, SD）和疾病进展（progressive disease, PD），有效率（response rate, RR）=（CR+PR）/总例数×100%，疾病控制率（disease control rate, DCR）=（CR+PR+SD）/总例数×100%。\n\n1.5 药物不良反应的评价\n所有患者在2个治疗周期前后进行血常规、肝肾功能、心肌酶、心电图及影像学检查以评价安全性。根据美国国立癌症研究所制订的通用药物毒性反应标准（National Cancer Institute-Common Toxicity Criteria, NCI-CTC）4.0版分级标准，对治疗期间或随访期间出现的各种不良事件进行评价。\n\n1.6 统计学方法\n采用SPSS 17.0软件进行统计与分析。以χ2检验比较两组患者基线水平、近期疗效、药物不良反应发生率，理论数小于5时采取Fisher确切概率法，P < 0.05为差异有统计学意义。\n\n2 结果\n2.1 近期疗效\n两组患者均完成2个周期治疗后4周行近期疗效评价。联合治疗组10例患者中CR 0例，PR 7例，SD 2例，PD 1例，RR为70.0%，DCR为90.0%。单纯治疗组10例患者中CR 0例，PR 5例，SD 2例，PD 3例，RR为50.0%，DCR为70.0%。两组的RR和DCR差异无统计学意义（均P > 0.05）（表 2）。\n\n2 两组患者近期疗效的比较\n\nThe comparison of two groups in the immediate curative effect\n\nGroup\tCases\tCR+PR\t\nχ2\n\t\nP\n\tCR+PR+SD\tχ2\n\t\nP\n\t\nCR: complete response; PR: partial response; SD: stable disease. \n\t\nCombined treatment group\t10\t7 (70%) \n\t0.833\t0.650\t9 (90%) \n\t1.250\t0.582\t\nSimple treatment group\t10\t5 (50%) \n\t7 (70%) \n\t\n2.2 不良反应\n两组20例患者均经股动脉穿刺成功率达100.0%，动脉灌注化疗术中未发生药物过敏等不良反应，术后未出现皮下血肿、假性动脉瘤等并发症。化疗药物相关的不良反应轻微，联合治疗组主要为1级-2级胃肠道反应30.0%（3/10）及血液毒性20.0%（2/10），本组未发生3级以上化疗药物不良反应。单纯治疗组主要为1级-2级胃肠道反应40.0%（4/10）及血液毒性40.0%（4/10）。两组胃肠道反应（χ2=0.220, P=0.999）及血液毒性（χ2=0.952, P=0.628）差异均无统计学意义。联合治疗组患者均未发生与深静脉置管相关的并发症，如深静脉血栓形成。重组人血管内皮抑制素主要的不良反应有心脏毒性、出血风险、高血压、蛋白尿等，本组仅有1例患者在接受第2周期治疗时出现1级心脏毒性，予对症治疗后好转，无其他严重不良反应。\n\n3 讨论\n重组人血管内皮抑制素是我国自主研发的一种新型血管内皮抑制剂，2005年9月被SFDA批准上市，2006年被《NCCN非小细胞肺癌临床实践指南（中国版）》收录，具有广谱抗肿瘤血管生成活性。重组人血管内皮抑制素是一种与细胞外基质胶原羧基末端具有同源性的内源性糖蛋白，它通过抑制内皮细胞一氧化氮合成酶的激活、阻断血管内皮生长因子（vascular endothelial growth factor, VEGF）介导的信号转导及抑制bcl-2/bcl-XL、bad表达促进内皮细胞凋亡等多种途径阻断血管生成，从而起到抑制肿瘤细胞生长的作用[8]。研究[9]表明重组人血管内皮抑制素使骨桥蛋白的表达下调, 进而诱导前基质金属蛋白酶（matrix metalloproteinase, MMP）-2、MMP-9的表达下降, 抑制肿瘤转移。研究[10]显示血管内皮抑素通过下调bcl-2蛋白表达，诱导肿瘤细胞凋亡。自2013年开始，美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）关于NSCLC的临床实践指南指出[11]：对于表皮生长因子受体（epidermal growth factor receptor, EGFR）及ALK突变未明或野生型的NSCLC患者，推荐使用重组人血管内皮抑制素联合化疗控制肿瘤进展。多项报道[2, 12, 13]显示：与单纯化疗比较，重组人血管内皮抑制素联合化疗能提高总有效率及临床收益率，并且降低11%的白细胞减少的风险，但在包括心脏毒性等其他不良反应方面没有差异。“血管正常化”一词是由Jain等[14]在2005年提出的：肿瘤内部的血管都是畸形异常的，从而导致血管渗透压的改变，组织内流体静力压升高，导致化疗药物不能正常进入肿瘤细胞内。血管内皮抑素可以改善修复肿瘤组织内部杂乱的血管网，使血管正常化，降低组织间压力，让化疗药物可以更直接的进入到组织内，杀伤肿瘤细胞。重组人血管内皮抑制素能让肿瘤血管系统暂时正常化，达到“血管正常化时间窗”[15]。此时化疗药物能更容易的进入到肿瘤组织中去，从而更好的达到杀灭肿瘤的治疗效果。研究[7, 16]表明重组人血管内皮抑制素的血管正常化时间窗出现在用药后的3 d-5 d，在此时间段内给予化疗药物，能获得最佳治疗效果。重组人血管内皮抑制素常规的给药方式是每天静点4 h，连续使用14 d，在一定程度上降低了患者的依从性和生活质量，最近有研究[7, 12]报道重组人血管内皮抑制素24 h持续静脉泵入的给药方式，可明显提高患者的依从性和生活质量，却不增加患者的不良反应，具有更好的耐受性。\n\n以三代化疗药物联合铂类的两药方案化疗是治疗晚期肺鳞癌的标准方案，但疗效进入了平台期。动脉灌注化疗是治疗晚期肺癌的有效方式之一。动脉灌注化疗可经导管将化疗药物直接送达肿瘤供养动脉，药物总剂量约为全身静脉化疗剂量的1/3，从而大大提高了患者对化疗药物的耐受性，且可以同时治疗肺部原发灶及转移灶，明显提高患者的中位生存期[5, 6]。许健等[17]将40例NSCLC患者分成重组人血管内皮抑制素联合GP方案双途径给药治疗组（试验组）和重组人血管内皮抑制素联合单纯GP方案单途径治疗组（对照组），两组均行GP方案动脉灌注化疗，结果显示试验组无进展生存时间有所延长，但总体生存期改善不明显，两组均未出现严重不良反应。\n\n本组研究基于上述理论，通过观察重组人血管内皮抑制素静脉持续泵入联合窗口期（第4天）动脉灌注化疗治疗晚期肺鳞癌10例患者与同期住院单纯行动脉灌注化疗治疗的10例患者比较，评价其近期疗效及安全性。结果显示联合治疗组患者的有效率和疾病控制率均高于单纯治疗组，但差异未达到统计学意义。联合治疗组患者的不良反应低于单纯治疗组，但差异无统计学意义。联合治疗组有1例患者在行第2周期重组人血管内皮抑制素泵入时出现了一过性的心悸，心电图显示为窦性心动过速，予对症药物处理后好转，未再出现心悸症状。我们认为重组人血管内皮抑制素可以提高动脉灌注化疗疗效，降低化疗毒副反应，且自身毒副反应轻微，患者的远期疗效值得期待。由于本研究样本量小，数据说服力相对较差，需要扩大病例数进一步研究探讨。\n==== Refs\nReferences\n1 Schiller JH Harrington D Belani CP Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer N Engl J Med 2002 346 2 92 98 10.1056/NEJMoa011954 11784875 \n2 Wang JW Sun Y Liu YY Results of randomized, multicenter, double-blind phase Ⅲ trial of rh-endostatin (YH-16) in treatment of advanced non-small cell lung cancer patients Zhongguo Fei Ai Za Zhi 2005 8 4 283 290 http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zgfazz200504007 21108883 王 金万 孙 燕 刘 永煜 重组人血管内皮抑素联合NP方案治疗晚期NSCLC随机、双盲、对照、多中心Ⅲ期临床研究 中国肺癌杂志 2005 8 4 283 290 http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zgfazz200504007 \n3 Zhi XY Shi YK Yu JM China's primary lung cancer diagnosis and treatment norms (2015 edition) Zhonghua Zhong Liu Za Zhi 2015 37 1 67 78 http://guide.medlive.cn/guideline/7722 25877323 支 修益 石 远凯 于 金明 中国原发性肺癌诊疗规范(2015年版) 中华肿瘤杂志 2015 37 1 67 78 http://guide.medlive.cn/guideline/7722 \n4 Teng JJ Han BH Shen J Clinical observation of chemotherapy combined endostar in advanced non-small cell lung cancer Lin Chuang Zhong Liu Xue Za Zhi 2008 13 2 171 175 http://med.wanfangdata.com.cn/Paper/Detail?id=PeriodicalPaper_lczlxzz200802022 滕 家俊 韩 宝惠 沈 洁 重组人血管内皮抑制素联合治疗30例晚期非小细胞肺癌的临床研究 临床肿瘤学杂志 2008 13 2 171 175 http://med.wanfangdata.com.cn/Paper/Detail?id=PeriodicalPaper_lczlxzz200802022 \n5 Xiao XS Insist upon the interventional therapy for lung cancer Jie Ru Fang She Xue Za Zhi 2008 13 7 153 154 http://kns.cnki.net/KCMS/detail/detail.aspx?filename=jrfs200803004&dbname=CJFD&dbcode=CJFQ 肖 湘生 坚守肺癌介入治疗的阵地 介入放射学杂志 2008 13 7 153 154 http://kns.cnki.net/KCMS/detail/detail.aspx?filename=jrfs200803004&dbname=CJFD&dbcode=CJFQ \n6 Ma CH Guo Z Intracranial arterial infusion chemotherapy for lung cancer complicated by brain metastasis: a clinical observation Jie Ru Fang She Xue Za Zhi 2011 20 9 692 695 http://www.cnki.com.cn/Article/CJFDTotal-JRFS201109006.htm 马 春华 郭 志 颅内动脉灌注化疗治疗肺癌脑转移临床观察 介入放射学杂志 2011 20 9 692 695 http://www.cnki.com.cn/Article/CJFDTotal-JRFS201109006.htm \n7 Zhou Q Hu JW Yin R Clinical observation of recombinant human endostatin durative transfusion combined with window period chemotherapy in advanced non-small cell lung cancer Lin Chuang Zhong Liu Xue Za Zhi 2014 19 12 1113 1117 http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=lczlxzz201412012 周 青 胡 静雯 尹 荣 重组人血管内皮抑素静脉泵入联合窗口期化疗治疗晚期非小细胞肺癌的临床观察 临床肿瘤学杂志 2014 19 12 1113 1117 http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=lczlxzz201412012 \n8 Folkman J Role of angiogenesis in tumor growth Semin Oncol 2002 29 6 Suppl 16 15 18 http://www.ncbi.nlm.nih.gov/pubmed/1378311 \n9 Ni Q ji H Zhao Z Endostar, a modified endostatin inhibits non small cell lung cancer cell in vitro invasion through osteopontin-related mechanism Eur J Pharmacol 2009 614 1-3 1 6 10.1016/j.ejphar.2009.04.032 19389394 \n10 Cheng X Li K Synergistic effect ofendostatin and cisplatin on Calu-6 lung cancer cells Tianjin Yi Yao 2008 36 5 371 374 http://www.wanfangdata.com.cn/details/detail.do?_type=degree&id=Y1407358 程 鑫 李 凯 血管内皮抑素与顺铂对Calu-6肺癌细胞联合作用的观察 天津医药 2008 36 5 371 374 http://www.wanfangdata.com.cn/details/detail.do?_type=degree&id=Y1407358 \n11 Ettinger DS Akerley W Borghaei H Non-small cell lung cancer, version 2. 2013 J Natl Compr Cane Netw 2013 11 6 645 653 10.6004/jnccn.2013.0084 \n12 Liu WJ Zeng XT Liu XQ Effectiveness of endostar combined with chemotherapy for advanced non-small cell lung cancer: a systematic review Zhongguo Xun Zheng Yi Xue Za Zhi 2011 11 11 1268 1279 10.3969/j.issn.1672-2531.2011.11.010 刘 文静 曾 宪涛 刘 晓晴 恩度联合化疗治疗晚期非小细胞肺癌疗效和安全性的系统评价 中国循证医学杂志 2011 11 11 1268 1279 10.3969/j.issn.1672-2531.2011.11.010 \n13 Rong B Yang S Li W Systematic review and meta-analysis of Endostar (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer World J Surg Oncol 2012 10 170 10.1186/1477-7819-10-170 22917490 \n14 Jain RK Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy Science 2005 307 5706 58 62 10.1126/science.1104819 15637262 \n15 Lin M Sessa W Antiangiogenic therapy:creating a unique \"window\" of opportunity Cancer Cell 2004 6 6 529 531 http://www.cell.com/cancer-cell/pdf/S1535-6108(04)00340-X.pdf 15607955 \n16 Jiang XD Dai P Qiao Y Clinical study on the recombinant human endostatin regarding improving the blood perfusion and hypoxia of non-small cell lung cancer Clin Transl Oncol 2012 14 6 437 443 10.1007/s12094-012-0821-3 22634532 \n17 Xu J Chen B Cao JM The clinical study of the dual-route administration with recombinant human endosatatin plus gemcitabine and cisplatin regimen on advanced non-small cell lung cancer Lin Chuang Zhong Liu Xue Za Zhi 2011 8 16 709 714 http://med.wanfangdata.com.cn/Paper/Detail?id=PeriodicalPaper_lczlxzz201108010 许 健 陈 波 曹 建民 重组人血管内皮抑素联合吉西他滨、顺铂方案双途径给药治疗晚期非小细胞肺癌的临床研究 临床肿瘤学杂志 2011 8 16 709 714 http://med.wanfangdata.com.cn/Paper/Detail?id=PeriodicalPaper_lczlxzz201108010\n\n",
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"issn_linking": "1009-3419",
"issue": "18(8)",
"journal": "Zhongguo fei ai za zhi = Chinese journal of lung cancer",
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"medline_ta": "Zhongguo Fei Ai Za Zhi",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D043169:Endostatins; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins",
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"publication_types": "D004740:English Abstract; D016428:Journal Article",
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"title": "Clinical Observation of Recombinant Human Vascular Endostatin Durative Transfusion Combined with Window Period Arterial Infusion Chemotherapy in the Treatment of
Advanced Lung Squamous Carcinoma.",
"title_normalized": "clinical observation of recombinant human vascular endostatin durative transfusion combined with window period arterial infusion chemotherapy in the treatment of advanced lung squamous carcinoma"
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"abstract": "Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the second line of therapy in diabetes mellitus type 2. They are frequently coprescribed with other noninsulin glucose-lowering medications. Diabetic ketoacidosis (DKA) with lower-than-anticipated glucose levels is an important SGLT2i-related adverse effect in postoperative patients. This case highlights the need for increased postoperative surveillance of patients on this group of medications. Ketonuria was managed with short-acting insulin infusion with dextrose-containing intravenous fluid, as a part of the ongoing intensive care treatment to which the patient responded well. Awareness of DKA with lower-than-anticipated glucose levels is an important clinical challenge, an entity that can be confused in the setting of major and complex surgeries. The frequency of this arcane and underreported diagnosis in the perioperative setting is unknown. How to cite this article: Vadi S, Lad V, Kapoor D. Perioperative Implication of Sodium-glucose Cotransporter-2 Inhibitor in a Patient Following Major Surgery. Indian J Crit Care Med 2021;25(8):958-959.",
"affiliations": "Department of Intensive Care Medicine, Kokilaben Dhirubhai Ambani Hospital and Medical Research Center, Mumbai, Maharashtra, India.;Department of Cardiovascular Surgery, Kokilaben Dhirubhai Ambani Hospital and Medical Research Center, Mumbai, Maharashtra, India.;Department of Endocrinology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Center, Mumbai, Maharashtra, India.",
"authors": "Vadi|Sonali|S|;Lad|Vidhyadhar|V|;Kapoor|Dheeraj|D|",
"chemical_list": null,
"country": "India",
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"doi": "10.5005/jp-journals-10071-23929",
"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229\n1998-359X\nJaypee Brothers Medical Publishers\n\n10.5005/jp-journals-10071-23929\nLetter to the Editor\nPerioperative Implication of Sodium-glucose Cotransporter-2 Inhibitor in a Patient Following Major Surgery\nVadi Sonali 1https://orcid.org/0000-0002-7341-2407\n\nLad Vidhyadhar 2https://orcid.org/0000-0002-5368-8756\n\nKapoor Dheeraj 3https://orcid.org/0000-0003-0369-3319\n\n1 Department of Intensive Care Medicine, Kokilaben Dhirubhai Ambani Hospital and Medical Research Center, Mumbai, Maharashtra, India\n2 Department of Cardiovascular Surgery, Kokilaben Dhirubhai Ambani Hospital and Medical Research Center, Mumbai, Maharashtra, India\n3 Department of Endocrinology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Center, Mumbai, Maharashtra, India\nSonali Vadi, Department of Intensive Care Medicine, Kokilaben Dhirubhai Ambani Hospital and Medical Research Center, Mumbai, Maharashtra, India, Phone: +91 22-4269-6969 e-mail: sonalivadi@hotmail.com\n8 2021\n25 8 958959\nCopyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ © Jaypee Brothers Medical Publishers. 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial 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.\nABSTRACT\n\nSodium-glucose cotransporter-2 inhibitors (SGLT2i) are the second line of therapy in diabetes mellitus type 2. They are frequently coprescribed with other noninsulin glucose-lowering medications. Diabetic ketoacidosis (DKA) with lower-than-anticipated glucose levels is an important SGLT2i-related adverse effect in postoperative patients. This case highlights the need for increased postoperative surveillance of patients on this group of medications. Ketonuria was managed with short-acting insulin infusion with dextrose-containing intravenous fluid, as a part of the ongoing intensive care treatment to which the patient responded well. Awareness of DKA with lower-than-anticipated glucose levels is an important clinical challenge, an entity that can be confused in the setting of major and complex surgeries. The frequency of this arcane and underreported diagnosis in the perioperative setting is unknown.\n\nHow to cite this article: Vadi S, Lad V, Kapoor D. Perioperative Implication of Sodium-glucose Cotransporter-2 Inhibitor in a Patient Following Major Surgery. Indian J Crit Care Med 2021;25(8):958–959.\n\nKeywords\n\nDiabetic ketoacidosis with lower-than-anticipated glucose levels\nPerioperative medicine\nSodium-glucose cotransporter-2 inhibitors\n==== Body\npmcSodium-glucose cotransporter-2 inhibitors (SGLT2i) are being hailed for their cardiovascular and renal protective effects. In view of evidence of a reduction in hospitalization for heart failure, cardiovascular-related deaths, and all-cause mortality, they are increasingly prescribed in patients with diabetes mellitus type 2 with cardiovascular disease. Diabetic ketoacidosis (DKA) with lower-than-anticipated glucose levels is an important SGLT2i-related adverse effect in postoperative patients. Decisions regarding discontinuation and restarting medications in the perioperative period are complex issues. Herein we highlight the need for increased postoperative surveillance of patients on this group of medications.\n\nA 56-year-old male, known hypertensive, sleep apnea, and diabetes mellitus type 2 (Acarbose—since a year and Metformin, Liraglutide, Lantus insulin, and Dapagliflozin—since 5 years) was hospitalized for coronary artery bypass grafting. His body mass index was at 41 kg/m2. Acarbose was taken 72 hours prior, and Metformin and Dapagliflozin were last taken 48 hours prior to the day of surgery. Preoperative blood glucose control was managed by intravenously administered customized scaled short-acting insulin. Intraoperative course was uneventful. He did not receive any steroids. Postoperative hemodynamics were stable. He complained of excessive thirst postoperatively. Arterial blood gas revealed metabolic acidosis. Given no other causes of metabolic acidosis and a medication history of SGLT2i, urine ketones were checked and reported “large.” His capillary blood glucose levels ranged from a minimum 107 mg/dL to maximum of 280 mg/dL. (Table 1) This was managed as DKA with lower-than-anticipated glucose levels. Postoperative urinary glucose was 2245 mg/dL. Subsequently, his beta-hydroxybutyrate levels came positive at 0.81 mmol/L. Stabilized, he was discharged on subcutaneous short and long-acting insulin. On follow-up, his fasting blood glucose and postprandial blood glucose have been under control with negative urine ketones.\n\nTable 1 Biochemical parameters, clinical trends during intensive care unit stay\n\nPostoperative ICU day\tTime\tpH (range: 7.35–7.45)\tHCO3- (range: 22–26 mEq/L)\tLactate\tAnion gap (range: 1–10)\tLowest and highest fingerstick glucose levels in 24 hours (mg/dL)\tUrine ketones\tSerum beta-hydroxybutyric acid (range: 0.02–0.27 mmol/L)\tIntake/output (in 24 hours)\tHuman actrapid insulin (units/24 hours)\t\n0\t1504\t7.37\t23.5\t1.47\t14.1\t107; 225\t—\t—\t3090/3620\t—\t\n2200\t7.33\t17.6\t1.67\t17.6\t\n0300\t7.26\t15.6\t1.63\t19.3\t\n1\t0600\t7.33\t16.5\t2.2\t18.8\t145; 249\tLarge\t0.81\t3870/4340\t48\t\n1430\t7.33\t17.6\t2.24\t16.9\t\n2300\t7.42\t23.3\t1.23\t5.8\t\n2\t0600\t7.44\t21.6\t1.39\t1.6\t152; 222\tModerate\t—\t2960/2750\t40\t\n1800\t7.40\t23.7\t1.24\t9.4\t\n3\t0800\t7.45\t22.3\t1.2\t9.5\t167; 242\tLarge\t—\t3000/2730\t27\t\n4\t0800\t7.37\t22.2\t1.26\t14.1\t120; 280\tModerate\t—\t2950/2700\t27\t\n5\t0600\t7.39\t22\t2.55\t\t145; 202\tLarge\t—\t600/450\t—\t\n\nInadequate clearance of SGLT2i and the stress of major surgery are precipitating factors for DKA with lower-than-normal glucose levels. An important point to remember is that SGLT2i aid reabsorption of ketone bodies. Consequent ketoacidosis may not be accompanied by ketonuria.1 SGLT2i causes glucosuria with a resultant reduction in insulin secretion and use. This leads to a reduction in insulin to glucagon ratio. Insulin requirements are masked. Hence, reduction in dose or discontinuation of insulin after major surgery should be avoided.2 SGLT2i-related urinary glucose losses may persist for several days.3 All oral hypoglycemic agents are conventionally withheld on the day of surgery. This may not hold true for the SGLT2i group of medication. American Association of Clinical Endocrinologists and American College of Endocrinology recommend withholding SGLT2i for at least 24 hours prior to any event that may precipitate DKA, to be restarted once the patient has resumed normal diet, while Food and Drug Administration4 recommends withholding for 3 days prior to surgery. Half-life of SGLT2i is 11 to 13 hours. However, their pharmacodynamic effects may persist beyond the five half-lives2 with glucosuria and ketonemia seen up to 9 to 10 days post-SGLT2i discontinuation.5 Hence, it would be prudent to withhold this group of medication for more than 5 days preoperatively, requiring coordination among the surgical, anesthesia, endocrinology, and intensive care unit teams. Perioperative monitoring of acid–base and ketone status is mandatory, with monitoring to be continued until the postoperative stress is resolved. SGLT2i may be reintroduced once the oral intake is resumed to normal.\n\nAwareness of DKA with lower-than-anticipated glucose levels is an important clinical challenge, an entity that can be confused in the setting of major and complex surgeries. The frequency of this arcane and underreported diagnosis in the perioperative setting is unknown. Patients with diabetes mellitus on SGLT2i, who develop metabolic acidosis, need to be knowingly investigated for DKA with lower-than-anticipated glucose levels. The optimal timing of discontinuation of SGLT2i’s preoperatively is undetermined but definitely needs to be longer than several of their elimination half-lives. We suggest withholding SGLT2i for at least 7 days prior to major surgery. Knowledge of the existence of this entity in the “real world” clinical practice with vigilance in its diagnosis by astute postoperative surveillance will help to identify more cases, thus influencing outcomes.\n\nORCID\n\nSonali Vadi https://orcid.org/0000-0002-7341-2407\n\nVidhyadhar Lad https://orcid.org/0000-0002-5368-8756\n\nDheeraj Kapoor https://orcid.org/0000-0003-0369-3319\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nREFERENCES\n\n1. Milder DA Milder TY Kam PCA. Sodium-glucose cotransporter type-2 inhibitors: pharmacology and perioperative considerations. Anaesthesia 2018; 73: 1008e18. DOI: 10.1111/anae.14251. 29529345\n2. Goldenberg RM Berard LD Cheng AY Gilbert JD Verma S Woo VC et al. SGLT2 inhibitor–associated diabetic ketoacidosis: Clinical review and recommendations for prevention and diagnosis. Clin Ther 2016; 38( 2654–64): e1. DOI: 10.1016/j.clinthera.2016.11.002.\n3. Handelsman Y Henry RR Bloomgarden ZT Dagogo-Jack S DeFronzo RA Einhorn D et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of sglt-2 inhibitors and diabetic ketoacidosis. Endocr Pract 2016; 22: 753– 762. DOI: 10.4158/ep161292.ps. 27082665\n4. https://www.medscape.com/viewarticle/927047.\n5. Pujara S Ioachimescu A. Prolonged ketosis in a patient with euglycemic diabetic ketoacidosis secondary to dapagliflozin. J Investig Med High Impact Case Rep 2017; 5( 2): 2324709617710040. DOI: 10.1177/2324709617710040.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0972-5229",
"issue": "25(8)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Diabetic ketoacidosis with lower-than-anticipated glucose levels; Perioperative medicine; Sodium-glucose cotransporter-2 inhibitors",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "958-959",
"pmc": null,
"pmid": "34733046",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "27082665;28003053;28589154;29529345",
"title": "Perioperative Implication of Sodium-glucose Cotransporter-2 Inhibitor in a Patient Following Major Surgery.",
"title_normalized": "perioperative implication of sodium glucose cotransporter 2 inhibitor in a patient following major surgery"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-319334",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DAPAGLIFLOZIN"
},
"d... |
{
"abstract": "We report on a 10-year-old boy with medically refractory pulmonary arterial hypertension (PAH) and end-stage right heart failure after closure of a ventricular septal defect. The boy was a candidate for lung transplantation (LTX), but an alternative option was to create an Eisenmenger physiology with right-to-left shunting. The shunt could be created either as an intracardiac or as an extracardiac shunt. We decided to create a Potts shunt, a direct anastomosis between the left pulmonary artery and the descending aorta. The Potts shunt functioned as a right-to-left shunt, thus reducing the afterload on the right ventricle. The boy's clinical condition improved markedly, so he was discharged two weeks after the procedure. The ultimate therapeutic option for medically refractory PAH is LTX or heart-lung transplantation, but because of the short life span after LTX, time was bought by postponing the time of transplantation.",
"affiliations": "Department of Cardiothoracic Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.",
"authors": "Petersen|Cecilie|C|;Helvind|Morten|M|;Jensen|Tim|T|;Andersen|Henrik Ørbæk|HØ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2150135113482739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2150-1351",
"issue": "4(3)",
"journal": "World journal for pediatric & congenital heart surgery",
"keywords": "congenital heart surgery; heart failure operations; heart–lung; lung; palliation; pediatric; pulmonary vascular resistance/hypertension; shunts (Potts shunt); transplantation",
"medline_ta": "World J Pediatr Congenit Heart Surg",
"mesh_terms": "D000714:Anastomosis, Surgical; D001013:Aorta, Thoracic; D002648:Child; D065627:Familial Primary Pulmonary Hypertension; D006345:Heart Septal Defects, Ventricular; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D011651:Pulmonary Artery",
"nlm_unique_id": "101518415",
"other_id": null,
"pages": "286-9",
"pmc": null,
"pmid": "24327497",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Potts shunt in a child with end-stage pulmonary hypertension after late repair of ventricular septal defect.",
"title_normalized": "potts shunt in a child with end stage pulmonary hypertension after late repair of ventricular septal defect"
} | [
{
"companynumb": "DK-ACTELION-A-CH2015-118547",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BOSENTAN\\BOSENTAN MONOHYDRATE"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nThe COMRADE studies are the first randomized controlled head-to-head trials comparing the efficacy and safety of intravitreal ranibizumab versus dexamethasone (DEX) in patients with macular oedema secondary to retinal vein occlusion (RVO). The COMRADE extension trial was designed to provide additional 6-month data of patients who completed the core studies.\n\n\nMETHODS\nIn this open-label, phase IV study patients who completed the COMRADE core studies were prospectively enrolled. Overall, 92 branch RVO (BRVO) patients (ranibizumab 52, DEX 40) and 83 central RVO (CRVO) patients (ranibizumab 61, DEX 22) were treated, and 94.6% of BRVO patients and 97.6% of CRVO patients completed the extension study. Patients were assigned to the same treatment group as in the core studies. Patients were monitored monthly and received either 0.5 mg ranibizumab or a 0.7 mg DEX implant as needed.\n\n\nRESULTS\nOver the course of the extension, treatment-emergent adverse events (TEAEs) of the study eye occurred in 55.8% of BRVO patients on ranibizumab and in 62.5% of those on DEX. Among CRVO patients, 65.5% in the ranibizumab group and 59.1% in the DEX group developed TEAEs. Overall, elevated intraocular pressure (IOP) was more frequent with DEX than ranibizumab treatment. Mean average change in best-corrected visual acuity (BCVA) in BRVO patients was significantly better for ranibizumab than DEX (p = 0.0249). The CRVO results were consistent with BRVO's, although not significant (p = 0.1119).\n\n\nCONCLUSIONS\nWhen used according to the European labels, ranibizumab revealed a better ocular safety profile and produced greater average BCVA gains than DEX. By the end of the additional 6-month study period, this difference in BCVA was more pronounced in BRVO as in CRVO patients. The main limitation of the COMRADE studies was that DEX patients received only a single intravitreal treatment during the first 6 months, which is presumably not adequate. However, frequent DEX implants could lead to more steroid-related side effects, especially to an increased intraocular pressure.",
"affiliations": "Georg-August-University Goettingen, University Eye Hospital, Goettingen, Germany.;Department for Ophthalmology, Ludwigshafen Hospital, Ludwigshafen, Germany.;Georg-August-University Goettingen, University Eye Hospital, Goettingen, Germany.;Georg-August-University Goettingen, University Eye Hospital, Goettingen, Germany.;Eye Hospital, University Hospital Leipzig, Leipzig, Germany.;Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany.;Department of Ophthalmology, St. Elisabeth-Hospital, Koeln-Hohenlind, Germany.;Department of Ophthalmology, University of Muenster Medical Center, Muenster, Germany.;University Eye Hospital Ulm, Ulm, Germany.;Department for Ophthalmology, University Hospital of Freiburg, Freiburg, Germany.;University of Bonn, University Eye Hospital, Bonn, Germany.;Novartis Pharma GmbH, Nuremberg, Germany.;Novartis Pharma GmbH, Nuremberg, Germany.;Georg-August-University Goettingen, University Eye Hospital, Goettingen, Germany.",
"authors": "Feltgen|Nicolas|N|http://orcid.org/0000-0002-6857-3003;Hattenbach|Lars-Olof|LO|;Bertelmann|Thomas|T|http://orcid.org/0000-0002-4017-2224;Callizo|Josep|J|;Rehak|Matus|M|;Wolf|Armin|A|;Berk|Hüsnü|H|;Eter|Nicole|N|;Lang|Gabriele E|GE|;Pielen|Amelie|A|;Schmitz-Valckenberg|Steffen|S|;Quiering|Claudia|C|;Rose|Uwe|U|;Hoerauf|Hans|H|;|||",
"chemical_list": "D020533:Angiogenesis Inhibitors; D005938:Glucocorticoids; D003907:Dexamethasone; D000069579:Ranibizumab",
"country": "England",
"delete": false,
"doi": "10.1111/aos.13770",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1755-375X",
"issue": "96(8)",
"journal": "Acta ophthalmologica",
"keywords": "\nCOMRADE\n; clinical trial; dexamethasone; head-to-head; intravitreal injection; macular oedema; ranibizumab; retinal vein occlusion; retreatment",
"medline_ta": "Acta Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D008266:Macula Lutea; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069579:Ranibizumab; D012169:Retinal Vein; D012170:Retinal Vein Occlusion; D013997:Time Factors; D016896:Treatment Outcome; D014792:Visual Acuity",
"nlm_unique_id": "101468102",
"other_id": null,
"pages": "e933-e941",
"pmc": null,
"pmid": "29855153",
"pubdate": "2018-12",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Comparison of ranibizumab versus dexamethasone for macular oedema following retinal vein occlusion: 1-year results of the COMRADE extension study.",
"title_normalized": "comparison of ranibizumab versus dexamethasone for macular oedema following retinal vein occlusion 1 year results of the comrade extension study"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1092938",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Graft-versus-host disease (GVHD) is related to considerable morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Cardiac complications associated with GVHD are uncommon, and coronary artery involvement is even more unusual. We report on a male pediatric patient with chronic GVHD who developed a fatal ventricular arrhythmia caused by coronary artery obstruction after HSCT. At 30 months after HSCT, he suddenly collapsed with ventricular fibrillation. After resuscitation, electrocardiography showed abnormal q-wave and ST changes in the inferior leads, suggesting a coronary event. Coronary angiography revealed complete obstruction of the proximal left anterior descending artery, subtotal obstruction of the mid left circumflex artery, and mild narrowing at the right coronary artery. This boy had none of the risk factors for coronary artery disease, and the only possible explanation for the cardiac event is GVHD. Coronary artery disease only rarely occurs as a cardiac event in children. However, coronary artery involvement should be recognized as one of the important manifestations of chronic GVHD in children.",
"affiliations": "Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University College of Medicine, Seoul, Korea.;Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University College of Medicine, Seoul, Korea.;Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University College of Medicine, Seoul, Korea.;Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University College of Medicine, Seoul, Korea.",
"authors": "Kim|Da Hyun|DH|0000-0002-8588-7848;You|Jung Jin|JJ|;Im|Ho Joon|HJ|;Ko|Jae Kon|JK|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13474",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(5)",
"journal": "Pediatric transplantation",
"keywords": "chronic graft-versus-host disease; coronary artery disease; hematopoietic stem cell transplantation",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D002675:Child, Preschool; D003324:Coronary Artery Disease; D016757:Death, Sudden, Cardiac; D003937:Diagnosis, Differential; D003952:Diagnostic Imaging; D004562:Electrocardiography; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13474",
"pmc": null,
"pmid": "31124210",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Coronary artery involvement in chronic graft-versus-host disease presenting as sudden cardiac arrest.",
"title_normalized": "coronary artery involvement in chronic graft versus host disease presenting as sudden cardiac arrest"
} | [
{
"companynumb": "KR-OTSUKA-2019_029954",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nTo determine outcome of children receiving carvedilol in addition to other standard drug therapy for treatment of dilated cardiomyopathy.\n\n\nMETHODS\nChildren receiving carvedilol for treatment of dilated cardiomyopathy with moderate to severe ventricular dysfunction were included into the study. Data on history, clinical examination and investigations were obtained and detailed echocardiography findings were recorded for the initial and all subsequent visits.\n\n\nRESULTS\nThirty-three children, mean age 26 ± 30 mo (range 7 mo to 138 mo) were enrolled. Carvedilol was initiated at a mean dose of 0.14 ± 0.03 mg/kg/d and the maintenance dose was 0.46 ± 0.14 mg/kg/d. At a follow up of 6-90 mo (mean of 28 ± 23 mo), functional class using Ross classification for pediatric heart failure improved from 2.7 to 1.3. The left ventricular ejection fraction rose from a basal value of 22 % ± 7 % (10-40 %) to 42 % ± 15 % (15-65 %) (p < 0.0001). Similarly, left ventricular fractional shortening increased significantly from 16 ± 6 % (8-34 %) to 21 ± 7 % (10-44 %) (p < 0.0001). One patient deteriorated and died of refractory heart failure. Carvedilol was discontinued in two more patients temporarily due to bronchospasm during respiratory infection.\n\n\nCONCLUSIONS\nThe present study suggests that improvement in ventricular function and clinical symptoms is seen on oral carvedilol added to standard drug therapy in pediatric patients with dilated cardiomyopathy and moderate to severe ventricular dysfunction. The drug is well tolerated with minimal side effects but close monitoring is required as it may worsen heart failure and bronchospasm.",
"affiliations": "Department of Pediatric Cardiology, All India Institute of Medical Sciences, New Delhi, India. anitasaxena@hotmail.com",
"authors": "Saxena|Anita|A|;Anil|Om Murty|OM|;Juneja|Rajnish|R|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol",
"country": "India",
"delete": false,
"doi": "10.1007/s12098-012-0954-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-5456",
"issue": "80(7)",
"journal": "Indian journal of pediatrics",
"keywords": null,
"medline_ta": "Indian J Pediatr",
"mesh_terms": "D000293:Adolescent; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D002311:Cardiomyopathy, Dilated; D000077261:Carvedilol; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D004452:Echocardiography; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011412:Propanolamines; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "0417442",
"other_id": null,
"pages": "549-54",
"pmc": null,
"pmid": "23412984",
"pubdate": "2013-07",
"publication_types": "D016428:Journal Article",
"references": "12853193;2017982;16716018;15607659;10471456;10328154;20390261;11806769;16596434;21503211;17848651;9665213;12475466;11295713;9412540;19378887;2057034;2883575;1614922;19383992;11456146;7817916;10714728;15261177;8941104;12040358",
"title": "Clinical and echocardiographic outcome in patients receiving carvedilol for treatment of dilated cardiomyopathy.",
"title_normalized": "clinical and echocardiographic outcome in patients receiving carvedilol for treatment of dilated cardiomyopathy"
} | [
{
"companynumb": "PHHY2015IN024378",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": null,
"dru... |
{
"abstract": "Whether or not reactivation of hepatitis B virus (HBV) might occur during corticosteroid therapy in hepatitis B surface antigen (HBsAg)-negative patients with adrenal insufficiency was investigated.\nWe consecutively enrolled 66 patients with adrenal insufficiency undergoing physiological corticosteroid replacement therapy at Saitama Medical University Hospital between June 2013 and June 2014, and 220 patients with rheumatic disease receiving a pharmacologic dose of corticosteroids served as the positive control group. The latter group was separated into 101 patients treated only with corticosteroids, and 119 patients given corticosteroids plus immunosuppressants and/or disease-modifying antirheumatic drugs (DMARDs). HBsAg and antibody (Ab) levels against HBs, and hepatitis B core (HBc) were determined in all the patients. In patients with positive HBsAb and/or HBcAb, real-time PCR was performed for HBV-DNA. The incidence rates of conversion to HBV-DNA-positive status were evaluated.\nHepatitis B virus reactivation occurred in six patients with rheumatic disease, three of whom were receiving a pharmacological dose of corticosteroids only, and three who were receiving corticosteroids with immunosuppressants and/or DMARDs. However, no reactivation occurred in patients receiving corticosteroid replacements for adrenal insufficiency. Maintenance and maximum corticosteroid doses administered to patients with rheumatic disease were significantly greater than those in patients with adrenal insufficiency.\nThese results suggest that, although corticosteroid replacement therapy for adrenal insufficiency might be safe with respect to HBV reactivation, attention should be paid to HBV reactivation during corticosteroid therapy in rheumatic disease patients, since the dose of corticosteroids administered is usually large, and since other immunosuppressants are co-administered.",
"affiliations": "Department of Endocrinology and Diabetes Saitama Medical University Saitama Japan.;Department of Rheumatology and Applied Immunology, Faculty of Medicine Saitama Medical University Saitama Japan.;Department of Endocrinology and Diabetes Saitama Medical University Saitama Japan.;Department of Endocrinology and Diabetes Saitama Medical University Saitama Japan.;Kawagoe Clinic Saitama Medical University Saitama Japan.",
"authors": "Hatano|Masako|M|https://orcid.org/0000-0002-4385-3674;Mimura|Toshihide|T|;Shimada|Akira|A|;Noda|Mitsuhiko|M|;Katayama|Shigehiro|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/edm2.71",
"fulltext": "\n==== Front\nEndocrinol Diabetes MetabEndocrinol Diabetes Metab10.1002/(ISSN)2398-9238EDM2Endocrinology, Diabetes & Metabolism2398-9238John Wiley and Sons Inc. Hoboken 10.1002/edm2.71EDM271Original ArticleOriginal ArticlesHepatitis B virus reactivation with corticosteroid therapy in patients with adrenal insufficiency HATANO et al.Hatano Masako https://orcid.org/0000-0002-4385-3674pata@saitama-med.ac.jp \n1\nMimura Toshihide \n2\nShimada Akira \n1\nNoda Mitsuhiko \n1\nKatayama Shigehiro \n3\n\n1 \nDepartment of Endocrinology and Diabetes\nSaitama Medical University\nSaitama\nJapan\n\n2 \nDepartment of Rheumatology and Applied Immunology, Faculty of Medicine\nSaitama Medical University\nSaitama\nJapan\n\n3 \nKawagoe Clinic\nSaitama Medical University\nSaitama\nJapan\n* Correspondence\n\nMasako Hatano, Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyamacho, Iruma‐gun, Saitama 350‐0495, Japan.\n\nEmail: pata@saitama-med.ac.jp\n09 5 2019 7 2019 2 3 10.1002/edm2.2019.2.issue-3e0007104 8 2018 16 4 2019 24 4 2019 © 2019 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nObjective\nWhether or not reactivation of hepatitis B virus (HBV) might occur during corticosteroid therapy in hepatitis B surface antigen (HBsAg)‐negative patients with adrenal insufficiency was investigated.\n\nPatients and Methods\nWe consecutively enrolled 66 patients with adrenal insufficiency undergoing physiological corticosteroid replacement therapy at Saitama Medical University Hospital between June 2013 and June 2014, and 220 patients with rheumatic disease receiving a pharmacologic dose of corticosteroids served as the positive control group. The latter group was separated into 101 patients treated only with corticosteroids, and 119 patients given corticosteroids plus immunosuppressants and/or disease‐modifying antirheumatic drugs (DMARDs). HBsAg and antibody (Ab) levels against HBs, and hepatitis B core (HBc) were determined in all the patients. In patients with positive HBsAb and/or HBcAb, real‐time PCR was performed for HBV‐DNA. The incidence rates of conversion to HBV‐DNA‐positive status were evaluated.\n\nResults\nHepatitis B virus reactivation occurred in six patients with rheumatic disease, three of whom were receiving a pharmacological dose of corticosteroids only, and three who were receiving corticosteroids with immunosuppressants and/or DMARDs. However, no reactivation occurred in patients receiving corticosteroid replacements for adrenal insufficiency. Maintenance and maximum corticosteroid doses administered to patients with rheumatic disease were significantly greater than those in patients with adrenal insufficiency.\n\nConclusion\nThese results suggest that, although corticosteroid replacement therapy for adrenal insufficiency might be safe with respect to HBV reactivation, attention should be paid to HBV reactivation during corticosteroid therapy in rheumatic disease patients, since the dose of corticosteroids administered is usually large, and since other immunosuppressants are co‐administered.\n\nadrenal insufficiencycorticosteroidshepatitis B virus reactivationrheumatic disease source-schema-version-number2.0component-idedm271cover-dateJuly 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.5 mode:remove_FC converted:08.07.2019\n\n\nHatano \nM \n, \nMimura \nT \n, \nShimada \nA \n, \nNoda \nM \n, \nKatayama \nS \n. Hepatitis B virus reactivation with corticosteroid therapy in patients with adrenal insufficiency . Endocrinol Diab Metab . 2019 ;2 :e00071\n10.1002/edm2.71 \n\n\n\n\nData Availability Statement: All data generated or analysed during this study are included in this published article.\n==== Body\n1 INTRODUCTION\nHepatitis B virus (HBV) reactivation occurring in patients undergoing cytotoxic chemotherapy and/or immunosuppressive therapy is a well‐recognized complication of considerable clinical importance. Reactivation of HBV is more often seen in hepatitis B carriers who are positive for hepatitis B surface (HBs) antigen (Ag) and for antibody (Ab) against hepatitis B core (HBc). Acute hepatitis, that is, de novo hepatitis, is likely to occur because of HBV reactivation during chemotherapy and/or immunosuppressive therapy given to patients with transplanted organs and leads to variable manifestations that range from subclinical serum aminotransferase elevation to fatal fulminant hepatitis. However, a few cases of HBV reactivation in patients with resolved infection as defined by negative HBsAg and positive HBcAb with or without HBsAb have been reported during chemotherapy or immunosuppressive therapy.1, 2 The incidence of de novo hepatitis due to HBV reactivation in HBsAg‐negative patients with malignant lymphoma treated with corticosteroid‐containing cytotoxic chemotherapy was reported to be 2.7% over a 4‐year period and 3.3% during a 12.4‐month follow‐up.3, 4 However, use of rituximab, an anti‐CD20‐directed monoclonal antibody, in combination with corticosteroid‐containing chemotherapy, has been frequently associated with HBV reactivation and resultant de novo hepatitis.4, 5, 6 Most of these reports come from the fields of oncology and transplantation, with a growing number of cases being reported in patients with rheumatic disease who are also undergoing immunosuppressive therapy. The incidence of HBV reactivation was reported to be 7/135 (5.2%) after a 1‐year prospective observation in rheumatoid arthritis patients with resolved hepatitis B treated with corticosteroids, immunosuppressants and/or disease‐modifying antirheumatic drugs (DMARDs).7 A recent prospective observational study in Japan has reported that HBV reactivation among rheumatic disease patients with resolved HBV infections treated with prednisone, immunosuppressants and/or biological DMARDs, occurred in 35/1042 (3.4%) of individuals over a period of 2 years.8 Estimated incidence rates of HBS reactivation and hence de novo hepatitis vary, likely due to differences among the patient populations studied, drugs administered and the duration of follow‐up.\n\nOf all the traditional immunosuppressive medications, corticosteroids have been most often implicated in the induction of HBV reactivation. The risk of HBV reactivation in patients with inflammatory bowel disease, vasculitis, sarcoidosis and autoimmune disease might differ, depending on whether the patients are HBsAg‐positive/HBcAb‐positive or HBsAg‐negative/HBcAb‐positive, whether the dosage of chronic prednisone therapy is low, moderate or high, or whether the duration is short or longer than 4 weeks.8, 9 However, the exact incidence rate of HBV reactivation in HBsAg‐negative/HBcAb‐positive patients with autoimmune disease such as rheumatoid arthritis treated only with corticosteroids has not been fully evaluated.\n\nOn the other hand, adrenal insufficiency is usually treated with optimal replacement dose corticosteroids, equivalent to 5 mg of prednisone/day, to achieve physiological plasma cortisol levels comparable to those in healthy individuals. The incidence of HBV reactivation in patients with adrenal insufficiency given a physiological dose of corticosteroids is also unknown. Therefore, we investigated the incidence of the reactivation of HBV in HBsAg‐negative patients in adrenal insufficiency patients with corticosteroid therapy. And we also evaluated the incidence rate of HBV reactivation in patients with rheumatic disease treated with corticosteroids with or without immunosuppressants and/or DMARDs as the positive control.\n\n2 PATIENTS AND METHODS\nFrom June 2013 to June 2014, at Saitama Medical University Hospital, we consecutively enrolled and investigated 66 HBsAg‐negative patients with primary or secondary adrenal insufficiency who were undergoing corticosteroid replacement therapy. We also consecutively enrolled and evaluated 220 HBsAg‐negative patients with rheumatic disease who were receiving a pharmacological dose of corticosteroids as the positive control. Of these, 101 patients were treated solely with corticosteroids, while 119 patients were treated with both corticosteroids and immunosuppressants and/or DMARDs. HBsAb, HbcAb and HBsAg were measured at the beginning of the study. HBsAb and HbcAb were measured every three to 6 months and at the end of study. In patients who were positive for HBsAb and/or HBcAb, real‐time PCR was performed for HBV‐DNA. Daily maintenance and maximum doses of corticosteroids (prednisone or equivalent) were evaluated retrospectively from their medical charts. During the course of treatment, the dose of corticosteroids was decreased and held stable: this was regarded as the maintenance dose. The current study was approved by the Institutional Review Board of Saitama Medical University Hospital, and the informed consent was obtained from all participants.\n\nThe levels of HBsAg, HBsAb and HBcAb were determined in all the patients at the beginning of the study. An HBsAg level of <0.04 IU/mL was considered to be negative. Anti‐HBs levels of ≥10 IU/L were defined as positive, as were HBcAb levels ≥1.0 s/co. Real‐time PCR was performed on HBV‐DNA in patients who were positive for HBsAb and/or HBcAb, and the resulting HBV‐DNA level was considered to be positive if the level was ≥2.1 log copies/mL. Patients who were converted to HBV‐DNA‐positive status were defined as those who were HBsAg‐negative at the start of the treatment but became HBV‐DNA‐positive during treatment. We determined the incidence rates of conversion to HBV‐DNA‐positive status in patients with adrenal insufficiency or rheumatic disease. The levels of aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) and γ‐GTP were also measured during the observation period to assess liver function.\n\n2.1 Statistical analysis\nAll the data are shown as mean ± SE. The chi‐squared test and ANOVA followed by a Tukey‐Kramer test were performed for comparisons, using JMP 9 statistical software. A P‐value of less than 0.05 was considered to be statistically significant.\n\n3 RESULTS\nA total of 66 patients (32 men and 34 women) had begun, or were receiving, corticosteroid replacement therapy for adrenal insufficiency. The diagnosis of diseases that result in adrenal insufficiency is shown in Table 1. The most common diagnosis was generalized hypopituitarism (n = 44), followed by isolated ACTH deficiency (n = 8), primary or postoperative adrenal insufficiency (n = 8), and so on. On the other hand, 220 patients (48 men and 172 women) were on corticosteroid treatment with or without immunosuppressants and/or DMARDs for various rheumatic diseases. Rheumatoid arthritis was the most common disease, with 80patients, followed by systemic lupus erythematosus (n = 46), overlap syndrome (n = 19) and polymyalgia rheumatica (n = 13), and so on.\n\nTable 1 Diagnosis of the patients' underlying diseases\n\nGroup\tDisease\tNo. of patients\t\nPatients with adrenal insufficiency\tPanhypopituitarism\t44\t\nIsolated ACTH deficiency\t8\t\nSheehan's syndrome\t2\t\nLymphocytic adenohypophysis\t2\t\nPrimary hypoadrenocorticism\t2\t\nPostoperative hypoadrenocorticism\t6\t\nCongenital adrenal hyperplasia\t2\t\nPatients with rheumatic disease\tBehçet's disease\t4\t\nMixed connective tissue disease\t8\t\nMicroscopic polyangiitis\t5\t\nPolymyositis・Dermatomyositis\t8\t\nPolymyalgia rheumatica\t13\t\nRheumatoid arthritis\t80\t\nSystemic lupus erythematosus\t46\t\nAdult Still's disease\t5\t\nSystemic scleroderma\t7\t\nOverlap syndrome\t19\t\nOther collagen disease\t25\t\nJohn Wiley & Sons, LtdTable 2 shows the patients' characteristics. Individuals with rheumatic disease were older than those with adrenal insufficiency. The duration of corticosteroid therapy did not differ among the three groups. The daily maintenance dose of corticosteroids was significantly different among the three groups (P < 0.0001). The doses of corticosteroids (prednisone or equivalent), that is 6.6 ± 0.5 mg and 6.5 ± 0.5 mg in patients with rheumatic disease treated with corticosteroids alone, and corticosteroids plus other immunosuppressants and DMARDs, respectively, were significantly larger than those (4.2 ± 0.2 mg) in patients with adrenal insufficiency (P < 0.05). Maximum daily doses of corticosteroids differed significantly among the three groups (P < 0.0047). The dose of corticosteroids in patients with rheumatic disease treated with only corticosteroids or corticosteroids plus other immunosuppressants and/or DMARDs, that is 24.1 ± 1.8 and 18.9 ± 1.8 mg, respectively, were significantly greater than 4.2 ± 0.2 mg in patients with adrenal insufficiency (P < 0.05). The levels of AST, ALT, LDH and γ‐GTP in the three groups are also shown in Table 2. No statistically significant difference was noted in these liver function tests.\n\nTable 2 Characteristics of the study population\n\n \tPatients with adrenal insufficiency\tPatients with rheumatic disease\t\nSteroids only\tSteroids + biological drugs\t\nNo. of patients\t66\t101\t119\t\nSex M/F\tM 32 F 34\tM 20 F 81\tM 28 F 91\t\nAge (years)\t53.5 ± 2.2 (19‐88)\t60.3 ± 1.6 (19‐84)\t61.0 ± 1.5 (19‐94)\t\nDuration of therapy (years)\t8.8 ± 1.0 (1‐42)\t10.2 ± 0.9 (1‐40)\t9.1 ± 0.7 (1‐35)\t\nMaintenance dose (mg)\t4.2 ± 0.2 (0.625‐10)\t6.6 ± 0.5 (1‐20)\t6.5 ± 0.5 (0.5‐40)\t\nMaximum dose (mg)\t4.2 ± 0.2 (0.625‐10)\t24.1 ± 1.8 (3‐60)\t18.9 ± 1.8 (1‐80)\t\nAST (μ/L)\t26.4 ± 1.1\t23.1 ± 1.0\t23.7 ± 1.1\t\nALT (μ/L)\t27.0 ± 2.2\t20.0 ± 1.5\t19.1 ± 0.9\t\nLDH (μ/L)\t190.1 ± 3.9\t212.8 ± 4.8\t215.8 ± 4.2\t\nγ‐GTP (μ/L)\t30.9 ± 3.9\t35.8 ± 8.0\t36.2 ± 4.4\t\nNote\nData are mean ± SE (range).\n\nAbbreviations: ALT, alanine transaminase; AST, aspartate transaminase; LDH, lactate dehydrogenase; γ‐GTP, γ‐glutamyltranspeptidase.\n\nJohn Wiley & Sons, LtdAs shown in Table 3, the number (percentage) of patients who showed negative for both HBsAb and HBcAb was 55/66 (83.3%), 89/101 (85.1%) and 100/119 (84.0%) in the adrenal insufficiency group, the rheumatic disease group treated with only corticosteroids, and the rheumatic disease group treated with immunosuppressive drugs and/or DMARDs, respectively. On the other hand, 11 patients showed positive for HBsAb and/or HBcAb in the adrenal insufficiency group, compared with 15 patients in the rheumatic disease group treated only with corticosteroids and 19 patients treated with immunosuppressive drugs and/or DMARDs, with no significant difference among the groups.\n\nTable 3 Results of HBsAb and HBcAb measurements\n\n \tPatients with adrenal insufficiency\tPatients with rheumatic disease\t\nSteroids only\tSteroids + biological drugs\t\nNo. of patients\t66\t101\t119\t\nHBsAb (−)・HBcAb (−)\t55\t86\t100\t\nHBsAb (−)・HBcAb (+)\t0\t3\t4\t\nHBsAb (+)・HBcAb (−)\t3\t1\t3\t\nHBsAb (+)・HBcAb (+)\t8\t11\t12\t\nAbbreviations: HBcAb, antibody against hepatitis B core; HBsAb, antibody against hepatitis B surface; HBsAg, hepatitis B surface antigen.\n\nJohn Wiley & Sons, LtdAs shown in Table 4, among those with resolved HBV infections, three patients each (2.9% and 2.5%) had converted to HBV‐DNA‐positive status in the rheumatic disease group treated only with corticosteroids, and with corticosteroids plus immunosuppressive drugs and/or DMARDs, but none had converted in the adrenal insufficiency group, although the difference among the three groups did not reach a significant level. The six patients who had converted to HBV‐DNA‐positive status were aged between 46 and 78 years; of these, five were aged 60 years and older. Five of the six patients were female. The duration of corticosteroid therapy in these patients ranged from 1 to 30 years. The maintenance daily dose of corticosteroids ranged from 2 to 45 mg. The maximum daily dose of corticosteroids ranged from 5 to 60 mg. Furthermore, all the patients were positive for HBcAb, and three were positive for HBsAb (Table 4). These six patients did not present any symptoms or signs of hepatitis, such as generalized fatigue or jaundice. None of the patients developed de novo hepatitis or fulminant hepatitis.\n\nTable 4 Characteristics of HBV‐reactivated patients\n\nCase\tAge (years) and sex (M/F)\tHBsAb\tHBcAb\tHBV‐DNA (Log copies/mL)\tALT (U/L)\tMaintenance dose of corticosteroids (mg)\tMaximum dose of corticosteroids (mg)\tTherapy duration (years)\tConcomitant medication\t\n1\t68 F\t+\t+\t3.4\t10\t5\t5\t30\tNone\t\n2\t46 F\t−\t+\t2.1\t11\t3\t60\t30\tNone\t\n3\t62 M\t−\t+\t2.1\t16\t8\t60\t22\tNone\t\n4\t71 F\t+\t+\t2.1\t44\t2\t5\t13\tTacrolimus hydrate, methotrexate\t\n5\t78 F\t+\t+\t2.1\t11\t45\t45\t1\tMelphalan\t\n6\t75 F\t−\t+\t3.7\t7\t6\t6\t4\tAbatacept, methotrexate\t\nAbbreviations: ALT, alanine transaminase; HBcAb, antibody against hepatitis B core; HBsAb, antibody against hepatitis B surface; HBsAg, hepatitis B surface antigen; HBV‐DNA, hepatitis B virus‐DNA.\n\nJohn Wiley & Sons, LtdIt should be noted that, among the patients who had converted to HBV‐DNA‐positive status, corticosteroids were administered as monotherapy in three patients and as combination therapy in three patients. Of these patients, one was co‐administered with melpharan, while two were co‐administered with methotrexate and either tacrolimus or abatacept (Table 4).\n\n4 DISCUSSION\nIn this study, we investigated the incidence of HBV reactivation among HBsAg‐negative patients treated with a physiological dose of corticosteroids as replacement therapy and a pharmacological dose for anti‐inflammatory and/or immunosuppressive purposes. First of all, patients who showed negative for both HBsAb and HBcAb at the beginning of and/or during the study corresponded to about 85% of the patients included in the study. They were believed to have not been exposed to HBV, although we cannot completely rule out the possibility that several patients had been exposed to HBV but turned out to be seronegative, that is, HBsAg‐negative. Those patients who had never been exposed to HBV during the study period provide no value in a study to elucidate the effects of corticosteroids on the reactivation of HBV. Still, it is meaningful to learn about how many patients were exposed to HBV, and how many were not during the study period. In the present study, 11 patients showed positive for HBsAb and/or HBcAb in the adrenal insufficiency group, compared with 15 patients in the rheumatic disease group treated with only corticosteroids, and 19 patients treated with immunosuppressive drugs and/or DMARDs. Generally speaking, positive HBcAb suggests previous HBV infection resulting in natural immunity, while positive HBsAb and negative HBcAb suggest previous successful vaccination resulting in immunity, rather than infection with HBV. However, in Japan, vaccination against HBV has been recommended only to infants born from HBsAg‐positive mothers since 1986. HBV vaccination has been also recommended to subjects who often come into contact with blood and other body fluids, such as medical and police personnel, but not widely accepted. Later, beginning 1 October 2016, all newborns were strongly advised to undergo HBV vaccination as part of the routine immunization program by the age of one. Practically, all newborns are now vaccinated against HBV. We have confirmed that three patients in the adrenal insufficiency group and four patients in the rheumatic group with positive HBsAb and negative HBcAb did not receive HBV vaccinations. The discrepancy between positive HBsAb and negative HbcAb and vice versa might be attributable to the period during which HBsAb and HBcAb were measured, since, when infection with HBV occurs, HBcAb usually turns positive immediately after exposure to HBV, and, while its potency may or may not weaken, HBsAb antibodies subsequently turn positive. In any event, fortunately, none had HBV reactivation in the adrenal insufficiency group, although, in the latter group consisting of 220 patients with rheumatic disease, HBV reactivation occurred in six cases, that is, 2.7%. We found no significant differences in the results of liver function tests between recurrent and nonrecurrent patients. This is consistent with the previous study which showed no differences in serum liver enzyme levels between patients with and without recurrent hepatitis B.5, 7 Fortunately, none of the patients developed de novo hepatitis in this study.\n\nSecondarily, our results in patients with rheumatic disease confirmed the previous studies in patients with rheumatic arthritis and other rheumatic diseases with resolved HBV infection conducted in Japan, which have reported that HBV reactivation occurred after administration of immunosuppressive agents and DMARDs at the rate of 5.2% during a 1‐year period or 3.4% during a 2‐year follow‐up,7, 8 respectively. However, the use of rituximab in combination with corticosteroids has been recently shown to increase the risk of HBV reactivation.4, 5, 6, 10 On the other hand, three out of 101 patients with rheumatic disease (2.9%) treated with corticosteroids only in the present study experienced HBV reactivation, confirming that of the traditional immunosuppressive medications, corticosteroids have most often been implicated as a significant predisposing factor for HBV reactivation. In fact, rheumatic disease patients treated with prednisone showed a higher risk ratio of 2.2 (95% confidence interval 1.0 to 4.6, P < 0.04) than those treated without prednisone.8\n\n\nResolved HBV infection is defined as an HBsAg‐ and HBV‐DNA‐negative status, but anti‐HBcAb or anti‐HBsAb remains positive. HBV exists as covalently closed circular DNA (cccDNA) in hepatocytes and mononuclear cells, even in patients with resolved HBV infection.9 There are several possible mechanisms for corticosteroid‐induced HBV reactivation. The first mechanism might be that corticosteroids directly cause HBV to proliferate because HBV has a glucocorticoid‐responsive element that has the same base sequence as the glucocorticoid receptor (GR), a hormone‐dependent nuclear receptor, at the initiation site of the viral gene.11 The second mechanism involved may be an indirect immunosuppressive effect on the host immune response which facilitates HBV replication. HBV persists for decades after patients' recovery from acute viral hepatitis, despite active maintenance of a cytotoxic T‐lymphocyte response.12 Glucocorticoid inhibits induction of gene expression of inflammatory cytokines and chemokines via action on NF‐κB and activation protein (AP)‐1. One study has reported that prednisone administered at a dose of 30 mg/d is sufficient to induce the genomic effects of corticosteroids in the body.13 In fact, a corticosteroid dose equivalent to 30 mg/d of prednisone results in the proliferation of HBV and imposes a risk of HBV reactivation associated with high‐dose steroids.\n\nIn contrast, it should be noted that we had no cases of HBV reactivation among adrenal‐insufficient patients on corticosteroid replacement therapy. The daily maintenance and maximum doses of corticosteroids were both 4.2 ± 0.2 mg, which were significantly lower than those prescribed to rheumatic disease patients. In recent reviews by Perrillo et al14 and Loomba and Liang,15 HBsAg‐positive/HBc antibody‐positive patients with inflammatory bowel disease, vasculitis, sarcoidosis and autoimmune disease who were treated with corticosteroids over 4 weeks at moderate (10‐20 mg/d prednisone or equivalent) or high doses (more than 20 mg/d prednisone or equivalent), were reported to be at a moderate or high risk of reactivation of HBV, the incidence of which was 1%‐10% or more than 10% of cases. HBsAg‐positive/HBcAb‐positive patients receiving a low dose of corticosteroids of <10 mg/d prednisone or equivalent over 4 weeks are regarded as being at low risk, and their incidence of HBV reactivation is estimated to be <1.0%. On the other hand, HBsAg‐negative/HBcAb‐positive patients with inflammatory and autoimmune disease treated with a high dose of corticosteroids of more than 20 mg/d prednisone or equivalent over 4 weeks, are regarded to be at moderate risk, and those treated with moderate or low dose of corticosteroids at 10‐20 mg/d or <10 mg/d prednisone or equivalent over 4 weeks, are regarded to be at low risk with an incidence rate of <1.0%. Based on the current study, the incidence of HBV reactivation in rheumatic disease patients treated at low doses of corticosteroids (6.5 mg prednisone or equivalent) might be lower than those reported in these reviews. Furthermore, no HBV reactivation occurred in patients with adrenal insufficiency whose treatment was replaced with a physiological dose of corticosteroids, that is, 4.2 mg of prednisone or equivalent per day, indicating that replacement therapy might be safe with respect to HBV reactivation. However, it should be noted that, in an inactive HBV carrier, HBV reactivation had occurred during a very low‐dose steroid treatment (2.5 mg of prednisone per day plus DMARDs such as sulfasalazine and hydroxychloroquine).16\n\n\nIt has been reported that a greater number of HBcAb‐positive and HBsAb‐negative patients experience HBV reactivation, compared with patients who are HBcAb‐negative and anti‐HBs‐positive.6, 17 In our study, all six HBV‐positive patients were positive for HBcAb, suggesting that HBcAb has considerable potential as a marker and screening tool for patients with resolved HBV infection. Our results suggest that special attention should be given to the possible reactivation of HBV in patients who are positive for HBcAb.\n\nIn our study, patients who experienced HBV reactivation were aged between 46 and 68 years, with five of the six patients aged over 60. Other studies have reported age to be significantly associated with HBV reactivation in HBsAg‐negative patients with B‐cell lymphoma or rheumatic disease treated with rituximab plus corticosteroid‐containing chemotherapy or corticosteroids, immunosuppressive drugs and/or DMARDs.8, 10 However, some rheumatic disease patients in their 20s and 30s treated with immunosuppressive and biological drugs were reported to show HBV reactivation.18 Moreover, in one Japanese study that evaluated 135 resolved hepatitis B patients with rheumatoid arthritis, age was not a predictive factor for HBV reactivation.7 Therefore, attention should be paid to not only the elderly but also to younger individuals with respect to HBV reactivation, especially when biological DMARDs are being co‐administered with corticosteroids. In addition, although the male gender has been reported to be more associated with HBV reactivation in patients with chemotherapy‐treated lymphoma,3, 5 five of the six patients in our present study were female. This is consistent with previous studies in rheumatic disease which report that the male gender was not necessarily associated with HBV reactivation on corticosteroids with or without biological agents.7, 8\n\n\nHui et al 4 reported temporal changes in HBV reactivation following chemotherapy in patients with resolved hepatitis B infection. It has been reported that the median time to convert to positive HBV‐DNA was 12 weeks, the median time from HBV‐DNA positivity to reappearance of HBsAg was 10 weeks, and the median time from reappearance of HBsAg to the onset of acute hepatitis was 18.5 weeks.4 Another report has described the occurrence of hepatitis after an average of 49 days following chemotherapy.19 In our study, however, the duration of corticosteroid therapy varied from 1 to 30 years in six rheumatic disease patients who had converted to HBV‐DNA‐positive status, suggesting that conversion to positive HBV‐DNA might be independent of treatment duration. Periodic assessment of HBV‐DNA levels as well as HBsAg may be important during corticosteroid therapy with or without immunosuppressive and molecular‐targeted drugs.\n\nThis study has several limitations. First, it was designed as a cross‐sectional observational study, not a randomly controlled prospective study. Second, the rate of incidence of HBV reactivation did not show a statistically significant difference among the three groups. Nevertheless, the difference is clear at a glance: HBV reactivation occurred in none of the 66 patients with adrenal insufficiency who were treated with a physiological dose of corticosteroids, but did occur in three out of 101 patients with rheumatic disease given a pharmacological dose of corticosteroids only, and in three out of 119 patients with rheumatic disease given a pharmacological dose of corticosteroids, together with immunosuppressive drugs and/or DMARDs. This might be due to the small number of patients observed and the relatively short observation period of only 13 months. To guarantee the safety of replacement therapy with a physiological dose of corticosteroids in patients with adrenal insufficiency, and to dispel their concerns for HBV reactivation, further prospective studies will be needed, with a longer observational period and with a larger population of patients with adrenal insufficiency. This should also apply to patients with rheumatic disease, to further ascertain the influence of treatment comprising corticosteroids and immunosuppressants with or without DMARDs.\n\nIn conclusion, our present study suggests that, although corticosteroid replacement therapy for adrenal insufficiency might be safe with respect to HBV reactivation, we should remain alert to the risk of HBV reactivation during corticosteroid therapy in patients with rheumatic disease, since the dose of corticosteroid administered is usually high, especially at the beginning, and since other immunosuppressive and molecular‐targeted drugs are co‐administered.\n\nCONFLICT OF INTEREST\nNothing to declare.\n\nAUTHOR CONTRIBUTION\nS Katayama, T Mimura, A Shimada and M Noda conceptualized and designed the study. M Hatano contributed in ethics submission, review of literature, data collection, analysis, interpretation of results and elaboration of manuscript and submission. S Katayama and M Hatano wrote the manuscript and T Mimura, A Shimada and M Noda substantially revised the manuscript.\n\nETHICAL STATEMENT\nThis study was approved by the Institutional Review Board of Saitama Medical University Hospital (No. 15‐053‐1) and the informed consent was obtained from all participants.\n\nACKOWLEDGEMENT\nWe would like to extend our special acknowledgement to Dr Nobuaki Nakayama, Department of Gastroenterology and Hepatology, Saitama Medical University Hospital for his valuable suggestion in interpreting data and writing the manuscript.\n\nDATA ACCESSIBILITY\nAll data generated or analysed during this study are included in this published article.\n==== Refs\nREFERENCES\n1 \n\nDervite \nI \n, \nHober \nD \n, \nMorel \nP \n. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab . 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Hepatology . 2009 ;49 :S13 ‐S21 .19399811 \n10 \n\nKusumoto \nS \n, \nTanaka \nY \n, \nSuzuki \nR \n, et al. Monitoring of hepatitis B virus (HBV) DNA and risk of HBV reactivation in B‐cell lymphoma: a prospective observational study . Clin Infect Dis . 2015 ;5 :719 ‐729 .\n11 \n\nChou \nCK \n, \nWang \nLH \n, \nLin \nHM \n, \nChi \nCW \n. Glucocorticoid stimulates hepatitis B viral gene expression in cultured human hepatoma cells . Hepatology . 1992 ;16 :13 ‐18 .1319949 \n12 \n\nRehermann \nB \n, \nFerrari \nC \n, \nPasquinelli \nC \n, \nChisari \nFV \n. The hepatitis B virus persists for decades after patient's recovery from acute viral hepatitis despite active maintenance of a cytotoxic T‐lymphocyte response . Nat Med . 1996 ;2 :1104 ‐1108 .8837608 \n13 \n\nButtgereit \nF \n, \nda Silva \nJ \n, \nBoers \nM \n, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology . Ann Rheum Dis . 2002 ;61 :718 ‐722 .12117678 \n14 \n\nPerrillo \nRP \n, \nGish \nR \n, \nYngve \nT \n, \nFalck‐Ytter \nYT \n. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy . Gastroenterology . 2015 ;48 :221 ‐244 .\n15 \n\nLoomba \nR \n, \nLiang \nTJ \n. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions . Gastroenterology . 2017 ;152 :1297 ‐1309 .28219691 \n16 \n\nBae \nJH \n, \nSohn \nJH \n, \nLee \nHS \n, et al. A fatal case of hepatitis B virus (HBV) reactivation during long‐term, very‐low‐dose steroid treatment in an inactive HBV carrier . Clin Mol Hepatol . 2012 ;18 :225 ‐228 .22893874 \n17 \n\nKoo \nYX \n, \nTan \nD \n, \nTan \nIB \n, et al. Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy . Cancer . 2010 ;116 :115 ‐121 .19899164 \n18 \n\nKawatani \nT \n, \nSuou \nT \n, \nTajima \nF \n, et al. Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies . Eur J Haematol . 2001 ;67 :45 ‐50 . 19.11553266 \n19 \n\nHsu \nC \n, \nTsou \nH‐H \n, \nLin \nS‐J \n, et al. Chemotherapy‐induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study . Hepatology . 2014 ;59 :2092 ‐2100 .24002804\n\n",
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"issn_linking": "2398-9238",
"issue": "2(3)",
"journal": "Endocrinology, diabetes & metabolism",
"keywords": "adrenal insufficiency; corticosteroids; hepatitis B virus reactivation; rheumatic disease",
"medline_ta": "Endocrinol Diabetes Metab",
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"nlm_unique_id": "101732442",
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"pages": "e00071",
"pmc": null,
"pmid": "31294085",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
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"title": "Hepatitis B virus reactivation with corticosteroid therapy in patients with adrenal insufficiency.",
"title_normalized": "hepatitis b virus reactivation with corticosteroid therapy in patients with adrenal insufficiency"
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"abstract": "BACKGROUND\nDiclofenac, a nonsteroidal anti-inflammatory drug, is not a documented cause of rhabdomyolysis in the Summaries of Product Characteristics held by major regulators. There are, however, eight published single case reports that associate rhabdomyolysis with diclofenac.\n\n\nOBJECTIVE\nTriggered by a serious local case report, this study was conducted to evaluate the evidence for a causal association between diclofenac and rhabdomyolysis.\n\n\nMETHODS\nA descriptive analysis of rhabdomyolysis associated with diclofenac was conducted by mining data from the WHO Global Database of Individual Case Safety Reports, VigiBase, and published case reports.\n\n\nRESULTS\n70 eligible cases were retrieved from VigiBase. The median age was 56.5 years (range 1-90). Where reported precisely (26 reports), the median time to onset of rhabdomyolysis following administration of diclofenac was 3 days. In 20 cases, diclofenac was reported as a sole suspect and was solely administered in 14 of these. In 30 cases, rhabdomyolysis abated following withdrawal of diclofenac. Seven of these cases fulfilled the WHO-UMC case-causality assessment criteria for 'probable'. Diclofenac was probably an indirect cause in another five reports where rhabdomyolysis ensued from injection-site necrosis. There were eight fatalities and intramuscular administration was over-represented in this group. In 27 patients taking lipid-lowering agents, the incidence of acute kidney injury with rhabdomyolysis was 62.9% compared with 37.1% for the whole cohort. Off-label use of diclofenac for minor or undiagnosed conditions was reported.\n\n\nCONCLUSIONS\nCurrently available data suggests a causal link between diclofenac and rhabdomyolysis either directly or indirectly.",
"affiliations": "Eritrean Pharmacovigilance Centre, National Medicines and Food Administration, Ministry of Health, Asmara, Eritrea. satiswt@gmail.com.;Eritrean Pharmacovigilance Centre, National Medicines and Food Administration, Ministry of Health, Asmara, Eritrea.;Akordat Hospital, Ministry of Health, Akordat, Eritrea.;Uppsala Monitoring Centre, Uppsala, Sweden.",
"authors": "Russom|Mulugeta|M|http://orcid.org/0000-0003-1939-5842;Fitsum|Yodit|Y|http://orcid.org/0000-0003-1008-1679;Abraham|Abiel|A|http://orcid.org/0000-0001-8516-3113;Savage|Ruth L|RL|http://orcid.org/0000-0002-8932-0849",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1007/s40801-021-00240-z",
"fulltext": "\n==== Front\nDrugs Real World Outcomes\nDrugs Real World Outcomes\nDrugs - Real World Outcomes\n2199-1154\n2198-9788\nSpringer International Publishing Cham\n\n33786776\n240\n10.1007/s40801-021-00240-z\nOriginal Research Article\nDiclofenac and the Risk of Rhabdomyolysis: Analysis of Publications and the WHO Global Pharmacovigilance Database\nhttp://orcid.org/0000-0003-1939-5842\nRussom Mulugeta satiswt@gmail.com\n\n1\nhttp://orcid.org/0000-0003-1008-1679\nFitsum Yodit 1\nhttp://orcid.org/0000-0001-8516-3113\nAbraham Abiel 2\nhttp://orcid.org/0000-0002-8932-0849\nSavage Ruth L. 345\n1 Eritrean Pharmacovigilance Centre, National Medicines and Food Administration, Ministry of Health, Asmara, Eritrea\n2 Akordat Hospital, Ministry of Health, Akordat, Eritrea\n3 grid.420224.2 0000 0001 2153 0703 Uppsala Monitoring Centre, Uppsala, Sweden\n4 grid.29980.3a 0000 0004 1936 7830 Division of Health Sciences, New Zealand Pharmacovigilance Centre, University of Otago, Dunedin, New Zealand\n5 grid.29980.3a 0000 0004 1936 7830 Department of General Practice, University of Otago, Christchurch, New Zealand\n30 3 2021\n30 3 2021\n9 2021\n8 3 263275\n28 2 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.\nBackground\n\nDiclofenac, a nonsteroidal anti-inflammatory drug, is not a documented cause of rhabdomyolysis in the Summaries of Product Characteristics held by major regulators. There are, however, eight published single case reports that associate rhabdomyolysis with diclofenac.\n\nObjective\n\nTriggered by a serious local case report, this study was conducted to evaluate the evidence for a causal association between diclofenac and rhabdomyolysis.\n\nPatients and Methods\n\nA descriptive analysis of rhabdomyolysis associated with diclofenac was conducted by mining data from the WHO Global Database of Individual Case Safety Reports, VigiBase, and published case reports.\n\nResults\n\n70 eligible cases were retrieved from VigiBase. The median age was 56.5 years (range 1–90). Where reported precisely (26 reports), the median time to onset of rhabdomyolysis following administration of diclofenac was 3 days. In 20 cases, diclofenac was reported as a sole suspect and was solely administered in 14 of these. In 30 cases, rhabdomyolysis abated following withdrawal of diclofenac. Seven of these cases fulfilled the WHO-UMC case-causality assessment criteria for ‘probable’. Diclofenac was probably an indirect cause in another five reports where rhabdomyolysis ensued from injection-site necrosis. There were eight fatalities and intramuscular administration was over-represented in this group. In 27 patients taking lipid-lowering agents, the incidence of acute kidney injury with rhabdomyolysis was 62.9% compared with 37.1% for the whole cohort. Off-label use of diclofenac for minor or undiagnosed conditions was reported.\n\nConclusion\n\nCurrently available data suggests a causal link between diclofenac and rhabdomyolysis either directly or indirectly.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\nKey Points\n\nDiclofenac is not known to cause rhabdomyolysis; it has only previously been associated with single case reports.\t\nTriggered by a serious case report, the causal relationship of diclofenac and rhabdomyolysis was assessed by analysing publications and the WHO global database of individual case safety reports.\t\nThe available evidence suggests a causal link between diclofenac and rhabdomyolysis that warrants attention from healthcare professionals and regulators.\t\n\nIntroduction\n\nDiclofenac is a widely used non-selective non-steroidal anti-inflammatory drug (NSAID). To our knowledge, diclofenac is not known to cause rhabdomyolysis. There were, however, eight single case reports published between 1996 and 2018 that associate rhabdomyolysis with diclofenac [1–8]. The summary of product characteristics (SmPC) of diclofenac, all dosage forms, approved by the Medicines and Healthcare Products Regulatory Authority of the United Kingdom [9] and the US Food and Drug Administration (FDA) [10] and safety reviews of diclofenac by the European Medicines Agency (EMA) [11] and Therapeutic Goods Administration of Australia (TGA) [12] do not mention rhabdomyolysis as an adverse effect.\n\nRhabdomyolysis is an extreme breakdown of skeletal muscle tissues characterized by muscle necrosis and the release of intracellular muscle constituents into the circulation. It is marked by elevated serum creatine kinase (CK), muscle pain and myoglobinuria and, in severe cases, could lead to extreme enzyme elevations, electrolyte imbalance and acute kidney injury in 10–50% of patients [13, 14]. Many conditions can lead to acquired rhabdomyolysis including trauma and crush syndrome, vascular ischaemia, toxins, infections and sepsis, metabolic disorders of salt and water, and a number of drugs [14].\n\nIn Eritrea, diclofenac sodium/potassium injection is widely used even without prescription for the management of acute febrile illnesses, rheumatoid arthritis, gouty arthritis and for moderate to severe pain of known or unknown causes. Recently, the Eritrean Pharmacovigilance Centre received a well-documented single case report of rhabdomyolysis in a young adult shortly after administration of diclofenac 75 mg/3 mL injection [intramuscular (IM)] prescribed for a febrile illness of unknown cause. This study was carried out to investigate the possibility of a causal link between diclofenac and rhabdomyolysis by mining data from the World Health Organization (WHO) Global Database for Individual Case Safety Reports (ICSRs), VigiBase [15] and literature evaluation.\n\nPatients and Methods\n\nStudy Design and Data Sources\n\nThis was a descriptive analysis of diclofenac and risk of rhabdomyolysis reported to the WHO Global Database for ICSRs, VigiBase [15]. VigiBase is a databank developed and maintained by the Uppsala Monitoring Centre (UMC), Sweden. It is the world’s largest pharmacovigilance database with around 21.5 million ICSRs (during data retrieval) submitted from member states since the establishment of the WHO Programme for International Drug Monitoring in 1968. There are currently 136 member states.\n\nData Retrieval Approach\n\nData mining in VigiBase was carried out on 27 February 2020 using the search criteria: ‘diclofenac’ as the drug substance and ‘rhabdomyolysis’ as a MedDRA reaction preferred term [16]. Retrieved data were exported to excel spreadsheets for further descriptive analysis. Using UMC’s tool developed for data mining and analysis, VigiLyze, demographic variables, diclofenac administration details, indications, co-reported adverse reactions with rhabdomyolysis, co-suspect, and concomitant medicines and patients’ medical histories where available were evaluated. Reaction outcomes, de-challenge and rechallenge information, and seriousness of the reactions were also retrieved. The information component (IC) for the diclofenac-rhabdomyolysis combination was also noted. The IC value is a measure of the disproportionality of a drug–adverse drug reaction (ADR) pair in the database [17]. A positive IC025 value (the lower border of the credible interval for the IC value > 0) is “a traditional threshold which indicates that a drug-ADR pair is reported more often than expected based on all reports in the database”, thus showing a statistical signal.\n\nTo exclude potential duplicate case reports, the first search was made by setting ‘de-duplicate’. After automatic removal of potential duplicates, reports were then manually reviewed one-by-one and those that were found to be additional potential duplicates or irrelevant/invalid were removed from the assessment. When two or more reports were suspected to be duplicates of a single case report, the one with better completeness of information was retained for analysis whilst any additional information from the other reports was added before they were removed.\n\nCase Assessment\n\nCausality assessment of the retrieved case reports was undertaken to ascertain the likelihood that they represented rhabdomyolysis as a previously undocumented or insufficiently documented adverse reaction to diclofenac. The WHO-UMC system for standardized case causality assessment was applied for this purpose using the criteria for the causality categories ‘certain’, ‘probable’, ‘possible’, ‘unlikely’, ‘unclassified’ and ‘unclassifiable’ [18]. An effort was made to identify ‘certain’ or ‘probable’ cases for best evidence of a causal relationship. This was carried out by finding reports in which diclofenac was the sole suspect medicine, the patient recovered on discontinuation of diclofenac, and there were no clear alternative causes for rhabdomyolysis. In addition, cases with more than one suspect medicine but with recovery following discontinuation of only diclofenac were included. For a ‘certain’ assessment, recurrence on rechallenge with diclofenac was also required. All abstracted case reports from all available data sources were examined as a case series by applying the Bradford Hill guidelines for causal inference, modified for pharmacovigilance [19]. This causality assessment framework includes nine viewpoints for consideration—strength of association, temporality, consistency, specificity, dose-response relationship, biological plausibility, experimental evidence, analogy and coherence—each of which, if fulfilled, provide additional support for the ADR hypothesis. Furthermore, sub-group analysis was made on the following two scenarios: (1) Case reports in which diclofenac was given by IM injection, as fatal outcomes were more often associated with this administration route. (2) Case reports with lipid-lowering agents reported as co-suspect, concomitant or interacting because of possible confounding due to the propensity of these medicines to cause rhabdomyolysis or the potential for a pharmacodynamic interaction with diclofenac.\n\nLabelling and Literature Search\n\nTo assess available documentation on a relationship between diclofenac and rhabdomyolysis, SmPCs of diclofenac approved by major regulatory authorities including the MHRA [9] and FDA [10] were reviewed. The online drug information databases such as Martindale: the Complete Drug Reference [20], Drugdex [21] and the SIDER side-effect resource [22] were also searched. Further, efforts were made to find relevant publications, including case reports, in Google Scholar, EMBASE and PubMed using the following search criteria in titles of articles: ‘Diclofenac’ AND ‘rhabdomyolysis’. Further, secondary search of relevant articles cited in the already retrieved ones was also carried out.\n\nResults\n\nCase Presentation\n\nDetails of the case of rhabdomyolysis associated with diclofenac reported from Eritrea are presented in Tables 1 and 2. This 25-year-old male patient developed local tissue necrosis at the site of an intragluteal diclofenac injection and subsequently rhabdomyolysis. The clinical progression was complex and tissue damage at the injection site, infection and prolonged immobility may all have contributed to rhabdomyolysis.Table 1 Case presentation of rhabdomyolysis associated with diclofenac injection in a 25- year- old male patient\n\nDecember (Dec) 2, 2018\tPatient admitted to emergency ward of a hospital with sudden onset of right hip joint swelling associated with pain and passage of bloody urine for a duration of 2 two days following use of diclofenac intramuscular, gluteal, for acute febrile illness of unknown origin\t\nDec 3–6, 2018\tPain and swelling progressed to the whole right thigh, associated with skin redness, discoloration and blister formation\t\nDec 6, 2018\tVomiting, dizziness, generalized body weakness, sudden onset drowsiness, profuse sweating. Provisional diagnosis: acute tubular necrosis and cellulitis possibly secondary to diclofenac injection. Treatment: ceftriaxone, hydrocortisone, paracetamol, pethidine, intravenous fluids\t\nDec 7, 2018\tTransferred to a national referral hospital. Investigations: anaemia, abnormal liver and renal function, leukocytosis, hypertriglyceridaemia (Table 2). Malaria and Helicobacter. pylori infection excluded. Intravenous cloxacillin and metronidazole commenced\t\nDec 7–12, 2018\tTransfused with 3 units whole blood, antibiotics continued. Onset confusion, anxiety, decreased level of consciousness, decreased urine output, cardiac ejection murmur and dyspnoea\t\nDec 12, 2018\tTransferred to Intensive Care Unit (ICU) with a working diagnosis of acute kidney injury and deep vein thrombosis (DVT)\t\nDec 12–27, 2018\tRemained in ICU. Urine output and thigh circumference monitored. Gluteal area swelling became necrotic and oozed blood that required daily debridement. DVT ruled out. Treatment: flucloxacillin, furosemide, allopurinol, IV fluids, calcium gluconate, sodium bicarbonate, blood components. Investigations: persisting renal and liver dysfunction, increased uric acid; white cell, red cell and platelet counts, serum cholesterol, high-density lipoprotein and low-density lipoprotein all normal (Table 2). Dark brown urine observed (sometime after initial haematuria) and serum creatine kinase elevated to 3500 IU/L. (normal range: 24–195). Urine myoglobin measurement was not available. Patient diagnosed with rhabdomyolysis and acute kidney injury probably secondary to diclofenac\t\nDec 27, 2018\tAfter gradual improvement transfer back to the medical ward. Discharged after a few days when he was almost recovered\t\n\nTable 2: Chronology of haematology and blood chemistry investigation results from the Eritrean case report of rhabdomyolysis and diclofenac. Normal ranges shown in last row.\n\nDate\tHb\tMCV\tMCHC\tAlb\tBUN\tCREAT\tAST\tALT\tALP\tNa\tK\tCl\tCa\tTG\tUric acid\t\n07/12/18\t8.66\t94\t39.5\t2.7\t199\t9.5\t1524\t254\t231\t131\t4.2\t93\t7.1\t475\t–\t\n10/12/18\t8.32\t101.2\t40.2\t2.1\t274\t13\t468\t141\t141\t124\t6\t87\t6\t218\t17.1\t\n12/12/18\t6.66\t97.7\t36\t2\t283\t14\t257\t92\t92\t119\t6.3\t86\t5.3\t186\t16.4\t\n13/12/18\t7.62\t90\t34.3\t2.1\t308\t15.5\t190\t142\t79\t120\t6.2\t89\t–\t–\t–\t\n14/12/18\t9.06\t95.3\t35.7\t2.1\t325\t15.9\t147\t142\t65\t126\t6.2\t92\t–\t–\t–\t\n17/12/18\t8.67\t92.9\t35.2\t2.1\t328\t17.5\t109\t117\t43\t132\t6.2\t81\t–\t–\t–\t\n19/12/18\t5.74\t94.8\t34\t2.3\t291\t17.4\t95\t126\t39\t125\t5\t81\t4.6\t232\t–\t\n20/12/18\t7.95\t91.4\t34.7\t–\t287\t16.3\t–\t–\t–\t124\t5.2\t85\t4.3\t–\t17\t\n21/12/18\t7.17\t92.4\t34.3\t–\t271\t14.9\t–\t–\t–\t132\t3.6\t80\t–\t–\t–\t\n24/12/18\t9.55\t90.5\t34\t5.3\t187\t11\t–\t–\t–\t127\t2.3\t79\t8\t–\t10.4\t\n28/12/18\t\t\t\t3.1\t107\t4.7\t153\t91\t193\t130\t2.6\t86\t7.9\t155\t4.8\t\nNormal ranges\t12.5–16.3 g/dl\t73.0–96.2 fL\t32.5–36.1 g/dL\t3.4–4.8 g/dL\t6–20 mg/dL\t0.4–1.2 mg/dL\t0–37 U/L\t0–37 U/L\t39–117 U/L\t135–145 mmol/L\t3.6–5.0 mmol/L\t101–111 mmol/L\t8.8–10.2 mg/dL\t0–200 mg/dL\t3.4–7.0 mg/dL\t\nHb haemoglobin, MCV mean cell volume, MCHC mean cell haemoglobin concentration, Alb albumin, BUN blood urea nitrogen;, Cr creatinine, AST aspartate aminotransferase, ALT alanine aminotransferase, T.Bil total bilirubin, ALP alkaline phosphatase, Na sodium, K potassium, Cl chlorine, Ca calcium, TG triglyceride\n\nResults of Literature and Labelling Search\n\nThe SmPCs of diclofenac, including that of the innovator company, approved by major regulatory authorities do not mention rhabdomyolysis as an adverse effect [9, 10, 23]. In other drug information sources, Martindale’s adverse drug reaction checker [20] for diclofenac does not include rhabdomyolysis but states “there may be pain and, occasionally, tissue damage at the site of injection when diclofenac is given intramuscularly”. Drugdex quotes one of the published case reports [21]. The innovator company of diclofenac, Novartis, advises healthcare professionals to strictly follow advice for administering diclofenac IM injections to avoid adverse events at the injection site, which may result in muscle weakness, paralysis, hypoaesthesia and injection-site necrosis [23]. In an analysis of drug-induced rhabdomyolysis reported to the FDA, 100 cases were found to be associated with diclofenac but causality assessment was not undertaken in this study [24].\n\nIn the medical literature (Google Scholar, EMBASE and PubMed), there were no other published studies that associated diclofenac and rhabdomyolysis except the eight case reports [1–8]. We have assessed the causality of the published case reports, shown in Table 3, with the available evidence. In all these reports diclofenac was the sole suspect medicine and duration of its use to onset of rhabdomyolysis was consistently short at less than 10 days. Three of the published case reports of rhabdomyolysis fit the WHO-UMC criteria for ‘probable’ reactions [1, 5, 6]. In addition, two other patients died due to rhabdomyolysis in close temporal relationship to diclofenac administration with no apparent alternative explanations, one following an overdose [2] and one after developing necrotizing fasciitis at the injection site [7]. The cases reported by Delrio et al. [3], Knobloch et al. [4] and Schechner et al. [8] are classified as ‘possible’. This is because the possibility that the patients were taking diclofenac for symptoms of rhabdomyolysis could not be excluded and in the case reported by Schechner et al. [8], a drug that is well known to cause rhabdomyolysis, cerivastatin, was concomitantly administered. This case report indicates how diclofenac may have increased the risk or severity of rhabdomyolysis with cerivastatin.Table 3 Available published case reports of rhabdomyolysis associated with diclofenac use as of February 2020\n\nCase report\tSex/age (years)\tSuspect mMedicines\tRoute\tDose\tDuration\tIndications\tRhabdomyolysis features\tTime to onset\tAction taken (suspects)\tOutcome\tComment\t\nErtekin et al. [1]\tM/45\tDiclofenac\n\nPantoprazole\n\n\tOral\n\nOral\n\n\t50 mg/day\n\n40 mg/day\n\n\t1 month\n\n1 week\n\n\tHeadache\n\nPyrosis\n\n\tMyalgia, fatigue, CK: 3,114 IU/L\t4 days\tWithdrawn\tRecovered\tInteraction postulated\t\nGuzel et al. [2]\tF/13m\tDiclofenac\tIM\t40 mg\tStat\tPain due to 10% second-2nd degree burns\tCardiorespiratory collapse, CK: 35,905 IU/L, urine dark red, metabolic acidosis\t15 mins\tNo further doses\tDied\tOverdose in child\t\nDelrio et al. [3]\tM/44\tDiclofenac\tIM then\n\nOral\n\n\t75 mg/day then 225 mg/day\t6 days\n\n7 days\n\n\tArthritis, joint and back pain, ?gout\tAnorexia, nausea, vomiting, SJS, EM, severe muscle weakness and tenderness, CK: 83,700 IU/L, myoglobinuria, myopathy (biopsy), AKI (mild)\t10 days\tWithdrawn after 13 days\tRecovered\t\t\nKnobloch et al. [4]\tM/22\tDiclofenac\tOral\t50 mg twice a day\t2 days\tMyalgia\tMyalgia increased and tenderness, CK: 18, 041 IU/L\n\nBlood myoglobin increased\n\n\t2 days\tWithdrawn\tRecovered\t\t\nManigandan et al. [5]\tM/50\tDiclofenac\tIM\tUnknown\t1 day\tJoint pains\tSevere myalgia, hypovolaemic shock, AKI, neutrophilia, metabolic acidosis, CK: 1,256 U/L, LDH: 1,800 IU/L\t3 days\tNo further doses\tRecovered\t\t\nBakkali et al. [6]\tM/50\tDiclofenac\tOral\t200 mg (4 × 50 mg tablets)/day\t24 hours\tUnknown\tGlossopharyngeal oedema, ARDS, metabolic acidosis, hyperkalaemia, CK above measurable range, AKI\thours\tNo further doses\tRecovered\t\t\nDemir et al. [7]\tM/37\tDiclofenac\tIM\tUnknown\t2 days\tUnknown\tNecrotising fasciitis, severe right leg tenderness, swelling and pain; CK: 3,815 U/L, myoglobinuria, air bubbles and micro-abscesses among muscles of thigh, AKI\t2 days\tAlready stopped\tDied\tNo history of chronic disease or other drug intake\t\nSchechner et al. [8]\tM/73\tCerivastatin and& diclofenac\tIM\t75 mg/day\t5 days\tLow-back pain\tAKI, CK: 17,800 U/L, hepatic damage, LDH: 3,662 U/L, calcium: 9 mg/dL\t2 days\tBoth drugs withdrawn\tRecovered\t\t\nNormal ranges: CK: 22–198 IU/L; LDH: 140–280 IU/L\n\nM male, F female, SJS Steven–Johnson syndrome, IM intramuscular, CK creatine kinase, AKI acute kidney injury, ARDS acute respiratory distress syndrome, IU International Unit, L litre, LDH lactate dehydrogenase, EM erythema multiforme\n\nReports in the WHO Global Database of Individual Case Safety Reports, VigiBase\n\nIn VigiBase, reports of rhabdomyolysis associated with diclofenac use first appeared in 1995. As of 27 February 2020, a total of 92 reports from 21 countries were identified and retrieved. Ten reports were removed by automated de-duplication. Manual case-by-case assessment revealed another 12 reports that were either invalid or potential duplicates, reducing the total reports for assessment to 70 (Fig. 1). Analysis of the 70 reports revealed that more than half were reported from 2012 onwards. They originated from 19 countries, mainly France (12), Germany (11), Japan (9), USA (7), and the UK (6). Over 60% of the reports were submitted by physicians. Age was given in 65 reports. The median was 56.5 years (range 1–90) and included two children. Approximately one-quarter (27%) of the adult patients were aged less than 44 years. Sex was reported in all but two reports and the reaction manifested more in males (ratio 1.96:1.00).Fig. 1 Summary results of the data mining inn the WHO global database of individual case safety reports (ICSRs) for the association of diclofenac and rhabdomyolysis using the MedDRA System Organ Class (SOC) and Preferred Terms (PTs) and diclofenac as substance (not in combination)\n\nIndications for diclofenac were listed in 40 reports. Ten patients were being treated for joint-related conditions and three for other specific musculoskeletal disorders. However, the majority of patients were being treated for non-specific, non-joint-related musculoskeletal pain or unspecified pain (14) or a variety of other conditions including headache, fever, abdominal and post-operative pain (13).\n\nTime to reaction onset (TTO), from the start of diclofenac treatment to onset of rhabdomyolysis, could be calculated precisely from 26 reports and approximately from a further six. From the 26 reports with precise dates, the median TTO was 3.0 days (range 1–87). For the six reports with less precise dates, TTO ranged from within 20 days to approximately 2 years. Overall, rhabdomyolysis onset was within 1 month of starting diclofenac in over 75% (26/32) of the reports for which TTO could be calculated precisely or approximately. The route of administration was oral (31), IM (14), rectal (5), topical (3), intravenous (IV) (1) and unknown or other (16).\n\nThe reaction was marked as serious in 54 case reports and outcome was reported as ‘recovered’ (25) or ‘recovered with sequelae’ (3), ‘recovering’ (16), ‘not yet recovered’ (6), ‘fatal’ (7) or unknown (13). Acute kidney injury (37.1%), increased CK, myalgia and metabolic acidosis were the most frequently co-reported reaction terms with rhabdomyolysis. Lipid-lowering agents were reported as co-suspects, interacting or concomitants in 27 reports.\n\nIn 20 case reports, diclofenac was reported as the sole suspected medicine, and in 14 of these 20 it was the sole administered medicine. Rhabdomyolysis was reported to have abated following withdrawal of diclofenac in ten of the 20 reports. The route of diclofenac administration in these reports was predominantly IM (11/20) in contrast with the whole dataset. Where diclofenac was not the sole suspect, lipid-lowering (LL) agents, paracetamol, furosemide and aspirin were the most frequently reported co-suspect medicines. In these case reports the route of diclofenac administration was predominantly oral.\n\nFatalities Overall, four males and three females died due to rhabdomyolysis. Two were children aged 2 years or less and five were adults with a median age of 39 years. Diclofenac was either the sole medicine or sole suspect medicine in four reports. The route of administration was IM (4), IV (1), rectal (1) and oral (1). Following IM injection, two patients developed a necrotizing soft tissue infection, one with sepsis (this patient had malignant cells in the bone marrow), and a third developed purpura fulminans. All are known complications of IM diclofenac injection and presumably led to rhabdomyolysis. The fourth IM injection was an overdose in a child who had 10% second-degree burns causing pain [2]. The patients who received rectal or oral administration, including the other child, had other exposures and conditions that were alternative explanations for rhabdomyolysis. The seventh patient was given diclofenac intravenously for thigh pain that was subsequently diagnosed as rhabdomyolysis.\n\nResults of Causality Assessment\n\nIn VigiBase, the calculated IC025 value of this drug-reaction combination was below zero (− 1.4); indicating that the diclofenac/rhabdomyolysis combination was not statistically prominent from background reporting. However, the close temporal relationship between diclofenac administration and rhabdomyolysis onset in many reports suggested that a causality assessment of the VigiBase case reports should be undertaken. Using the WHO–UMC system for standardized case-causality assessment, the ten reports in which diclofenac was the sole suspect or sole medicine administered and full or partial recovery had occurred after diclofenac withdrawal were scrutinized. Five of the ten reports did not include alternative explanations for rhabdomyolysis such as concomitant medicines and/or co-morbidities and these were classed as ‘probable’. Two other reports that did include a co-suspect medicine were also classified as ‘probable’ for the following reasons. In one, celecoxib was reported as co-suspect but the patient recovered following withdrawal of diclofenac only and no other alternative explanation was found. In the other report, diclofenac and pantoprazole were reported as interacting leading to rhabdomyolysis. However, the interaction theory is not sound and there is no external evidence for proton pump inhibitors causing rhabdomyolysis; hence this report was categorized as ‘probable’ for diclofenac. Of these seven ‘probable’ reports in VigiBase, three are shown in Table 3 as they were also published [1, 5, 6] and the remainder are shown in Table 4.Table 4 Unpublished individual case safety reports of rhabdomyolysis associated with diclofenac in the WHO global database with causality classified as ‘“probable’”\n\nReport number\tMedicines both suspected (S) and Concomitant (C)\tRoute\tIndication\tTime to onset\tReaction\tAction taken with medicines\tOutcome\tNotes/ references\t\n1\tDiclofenac (S)\n\nBupivacaine (C)\n\n\tRectal\n\nEpidural\n\n\tUnknown,\n\nnNormal delivery\n\n\t3 days\tRhabdomyolysis\tDiclofenac withdrawn\tRecovered\t\t\n2\tDiclofenac (S)\n\nRebamipide (C)\n\n\tUnknown\n\nUnknown\n\n\tMyalgia\t3 months\tRhabdomyolysis, CK: 490.5 IU/L, bBlood myoglobin: 940\tDiclofenac withdrawn\n\nRebamipide continued\n\n\tRecovered\t\t\n3\tDiclofenac (S)\n\nCelecoxib (S)\n\nParacetamol (C)\n\n\tUnknown\tPain\tUnknown\tRhabdomyolysis\tDiclofenac and paracetamol withdrawn; celecoxib continued\tRecovering\tVery small amount of published case report evidence for paracetamol being causal\t\n4\tDiclofenac\tUnknown\tBackache\tWithin 5 months\tRhabdomyolysis\n\nAKI\n\n\tDiclofenac withdrawn\tRecovered\tDehydrated\t\nNormal ranges: CK: 22–198 IU/L; LDH: 140–280 IU/L\n\nIM intramuscular, CK creatine kinase, AKI acute kidney injury, IU International Unit, L litre, LDH lactate dehydrogenase\n\nA further five patients, including the case report from Eritrea, developed rhabdomyolysis subsequent to injection-site tissue necrosis, probably or certainly caused by diclofenac, so that it was an indirect cause of rhabdomyolysis.\n\nNo case reports were assessed as showing a ‘certain’ direct causal relationship as no patients were re-challenged. The majority of the remainder of the reports were assessed as ‘possible’ as there were co-suspect or concomitant medicines or clinical conditions that could have been alternative explanations for rhabdomyolysis. This group also included patients who appeared to develop rhabdomyolysis indirectly as a result of adverse reactions that were possibly diclofenac related such as purpura fulminans, hepatic necrosis and seizures.\n\nSub-Group Analysis\n\nIntramuscular Administration\n\nBecause the patient in our case history was given diclofenac by IM administration and IM diclofenac was given in four fatalities that seemed most likely to be attributable to diclofenac, we analysed separately the 14 reports where diclofenac was given IM. There were seven females and seven males with a median age of 46.0 years (range 1–75 years) in this group. Five described tissue necrosis associated with the diclofenac injection and one purpura fulminans, which can be caused by diclofenac injection or infection. All of these may have caused sufficient tissue damage that could have led to rhabdomyolysis. It is important to highlight that in 11 of the 14 cases administered IM (including the well-documented case presentation reported from Eritrea), diclofenac was the sole suspect and, in nine of these, diclofenac was solely administered. Indications for IM diclofenac, reported for 11 patients, were arthralgia, spondyloarthropathy, aching joints, lumbago, unspecified pain or ache, abdominal pain, depression, acute febrile illness and common cold syndrome (headache, fever and muscle pain).\n\nReports with Co-Prescribed Lipid-Lowering Agents\n\nThere were 27 reports in which LL agents, known to cause rhabdomyolysis, were listed as co-suspect, interacting or concomitant with diclofenac. These included 17 males and ten females with a median age of 66.0 years (range 41–90). Indications for diclofenac in these reports were joint-related (6), other specified musculoskeletal pain (3), unspecified pain (2), headache (1) and pyrexia (1). For 14 patients the indication was not stated. Routes of diclofenac administration were oral (16), IM (2), cutaneous (2), rectal (1) and not stated (6). At the time of reporting, 17 patients had recovered or were recovering, three had recovered with sequelae and two had not recovered from rhabdomyolysis. The outcome for the remaining five was unknown. There were no reports of fatalities, but for eight patients the rhabdomyolysis was life threatening.\n\nThe TTO of rhabdomyolysis was assessed from the start dates of diclofenac and LL agents. The median TTOs for diclofenac, where stated precisely (ten reports), was 4.5 days (range 0–19). Two other reports gave TTOs for diclofenac of 2–3 months and 1–2 years. TTOs for LL agents were stated in ten reports. For nine reports TTOs for LL agents ranged widely from 0 days to 9 years (6 within 4 months and three at 2, 5 and 9 years). In the tenth report, three LL agents were listed and diclofenac was commenced after the onset dates for rhabdomyolysis and acute kidney injury (AKI).\n\nThe proportion of patients who developed AKI with rhabdomyolysis in the LL group was 62.9% (17/27) compared with 37.1% for all of the 70 reports. Diclofenac alone can cause or exacerbate AKI. Concomitant medicines that may have contributed to AKI include: angiotensin-converting enzyme inhibitors (ACEis) and angiotensin 2 receptor blockers (A2RBs) (11/27, 40.7%). Only three of the remaining 43 patients in the whole dataset of 70 were taking either ACEis or A2RBs (7.0%). All eight patients who were taking the ‘triple whammy’ (NSAID, diuretic and ACEi or A2RB), which predisposes to renal failure, were in this LL group and all developed AKI with rhabdomyolysis. Another risk was that four patients were taking additional NSAIDs concomitantly with diclofenac.\n\nDiscussion\n\nThe multifactorial nature of rhabdomyolysis makes this causal association challenging. On top of this, several published and VigiBase case reports had potential confounders that would lead to confounding bias. Nevertheless, the short time interval in a substantial number of reports between starting diclofenac and onset of rhabdomyolysis suggests that there is a relationship between the two. Our study suggests four possible explanations for the close temporal relationship between diclofenac use and rhabdomyolysis: (1) A small number of published and VigiBase case reports suggest diclofenac may occasionally be directly causal; (2) diclofenac may be indirectly causal following extensive tissue necrosis with IM injection or other diclofenac-related adverse reactions; (3) diclofenac may transform subclinical rhabdomyolysis with LL agents to overt disease and increase the risk of associated AKI; (4) the relationship may be non-causal if the symptoms for which diclofenac was prescribed were due to rhabdomyolysis.\n\nThe fact that diclofenac was reported as a sole suspected medicine and solely administered in a substantial number of cases shows specificity of the association and, thus, strengthens causation. To minimize the effect of confounders, causality was assessed using the WHO-UMC criteria. Reports were sought in which diclofenac was reported as a sole suspect and the patients recovered following withdrawal of diclofenac (positive dechallenge) with no reported alternative explanations for rhabdomyolysis. These reports, classified as ‘probable’, provide the best evidence in VigiBase of a causal relationship between the two. There was also evidence of an indirect causal effect particularly related to injection-site necrosis.\n\nThe strength of association or IC value was found to be negative for this combination in VigiBase. This tells us that rhabdomyolysis has not been more frequently reported than expected in the WHO global database, which is not in favour of the causal association. However, disproportionality analysis is a filter that reduces the possibility of missing causal associations but a lack of a statistical signal should not deter further investigation if there are well-documented ICSRs with evidence of causality. The eight published case reports that associate rhabdomyolysis and diclofenac [1–8] and the cases reported in VigiBase, submitted by different countries, indicate that the association is consistent. This observation is also supported by a study that assessed 8,610 cases of drug-induced rhabdomyolysis reported to the FDA, in which 100 cases were associated with diclofenac [24]. This is in excess of the reports from the USA in VigiBase since the FDA database includes reports from market-authorization holders of adverse events occurring in non-USA countries if the medicine is marketed in the USA.\n\nOne possible mechanism by which diclofenac could cause rhabdomyolysis has been hypothesized. An in vitro study involving artificially expressing human organic anion transporter (hOAT) receptors showed that hOAT3 interacted with acetaminophen and diclofenac [25]. Expression of hOAT3 is predominantly in the kidneys but it has been demonstrated in skeletal muscle using Northern blot analysis. The authors stated that although precise immunohistochemical analysis should be performed, it is possible that hOAT3 mediates the accumulation of NSAIDs in skeletal muscle. Hypothetically this could lead to the induction of rhabdomyolysis in some individuals, but it requires to be substantiated with further studies [25].\n\nDiclofenac may also indirectly cause rhabdomyolysis as a complication of a known diclofenac-related adverse reaction. For example, the five reports of injection-site reactions causing extensive tissue necrosis, where rhabdomyolysis appears to be a consequence, might be because of muscle injury and infection. One of the published case reports not in VigiBase also describes a similar indirect effect through necrotizing fasciitis that was fatal [7]. The indications in some reports, such as short-term non-specific muscle pain, suggest that another explanation for an observed association is the inadvertent use of diclofenac to treat early unrecognized rhabdomyolysis symptoms leading to confounding by indication.\n\nThe study also highlights off-label use of diclofenac and inappropriate IM administration. It is important to reflect that in 11 of the 14 cases administered IM, diclofenac was the sole suspect and in nine cases diclofenac was solely administered. Also, this group was younger on average than the total dataset, and four of the seven fatalities in the whole dataset were related to IM injection (three with injection-site necrosis or purpura fulminans and one due to an overdose in a child). Prevention of this rare but serious injection-site reaction should be possible in many cases. As diclofenac is a commonly prescribed and potentially overused drug, healthcare professionals need to be aware of the potential risk and take some measures to prevent or minimize it. Taking the lowest effective dose for the shortest possible time, administering deep intragluteal injection into the upper outer quadrant, and using the Z-track injection method (believed to be a safe method of IM injection) would prevent or minimize tissue necrosis that triggers rhabdomyolysis [26, 27].\n\nPrevention may also be possible if off-label use, such as for fever and respiratory symptoms, is avoided and IM administration is confined to patients for whom there is a strong indication for this medicine and who cannot take it by the oral or rectal route. According to the EMA/MHRA SmPC, therapeutic indications of diclofenac are rheumatoid arthritis, osteoarthrosis, low back pain, migraine attacks, acute musculoskeletal disorders and trauma, ankylosing spondylitis, acute gout, control of pain and inflammation in orthopaedic, dental and other minor surgery, pyrophosphate arthropathy and associated disorders [9].\n\nAKI was the most frequently co-reported reaction with rhabdomyolysis, at 37.1%, which is within the reported range of 10–50% [14, 28]. However, in the subgroup of patients taking LL agents with diclofenac, the proportion of AKI was much higher at 62.9% (17/27). This is an important observation since development of AKI appears to increase the risk of a fatal outcome with rhabdomyolysis [28]. It is known that rhabdomyolysis may be subclinical [29], and, hence, it is possible that the addition of diclofenac to LL agents aggravated it or increased the risk of associated AKI. It is also possible that diclofenac was prescribed for early and unrecognized symptoms of rhabdomyolysis in these patients.\n\nDuring rhabdomyolysis, water is taken up into muscle tissue leading to extracellular hypovolaemia and therefore vasoconstriction. Diclofenac blocks the renal prostaglandin activity that would allow vasodilatation in the kidney in these circumstances. Hence, glomerular blood flow is reduced and renal impairment can occur. Furthermore, the myoglobin released during rhabdomyolysis is easily filtered into the urine and causes renal tubular obstruction [14, 30–32]. Reabsorption of myoglobin can occur in the proximal renal tubules but any adverse effects of diclofenac on renal tubules could theoretically inhibit this reabsorption. As 40% of the patients taking LL agents were on ACEis or angiotensin receptor blockers and the majority of these were also taking diuretics, the adverse effect of diclofenac on kidney function would have been compounded [33].\n\nLimitations\n\nThis study has some limitations. The cases are captured from the WHO global database of ICSRs, which holds suspected cases that vary with regard to their source and completeness. Thus, the authors could not validate the diagnosis of rhabdomyolysis. Due to lack of denominator information in spontaneous reporting, this study cannot quantify the incidence of rhabdomyolysis associated with diclofenac. The subgroup numbers and numbers of fatalities are small so that larger studies are needed to confirm or refute the hypotheses generated from the observations.\n\nConclusion\n\nIn conclusion, the plausible temporal relationship, specificity and consistency of the association observed, and the suggested possible biological mechanism, are in agreement with several Bradford Hill criteria. In addition, the cases with positive dechallenge and the published and VigiBase cases fulfilling WHO-UMC causality criteria suggest a possible causal link between diclofenac and rhabdomyolysis. It is, however, important to note that this causal inference is made based on the limited available information in the medical literature and WHO global database of ICSRs; thus, conclusions could change in the future with studies that may strengthen or weaken the evidence.\n\nRhabdomyolysis is a life-threatening condition that could lead to complications such as metabolic instability, acute renal failure, disseminated intravascular coagulation and cardiac arrest [34], and thus avoidance of diclofenac where possible, early diagnosis and aggressive management are important to avoid its complications. From a practical aspect, it is important to reflect on the rare but potentially fatal reactions related to IM diclofenac, the young age of those fatally affected, and the increased risk of serious renal complications of rhabdomyolysis attributed to the concomitant use of LL agents, diclofenac and other agents that may contribute. As diclofenac is among the commonly prescribed and potentially overused drugs [35], avoidance of off-label use and unnecessary IM administration, especially for minor conditions, and correct administration where it is indicated are likely to reduce the risk. Also, before diclofenac is prescribed, there needs to be alertness to the possibility that unexplained musculoskeletal symptoms may be early manifestations of rhabdomyolysis. It is also well known that combinations of diclofenac with other agents that synergistically adversely affect renal function should be avoided. Finally, we recommend healthcare professionals be aware that diclofenac needs to be discontinued if rhabdomyolysis is suspected.\n\nAcknowledgements\n\nWe would like to thank Dr. Qun-Ying Yue from the Uppsala Monitoring Centre, Sweden, for her review and valuable contributions.\n\nDeclarations\n\nFunding\n\nNo funding was used for this study.\n\nConflict of Interest\n\nThe authors declare that they have no competing interests.\n\nEthics Approval\n\nInformation of all cases retrieved from the WHO global database of individual case safety reports is de-identified and ethical approval is not required.\n\nConsent to Participate\n\nInformed consent to participate in the study was obtained from the Eritrean patient (case report).\n\nConsent for Publication\n\nThough informed consent was obtained from the case reported from Eritrea, the patient’s details (including name, images, residence, admitting and referral hospitals) are also completely anonymized.\n\nAvailability of Data and Material\n\nThe datasets generated and analyzed during the current study are not publicly available due to agreements between contributors of data to the database used (VigiBase) and the custodian of the database. National Centres (mainly drug regulatory authorities) constituting the WHO Programme for International Drug Monitoring (PIDM) contribute data to VigiBase and the Uppsala Monitoring Centre is the custodian in its capacity as WHO Collaborating Centre for International Drug Monitoring. Some subsets of the data may be available from the corresponding author on reasonable request.\n\nCode Availability\n\nNot applicable.\n\nAuthor Contributions\n\nMR and YF contributed to the conception the study. The case from Eritrea was reported, investigated and written by AA and all the authors contributed to the study design. RS, MR and YF contributed to the analysis of publications, data analysis and their interpretation. MR and RS drafted the article, and it was reviewed by the rest of the authors. Finally, all authors read and approved the final manuscript.\n\nDisclaimer\n\nThe authors are indebted to the National Centres that make up the WHO Programme for International Drug Monitoring and contribute reports to VigiBase. However, the opinions and conclusions of this study are not necessarily those of the various centres nor of the WHO.\n==== Refs\nReferences\n\n1. Ertekin YH Yakar B Ertekin H Diclofenac- and pantoprazole-induced Rhabdomyolysis: a potential drug interaction Drug Saf Case Rep. 2015 10 1 4 10.1007/s40800-015-0012-6\n2. Güzel A Biner Orhaner B Aylanç H Fatal acute diclofenac-induced Rhabdomyolysis in a pediatric patient Balkan Med J. 2011 28 102 103 10.5174/tutfd.2009.02192.0\n3. Delrio FG Park Y Herzlich B Grob D Diclofenac-lnduced rhabdomyolysis Am J Med Sci. 1996 312 95 97 10.1016/S0002-9629(15)41764-1 8701974\n4. 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Summary of product characteristics of diclofenac tablet50mg. 2020. https://www.medicines.org.uk/emc/product/4333/smpc. Accessed 4 May 2020.\n10. US FDA. Prescribing information of diclofenac sodium delayed release tablet. 2020. https://www.drugs.com/pro/diclofenac.html. Accessed 4 May 2020.\n11. European Medicines Agency. Assessment report for diclofenac containing medicinal products (systemic formulations). EMA/544760/2013. September 2013. 2013. https://www.ema.europa.eu/documents/referral/diclofenac-article-31-referral-prac-assessment-report_en.pdf.\n12. Australian Government, Department of Health. Therapeutic Goods Administration. Safety review of diclofenac. Version 2.1, October 2014. 2014.\n13. Keltz E, Khan FY, Mann G. Rhabdomyolysis. The role of diagnostic and prognostic factors. Muscles Ligaments Tendons J. 2014;3:303–12. https://www.ncbi.nlm.gov/pmc/articles/PMC3940504/.\n14. Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care. 2014;18:224. http://ccforum.com/content/18/3/224.\n15. Lindquist M VigiBase, the WHO Global ICSR Database System: basic facts Drug Inf J. 2008 42 409 419 10.1177/009286150804200501\n16. https://www.meddra.org/. Accessed Feb 2020.\n17. Bate A Lindquist M Edwards IR Olsson S Orre R Lansner A A Bayesian neural network method for adverse drug reaction signal generation Eur J Clin Pharmacol. 1998 54 315 321 10.1007/s002280050466 9696956\n18. WHO-Uppsala Monitoring Centre. The use of the WHO-UMC system for standardized case causality assessment. 2020. https://www.who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf. Accessed 4 May 2020.\n19. Shakir SA Layton D Causal association in pharmacovigilance and pharmacoepidemiology: thoughts on the application of the Austin Bradford-Hill criteria Drug Saf. 2002 25 6 467 471 10.2165/00002018-200225060-00012 12071785\n20. Buckingham R (ed). Martindale: The Complete Drug Reference. [online] London: Pharmaceutical Press. http://www.medicinescomplete.com.cmezproxy.chmeds.ac.nz/. Accessed on 20 May 2020.\n21. www.micromedexsolutions.com. Accessed on 20 May 2020.\n22. Kuhn M, Letunic I, Jensen LJ, Bork P. The SIDER database of drugs and side effects. Nucl Acids Res. 2015. 10.1093/nar/gkv1075. http://sideeffects.embl.de/drugs/3032/. Accessed on 13 Jan 2021.\n23. Novartis Pharmaceuticals UK Ltd. Summary of product characteristics of diclofenac sodium (Voltarol ampoules) 75mg/3ml). Updated January 2020. 2020. https://www.medicines.org.uk/emc/product/1043/smpc https://www.medicines.org.uk/emc/product/4333/smpc. Accessed 4 May 2020.\n24. Oshima Y. Characteristics of drug-associated rhabdomyolysis: analysis of 8,610 cases reported to the U.S. Food and Drug Administration. Intern Med. 2011;50:845–53. 10.2169/internalmedicine.50.4484.\n25. Khamdang S Interactions of human organic ion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs Pharmacology 2002 303 534 539\n26. Uri O Behrbalk E Tissue necrosis following intramuscular administration of various drugs (Nicolau syndrome): Clinical presentation, pathophysiology and treatment Harefuah 2009 148 186 188 19485279\n27. Giving Z-track injections, Nursing. 2002;32(9):81. https://journals.lww.com/nursing/fulltext/2002/09000/giving_z_track_injections.56.aspx.\n28. Ward MM Factors predictive of acute renal failure in rhabdomyolysis Arch Intern Med. 1988 148 1553 1557 10.1001/archinte.1988.00380070059015 3382301\n29. Huerta-Alardin AL Varon J Marik PE Bench-to-bedside review: rhabdomyolysis: an overview for clinicians Crit Care 2005 9 1158 1169 10.1186/cc2978\n30. Daher E Zanetta DM Cavalcante MB Risk factors for death and changing patterns in leptospirosis acute renal failure Am J Trop Med Hyg. 1999 61 630 10.4269/ajtmh.1999.61.630 10548299\n31. Lima RS da Silva Junior GB Liborio AB Acute kidney injury due to rhabdomyolysis Saudi J Kidney Dis Transpl. 2008 19 721 18711286\n32. Daher Ede F Zanetta DM Abdulkader RC Pattern of renal function recovery after leptospirosis acute renal failure Nephron Clin Pract. 2004 98 c8 c14 10.1159/000079922 15361699\n33. Toto RD Renal insufficiency due to angiotensin-converting enzyme inhibitors Miner Electrol Metab. 1994 20 193 200\n34. Counselman FL. Rhabdomyolysis. Emergency Medicine Comprehensive study guide, 5th edn., vol. 271. McGraw-Hill Companies; 2000. pp. 1841–5.\n35. Internet: China Diclofenac Investigation Market Report, 2019-2023. 2020. https://www.businesswire.com/news/home/20190822005517/en/China-Diclofenac-Investigation-Market-Report-2019-2023. Accessed on 13 Jan 2021.\n\n",
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"title": "Diclofenac and the Risk of Rhabdomyolysis: Analysis of Publications and the WHO Global Pharmacovigilance Database.",
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"abstract": "Multiple sclerosis (MS) is typically a disease of young adults. Childhood MS can be defined in patients under 18 years of age, although some authors set the limit un-der the age of 16 formerly known as \"early-onset multiple sclerosis\" or \"juvenile multiple sclerosis\", seen in 3-5% of all MS patients. Nowadays, owing to ever-evolving, better diagnostic tools and well-traced, strictly defined diagnostic criteria, childhood MS is showing an increasing incidence worldwide (0.05-2.85/100 000). MS is characterized by recurrent episodes of the central nervous system with demyelination separated in space and time. In childhood almost exclusively the relapsing-remitting (RR) type of MS occurs. Based on experience in adults, the goal in the pediatric population is also the early diagnosis, to initiate adequate DMT as soon as possible and to achieve symptom relief and good quality of life. Based on efficacy and safety studies in the adult population, inter-feron β-1a and glatiramer acetate were first approved by the FDA and EMA for the treatment of childhood MS also. The increased relapse rate and rapid progression of childhood MS and unfavorable therapeutic response to nearly 45% of the first DMT necessitated the testing of more effective and second-line drugs in the population under 18 years of age (PARADIGMS, CONNECT). Although natalizumab was reported to be effective and well-tolerated in highly active RRMS in childhood, evidence based studies were not yet available when our patients' treatment started. In this article, we report on the successful treatment of three active RRMS patients with individually authorized off-label use of natalizumab.",
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"abstract": "Revascularization of atherosclerotic renal artery stenosis may cure hypertension, but paradoxically, improvement in systemic blood pressure in response to successful revascularization may precipitate ischemia in other organs affected by previously silent atherosclerotic disease. We describe bowel ischemia secondary to preexisting celiac artery stenosis after revascularisation. Prior knowledge of multivessel disease facilitated prompt diagnosis and management of this condition.",
"affiliations": "Division of Nephrology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.;Division of Vascular Surgery, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.;Division of Vascular Surgery, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.;Division of Nephrology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.;Division of Nephrology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: mruzicka@toh.ca.",
"authors": "Sriperumbuduri|Sriram|S|;Hajjar|George|G|;Jetty|Prasad|P|;Hiremath|Swapnil|S|;Ruzicka|Marcel|M|",
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"mesh_terms": "D050197:Atherosclerosis; D002445:Celiac Artery; D003106:Colon; D006801:Humans; D006978:Hypertension, Renovascular; D008297:Male; D065666:Mesenteric Ischemia; D008875:Middle Aged; D011183:Postoperative Complications; D012077:Renal Artery; D012078:Renal Artery Obstruction; D012086:Reoperation; D016896:Treatment Outcome",
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"abstract": "Clarithromycin is a commonly used antibiotic. Neuropsychiatric adverse effects are recognized, but the occurrence of seizures and status epilepticus (SE) has been rarely reported. We report the case of an elderly patient who developed generalized tonic-clonic seizures (GTCS) followed by nonconvulsive status epilepticus (NCSE), 2 days after starting clarithromycin. Other causes of seizures were excluded by magnetic resonance imaging (MRI) of the brain, CSF analysis, and routine laboratory studies, thus establishing the causal role of clarithromycin. Clarithromycin was stopped and parenteral antiepileptic drugs started, which controlled the status. In the elderly, symptoms like delirium, drowsiness, confusion, or seizures can occur due to an underlying systemic disease, brain pathology, or adverse effects of medications, all of which must be correctly differentiated. This case illustrates the occurrence of seizures and SE due to clarithromycin. Awareness about this possibility will help physicians recognize and treat such situations promptly. How to cite this article: Seetharam R, Iyer RB, Nooraine J, Ramachandran J. Clarithromycin-induced Seizures and Status Epilepticus. Indian J Crit Care Med 2021;25(8):945-947.",
"affiliations": "Department of Neurology, Vikram Hospital, Bengaluru, Karnataka, India.;Department of Neurology, Vikram Hospital, Bengaluru, Karnataka, India.;Department of Neurology, Vikram Hospital, Bengaluru, Karnataka, India.;Department of Neurology, Vikram Hospital, Bengaluru, Karnataka, India.",
"authors": "Seetharam|Raghavendra|R|;Iyer|Rajesh B|RB|;Nooraine|Javeria|J|;Ramachandran|Jaychandran|J|",
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"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229\n1998-359X\nJaypee Brothers Medical Publishers\n\n10.5005/jp-journals-10071-23900\nCase Report\nClarithromycin-induced Seizures and Status Epilepticus\nSeetharam Raghavendra 1https://orcid.org/0000-0002-4357-0332\n\nIyer Rajesh B 2https://orcid.org/0000-0002-2181-069x\n\nNooraine Javeria 3https://orcid.org/0000-0001-8903-2188\n\nRamachandran Jaychandran 4https://orcid.org/0000-0002-8843-7551\n\n1–4 Department of Neurology, Vikram Hospital, Bengaluru, Karnataka, India\nRaghavendra Seetharam, Department of Neurology, Vikram Hospital, Bengaluru, Karnataka, India, Phone: +91 9945422445; +91-80-71004500, e-mail: raghavneuro@yahoo.com\n8 2021\n25 8 945947\nCopyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ © Jaypee Brothers Medical Publishers. 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial 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.\nABSTRACT\n\nClarithromycin is a commonly used antibiotic. Neuropsychiatric adverse effects are recognized, but the occurrence of seizures and status epilepticus (SE) has been rarely reported. We report the case of an elderly patient who developed generalized tonic-clonic seizures (GTCS) followed by nonconvulsive status epilepticus (NCSE), 2 days after starting clarithromycin. Other causes of seizures were excluded by magnetic resonance imaging (MRI) of the brain, CSF analysis, and routine laboratory studies, thus establishing the causal role of clarithromycin. Clarithromycin was stopped and parenteral antiepileptic drugs started, which controlled the status. In the elderly, symptoms like delirium, drowsiness, confusion, or seizures can occur due to an underlying systemic disease, brain pathology, or adverse effects of medications, all of which must be correctly differentiated. This case illustrates the occurrence of seizures and SE due to clarithromycin. Awareness about this possibility will help physicians recognize and treat such situations promptly.\n\nHow to cite this article: Seetharam R, Iyer RB, Nooraine J, Ramachandran J. Clarithromycin-induced Seizures and Status Epilepticus. Indian J Crit Care Med 2021;25(8):945–947.\n\nKeywords\n\nAdverse effects\nAntibiotics\nClarithromycin\nNeurotoxicity\nNonconvulsive status epilepticus\n==== Body\npmcINTRODUCTION\n\nClarithromycin is a commonly used macrolide antibiotic indicated in a variety of infections. It has been reported to cause neuropsychiatric adverse effects.1,2 Acute delirium and psychosis have been prominent observations.3–5 Nonconvulsive status epilepticus (NCSE) due to clarithromycin therapy has been rarely reported. NCSE often manifests as delirium or confusional states. Diagnosis in the setting of infections, particularly in the elderly, requires a high index of suspicion. Identification of the cause of NCSE is of paramount importance, especially if it is drug-induced, so that immediate corrective measures can be adopted. We report the case of an elderly patient who developed generalized tonic-clonic seizures (GTCS) followed by NCSE due to clarithromycin and discuss its presentation, diagnosis, and management.\n\nCASE DESCRIPTION\n\nA 71-year-old hypertensive, nondiabetic gentleman had been experiencing epigastric discomfort for a few weeks for which he underwent gastro-duodenoscopy. He was diagnosed to have a duodenal ulcer and started on amoxicillin 1500 mg, clarithromycin 1000 mg, and pantoprazole 80 mg daily in two divided doses. Two days later, he suddenly developed two episodes of unprovoked GTCS. He had no fever, headache, altered sensorium, or any other relevant antecedent symptoms. There was no history of any other neurological symptoms. He was investigated further for the seizures. Magnetic resonance imaging (MRI) of the brain (1.5 Tesla) was normal except for few nonspecific white matter signal changes. Routine hematological and biochemical parameters were normal. Electroencephalogram (EEG) was also normal (Fig. 1A). He was started on levetiracetam 500 mg twice daily and discharged home. Gastroenterology medicines were continued.\n\nFigs 1A to C EEG was done in a 71-year-old with two episodes of seizures within 24 hours depicted in the bipolar montage (1–70 Hz). Initial EEG was normal (A). Three days later when he presented with a confusional state, EEG was repeated, which showed features of NCSE in the form of generalized rhythmic theta activity intermixed with spikes (B). He was treated with injection lorazepam that controlled the NCSE with the reappearance of background activity with an increased nonspecific slowing in comparison with baseline (C)\n\nThree days later, he was brought back with prolonged confusional state. On examination, he was disoriented, confused, poorly comprehending, and responded inappropriately. He was afebrile and had stable vital parameters. He was suspected to be in NCSE, and an emergency EEG was done, which confirmed NCSE (Fig. 1B). He was treated with injection lorazepam that controlled the status (Fig. 1C). He was continued on injection fosphenytoin, injection levetiracetam, and subsequently oral clobazam was also added. Repeat MRI of the brain showed no new findings. CSF analysis was normal. Biochemical and hematological tests were again normal. As no other etiology was evident, the cause of NCSE was attributed to his medications. Since amoxicillin has a very low potential to cause neurotoxicity, clarithromycin was the likely causative and was withdrawn. Continuous EEG monitoring was done, which showed intermittent nonconvulsive seizures during the next 24 hours. He improved over the next 36 hours with no further clinical or electrographic seizures. He remained seizure-free subsequently, and his antiepileptic medications were gradually tapered.\n\nDISCUSSION\n\nDrug-induced SE is rare and accounts for less than 5% of all cases of SE.6 Various classes of antibiotics, immuno, and chemotherapeutic agents have been associated with neurotoxicity and seizures. Geriatric patients are at higher risk for adverse drug reactions due to age-related pharmacokinetic alterations.7\n\nClarithromycin is more likely to cause neurotoxicity due to its higher lipid solubility and manifests as visual hallucinations, acute delirium, psychosis, and very rarely seizures.1,8 Bandettini et al. reported 38 patients with clarithromycin-induced neurotoxicity among whom only one patient had NCSE. Neuropsychiatric symptoms in this series were observed between 1 and 10 days of clarithromycin therapy, which resolved on discontinuation of the drug.1 Our patient developed seizures from the third day of clarithromycin therapy. Our observations suggest that clarithromycin can cause GTCS, focal unaware seizures and NCSE.\n\nClarithromycin neurotoxicity has been attributed to direct neurotoxicity of the active metabolite 14-hydroxyclarithromycin, alterations of cortisol and prostaglandin metabolism, and inhibitory action on glutaminergic transmission. Clarithromycin-induced allosteric modulation of GABAA receptors with increased cellular excitability may be another reason for seizures.8–10\n\nDrug-induced neurotoxicity presents as hallucinations, psychosis, confusional states, and rarely NCSE. In the elderly, systemic infections, metabolic derangement, and intracranial infections too have a similar presentation. Therefore, a high index of suspicion is required in such situations. EEG is essential in establishing the diagnosis of NCSE and monitoring therapy. Prompt withdrawal of the offending agent along with routine measures for managing SE has yielded good outcomes. Limited data suggest using benzodiazepines as initial therapy followed by phenobarbitone as second-line therapy for drug-induced SE.11 Awareness about the neurotoxic adverse effects of antibiotics like Clarithromycin will help physicians manage such situations effectively.\n\nStatement of Ethics\n\nThe study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.\n\nConsent\n\nWritten informed consent was obtained from the patient to publish this case report along with the accompanying EEG images. The patient’s identity has been concealed.\n\nAuthor Contributions\n\nRaghavendra Seetharam—Diagnosed and treated the case, conceived the case report, and prepared the initial manuscript.\n\nRajesh B Iyer—Analyzed the case, reviewed the literature, and prepared the discussion and final manuscript.\n\nJaveria Nooraine—Monitored and reported the EEG and provided the figures and legends.\n\nJaychandran Ramachandran—Treated the patient and monitored clinical progression. Contributed to preparing the case report.\n\nORCID\n\nRaghavendra Seetharam https://orcid.org/0000-0002-4357-0332\n\nRajesh B Iyer https://orcid.org/0000-0002-2181-069x\n\nJaveria Nooraine https://orcid.org/0000-0001-8903-2188\n\nJaychandran Ramachandran https://orcid.org/0000-0002-8843-7551\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nREFERENCES\n\n1. Bandettini di Poggio M Anfosso S Audenino D Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011; 18( 3): 313– 318. DOI: 10.1016/j.jocn.2010.08.014. 21269833\n2. Geiderman JM. Central nervous system disturbances following clarithromycin ingestion. Clin Infect Dis 1999; 29( 2): 464– 465. DOI: 10.1086/520248. 10476775\n3. Ozsoylar G Sayin A Bolay H. Clarithromycin monotherapy-induced delirium. J Antimicrob Chemother 2007; 59( 2): 331. DOI: 10.1093/jac/dkl480. 17208955\n4. Vicente de Vera C García M Pifarre Teixido R Barbe F. Delirium induced by clarithromycin in a patient with community-acquired pneumonia. Eur Respir J 2006; 28( 3): 671– 672. DOI: 10.1183/09031936.06.00039006. 16946100\n5. Shah M Subhani M Rizvon K Mustacchia P. Transient psychotic episode induced by helicobacter pylori triple therapy treatment. Case Rep Gastroenterol 2012; 6( 2): 381– 386. DOI: 10.1159/000339713. 22855656\n6. Cock HR. Drug-induced status epilepticus. Epilepsy Behav 2015; 49: 76– 82. DOI: 10.1016/j.yebeh.2015.04.034. 26210064\n7. Mattappalil A Mergenhagen KA. Neurotoxicity with antimicrobials in the elderly: a review. Clin Ther 2014; 36( 11): 1489– 1511.e4. DOI: 10.1016/j.clinthera.2014.09.020. 25450476\n8. Ma TK Chow KM Choy AS Kwan BC Szeto CC Li PK. Clinical manifestation of macrolide antibiotic toxicity in CKD and dialysis patients. Clin Kidney J 2014; 7( 6): 507– 512. DOI: 10.1093/ckj/sfu098. 25859365\n9. Scott PJ Shao X Desmond TJ Hockley BG Sherman P Quesada CA et al. Investigation of proposed activity of clarithromycin at GABAA receptors using [(11)C]Flumazenil PET. ACS Med Chem Lett 2016; 7( 8): 746– 750. DOI: 10.1021/acsmedchemlett.5b00435. 27563397\n10. Bichler EK Elder CC García PS. Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABAergic signaling. J Neurophysiol 2017; 117( 1): 93– 103. DOI: 10.1152/jn.00134.2016. 27733592\n11. Shah AS Eddleston M. Should phenytoin or barbiturates be used as second-line anticonvulsant therapy for toxicological seizures? Clin Toxicol (Phila) 2010; 48( 8): 800– 805. DOI: 10.3109/15563650.2010.521506. 20923393\n\n",
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"title": "Clarithromycin-induced Seizures and Status Epilepticus.",
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"abstract": "Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia in patients with a malignancy. When these laboratory abnormalities develop rapidly, clinical complications such as cardiac arrhythmias, acute renal failure, seizures, or death may occur. TLS is caused by rapid release of intracellular contents by dying tumor cells, a condition that is expected to be common in hematologic malignancies. However, TLS rarely occurs with solid tumors, and here we present the second chemotherapy-induced TLS in a patient with advanced gastric adenocarcinoma to be reported in the literature. We also provide information regarding the total cases of TLS in solid tumors reported from 1977 to present day. Our methodology involved identifying key articles from existing reviews of the literature and then using search terms from these citations in MEDLINE to find additional publications. We relied on a literature review published in 2003 by Baeksgaard et al., where they gathered all total 45 cases reported from 1977 to 2003. Then, we looked for new reported cases from 2004 to present day. All reports (case reports, brief reports, letters to editor, correspondence, reviews, journals, and short communications) identified through these searches were reviewed and included.",
"affiliations": "Department of Nephrology and Hypertension, Jackson Memorial Hospital, 1611 North West 12th Avenue, Miami, FL 33101, USA.",
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"doi": "10.1155/2012/468452",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 2268547010.1155/2012/468452Case ReportAn Unusual Presentation of Tumor Lysis Syndrome in a Patient with Advanced Gastric Adenocarcinoma: Case Report and Literature Review Vodopivec Danica Maria \n*Rubio Jose Enrique \nFornoni Alessia \nLenz Oliver \nDepartment of Nephrology and Hypertension, Jackson Memorial Hospital, 1611 North West 12th Avenue, Miami, FL 33101, USA*Danica Maria Vodopivec: danica.vodopivec19@gmail.comAcademic Editor: Glenn Bubley\n\n2012 27 5 2012 2012 46845228 11 2011 22 2 2012 13 3 2012 Copyright © 2012 Danica Maria Vodopivec et al.2012This 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.Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia in patients with a malignancy. When these laboratory abnormalities develop rapidly, clinical complications such as cardiac arrhythmias, acute renal failure, seizures, or death may occur. TLS is caused by rapid release of intracellular contents by dying tumor cells, a condition that is expected to be common in hematologic malignancies. However, TLS rarely occurs with solid tumors, and here we present the second chemotherapy-induced TLS in a patient with advanced gastric adenocarcinoma to be reported in the literature. We also provide information regarding the total cases of TLS in solid tumors reported from 1977 to present day. Our methodology involved identifying key articles from existing reviews of the literature and then using search terms from these citations in MEDLINE to find additional publications. We relied on a literature review published in 2003 by Baeksgaard et al., where they gathered all total 45 cases reported from 1977 to 2003. Then, we looked for new reported cases from 2004 to present day. All reports (case reports, brief reports, letters to editor, correspondence, reviews, journals, and short communications) identified through these searches were reviewed and included.\n==== Body\n1. Introduction\nTumor lysis syndrome is a life-threatening oncologic emergency that occurs when a large amount of malignant tumor cells breakdown rapidly and release their intracellular contents into the systemic circulation causing electrolyte and metabolic disturbances, such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure may be the final consequences of these biochemical derangements [1–8].\n\nTumor lysis syndrome develops usually after the initiation of chemotherapy but in rare cases may arise spontaneously before any antitumor therapy has been initiated [1, 4–19] (Table 1) (Figure 1). TLS is common in patients with hematologic malignancies with high growth rates or a large disease burden, but it is rarely observed in patients with solid tumors of which to date there are only 100 cases described in the literature [1–93] (Table 1) (Figure 2).\n\nTo the best of our knowledge, the present study case is the second report describing TLS following chemotherapy for advanced gastric adenocarcinoma [37]. Also, a review of the literature regarding TLS in solid tumors is presented and recommendations for management are discussed.\n\n2. Case Report\nThe patient is a 57-year-old Hispanic man with a history of stage III moderately differentiated gastric adenocarcinoma intestinal type, diagnosed in late 2006. He was enrolled in a clinical trial for a new regimen of neoadjuvant chemotherapy consisting of oxaliplatin (85 mg/m² i.v. over 2 hours on days 1 and 15), docetaxel (25 mg/m² i.v. over 30 minutes on days 1, 8, 15), floxuridine (110 mg/kg i.v. over 24 hours on days 1, 8, 15), and leucovorin calcium (500 mg/m² i.v. over 24 hours on days 1, 8, 15) with treatment repeated every 4 weeks. After the second course (January 2007), he underwent resective therapy (partial gastrectomy) followed by 2 more cycles of the above-mentioned chemotherapy regimen as an adjuvant therapy.\n\nFive months later, recurrence of the primary tumor was found in the liver; therefore, the patient was started on a different regimen (paclitaxel 120 mg/m², floxuridine 150 mg/kg, leucovorin 500 mg/m², and cisplatin 100 mg/m²), and liver segmentectomy was performed. \n\nUnfortunately, patient failed regular controls, and by 2011 a CT of the chest and abdomen revealed extensive metastatic liver nodules which ranged from 3.5 cm to sub-centimeter in size, and metastasis to the sternum were also found. Consequently, he was again included in the initial experimental chemotherapy regimen as a first line therapy for his metastatic disease (oxaliplatin, docetaxel, floxuridine, and leucovorin). \n\nSeven days after receiving the first chemotherapy cycle, he developed nausea, vomiting, oliguria, generalized weakness, and was referred to the emergency department by his oncologist due to abnormal laboratory data (Table 2). \n\nOn arrival the patient was alert and appeared in poor general condition, pale, volume depleted with low blood pressure (102/63 mmHg), tachycardia (102/min), respiratory rate of 20/min, and body temperature of 36.6°C. A firm, nontender, 2 cm below the costal margin of the right midclavicular line hepatomegaly was appreciated. There was no peripheral lymphadenopathy, and laboratory findings are shown on Table 2. \n\nUrinalysis determined urine pH of 5.0 (4.5–7.5). The chest radiograph appeared to be normal. An EKG demonstrated atrial fibrillation with rapid ventricular response, left anterior fascicular block, and peaked T waves (Figure 3). A renal ultrasound examination revealed an increased bilateral cortical echogenicity but no evidence of hydronephrosis. \n\nA diagnosis of chemotherapy-induced TLS with acute renal failure was made. The patient was given vigorous volume expansion, intravenous sodium bicarbonate, calcium gluconate, insulin given together with 50% dextrose, and allopurinol. His laboratory data did not improve and hemodialysis was started. The patient underwent a total of 6 hemodialysis over a course of two weeks and was discharged 18 days after with normal serum electrolyte and metabolic parameters. However, his renal function continued to be impaired with a serum creatinine of 3.86 mg/dL, blood urea nitrogen of 23 mg/dL, and eGFR of 16. \n\n3. Review of the Literature\nTLS is an oncologic emergency characterized by severe electrolyte and metabolic abnormalities due to a rapid and massive lysis of malignant cells with the release of intracellular contents into the bloodstream, overwhelming the excretory and reutilization capacities of the body, leading to hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia [1–8]. As a consequence, these biochemical disorders can become clinically relevant and present as renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure [1–8]. Cairo and Bishop published the most complete and often referenced definition of TLS in 2004. They classified TLS into two groups, separating patients exhibiting only laboratory findings of TLS from those with potentially life-threatening clinical presentations. Cairo and Bishop definitions of laboratory and clinical TLS are summarized in Table 3 [1–4, 6, 7]. \n\nIn the setting of a malignancy with a high proliferation rate, large tumor burden, and/or high sensitivity to treatment, initiation of anticancer treatment, such as chemotherapy, radiotherapy, resective surgical procedures, immunotherapy, hormonotherapy, radiofrequency ablation, or sometimes glucocorticoid therapy alone may result in the rapid lysis of tumor cells [1, 5–8] (Table 1) (Figure 1). In addition, TLS can occur spontaneously from the tumor necrosis prior the onset of anticancer therapy [1, 4–19] (Table 1) (Figure 1). \n\nTumor and host-related factors associated with an increased risk of TLS in solid tumors are mentioned in Table 4 [1–8]. The tumor-related risk factors are common characteristics of hematological malignancies, where TLS is a well-known clinical problem, especially in acute lymphoblastic leukemias and high-grade non-Hodgkin's lymphomas, and particularly in Burkitt's lymphoma [1–7]. However, TLS can rarely occur in solid tumors that have a high proliferative rate, large tumor burden, and high sensitivity to cytotoxic therapy [1, 4, 6]. \n\nAccording to the literature review, there have been 100 reported cases of TLS in patients with solid tumors from the first report in 1977 to 2011 (Table 1) (Figure 2), including small cell carcinomas [9, 20–30], squamous cell carcinomas [10, 11], adenocarcinomas of the lung [12, 31–33], mixed small cell and nonsmall cell lung carcinoma [34], gastrointestinal carcinomas [13–15, 35–42], hepatoblastomas [43, 44], hepatocellular carcinomas [15, 45–53], renal carcinomas [54–56], transitional cell carcinoma [57], prostate carcinomas [58–61], breast carcinomas [16, 30, 62–68], ovarian carcinomas [69, 70], endometrial carcinoma [71], vulva carcinomas [72, 73], thymomas [74, 75], melanomas [76–82], gestational trophoblastic neoplasia [83], germ cell tumors [17, 18, 64, 84, 85], neuroblastomas [86, 87], medulloblastomas [88, 89], and sarcomas [19, 90–93]. Most cases regarded as TLS in solid tumors were chemotherapy-induced, even though various other causes were pointed out for TLS in solid tumors as well [3] (Table 1) (Figure 1). The dominant factor for developing TLS in solid tumors, which occurred in all 100 cases, was having a large tumor burden. Another relevant fact was the presence of metastatic disease observed in 83% of all cases, of which the liver was the most affected organ; thus, the remaining 17% presented with bulky primary tumor. \n\nOther risk factors for developing TLS in solid tumors included pretreatment increased LDH, renal impairment, hyperuricemia, and hyperphosphatemia found in 86% (43/50), 26% (18/69), 42% (21/50), and 14% (6/44) of the evaluable patients in which specific results were reported, respectively. \n\nIn 7% of the cases, we found hydronephrosis as a high risk for developing TLS due to compression of the genitourinary tract by the tumor, being particular hazard neoplasms such as germ cell tumor, prostate cancer, retroperitoneal sarcoma, and uterus carcinoma. \n\nIrrespective of the cancer type, there is a 20–50% increase in mortality for undiagnosed or late-diagnosed TLS cases in solid tumors [8]. This high mortality rate may be due to the fact that in solid tumors, contrary to what is observed in hematological malignancies, TLS is usually evident after a few days within treatment when the patient may have already left the hospital [3, 8]. Another cause is that in hematological malignancies, prophylactic measures are more often implemented, and awareness of the syndrome is higher. The fatality rate of the 100 cases presenting TLS in solid tumors was found to be 41%. \n\nSymptoms associated with TLS strongly reveal electrolyte and metabolic irregularities, which are hyperkalemia, hyperphosphatemia, secondary hypocalcemia, and hyperuricemia [1–8]. Hyperkalemia, which takes place within 12 to 24 hours from the antineoplastic treatment's initiation, becomes the earliest and most severe laboratory finding [3]. The clinical manifestations for hyperkalemia include lethargy, weakness, paresthesias, muscle cramps, nausea, vomiting, and abnormalities in the electrocardiogram, such as peaked T waves, prolonged PR interval, widened QRS complexes, ventricular tachycardia, ventricular fibrillation, or asystole [2–5]. Since the phosphorus concentration is higher in malignant cells than in normal cells (4 : 1), accelerated tumor breakdown usually leads to hyperphosphatemia with the subsequent secondary hypocalcemia [1, 3–7]. Both electrolyte disturbances, hyperphosphatemia and hypocalcemia, may cause a variety of symptoms, such as nausea, vomiting, lethargy, muscle cramps, tetany, seizures, cardiac arrhythmias, and/or acute renal failure [2–6]. Accumulation of uric acid may increase the urinary uric acid concentration to a point where precipitation occurs, and acute renal failure may be the consequence. The widespread use of agents lowering uric acid production or excretion is responsible for nephrocalcinosis, becoming a major mechanism of acute renal failure in TLS [1–3, 6]. However, calcium phosphate precipitation does not only occur in the kidneys, but also in other soft tissues such as the heart, where it may induce cardiac arrhythmias [1–3, 6]. \n\nThe fact that urine is acidic facilitates uric acid to precipitate, thus excessive overproduction and over excretion could accumulate uric acid in the form of crystal precipitation in the renal tubules, leading to obstructive uropathy with acute kidney injury [1, 2, 4, 5, 8, 65]. Uric acid or calcium phosphate accumulation does not always imply urinary tract symptoms; however, flank pain due to renal pelvic or ureteral stone formation may occur [1, 4]. The urinalysis quite often discloses a number of uric acid crystals, amorphous urates, calcium phosphate crystals, and/or hematuria [1, 4]. \n\nThe treatment principles for TLS are prevention, early diagnosis, and proper management of disorders [3]. In 2008, an international expert panel published evidence-based guidelines, for the prevention and treatment of TLS depending on the malignancy risk category. According to this evidence-based guidelines unless tumor and/or host-related risk factors are associated, solid tumors are considered low risk (<1%) for developing TLS. Thus, adequate recommendations for the prevention and management of TLS in solid tumors are accurate hydration prior to therapy and a “watch and wait” approach with close monitoring on looking for the first biologic derangements characterizing TLS (hyperuricemia, hyperphosphatemia, hypocalcemia, increased creatinine level) without any form of prophylactic hypouricemic therapy or phosphate binders [1–3, 6, 37]. \n\nOnce TLS is established, the standard therapy strategy for treating TLS is based on volume expansion, decreasing the metabolic abnormalities, and in most cases providing supportive treatment of renal failure [1, 5, 8]. \n\nAdministration of fluids is important because it increases renal blood flow, glomerular filtration, and reduces the urinary supersaturation of uric acid, calcium, and phosphate [2, 4, 5, 7]. Patients should receive 3 l/m²/day (200 mL/Kg/day if ≤10 kg) and have a urine output ≥100 mL/m²/h (3 mL/kg/h if ≤10 kg) [2–4, 6]. In the absence of obstructive uropathy and/or hypovolemia, diuretics may be used to maintain the adequate urine output [2–4, 6, 7]. The utility of low-dose dopamine to enhance renal blood flow is not as clear [3]. \n\nMaintaining urine pH above 7 with the aid of acetazolamide and/or sodium bicarbonate for the prevention and/or treatment of TLS may reduce the precipitation of uric acid crystals but at the same time may decrease the solubility of calcium phosphate or xanthine, and in the setting of acute renal failure, metabolic alkalosis may be an unintended consequence [1, 3, 4, 6, 7]. Consequently, the use of sodium bicarbonate should be restricted to those patients with severe metabolic acidosis [1]. \n\nHyperkalemia may be an acute life-threatening emergency in patients with TLS. In case of hyperkalemia, cardiac membrane stabilization with 10% calcium gluconate may not be effective in the setting of severe hyperphosphatemia, and given an increased risk of calcium phosphate tissue precipitation, calcium administration is only appropriate for symptomatic hypocalcemia (arrhythmia, hypotension, tetany, or muscle cramps) [1, 7]. Consequently, measures to reduce serum potassium or enhance potassium excretion should have priority. These include primarily insulin and beta-2 agonists to shift potassium into cells and volume expansion and loop diuretics to enhance potassium elimination. Sodium bicarbonate may be used as a slow continuous infusion in the face of severe acidosis. Exchange resins may be administered but should not be relied upon in the setting of acute hyperkalemia due to their unpredictable efficacy. For patients with renal failure, dialysis should be initiated as soon as possible [1–7]. For hyperphosphatemia, phosphate binders and/or hypertonic dextrose with insulin may be used [1–7]. \n\nAllopurinol is a competitive inhibitor of xanthine oxidase (Figure 4), and it has been successfully prescribed for the treatment of hyperuricemia. Allopurinol is metabolized to oxypurinol, which in turn inhibits xanthine oxidase; therefore, it blocks the metabolic process of xanthine and hypoxanthine to uric acid, leading to an increase in the levels of these two metabolites [1, 3–6]. As a result, patients with massive TLS who have been prescribed allopurinol may develop xanthine precipitation leading to acute renal failure [1, 2, 4, 5, 7, 65]. This can be avoided by replacing allopurinol with urate oxidase, which catabolizes uric acid to the more soluble compound allantoin [1–6] (Figure 4). Urate oxidase is an enzyme that can be found in many mammals except humans [1, 3, 4, 6]. The two available commercial forms of urate oxidase are a nonrecombinant form (uricozyme) and a recombinant form (rasburicase), which is the preferred one. Rasburicase has been shown to be more effective than allopurinol, since it has higher uricolytic effect [1, 3–7], it does not increase xanthine levels [1, 2, 4, 5, 7], and it reduces high uric acid levels prior treatment initiation [1–7]. \n\nIn some patients, despite prophylactic and therapeutic measures, acute renal failure ensues, and its management includes careful monitoring of fluid intake and output, electrolyte balance, hypertension control [4], and renal dialysis [94]. Indications for renal replacement therapy include volume overload with pulmonary edema or hypertension that is refractory to therapy, low urine output (oliguria), persistent or symptomatic hyperkalemia, hyperphosphatemia, hypocalcemia, and/or hyperuricemia despite conservative measures, metabolic acidosis with pH less than 7.2 or bicarbonate less than 10 mEq/l, rapidly rising blood urea nitrogen greater than 150 mg/dL, and neurologic symptoms secondary to uremia or electrolyte imbalance [4, 95]. From the above-mentioned criteria, oliguria and other biochemical disturbances related to TLS have become more frequent indications for dialysis than hyperuricemia since the introduction of rasburicase [2, 94]. Both hemodialysis and hemofiltration are affective, while peritoneal dialysis is not [94, 96]. Dialysis should be continued until proper renal function is reestablished.\n\n4. Discussion\nOur patient with metastatic gastric adenocarcinoma developed metabolic (hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia) and clinical (cardiac arrhythmia and acute renal failure) derangements 7 days after instituting chemotherapy, meeting CTLS diagnostic criteria. According to previous reports, there are 2 patients with advanced gastric adenocarcinomas who developed TLS documented in the literature (34, 35), although only one occurred after chemotherapy [37] (Table 5). Therefore, our case would be the second gastric adenocarcinoma chemotherapy-induced TLS but the first to be reported after the use of the experimental chemotherapeutic regimen consisting on oxaliplatin, leucovorin, floxuridine, and docetaxel. \n\nChemotherapy-related nephrotoxicity was less likely due to the fact that the anticancer agents the patient was receiving are not considered to be nephrotoxic, except for oxaliplatin and docetaxel which have less than a 1% probability of causing renal failure, and it usually occurs with high doses and after repeated exposures. \n\nLarge tumor burden, multiple metastases to liver and bone, the use of combination chemotherapy drugs, pretreatment elevated LDH, and dehydration were the risk factors that placed the patient in a high-risk group for developing TLS [1–8], although his renal function and uric acid levels were normal before getting anticancer treatment. \n\nThe purpose for giving sodium bicarbonate to the patient was to correct the metabolic acidosis, rather than alkalinizing urine. Despite intensive medical treatment, the patient developed refractory electrolyte imbalances, metabolic acidosis, uremia, and oliguria. Thus, hemodialysis was performed with an improvement of the mentioned abnormalities, and the TLS was resolved. However, his renal function never returned to baseline, which has been linked to increased morbidity and mortality. \n\nEven though solid tumors with high sensitivty to therapy are considered to be at high risk for developing TLS, we noticed that the syndrome was also present in tumor types considered as relatively insensitive to therapy such as melanoma, sarcoma, hepatocellular carcinoma, vulvar carcinoma, non-small cell lung cancer, and gastric cancer. According to our observations, the predominant risk factors to induce TLS in solid tumors are large tumor burden and liver metastases, rather than tumor sensitivity to therapy agents. \n\nLiver metastases in solid tumors were found in most TLS cases, regardless whether patients had liver function abnormalities or not [3]. Apparently, liver involvement creates a risk for the development of TLS in solid malignancies, possible causes being high purine pools, increased tumor burden, and/or impaired uric acid metabolism [3].\n\n5. Conclusion\nEven though TLS in solid tumors is a rare condition, physicians should be aware of it, especially in therapy-sensitive large burden tumors with metastatic disease, increased pretreatment LDH, renal impairment, hyperuricemia, and hyperphosphatemia, all of which are here documented to be mayor risk factors for the development of TLS. \n\nIf there is a possibility to develop TLS, the metabolic abnormalities should always be corrected before starting an anticancer regimen, since prevention is the best way to reduce its high morbidity and mortality. \n\nIn conclusion, TLS in solid tumors requires special attention for its prevention, early diagnosis, and management due to its poor clinical course. Physicians should be alert since improvement in the anticancer treatment may increase the incidence of TLS in solid tumors.\n\nFigure 1 Etiology of tumor lysis syndrome. TACE: transarterial chemoembolization. Others include surgery, bisphosphonates, radiofrequency, combination of different cancer therapies.\n\nFigure 2 Reported cases of tumor lysis syndrome in solid tumors.\n\nFigure 3 EKG from the patient's admission showing atrial fibrillation with rapid ventricular response and peaked T waves.\n\nFigure 4 Mechanism of action of hypouricemic agents. Hyperuricemia is a consequence of the catabolism of purine nucleic acids to hypoxanthine and xanthine and then to uric acid via the enzyme xanthine oxidase. Allopurinol is a competitive inhibitor of the enzyme xanthine oxydase. Rasburicase (exogenous urate oxidase) leads uric acid to a more soluble compound, allantoin. \n\nTable 1 Reported cases of tumor lysis syndrome in solid tumors (1977–2011).\n\nTumor type\tTreatment\tOutcome of TLS\tYear published\tReference\t\nSmall cell carcinoma\tDOXO, CDDP, VP-16, VCR\tDied\t1983\t[20]*\t\nDOXO, CTX, VCR\tResolved\t1983\t[21]*\t\nCCNU, CTX, MTX\tDied\t1988\t[22]*\t\nCDDP, VP-16\tResolved\t1988\t[22]†\n\t\nDOXO, CTX, VCR\tResolved\t1990\t[23]*\t\nDOXO, IF\tResolved\t1991\t[24]‡\n\t\nCDDP, VP-16\tResolved\t1997\t[25]*\t\nCDDP, VP-16\tResolved\t1997\t[26]*\t\nCDDP, VP-16\tDied\t1999\t[27]*\t\nCDDP, VP-16\tDied\t2001\t[28]*\t\nTOPO\tDied\t2002\t[29]*\t\nCBCDA, VP-16\tResolved\t2005\t[30]*\t\nNone\tDied\t2011\t[9]*\t\n\n\n\t\nSquamous cell carcinoma\tNone\tResolved\t2009\t[10]#\n\t\nNone\tDied\t2009\t[11]##\n\t\n\n\n\t\nAdenocarcinoma of the lung\tCPT-11, CDDP\tResolved\t1998\t[31]\t\n\n\tNone\tDied\t2000\t[12]\t\n\n\tZOL\tDied\t2005\t[32]\t\n\n\tDTX\tDied\t2006\t[33]\t\n\n\n\t\nMixed small cell and nonsmall cell tumor of the lung\tCBCDA, PTX\tDied\t2002\t[34]\t\n\n\n\t\nGI tract\tNone\tDied\t1997\t[13]\t\nSUN\tResolved\t2007\t[35]\t\nIMA\tDied\t2007\t[36]\t\n\n\n\t\nGastric cancer\tNone\tResolved\t2001\t[14]\t\nCAP, CDDP\tResolved\t2008\t[37]\t\nOX, LV, FUDR, DTX\tResolved\t2011\tCurrent case\t\n\n\n\t\nColorectal cancer\tCPT-11\tDied\t1996\t[38]\t\nCPT-11\tDied\t2000\t[39]\t\nNone\tResolved\t2003\t[15]\t\n5-FU, LV, CPT-11\tDied\t2004\t[40]\t\nCE\tDied\t2008\t[41]\t\nCPT-11, 5-FU, F, BEV\tDied\t2008\t[42]\t\n\n\n\t\nHepatoblastoma\tS\tDied\t1990\t[43]\t\nCDDP, VCR, 5-FU\tResolved\t2010\t[44]\t\n\n\n\t\nHepatocellular carcinoma\tTACE\tDied\t1998\t[45]\t\nTACE\tResolved\t1998\t[45]\t\nNone\tDied\t2003\t[15]\t\nRF\tResolved\t2005\t[46]\t\nTH\tDied\t2006\t[47]\t\nTOCE\tDied\t2007\t[48]\t\nTACE\tResolved\t2008\t[49]\t\nTACE\tResolved\t2009\t[50]\t\nTACE\tResolved\t2009\t [50]\t\nSOR\tDied\t2009\t[51]\t\nSOR\tResolved\t2010\t[52]\t\nSOR\tResolved\t2010\t[53]\t\n\n\n\t\nRenal carcinoma\tSUN\tResolved\t2007\t[54]\t\nSUN\tResolved\t2010\t[55]\t\nSUN\t??\t2011\t[56] \t\n\n\n\t\nTransitional cell carcinoma\tGC\tDied\t2007\t[57] \t\n\n\n\t\nProstate cancer\tDTX\tDied\t2004\t[58]\t\nCAB\tDied\t2004\t[59]\t\nPTX\tResolved\t2005\t[60]\t\nCAB\tDied\t2007\t[61]\t\n\n\n\t\nBreast carcinoma\tTX\tResolved\t1986\t[62]\t\n5-FU, DOXO, CTX\tDied\t1987\t[63]\t\nCTX, MTX, 5-FU\tResolved\t1989\t[64]\t\nMIT\tResolved\t1994\t[65]\t\nNone\tDied\t1995\t[16]\t\nPTX\tDied\t1997\t[66]\t\nRT\tDied\t2000\t[67]\t\nCAP\tDied\t2004\t[68]\t\n5-FU, EPR, CTX\tResolved\t2005\t[30]\t\n\n\tGC, CDDP\tResolved\t2005\t[30]\t\n\n\n\t\nOvarian cancer\tCBCDA, CTX\tResolved\t1993\t[69]\t\nTOPO\tResolved\t2005\t[70]\t\n\n\n\t\nEndometrial cancer\tCBCDA, PTX\tDied\t2010\t[71]\t\n\n\n\t\nVulvar carcinoma\tCDDP, 5-FU\tResolved\t1993\t[72]\t\nCDDP, 5-FU\tDied\t1998\t[73]\t\n\n\n\t\nThymoma\tCDDP, DOXO, CS\tResolved\t1997\t[74]\t\nS\tResolved\t2004\t[75]\t\n\n\n\t\nMelanoma\tTNF-alpha, mAb\tDied\t1994\t[76]\t\nIL-1, IF-alpha, CDDP. VIN, DTIC\tResolved\t1999\t[77]\t\nCDDP, DTIC, IF-alpha\tDied\t2001\t[78]\t\nCS\tResolved\t2002\t[79]\t\nCDDP, VIN, DTIC, IF-alpha, IL-2\tResolved\t2004\t[80]\t\nTAI-CDDP\tResolved\t2009\t[81]\t\nCS\tDied\t2009\t[82]\t\n\n\n\t\nGestational trophoblastic neoplasia\tVP-16, MTX, DACT, CTX, VCR\tResolved\t2010\t[83]\t\n\n\n\t\nGerm cell tumor\tVIN, BL\tResolved\t1989\t[64]\t\nCDDP, VP-16, BL\tResolved\t2000\t[84]\t\nNone\tResolved\t2001\t[17]\t\nNone\tResolved\t2001\t [17]\t\nBL, VP-16, CDDP\tDied\t2008\t[85]\t\nVP-16, CBCDA\tResolved\t2008\t[85]\t\nVP-16, CBCDA\tDied\t2008\t[85]\t\nNone\tDied\t2010\t[18]\t\n\n\n\t\nNeuroblastoma\tVCR, TN, RT\tResolved\t1994\t[86]\t\nRT\tResolved\t1994\t[86]\t\nVCR, TN, RT\tResolved\t1994\t[86]\t\nCTX, TN\tResolved\t1994\t[86]\t\nCTX, DOXO, VCR\tResolved\t2003\t[87]\t\n\n\n\t\nMedulloblastoma\tRT\tResolved\t1984\t[88]\t\nCDDP, VP-16\tResolved\t2003\t[89]\t\n\n\n\t\nSarcoma\tCTX, ALT\tResolved\t1993\t[90]\t\nCBCDA, EPR, VCR\tResolved\t1993\t[91]\t\nCDDP, A, DTIC\tResolved\t2009\t[92]\t\nNone\tResolved\t2010\t[19]\t\nNone\tResolved\t2010\t [19]\t\nVCR, ACT-D, CTX\tResolved\t2011\t[93]\t\n\n\n\t\nTotal\t\n\tD: 41; R: 58;\n ??: 1\t100\t\n\t\n 5-fluoracilo (5-FU), tumor necrosis factor alpha (TNF-alpha), interferon-alpha (IF-alpha), anti-GD3 ganglioside monoclonal antibody (mAb), transarterial chemoembolization (TACE), transarterial oil chemoembolization (TOCE), autolymphocyte therapy (ALT), combined androgen blockade (CAB), Doxorubicin (DOXO), cisplatin (CDDP), etoposide (VP-16), vincristine (VCR), cyclophosphamide (CTX), lomustine (CCNU), methotrexate (MTX), ifosfamide (IF), topotecan (TOPO), carboplatin (CBCDA), paclitaxel (PTX), zoledronic acid (ZOL), vinblastine (VIN), bleomycin (BL), teniposide (TN), radiotherapy (RT), surgery (S), 5-fluoracilo (5-FU), tamoxifen (TX), mitoxantrone (MIT), capecitabine (CAP), gemcitabine (GC), irinotecan (CPT-11), docetaxel (DTX), corticosteroids (CS), sunitinib (SUN), imatinib (IMA), cetuximab (CE), folinic acid (F), bevacizumab (BEV), dacarbazine (DTIC), oxaliplatin (OX), floxuridine (FUDR), leucovorin (LV), interleukin-1 (IL-1), interleukin-2 (IL-2), transcatheter arterial infusion of cisplatin (TAI-CDDP), radiofrequency (RF), thalidomide (TH), sorafenib (SOR), adriamycin (A), actinomycin-D (ACT-D), dactinomycin (DACT), epirubicin (EPR), died (D), resolved (R), inaccessible data (??), small cell carcinoma: lung (*), colon (†), skin (‡); squamous cell carcinoma: lung (#), maxillary sinus (##); none= TLS developed spontaneously. References: [9–93].\n\nTable 2 Laboratory values before and after chemotherapy.\n\nParameters\tNormal ranges\tPatient's baseline\tAbnormal data for which patient was referred to ER*\tAt ER*\t\nLeukocytes (/mm³)\t4,500–11,000\t12,000\t6,500\t7,400\t\nHemoglobin (g/dL)\t14–18\t11\t8.6\t9.6\t\nHematocrit (%)\t42–52\t34\t26.9\t30\t\nPlatelets (/mm³)\t150,000–400,000\t327,000\t39,000\t37,000\t\nGlucose (mg/dL)\t74–106\t86\t95\t104\t\nSodium (mEq/L)\t135–147\t138\t130\t127\t\nPotassium (mEq/L)\t3.5–5\t4\t8.4\t8.7\t\nPhosphorus (mg/dL)\t3.0–4.5\t—\t—\t13.9\t\nCalcium (mg/dL)\t8.4–10.2\t8.4\t5.4\t5.4\t\nUric acid (mg/dL)\t3.0–8.2\t4.3\t17.8\t17.6\t\nBUN (mg/dL)\t9–20\t18\t175\t183\t\nCreatinine (mg/dL)\t0.8–1.5\t1.00\t15.4\t14.98\t\nTotal bilirubin (mg/dL)\t0.2–1.3\t0.5\t0.8\t0.7\t\nAlkaline phosphatase (U/L)\t38–126\t381\t235\t254\t\nAST/ALT (U/L)\t15–46/21–72\t48/30\t44/53\t46/58\t\neGFR (mL/min)\t>60\t>60\t3\t3\t\nLDH (U/L)\t0–250\t9,027\t—\t—\t\npH\t7.35–7.45\t—\t—\t7.17\t\nPaCO2 (mmHg)\t33–44\t—\t—\t28\t\nBicarbonate (mEq/L)\t22–28\t—\t—\t10\t\n BUN: blood urea nitrogen; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase. *7 days after chemotherapy.\n\nTable 3 Classification of tumor lysis syndrome by Cairo and Bishop.\n\n Laboratory TLS (LTLS)\tUric acid ≥8.0 mg/dL\tPhosphorus ≥4.5 mg/dL\tPotassium ≥6.0 mmol/L\tCalcium ≤7.0 mg/dL or ionized calcium <1.12\t\nClinical TLS (CTLS)\tAcute renal failure\tCardiac arrhythmia\tSeizure\tSudden death\t\nReferences: [1–4, 6, 7].\n\nTable 4 Risk factors for tumor lysis syndrome is solid tumors.\n\n Tumor-related factors\tHost-related factors\t\n Tumor extension\t Cell lysis potential\t Pretreatment laboratory findings\t(i) Low urinary flow \n (ii) Dehydration and/or inadequate hydration \n (iii) Preexisting nephropathy*\n (iv) Exposure to nephrotoxins \n (v) Hypotension \n (vi) Obstructive uropathy\t\n(i) Large tumor burden\n(ii) Bulky tumor (≥10 cm)\n (iii) Extensive metastasis ∧\n\n (iv) Extrinsic compression of the genitourinary tract by the tumor\t(i) High proliferative rate \n (ii) High sensitivity to anticancer therapy \n (iii)Type and intensity of initial anticancer therapy (using a combination of multiple chemotherapists)\t(i) Elevated LDH \n (ii) Elevated serum creatinine \n (iii) Elevated serum uric acid \n (iv) Elevated serum phosphate\t\n LDH: lactate dehydrogenase. ∧hepatomegaly, splenomegaly, and nephromegaly due to metastasis. Bone marrow infiltration. *A patient with preexisting nephropathy from hypertension, diabetes, gout, or other causes is at greater risk for developing acute kidney injury and TLS. References: [1–8].\n\nTable 5 Similarities and differences between chemotherapy-induced TLS in advanced gastric adenocarcinoma reported in 2008 and our case.\n\nSimilarities\tDifferences\t\n(i) Massive liver metastasis \n (ii) Elevated pretreatment LDH \n (iii) Large tumor burden \n-Outcome of TLS: resolved\tCharacteristics\t2008 case\tActual case\t\nHistology\tPoorly differentiated\tModerately differentiated\t\nTumor extension\tPrimary bulky tumor is present\tPrimary tumor was not present (previously resected)\t\nPretreatment laboratory data\tSlightly elevated serum uric acid\t—\t\nElevated serum phosphate\t\nHost-related risk factors for developing TLS\t—\tDehydration\t\nChemotherapy regimen\tCapecitabine and cisplatin\tOxaliplatin, leucovorin, floxuridine, and docetaxel\t\nOnset of TLS after receiving chemotherapy\t3 days\t7 days\t\nReference: [37].\n==== Refs\n1 Larson R Pui CH Tumor lysis syndrome 2011, http://www.uptodate.com/contents/tumor-lysis-syndrome?source=search_result&search=tumor+lysis+syndrome&selectedTitle=1~58 \n2 Howard SC Jones DP Pui CH The tumor lysis syndrome New England Journal of Medicine 2011 364 19 1844 1854 21561350 \n3 Gemici C Tumour lysis syndrome in solid tumours Clinical Oncology 2006 18 10 773 780 17168213 \n4 Cairo MS Bishop M Tumour lysis syndrome: new therapeutic strategies and classification British Journal of Haematology 2004 127 1 3 11 15384972 \n5 Davidson MB Thakkar S Hix JK Bhandarkar ND Wong A Schreiber MJ Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome American Journal of Medicine 2004 116 8 546 554 15063817 \n6 Mughal TI Ejaz AA Foringer JR Coiffier B An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome Cancer Treatment Reviews 2010 36 2 164 176 20031331 \n7 Coiffier B Altman A Pui CH Younes A Cairo MS Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review Journal of Clinical Oncology 2008 26 16 2767 2778 18509186 \n8 Coiffier B Acute tumor lysis syndrome—a rare complication in the treatment of solid tumors Onkologie 2010 33 10 498 499 20926895 \n9 Jallad B Hamdi T Latta S Alhosaini MN Kheir F Iroegbu N Tumor lysis syndrome in small cell lung cancer: a case report and review of the literature Onkologie 2011 34 3 129 131 21358219 \n10 Shenoy C Acute spontaneous tumor lysis syndrome in a patient with squamous cell carcinoma of the lung QJM 2009 102 1 71 73 18829711 \n11 Abboud M Shamseddine A Maxillary sinus squamous cell carcinoma presenting with fatal\ntumor lysis syndrome: a case report and review of the literature Case Reports in Oncology 2009 2 229 233 20737042 \n12 Feld J Mehta H Burkes RL Acute spontaneous tumor lysis syndrome in adenocarcinoma of the lung: a case report American Journal of Clinical Oncology 2000 23 5 491 493 11039510 \n13 Crittenden DR Ackerman GL Hyperuricemic acute renal failure in disseminated carcinoma Archives of Internal Medicine 1977 137 1 97 99 831657 \n14 Woo IS Kim JS Park MJ Spontaneous acute tumor lysis syndrome with advanced gastric cancer Journal of Korean Medical Science 2001 16 1 115 118 11289389 \n15 Vaisban E Braester A Mosenzon O Kolin M Horn Y Spontaneous tumor lysis syndrome in solid tumors: really a rare condition? 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Bar-Ziv J Catane R Tumor lysis syndrome in nonhematologic malignancies: report of a case and review of the literature American Journal of Clinical Oncology 1994 17 6 502 505 7977169 \n66 Ustundag Y Boyacioglu S Haznedaroglu IC Baltali E Acute tumor lysis syndrome associated with paclitaxel Annals of Pharmacotherapy 1997 31 12 1548 1549 \n67 Rostom AY El-Hussainy G Kandil A Allam A Tumor lysis syndrome following hemi-body irradiation for metastatic breast cancer Annals of Oncology 2000 11 10 1349 1351 11106126 \n68 Mevlüt K Orhan E Huseyin E Nilufer G Tumor lysis syndrome following a single dose of capecitabine The Annals of Pharmacotherapy 2004 38, article 902 \n69 Bilgrami SFA Fallon BG Tumor lysis syndrome after combination chemotherapy for ovarian cancer Medical and Pediatric Oncology 1993 21 7 521 524 8341221 \n70 Chan JK Lin SS McMeekin DS Berman ML Patients with malignancy requiring urgent therapy: case 3. Tumor lysis syndrome associated with chemotherapy in ovarian cancer Journal of Clinical Oncology 2005 23 27 6794 6795 16170188 \n71 Godoy H Kesterson JP Lele S Tumor lysis syndrome associated with carboplatin and paclitaxel in a woman with recurrent endometrial cancer International Journal of Gynecology and Obstetrics 2010 109 3 p. 254 \n72 Shamseddine AI Khalil AM Wehbeh MH Acute tumor lysis syndrome with squamous cell carcinoma of the vulva Gynecologic Oncology 1993 51 2 258 260 8276304 \n73 Khalil A Chammas M Shamseddine A Seoud M Fatal acute tumor lysis syndrome following treatment of vulvar carcinoma: case report European Journal of Gynaecological Oncology 1998 19 4 415 416 9744741 \n74 Yokoi K Miyazawa N Kano Y Tumor lysis syndrome in invasive thymoma with peripheral blood T-cell lymphocytosis American Journal of Clinical Oncology 1997 20 1 86 89 9020297 \n75 Trobaugh-Lotrario AD Liang X Janik JS Lovell MA Odom LF Difficult diagnostic and therapeutic cases: case 2. thymoma and tumor lysis syndrome in an adolescent Journal of Clinical Oncology 2004 22 5 955 957 14990653 \n76 Minasian LM Szatrowski TP Rosenblum M Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor- α and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma Blood 1994 83 1 56 64 8274754 \n77 Castro MP VanAuken J Spencer-Cisek P Legha S Sponzo RW Acute tumor lysis syndrome associated with concurrent biochemotherapy of metastatic melanoma: a case report and review of the literature Cancer 1999 85 1055 1059 10091788 \n78 Stoves J Richardson D Patel H Tumour lysis syndrome in a patient with metastatic melanoma treated with biochemotherapy Nephrology Dialysis Transplantation 2001 16 1 188 189 \n79 Habib GS Saliba WR Tumor lysis syndrome after hydrocortisone treatment in metastatic\nmelanoma: a case report and review of the literature American Journal of the Medical Sciences 2002 323 3 155 157 11908861 \n80 Busam KJ Wolchok J Jungbluth AA Chapman P Diffuse melanosis after chemotherapy-induced tumor lysis syndrome in a patient with metastatic melanoma Journal of Cutaneous Pathology 2004 31 3 274 280 14984582 \n81 Nakamura Y Nakamura Y Hori E Tumor lysis syndrome after transcatheter arterial infusion of cisplatin and embolization therapy for liver metastases of melanoma International Journal of Dermatology 2009 48 7 763 767 19570088 \n82 Borne E Serafi R Piette F Mortier L Tumour lysis syndrome induced by corticosteroid in metastatic melanoma presenting with initial hyperkalemia Journal of the European Academy of Dermatology and Venereology 2009 23 7 855 856 19646138 \n83 Schuman S Pearson JM Lucci JA Twiggs LB Metastatic gestational trophoblastic neoplasia complicated by tumor lysis syndrome, heart failure, and thyrotoxicosis: a case report Journal of Reproductive Medicine for the Obstetrician and Gynecologist 2010 55 10 441 444 21043373 \n84 Blanke CD Hemmer MPA Witte RS Acute tumor lysis syndrome with choriocarcinoma Southern Medical Journal 2000 93 9 916 919 11005356 \n85 Feres G Salluh JI Ferreira C Soares M Severe acute tumor lysis syndrome in patients with germ-cell tumors Indian Journal of Urology 2008 24 4 555 557 19468517 \n86 Hain RDW Rayner L Weitzman S Lorenzana A Acute tumour lysis syndrome complicating treatment of stage IVS neuroblastoma in infants under six months old Medical and Pediatric Oncology 1994 23 2 136 139 8202037 \n87 Kushner BH LaQuaglia MP Modak S Cheung NKV Tumor lysis syndrome, neuroblastoma, and correlation between serum lactate dehydrogenase levels and MYCN-amplification Medical and Pediatric Oncology 2003 41 1 80 82 12764755 \n88 Tomlinson GC Solberg LA Acute tumor lysis syndrome with metastatic medulloblastoma. A case report Cancer 1984 53 8 1783 1785 6199103 \n89 Baeksgaard L Sorensen JB Acute tumor lusis syndrome in solid tumors—a case report and review of the literature Cancer Chemotherapy and Pharmacology 2003 51 187 192 12655435 \n90 Gold JE Malamud SC LaRosa F Osband ME Adoptive chemoimmunotherapy using ex vivo activated memory T-cells and cyclophosphamide: tumor lysis syndrome of a metastatic soft tissue sarcoma American Journal of Hematology 1993 44 1 42 47 8342564 \n91 Khan J Broadbent VA Tumor lysis syndrome complicating treatment of widespread metastatic abdominal rhabdomyosarcoma Pediatric Hematology and Oncology 1993 10 2 151 155 8318370 \n92 Qian KQ Ye H Xiao YW Bao YY Qi CJ Tumor lysis syndrome associated with chemotherapy in primary retroperitoneal soft tissue sarcoma by ex vivo ATP-based tumor chemo-sensitivity assay (ATP-TCA) International Journal of General Medicine 2009 2 1 4 20360879 \n93 Hiraizumi Y Kamoy S Inde Y Kurose K Ohaki Y Takeshita T A case of tumor lysis syndrome following chemotherapy for a uterine epithelioid leiomyosarcoma with focal rhabdomyosarcomatous differentiation The Journal of Obstetrics and Gynaecology Research 2011 37 1 6 20731766 \n94 Will A Tholouli E The clinical management of tumour lysis syndrome in haematological malignancies British Journal of Haematology 2011 154 1 3 13 21554259 \n95 Zonfrillo MR Management of pediatric tumor lysis syndrome in the emergency department Emergency Medicine Clinics of North America 2009 27 3 497 504 19646650 \n96 Seth R Bhat AS Management of common oncologic emergencies Indian Journal of Pediatrics 2011 78 6 709 717 21399956\n\n",
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"title": "An unusual presentation of tumor lysis syndrome in a patient with advanced gastric adenocarcinoma: case report and literature review.",
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"abstract": "BACKGROUND\nThe mechanisms of action of MTX (methotrexate) in the treatment of RA (rheumatoid arthritis) and PsA (psoriatic arthritis) is related to its antifolic activity, due to the high affinity for enzymes that require folate cofactors as dihydrofolate reductase and to the anti-inflammatory activity derivated from the inhibition of thymidylate synthetase that leads to the over-production of adenosine.\nOur patient was a 41-year-old female, affected by PsA in treatment since 2 years with low-dose methylprednisolone and low-dose subcutaneous MTX. The treatment was effective. The patient subacutely developed a severe paraparesis with impossibility of gait or standing without aid and was admitted to a Neurology Department where the cause of the paraparesis was not clear in spite of accurate radiological neurophysiologic and laboratory tests. Therefore, she was admitted in a rehabilitation unit.\nParaparesis in PsA patient in treatment with methotrexate. MTX toxicity was hypothesized; therefore the drug was discontinued while i.m. folic acid and cyanocobalamin were administered for 20 days. The diagnosis was clinical, based on neurological examination (paraparesis) and on the chronic use of MTX (hypothesis of toxicity).\n\n\nRESULTS\nThe patient obtained a complete resolution of paraparesis. Genetic analyses showed associated a compound heterozygosity for the c.1298A>C and c.677C>T variants of methylenetetrahydrofolate reductase (MTHFR) gene.\n\n\nCONCLUSIONS\nNeurological side effects of MTX are uncommon. In literature no previous case of MTX induced paraparesis in patients treated with low-dose MTX for chronic arthritis has been described. The association between the gene polymorphisms of MTHFR (c.1298A>C and c.677C>T) and MTX toxicity in arthritis patients is confirmed. The case also confirms that folates are a precious antidote of MTX toxicity.",
"affiliations": "Rheumatology and Rehabilitation Unit-Maugeri Clinical Scientific Institutes-IRCCS, Pavia, Italy.;Rheumatology and Rehabilitation Unit-Maugeri Clinical Scientific Institutes-IRCCS, Pavia, Italy.;Clinical Biochemistry Unit, Maugeri Clinical Scientific Institutes, IRCCS, Pavia.;Maugeri Clinical Scientific Institutes.;Neurology Unit, Misericordia Hospital, Grosseto.;Molecular Medicine and Genetics.;Molecular Medicine and Genetics, Azienda Ospedaliera Universitaria Senese, Siena and Clinical Genetics Usl Sudest, Misericordia Hospital, Grosseto, Italy.",
"authors": "Saviola|Gianantonio|G|;Abdi-Ali|Lul|L|;Sacco|Silvano|S|;Comini|Laura|L|;Plewnia|Katrin|K|;Rossi|Maja|M|;Orrico|Alfredo|A|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30544400MD-D-18-0462110.1097/MD.0000000000013350133506900Research ArticleClinical Case ReportComplete clinical and functional recovery following low-dose methotrexate related paraparesis in a patient with compound c.1298A>C AND c.677C>T MTHFR polymorphism A case reportSaviola Gianantonio MDa∗Abdi-Ali Lul MDaSacco Silvano BSc, PhDcComini Laura BSc, PhDbPlewnia Katrin MDdRossi Maja MDeOrrico Alfredo MDfNA. a Rheumatology and Rehabilitation Unit—Maugeri Clinical Scientific Institutes—IRCCS, Pavia, Italyb Maugeri Clinical Scientific Institutesc Clinical Biochemistry Unit, Maugeri Clinical Scientific Institutes, IRCCS, Paviad Neurology Unit, Misericordia Hospital, Grossetoe Molecular Medicine and Geneticsf Molecular Medicine and Genetics, Azienda Ospedaliera Universitaria Senese, Siena and Clinical Genetics Usl Sudest, Misericordia Hospital, Grosseto, Italy.∗ Correspondence: Gianantonio Saviola, Rheumatology and Rehabilitation Unit, Maugeri Clinical Scientific Institutes, IRCCS, Via Ospedale, 36, 46042, Castel Goffredo, Mantua, Italy (e-mail: gianantonio.saviola@icsmaugeri.it).12 2018 10 12 2018 97 49 e1335011 7 2018 26 10 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This 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:\nThe mechanisms of action of MTX (methotrexate) in the treatment of RA (rheumatoid arthritis) and PsA (psoriatic arthritis) is related to its antifolic activity, due to the high affinity for enzymes that require folate cofactors as dihydrofolate reductase and to the anti-inflammatory activity derivated from the inhibition of thymidylate synthetase that leads to the over-production of adenosine.\n\nPatient concerns:\nOur patient was a 41-year-old female, affected by PsA in treatment since 2 years with low-dose methylprednisolone and low-dose subcutaneous MTX. The treatment was effective. The patient subacutely developed a severe paraparesis with impossibility of gait or standing without aid and was admitted to a Neurology Department where the cause of the paraparesis was not clear in spite of accurate radiological neurophysiologic and laboratory tests. Therefore, she was admitted in a rehabilitation unit.\n\nDiagnosis and interventions:\nParaparesis in PsA patient in treatment with methotrexate. MTX toxicity was hypothesized; therefore the drug was discontinued while i.m. folic acid and cyanocobalamin were administered for 20 days. The diagnosis was clinical, based on neurological examination (paraparesis) and on the chronic use of MTX (hypothesis of toxicity).\n\nOutcomes:\nThe patient obtained a complete resolution of paraparesis. Genetic analyses showed associated a compound heterozygosity for the c.1298A>C and c.677C>T variants of methylenetetrahydrofolate reductase (MTHFR) gene.\n\nLessons:\nNeurological side effects of MTX are uncommon. In literature no previous case of MTX induced paraparesis in patients treated with low-dose MTX for chronic arthritis has been described. The association between the gene polymorphisms of MTHFR (c.1298A>C and c.677C>T) and MTX toxicity in arthritis patients is confirmed. The case also confirms that folates are a precious antidote of MTX toxicity.\n\nKeywords\nfolic acidmethotrexateparaparesispsoriatic arthritisrehabilitationOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMethotrexate (MTX) is a folic antagonist developed in1948 as an innovative antineoplastic drug for treating childhood leukemia. Side effects obviously depend on the dose and sometimes on the way of administration of the drug. Given that MTX acts on rapidly dividing cells, the earliest symptoms of toxicity are oral ulcerations and dyspepsia. However, the most common side effect is hepatotoxicity first described in patients taking a weekly dose of 25 to 50 mg. Acute and chronic encephalopathies are the most common types of MTX-induced neurotoxicity.[1,2]\n\nThe mechanisms of action of low-dose MTX in the treatment of arthritis may be more anti-inflammatory than antiproliferative. In particular, the cellular effects are related to its antifolic activity, due to the high affinity for enzymes that require folate cofactors as dihydrofolate reductase; the anti-inflammatory activity derives from the inhibition of thymidylate synthetase that in turn leads to the over-production of adenosine, a potent anti-inflammatory molecule.[3]\n\nNeurological side effects of MTX are uncommon.[4] In our experience and in literature no previous case of MTX-induced paraparesis in patients treated with low-dose MTX for chronic arthritis has been described. However, in a previous case report, a 54-year-old woman with leptomeningeal metastasis from breast cancer treated with intrathecal MTX developed a high-grade spastic paraparesis with muscle power 1–2 on MRC scale. The patient was treated with: i.v. S-adenosylmetionine, folinate, cyanocobalamin, and oral methionine with a marked improvement. After 1 month, residual paraparesis was evaluated as Medical Research Council (MRC) grade 3–4. As highlighted, at genetic analyses the patient showed a homozygosity for the c.1298A>C variant of the methylenetetrahydrofolate reductase (MTHFR) gene.[5] Here we report about the case of a severe paraparesis in course of treatment with low dose MTX for PsA that obtained a complete resolution with discontinuation of the drug added to administration of folic acid and rehabilitation.\n\n2 Case report\nOur patient was a 41-year-old female, wedding photographer, affected by psoriatic arthritis (PsA) in treatment since 2 years with low-dose methylprednisolone (4 mg/day) and low-dose subcutaneous MTX (mean dose of 7.5 mg/week). The treatment was effective, the arthritis had reached a satisfying degree of remission and the patient could continue her job that requires a long-distance driving, to stand for some hours, and to move very quickly. In April 2016 blood count was tested twice, respectively, 1 months and 1 week before the admission to the hospital, because of a vague weakness. Blood count was completely normal, and no fever or any other sign of infection was present. In a few days, after an insidious onset of symptoms, the patient developed a severe paraparesis with impossibility of gait or standing without aid. Therefore, she was admitted to a Neurology Department. Neurological examination showed a severe hypotonic paraparesis with weakness (MRC grade 1) of all muscles and of the lower limbs. Upper limbs were not affected. No sensory abnormalities were found. Deambulation was severely paraparethic and impossible without bilateral aid. Plain-RX of thoracic and lumbar, brain and spine magnetic resonance with gadolinium were normal. A Guillen-Barre syndrome was excluded because: electromyography of the upper and lower limbs was negative, tendon reflexes were normal, lumbar puncture showed absence of cells and normal range of proteins (absence of typical albumin-cytological dissociation). Somatosensorial evocated potentials of lower limbs were normal; isoelectrofocusing for oligoclonal bands was negative. Blood examinations showed only a moderate and transient neutrophilic leukocytosis. After 2 months of rehabilitation, the paraparesis was still present but the patient could stand up with a little help and could walk for a short stretch with a medical walker or 2 walking sticks. At that time MTX toxicity was hypothesized, therefore the drug was discontinued. Daily i.m. folic acid (0.9 mg) and cyanocobalamin (2 mg) were administered for 20 days. This schedule, based on the administration of high doses of folate and vitamin B 12, was similar to the one used in the case reported in the introduction chapter.[5] After this brief treatment, the patient completely recovered being able to stand up and to walk without any help. At the same time, PsA worsened and needed to be treated with a new disease modifying antirheumatic drug (DMARD). Genetic analyses showed associated a compound heterozygosity for the c.1298A>C and c.677C>T variants of methylenetetrahydrofolate reductase (MTHFR) gene. After 2-year follow-up the patient does not show any neurological sign or symptom. Informed written consent was obtained from the patient for publication of this case report.\n\n3 Discussion\nThis is the first reported case of paraparesis in a rheumatological patient in treatment with low-dose MTX for chronic arthritis. The complete resolution of paraparesis was obtained by MTX discontinuation followed by treatment with im folic acid and cyanocabalamin and rehabilitation. MTX acts as an inhibitor of folate pathway enzymes. MTHFR is an enzyme that catalyzes the conversion of omocysteine to methionine, a crucial step in the folate pathway. The association between the gene polymorphisms of MTHFR (c.1298A>C and c.677C>T) and MTX toxicity in RA patients has been demonstrated in a meta-analysis (respectively P = .012 and P = .017) and in previous other papers.[6,7,8] The associated compound heterozygosity for the c.1298A>C and c.677C>T variants of MTHFR gene can explain the risk of toxicity as well as the immediate and complete resolution of the paraparesis and the consequent flare of PsA, after using folic acid, thus confirming that folates are a precious antidote of MTX toxicity.[3,9] Folic acid supplementation is often used during treatment of chronic arthritis with MTX. van Ede and colleagues[10] in 2001 proposed to add folate to MTX to avoid the increase of liver enzymes, a common side effect of MTX. However, the addition of folic acid was shown to reduce the efficacy of the drug. Indeed, to obtain an effective amelioration of disease activity (following ACR criteria) the dosage of MTX must be increased by 20% to 25%.[10] In our case the patient was treated without folic supplementation because of the efficacy of low dosage of MTX (7.5 mg/week) and no sign of liver toxicity.\n\nIn the future, to personalize the treatment of chronic arthritis with MTX, also the detection of MTHFR polymorphism should be considered. Consequently, the use of folic acid supplementation in course of therapy with MTX should be decided case by case, to avoid the lack of efficacy and the risk of toxicity.[9,10] In paraparesis patients also the role of rehabilitation should be considered as a necessary and effective part of the treatment.\n\nAuthor contributions\nConceptualization: Gianantonio Saviola, Lul Abdi-Ali\n\nData curation: Gianantonio Saviola, Katrin Plewnia\n\nFormal analysis: Maja Rossi, Alfredo Orrico.\n\nInvestigation: Katrin Plewnia, Alfredo Orrico, Maja Rossi.\n\nMethodology: Laura Comini.\n\nSupervision: Lul Abdi-Ali, Laura Comini.\n\nVisualization: Katrin Plewnia.\n\nWriting – original draft: Gianantonio Saviola, Lul Abdi-Ali, Katrin Plewnia, Alfredo Orrico.\n\nWriting – review & editing: Laura Comini, Silvano Sacco.\n\nAbbreviations: MTX = methotrexate, RA = rheumatoid arthritis, PsA = psoriatic arthritis, MTHFR = methylenetetrahydrofolate reductase, MRC = Medical Research Council, DMARD = disease modifying antirheumatic drug.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Benedek TG \nMethotrexate: from its introduction to non-oncologic therapeutics to anti-TNF-α . Clin Exp Rheumatol \n2010 ;28 (5 suppl 61) :S3–8 . Epub 2010 Oct 28. Review .\n[2] Williams HJ Willkens RF Samuelson CO Jr \nComparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial . Arthritis Rheum \n1985 ;28 :721–30 .3893441 \n[3] Cutolo M Sulli A Pizzorni C \nAnti inflammatory mechanism of methotrexate in rheumatoid arthritis . Ann Rheum Dis \n2001 ;60 :729–35 .11454634 \n[4] Taylor OA Hockenberry MJ McCarthy K \nEvaluation of biomarkers of oxidative stress and apoptosis in patients with severe methotrexate neurotoxicity: a case series . J Pediatr Oncol Nurs \n2015 ;32 :320–5 .25637187 \n[5] Ackermann R Semmler A Maurer GD \nMethotrexate-induced myelopathy responsive to substitution of multiple folate metabolites . J Neurooncol \n2010 ;97 :425–7 .19821069 \n[6] Song GG Bae SC Lee YH \nAssociation of the MTHFRC677T and A1298C polymorphism with methotrexate toxicity in rheumatoid arthritis: a meta-analysis . Clin Rheumatol \n2014 ;33 :1715–24 .24794492 \n[7] Chung IM Ketharnathan S Thiruvengadam M \nRheumatoid arthritis: the stride from research to clinical practice . Int J Mol Sci \n2016 ;17 :pii: E900.\n[8] Uribarri M Ruiz-Larrañaga O Arteta D \nInfluence of MTHFR C677T polymorphism on methotrexate monotherapy discontinuation in rheumatoid arthritis patients: results from the GAPAID European project . Clin Exp Rheumatol \n2015 ;33 :699–705 . Epub 2015 Aug 27 .26314492 \n[9] Khanna D Park GS Paulus HE \nReduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies . Arthritis Rheum \n2005 ;52 :3030.16200612 \n[10] van Ede AE Laan RF Rood MJ \nEffect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study . Arthritis Rheum \n2001 ;44 :1515–22 .11465701\n\n",
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"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008727:Methotrexate; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D020335:Paraparesis; D011110:Polymorphism, Genetic",
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"title": "Complete clinical and functional recovery following low-dose methotrexate related paraparesis in a patient with compound c.1298A>C AND c.677C>T MTHFR polymorphism: A case report.",
"title_normalized": "complete clinical and functional recovery following low dose methotrexate related paraparesis in a patient with compound c 1298a c and c 677c t mthfr polymorphism a case report"
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"abstract": "Programmed death receptor 1 (PD1) checkpoint inhibitors are known for immune mediated toxicities such as colitis, endocrinopathies and pneumonitis. However, other rare adverse effects are reported in the literature. Nivolumab is an anti-PD1 immunotherapy used in the second line of non-small cell lung cancer (NSCLC). We report two cases of rare toxicities occurring under nivolumab in patients without a history of dysimmunity. A 79-year-old patient with a large-cell carcinoma showed a muscle weakness after the second course, revealing myositis with a CPK grade IV elevation as well as symptoms of myasthenia. The diagnosis of myositis was confirmed by a muscle biopsy. An 82-year-old patient followed for bronchial adenocarcinoma with EGFR mutation, presented with nivolumab shoulder and hip pain with extreme fatigue. After further investigations, the diagnosis of systemic erythematosus lupus was retained. Investigations led to the diagnosis of systemic lupus erythematosus. For both patients treatment was interrupted and systemic corticosteroid therapy was initiated permitting resolution of symptoms. The occurrence of symptoms of dysimmunity should attract the attention of the clinician, leading to discontinuation of anti-PD1 therapy and corticosteroid therapy. Retreatment after symptoms resolution must be collegially discussed if no alternative therapeutic is available.",
"affiliations": "Service de pneumologie, CHU d'Angers, 4, rue Larrey, 49933 Angers, France. Electronic address: gonzague.dechabot@chu-angers.fr.;Service de pneumologie, CHU d'Angers, 4, rue Larrey, 49933 Angers, France.;Service de pneumologie, CHU d'Angers, 4, rue Larrey, 49933 Angers, France.;Service de neurologie, CHU Angers, centre de référence des maladies neuromusculaires Aquitaine-Occitanie-Caraïbes, 4, rue Larrey, 49933 Angers, France.;Service de rhumatologie, CHU d'Angers, 4, rue Larrey, 49933 Angers France.;Service de pneumologie, CHU d'Angers, 4, rue Larrey, 49933 Angers, France.;Service de pneumologie, CHU d'Angers, 4, rue Larrey, 49933 Angers, France.",
"authors": "de Chabot|G|G|;Justeau|G|G|;Pinquié|F|F|;Nadaj-Pakleza|A|A|;Hoppé|E|E|;Hureaux|J|J|;Urban|T|T|",
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"title": "Unexpected adverse events of immunotherapies in non-small cell lung cancer: About 2 cases.",
"title_normalized": "unexpected adverse events of immunotherapies in non small cell lung cancer about 2 cases"
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"activesubstancename": "PYRIDOSTIGMINE"
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"drugadditional": "1",
... |
{
"abstract": "A 61-year-old Caucasian woman presented to the emergency room complaining of left-sided chest pain and altered mentation for 3 days. Her medical history included liver cirrhosis and coronary artery disease. On admission, she was found to have methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. Due to a decline in mental status, a lumbar puncture was performed and cerebrospinal fluid cultures grew MRSA. She was treated initially with vancomycin. Ceftaroline was later added, due to the high burden of disease and difficulty in clearing her infection. After initiation of ceftaroline, bacteraemia cleared and mental status improved, however, she developed haemolytic anaemia. Ceftaroline was stopped and vancomycin continued. Staphylococcal meningitis is a rare occurrence, estimated at a rate of only 1%-10% of all bacterial meningitis cases. Ceftaroline seems to be a suitable option for disseminated MRSA infection, including MRSA meningitis, when the clinical response to vancomycin is inadequate. Further studies are warranted in order to establish adequate dosing while avoiding adverse effects.",
"affiliations": "Department of Internal Medicine, University of Florida Health at Jacksonville, Jacksonville, Florida, USA.;Department of Internal Medicine, University of Florida Health at Jacksonville, Jacksonville, Florida, USA.;Department of Internal Medicine, University of Florida Health at Jacksonville, Jacksonville, Florida, USA.;Department of Internal Medicine, University of Florida Health at Jacksonville, Jacksonville, Florida, USA.;Department of Internal Medicine, University of Florida Health at Jacksonville, Jacksonville, Florida, USA.",
"authors": "Verdecia|Jorge|J|;Hernandez|Jarelys|J|;Izzo|Christopher|C|;Sottile|Elisa|E|;Isache|Carmen|C|",
"chemical_list": "D000890:Anti-Infective Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-229114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "drugs: infectious diseases; infections; meningitis; pneumonia (infectious disease); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D000890:Anti-Infective Agents; D016470:Bacteremia; D017809:Fatal Outcome; D005260:Female; D017051:Hospice Care; D006801:Humans; D016920:Meningitis, Bacterial; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D018805:Sepsis; D013203:Staphylococcal Infections",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31466968",
"pubdate": "2019-08-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24807197;22198499;21975274;21195973;2810603;18159511;29409664;21208910;25274007",
"title": "Methicillin-resistant Staphylococcus aureus (MRSA) sepsis complicated by warm autoimmune haemolytic anaemia secondary to antimicrobial therapy.",
"title_normalized": "methicillin resistant staphylococcus aureus mrsa sepsis complicated by warm autoimmune haemolytic anaemia secondary to antimicrobial therapy"
} | [
{
"companynumb": "US-AXELLIA-002685",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTAROLINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nAcne vulgaris is a puberty-onset chronic inflammatory disease of the pilosebaceous unit. Isotretinoin is a derivative of vitamin A commonly used for severe and nodulocystic acne. While isotretinoin has many side effects related to the eye, visual system and lacrimation, there is no information regarding isotretinoin's influence on contrast sensitivity.\n\n\nOBJECTIVE\nTo investigate the effect of isotretinoin on visual contrast sensitivity and the amount of lacrimation.\n\n\nMETHODS\nThe study included 25 patients (16 females and 9 males) who underwent isotretinoin treatment. The treatment duration ranged from 4 to 7 months. Patients were examined both before the start and at the end of treatment using the Schirmer test in each eye. The contrast sensitivity measurement was performed both individually for each eye and in a binocular fashion using the Pelli-Robson Sensitivity Chart.\n\n\nRESULTS\nThe results of the Schirmer test before treatment were 19.74 ± 3.63 mm for the right eye and 19.66 ± 3.63 mm for the left eye. Post-treatment measurement results were 17.24 ± 3.5 mm for the right eye and 16.68 ± 3.73 mm for the left eye. There was a statistically significant difference between the before and after treatment measurements (p < 0.000). Before treatment, contrast sensitivity was 1.45 ± 0.19 for the right eye and 1.42 ± 0.2 for the left eye. The binocular measurement was 1.54 ± 0.14. After treatment, the right eye was 1.47 ± 0.19, the left eye was 1.46 ± 0.18, and the binocular measurement was 1.54 ± 0.18. There were no statistically significant differences between before and after treatment (p > 0.05).\n\n\nCONCLUSIONS\nThere are contradicting reports on the results of the Schirmer test. The only similar study that has evaluated contrast sensitivity used the drug acitretin, the results of which are consistent with those the present study.\n\n\nCONCLUSIONS\nOur study is significant in that it is the first to investigate the effects of isotretinoin on visual contrast sensitivity that is closely associated with real-world performance. Our results need to be supported by future studies.",
"affiliations": "a Department of Dermatology and.;b Department of Ophthalmology , Faculty of Medicine, Abant Izzet Baysal University , Bolu , Turkey.",
"authors": "Polat|Mualla|M|;Kükner|Şahap|Ş|",
"chemical_list": "D003879:Dermatologic Agents; D015474:Isotretinoin",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2016.1141419",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "36(1)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Acne vulgaris; contrast sensitivity; isotretinoin; lacrimation",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000152:Acne Vulgaris; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D015350:Contrast Sensitivity; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D015474:Isotretinoin; D008297:Male; D013666:Tears; D055815:Young Adult",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "35-38",
"pmc": null,
"pmid": "26911891",
"pubdate": "2017-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "The effect of oral isotretinoin on visual contrast sensitivity and amount of lacrimation in patients with acne vulgaris.",
"title_normalized": "the effect of oral isotretinoin on visual contrast sensitivity and amount of lacrimation in patients with acne vulgaris"
} | [
{
"companynumb": "TR-AKORN PHARMACEUTICALS-2017AKN00202",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nUnlike anastrozole, the effect of long-term exemestane (EXE) therapy on bone mineral density (BMD) is still unknown. We assessed changes in BMD from baseline to 5 years of EXE treatment.\n\n\nMETHODS\nPostmenopausal women with endocrine-responsive breast cancer receiving EXE as adjuvant therapy were enrolled in this study. EXE was administered for 5 years. The BMD of the lumbar spine (LS) and femoral neck (FN) was assessed by dual-energy X-ray absorptiometry at baseline and after 6 months and 1, 2, 3, 4, 5 and 6 years. Oral bisphosphonate (Bis) treatment was initiated when patients were diagnosed with osteoporosis with a T-score of -2.5 or lower.\n\n\nRESULTS\nEighty-one patients were enrolled in the study between 2005 and 2010. The median follow-up period was 54.9 months. Forty-two patients were administered Bis. Overall, the BMD of the LS increased by 7.3% from baseline and that of the FN increased by 3.4% with 5 years of EXE treatment. At the sixth year (i.e. 1 year after the treatment), BMD of the LS increased by 7.2% and that of the FN increased by 5.7%. Furthermore, the BMD of the FN increased by 12.0% in patients treated upfront with Bis and by 1.2% in those not treated with Bis (P = 0.0262). Fractures developed in nine patients (11.1%) and seven (8.6%) had fragility fractures.\n\n\nCONCLUSIONS\nOral Bis improves BMD of the FN in patients with osteoporosis. Five-year EXE treatment with proper addition of Bis helps maintain the BMD of the LS and FN at the sixth year.",
"affiliations": "Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.;Department of Breast Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.",
"authors": "Hirano|Akira|A|http://orcid.org/0000-0002-8459-4920;Inoue|Hiroaki|H|;Ogura|Kaoru|K|;Hattori|Akinori|A|;Yukawa|Hiroko|H|;Sakaguchi|Shiho|S|;Matsuoka|Aya|A|;Tanaka|Natsuko|N|;Kodera|Asaka|A|;Kamimura|Mari|M|;Naritaka|Yoshihiko|Y|;Shimizu|Tadao|T|",
"chemical_list": "D000730:Androstadienes; D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C056516:exemestane",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.13034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "14(5)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "bisphosphonates; bone mineral density; breast cancer; exemestane",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000368:Aged; D000730:Androstadienes; D000970:Antineoplastic Agents; D015519:Bone Density; D050071:Bone Density Conservation Agents; D001943:Breast Neoplasms; D004164:Diphosphonates; D005260:Female; D006801:Humans; D008875:Middle Aged; D010024:Osteoporosis; D017698:Postmenopause",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "e238-e242",
"pmc": null,
"pmid": "29932305",
"pubdate": "2018-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Long-term effect of exemestane therapy on bone mineral density supported by bisphosphonates: Results of 5-year adjuvant treatment in postmenopausal women with early-stage breast cancer.",
"title_normalized": "long term effect of exemestane therapy on bone mineral density supported by bisphosphonates results of 5 year adjuvant treatment in postmenopausal women with early stage breast cancer"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1077381",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EXEMESTANE"
},
"drugadditional": "3",
... |
{
"abstract": "A middle-aged man presented to emergency services with central vision loss in the setting of flu-like illness with fever. A striking subfoveal abscess was observed in the right fundus. Focal acute chorioretinal inflammation was noted in the asymptomatic fellow eye. Staphylococcus aureus septicaemia was subsequently diagnosed. He presented with undiagnosed HIV infection and latent syphilis. Serial high-definition multimodal retinal imaging showcased resolution of the dome-shaped subretinal abscess following treatment with intravenous flucloxacillin. A chorioretinal scar swiftly replaced the subfoveal abscess. Peripheral right vision and full left vision was retained. Vision loss due to endogenous endophthalmitis in systemic sepsis is an emergency requiring prompt multidisciplinary care. Sight and life are at risk-thus this is not a diagnosis to miss! Early recognition is paramount to health and in retaining vision. We briefly review relevant literature and portray how multimodal imaging guided response to treatment of acute subretinal abscess.",
"affiliations": "Department of Ophthalmology, Royal Bolton Hospital NHS Foundation Trust, Bolton, UK.;Department of Infectious Diseases, Manchester University NHS Foundation Trust, Manchester, UK.;Department of Sexual Medicine, Manchester University NHS Foundation Trust, Manchester, UK.;Department of Ophthalmology, Royal Bolton Hospital NHS Foundation Trust, Bolton, UK.",
"authors": "Prajapati|Rita|R|;Newton|Pippa|P|;Ahmad|Sameena|S|;Kelly|Simon P|SP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005436:Floxacillin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227288",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2018-22728810.1136/bcr-2018-227288Unusual Presentation of More Common Disease/Injury1506Case ReportAcute subretinal abscess in Staphylococcus aureus septicaemia with endophthalmitis showcased by multimodal retinal imaging and with 2-year follow-up Prajapati Rita 1Newton Pippa 2Ahmad Sameena 3Kelly Simon 1\n1 \nDepartment of Ophthalmology, Royal Bolton Hospital NHS Foundation Trust, Bolton, UK\n\n2 \nDepartment of Infectious Diseases, Manchester University NHS Foundation Trust, Manchester, UK\n\n3 \nDepartment of Sexual Medicine, Manchester University NHS Foundation Trust, Manchester, UK\nCorrespondence to Simon Kelly, simon.kelly@boltonft.nhs.uk2018 28 11 2018 28 11 2018 11 1 e22728823 10 2018 © BMJ Publishing Group Limited 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2018This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/A middle-aged man presented to emergency services with central vision loss in the setting of flu-like illness with fever. A striking subfoveal abscess was observed in the right fundus. Focal acute chorioretinal inflammation was noted in the asymptomatic fellow eye. Staphylococcus aureus septicaemia was subsequently diagnosed. He presented with undiagnosed HIV infection and latent syphilis. Serial high-definition multimodal retinal imaging showcased resolution of the dome-shaped subretinal abscess following treatment with intravenous flucloxacillin. A chorioretinal scar swiftly replaced the subfoveal abscess. Peripheral right vision and full left vision was retained. Vision loss due to endogenous endophthalmitis in systemic sepsis is an emergency requiring prompt multidisciplinary care. Sight and life are at risk—thus this is not a diagnosis to miss! Early recognition is paramount to health and in retaining vision. We briefly review relevant literature and portray how multimodal imaging guided response to treatment of acute subretinal abscess.\n\nHIV / AIDSretinainfectious diseasesophthalmologyeyespecial-featureunlocked\n==== Body\nBackground\nEndogenous endophthalmitis (EE)—also termed metastatic endophthalmitis—is ocular inflammation resulting from haematogenous spread of an infectious agent into the eye and is less frequent than exogenous endophthalmitis. The latter follows direct inoculation after ocular surgery or trauma. Endogenous bacterial endophthalmitis (EBE) is a rare sight-threatening emergency and may manifest during life-threatening systemic sepsis. The foci of primary infection is often in the lung, liver, endocardium or urinary tract.1 The British Ophthalmic Surveillance Unit (BOSU) study recently estimated the incidence of EE in the UK to be at least 1 case per million population per year.2 Jackson et al in a systematic review opined that prognosis of EBE largely depends on prompt recognition and treatment and further observed that 33% of reported patients had delayed diagnosis or were misdiagnosed.1 Furthermore, few eyes in that analysis recovered good vision and some were enucleated or eviscerated.1 Blurred vision and floaters are frequent presenting complaints, and clinical findings have largely been centred on intraocular inflammation. Where a view of the fundus is possible retinal haemorrhages, cotton wool spots, chorioretinitis and on occasion subretinal abscesses may be identified.1–3 Such subretinal abscesses are infrequent in EBE.2 4\n\n\nIndividuals at greatest risk of EE include immunocompromised patients; including those on immunosuppressive therapy or HIV, patients with prolonged indwelling devices/catheters and those with underlying systemic comorbidities such as diabetes.1–4\n\n\nEBE is thought to have become less frequent since the advent of aggressive treatment of bacterial sepsis. Gram-positive organisms such as Staphylococcus aureus and streptococci are bacteria most frequently responsible for EBE in the Western world.1 Sadiq et al have suggested guidelines for the treatment of metastatic EE.5\n\n\nWhile ophthalmic signs and visual symptoms in EE are well recognised, there are few reports of optical coherence tomography (OCT) in EBE during the acute phase as such patients are often too unwell for such imaging. Recent case reports have highlighted the utility of OCT imaging in EE with systemic infection from fungi and from yeast.6–11\n\n\n\nS. aureus bacteraemia (SAB) is an important cause of morbidity and mortality and has been extensively reviewed by others.12 When SAB is associated with endophthalmitis, it is a cause for concern because it may be difficult to diagnose and challenging to manage. Four of the 15 patients with endophthalmitis associated with SAB died within 12 weeks after onset of SAB in a large single centre prospective study in South Korea.13 Subretinal abscesses have been described in association with SAB following spread from various primary sites of infection such as from vertebral osteomyelitis.14 Fortun et al recently described 11 eyes of 7 patients with EBE with subretinal abscesses secondary to methicillin resistant Staphloccus aureus (MRSA) bacteraemia and provided publication of one OCT image in that case series.4 Kansal et al also provided an OCT image in a case report of EBE secondary to axillary phlegmon.15 Enhanced depth imaging OCT (EDI-OCT) has also recently also been used to diagnose choroidal lesions suspected to be due to bacterial sepsis.16 In the BOSU study, there were 4 reports of retinal abscess in the 62 cases of EE but the authors do not state if these occurred in fungal or bacterial EE infections or provide details of OCT imaging.2 As there have been very few reports of subretinal abscess studied with OCT or multimodal imaging in acute EE and a scarcity in EBE, we present such a case and where the striking multimodal images guided patient care during life-threatening sepsis.\n\nCase presentation\nA middle-aged man presented with a 1-day history of painless loss of right central vision. He had felt unwell for several days prior with dry cough, flu-like illness and fevers. There was no medical or ophthalmic history of note bar moderate myopia. He had been self-medicating with over the counter ibuprofen and co-codamol. He was a non-smoker and drank occasional alcohol. On further questioning, he was a male who had sex with men and had previously had unprotected sex. He had also experienced occupational needle-stick injuries and had never had a HIV test. There was no history of recreational drug use.\n\nVisual acuity; hand movements only right eye and 6/6 Snellen left eye. Anterior ocular segment examination was unremarkable bar sluggish pupils that were poor to dilate. Imaging was undertaken on white light colour fundus camera and multicolour confocal scanning laser ophthalmoscopy with linked OCT (Spectralis Heidelberg Instruments, Germany). Digital callipers on the instrument were used to measure retinal lesions. Visual field testing; right central scotoma and left full field of vision.\n\nAn area of white-yellow chorioretinal inflammation with elevation was apparent at the right fovea with retinal haemorrhage. There was mild vitritis. The OCT image showed neurosensory retina was elevated over a dome-shaped subretinal mass of area 18 mm2 at retinal surface, apical height 1370 µm above Bruch’s membrane (figure 1, video 1). White centred retinal haemorrhages—also known as Roth’s spot—was observed in right mid-peripheral posterior pole. A fluffy edged circular area of acute chorioretinal inflammation (diameter 1150 µm) without detectable vitritis was noted in the nasal retina of the asymptomatic left eye (figure 2). A diagnosis of toxoplasmosis was initially suspected in view of the fundal findings.\n\nFigure 1 Baseline visit, right eye. A striking subretinal abscess involves the fovea. Multicolour and colour fundus images on top panel. Linked near-infrared and OCT on lower panel. OCT, optical coherence tomography.\n\nVideo 1 Baseline visit, right eye. Macular cube video of linked near-infrared (left side of screen) and OCT (right side of screen) images on presentation. OCT, optical coherence tomography.\n\n10.1136/bcr-2018-227288.video015853278225001BMJ Journals Video Playerbcr2018227288media1Figure 2 Baseline; left eye. Multicolour and colour fundus images show chorioretinal inflammation in nasal aspect of left fundus on presentation.\n\nThat evening, he became more unwell and was seen by the Infectious Diseases Team on call. He was more drowsy, lethargic and had poor oral intake. He had passed little urine during the day. His observations on presentation revealed a fever of 40°C, pulse 134 bpm and his blood pressure was 162/98. Examination revealed cervical lymphadenopathy and clinical dehydration. He was mildly confused and there were no features of meningism. Chest was clear on auscultation and heart sounds were normal with no peripheral stigmata evidence of endocarditis. Abdominal examination revealed an enlarged liver and palpable splenic tip. Hepatosplenomegaly was later confirmed on ultrasound.\n\nInvestigations\nInitial laboratory investigations revealed elevated C reactive protein 148 mg/L; (normal <5); low haemoglobin (8.5 g/dL; normal 13.0–18.0), reduced lymphocytes in the setting of a normal white cell count (0.78 g/Lx109/L; normal 1.5–4.0 and 8.5×109/L; normal 4–11, respectively); low platelets (130×109/L; normal 150–400) and stage 4 acute kidney injury (AKI) urea 21.5; (normal 2.5–7.8) creatinine 314 µmol/L; (normal 60–120) with estimated glomerular filtration rate (corrected for ethnicity) (eGFR) 19 mL/min/1.73 m2. Blood lactate level was normal (2.1 mmol/L) and serum bicarbonate was slightly low (20 mmol/L; normal 22–29). Blood film revealed red cell fragments consistent with early features of disseminated intravascular coagulation (DIC). The activated partial thromboplastin time was raised at 42.6 s (range 24.7–36.1). Liver function tests were normal except for albumin (18 g/L; normal 35–50), globulin (49 g/L; normal 25–42) and aspartate aminotransferase (87 IU/L; normal 3–34). The creatine kinase level was raised (625 IU/L; <200).\n\nDifferential diagnosis\nToxoplasmosis in a patient with suspected immunosuppression was the initial working diagnosis. He was also treated for presumed sepsis in addition to the management of his AKI. Immediate antimicrobial therapy was commenced with clindamycin (intravenous 600 mg four times a day), calcium folinate (orally 15 mg once a day), pyrimethamine (200 mg orally, then 75 mg once a day) and meropenem (intravenous 2 g two times a day).\n\nTreatment\nBlood cultures grew methicillin sensitive S. aureus (MSSA) and high-dose intravenous flucloxacillin was commenced (2 g four times a day). Intravenous ganciclovir (1.25 mg/kg/day, standard dose reduced according to eGFR) was also given in case of cytomegalovirus (CMV) retinitis. His blood CMV viral load later came back at 500 copies/mL, just at the limit of sensitivity for the assay and his blood cryptococcal antigen was negative. These findings, together with subsequent ophthalmology review, led us to believe that the fundus lesion was not CMV or cryptococcal related and ganciclovir therapy was stopped.\n\nOutcome and follow-up\nThe bacteraemia was quickly controlled and blood cultures 2 days after admission and all subsequent cultures were negative. Meropenem was continued for 10 days in case of a central nervous system infection. CT and MRI brain imaging normal. A lumbar puncture was initially delayed due to concerns of early DIC, but when performed on day 7 of admission, was sterile (no bacterial or fungal or mycobacterial growth). HIV antibody test positive and avidity testing was consistent with an established infection. HIV viral load 1.14 ((log 6.06) copies/mL) and CD4 count was 12 cells/mm3 (normal range 300–1400 cells/mm3), indicating significant immunosuppression. He was informed of HIV diagnosis and commenced on Pneumocystis jirovecii pneumonia (Dapsone, then was switched to Atovaquone), and Mycobacterium avium complex prophylaxis (azithromycin 1.25 g/once a week). He started antiretroviral therapy with raltegravir, abacavir and lamivudine (dosed according to eGFR) around 2 weeks postpresentation and has had a good virological and immunological response to therapy. His latest HIV viral load is <50 copies/mL and his CD4 count was 267 cells/mm3 (normal range 300–1400 cells/mm3). Syphilis serology was consistent with latent disease (Treponema pallidum particle agglutination assay titre 1 in 320; RPR, rapid plasma reagin negative) and there was no serological evidence of human T-lymphotropic virus infection. Toxoplasma IgG antibody positive and IgM negative, indicating prior Toxoplasma infection. Quantiferon-tuberculosis (TB) Gold test was negative consistent with no prior exposure to TB and there was evidence of prior varicella-zoster infection. He had active hepatitis C infection (genotype 1; viral load 2.18 million IU/mL).\n\nHis AKI on admission was multifactorial in nature with incipient acute tubular necrosis, recent non-steroidal anti-inflammatory drug (NSAIDs) usage, glomerulonephritis secondary to sepsis or hepatitis C infection and possible HIV-associated nephropathy all being potential aetiological factors. The NSAIDs were stopped and he was rehydrated with intravenous fluids. His urine contained red and white blood cells and was negative for microbial culture. His serum creatinine peaked to 361 µmol/L (normal 62–124) on the second day of admission but there was no evidence of hyperkalaemia or profound acidosis and he did not require renal replacement therapy. He did develop nephrotic syndrome (urine protein was 5.67 g/L) and later during his admission developed significant pitting peripheral oedema to waist level and hypertension. A furosemide infusion was commenced and once his renal function had improved he was commenced on an ACE inhibitor. He remained under regular review by the renal team and a decision was made not to undertake a renal biopsy on the basis of clinical improvement. In view of his nephrotic syndrome, he was commenced on low-dose prophylactic clexane on day 5 of admission and this was continued for a duration of around 2 months. On discharge, his creatinine had improved to 170 µmol/L (normal 62–124; eGFR was 40 mL/min/1.73 m2 corrected for ethnicity) and at time of last follow-up (27 months postpresentation) his creatinine was 92 µmol/L (normal 62–124; eGFR was 84 mL/min/1.73 m2, corrected for ethnicity).\n\nThe source for the bacteraemia was not found. He developed a painful lesion on his left index finger on day 5 postpresentation raising the possibility of an embolic source. A transthoracic and transoesophageal echocardiogram did not reveal any vegetations on his cardiac valves. An incidental patent foramen ovale was detected. CT thorax scan showed scattered ill-defined pulmonary nodules, the largest measuring 1.2 cm in diameter. One pulmonary nodule contained a tiny central cavity. The lesions were thought to be infective in aetiology and septic emboli was in the differential diagnosis. It was not possible to determine whether there were any renal infarcts as a non-contrast scan was performed in view of his AKI. His illness may have been an initial viral infection, such as influenza, complicated by a secondary bacterial infection (MSSA). Unfortunately, respiratory viral throat and nasal swabs were not taken on presentation so it is not possible to exclude such infection.\n\nFor the first 2 weeks, the patient was too unwell to attend for slit lamp examination or retinal imaging. Bedside ophthalmoscopy examinations were undertaken on a weekly basis on the ward by two experienced ophthalmologists. Intravitreal antibiotics were withheld as it was deemed the patient’s funduscopy signs were responding to systemic antibiotic treatment. Intravitreal sampling for microbiology examination was not undertaken for the same reason and because of the practicalities of so doing during critical illness.\n\nThe patient improved over several weeks and discharged home on day 28 on outpatient parenteral antimicrobial therapy (OPAT) to complete a 6-week course of intravenous flucloxacillin. At the time of OPAT completion inflammatory markers were normal. The ophthalmic working diagnosis was revised to bacterial subretinal abscess when the severity of systemic sepsis was better understood in the context of the multimodal images and negative Toxoplasma IgM serology. The dome-shaped elevation of the right fovea from the underlying abscess was observed to reduce by ophthalmoscopy undertaken the bedside. Repeat multimodal imaging was undertaken at day 30 by which time the former foveal abscess was replaced by full thickness chorioretinal atrophic central circular scar (diameter 1 mm) with surrounding intraretinal exudates (figure 3). These exudates later disappeared. At 2 years follow-up, a right foveal chorioretinal scar remains (figure 4). The lesion in left nasal retina resolved into a scar without visual impairment (figure 5). Final visual acuity is 6/60 right and 6/6 left eye. The right central visual field defect stabilised. The right central scotoma persists at follow-up unchanged in size from that at presentation. The left field of vision is full and was not unaffected.\n\nFigure 3 Day 30; right eye. Regression of the subretinal abscess into atrophic scar involving the fovea is by then apparent. Exudates are seen temporally. Colour fundus, multicolour, and optical coherence tomography images\n\nFigure 4 Year 2 visit; right eye. Atrophic scar involving the fovea. Exudates previously seen temporally are no longer apparent. Colour fundus, multicolour, and optical coherence tomography images.\n\nFigure 5 Year 2 visit: left eye. Small atrophic scar in nasal retina is apparent. Multicolour image left panel. Near-red reflectance image with linked OCT on right panel. OCT, optical coherence tomography.\n\nDiscussion\nThis case highlights the complexities of diagnosis and management of acute vision loss in severe sepsis and draws attention to the need for multidisciplinary involvement and aggressive and prolonged intravenous antibiotic treatment of S. aureus septicaemia. When visual symptoms are present in the setting of systemic sepsis, urgent ophthalmic consultation is advised. EBE is an ophthalmic emergency, sight and life are at risk. When a view of the fundus is possible, multimodal retinal imaging may be of merit if swiftly undertaken—where clinically possible—to refine the diagnosis and guide response of fundus lesion size to antimicrobial treatment. Importantly the patient’s condition may deteriorate requiring high dependency care and precluding such ophthalmic imaging and or slit-lamp biomicroscopy. Furthermore, the fundus view becomes obscured once significant vitritis develops. In such circumstances, binocular indirect ophthalmoscopy (BIO) is often only practicable. BIO examinations are observer dependent and documentation is subjective. Modern retinal imaging allows precise digital mapping of lesions by retinal layers and thus facilitates serial objective measurement and change analysis. Our patient presented early to ophthalmic services as the subfoveal location of the abscess caused early symptoms. The ophthalmoscopy findings of subretinal abscess, Roth’s spots and bilateral involvement in the setting of fever heralded systemic septic emboli. The sexual history raised the suspicion of immunocompromise from undiagnosed HIV infection. Early multimodal imaging allowed better appreciation of tissues involved in the subretinal abscess. The acute OCT findings in our patient were similar to the only two other reported cases of bacterial subretinal abscess we are aware of.4 15 Of interest Salvetti et al described EDI-OCT imaging in a patient a choroidal abscess in the setting of suspected sepsis.16\n\n\nThankfully, our patient with confirmed severe sepsis together with early features of DIC, multiple septic emboli and profound immunosuppression, demonstrated a pleasing response to intravenous treatment without the need for intravitreal antibiotics. This suggests a therapeutic level of systemic antibiotic reached the subretinal space and as was also reported in a single patient in the case series by Fortun et al that was attended to prior to development of significant vitritis.4 Such serial monitoring assisted in sepsis management in gauging response of the abscess to antimicrobial therapy and facilitated telemedicine consultation with tertiary ophthalmic specialist uveitis care. This case also highlighted a number of challenges including the decision of when to anticoagulate in view of features of early DIC and nephrotic syndrome through careful analysis of risk and benefit and communication between the different teams.\n\nThe presenting large size and location (subfoveal) in right eye of our patient was likely ab initio to result in a poor prognosis for right central visual acuity. Despite the loss of right visual acuity it is pleasing that the right visual field was retained with only a small central scotoma persisting and which did not enlarge from that plotted on perimetry on presentation. The patient was able to return to employment and to satisfy legal requirements for motoring.\n\nLearning points\nPrompt diagnosis and aggressive rapid management of endogenous bacterial endophthalmitis is necessary. Life and sight are at risk.\n\nOphthalmologist should beware of systemic sepsis. Risk factors should be asked for.\n\nExtensive examination is essential in identifying source of infection of unknown origin and requires multidisciplinary approach with good communication between teams.\n\nMultimodal retinal imaging provides exceptional detail of retinal microstructure and is of merit in mapping antimicrobial treatment response in retinal infection.\n\nWe thank NP Jones, Manchester Royal Eye Hospital for clinical care and comments on this manuscript. We thank Jenny O’ Connell, Royal Bolton Hospital for clinical imaging.\n\nContributors: RP, PN, SA and SPK were involved in clinical care of the patient. RP and SPK: review and synthesis of literature, figures, data collection, data interpretation, writing up paper, proof reading, revision and final approval of version. RP, PN, SA and SPK were involved in revising the manuscript critically for important intellectual content. Final approval of the version published has been agreed by RP, PN, SA and SPK.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nJackson TL , Paraskevopoulos T , Georgalas I \nSystematic review of 342 cases of endogenous bacterial endophthalmitis . Surv Ophthalmol \n2014 ;59 :627 –35 . 10.1016/j.survophthal.2014.06.002 \n25113611 \n2 \nMaling S , King C , Davies N \nA British Ophthalmological Surveillance Unit Study on metastatic endogenous endophthalmitis . Eye \n2018 ;32 :743 –8 . 10.1038/eye.2017.284 \n29328066 \n3 \nNishida T , Ishida K , Niwa Y , et al \nAn eleven-year retrospective study of endogenous bacterial endophthalmitis . J Ophthalmol \n2015 ;2015 :1 –11 . 10.1155/2015/261310 \n\n4 \nFortun J , Modi YS , Bessette A , et al \nClinical features and management of subretinal abscesses secondary to methicillin-resistant staphylococcus aureus endogenous endophthalmitis . Ophthalmic Surg Lasers Imaging Retina \n2017 ;48 :134 –42 . 10.3928/23258160-20170130-07 \n28195616 \n5 \nSadiq MA , Hassan M , Agarwal A , et al \nEndogenous endophthalmitis: diagnosis, management, and prognosis . J Ophthalmic Inflamm Infect \n2015 ;5 :32 \n10.1186/s12348-015-0063-y \n26525563 \n6 \nStephens JD , Adam MK , Todorich B , et al \nOptical coherence tomography findings in endogenous fungal chorioretinitis, retinitis, and endophthalmitis . Ophthalmic Surg Lasers Imaging Retina \n2017 ;48 :894 –901 . 10.3928/23258160-20171030-04 \n29121358 \n7 \nRodrigues IA , Jackson TL \nA high-definition view of endogenous fungal endophthalmitis . Lancet Infect Dis \n2014 ;14 :358 \n10.1016/S1473-3099(13)70216-0 \n24670628 \n8 \nAdam CR , Sigler EJ \nMultimodal imaging findings in endogenous Aspergillus endophthalmitis . Retina \n2014 ;34 :1914 –5 . 10.1097/IAE.0000000000000135 \n24695061 \n9 \nLavine JA , Mititelu M \nMultimodal imaging of refractory Candida chorioretinitis progressing to endogenous endophthalmitis . J Ophthalmic Inflamm Infect \n2015 ;5 :24 \n10.1186/s12348-015-0054-z \n\n10 \nAmphornphruet A , Silpa-Archa S , Preble JM , et al \nEndogenous cryptococcal endophthalmitis in immunocompetent host: case report and review of multimodal imaging findings and treatment . Ocul Immunol Inflamm \n2018 ;26 :518 –22 . 10.1080/09273948.2017.1298820 \n28448725 \n11 \nInvernizzi A , Symes R , Miserocchi E , et al \nSpectral domain optical coherence tomography findings in endogenous candida endophthalmitis and their clinical relevance . Retina \n2018 ;38 :1011 –8 . 10.1097/IAE.0000000000001630 \n28492430 \n12 \nTong SY , Davis JS , Eichenberger E , et al \n\nStaphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management . Clin Microbiol Rev \n2015 ;28 :603 –61 . 10.1128/CMR.00134-14 \n26016486 \n13 \nJung J , Lee J , Yu SN , et al \nIncidence and risk factors of ocular infection caused by staphylococcus aureus bacteremia . Antimicrob Agents Chemother \n2016 ;60 :2012 –7 . 10.1128/AAC.02651-15 \n26824952 \n14 \nSteeples LR , Jones NP \nStaphylococcal endogenous endophthalmitis in association with pyogenic vertebral osteomyelitis . Eye \n2016 ;30 :152 –5 . 10.1038/eye.2015.200 \n26449198 \n15 \nKansal V , Rahimy E , Garg S , et al \nEndogenous methicillin-resistant Staphylococcus aureus endophthalmitis secondary to axillary phlegmon: a case report . Can J Ophthalmol \n2017 ;52 :e97 –e99 . 10.1016/j.jcjo.2016.11.016 \n28576230 \n16 \nSalvetti AP , Pellegrini M , Bottoni F , et al \nEndogenous bacterial endophthalmitis masquerading as an intraocular tumor . Saudi J Ophthalmol \n2016 ;30 :71 –4 . 10.1016/j.sjopt.2015.11.003 \n26949365\n\n",
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"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "HIV / AIDS; eye; infectious diseases; ophthalmology; retina",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000038:Abscess; D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents; D003937:Diagnosis, Differential; D042241:Early Diagnosis; D009877:Endophthalmitis; D015818:Eye Infections, Bacterial; D005436:Floxacillin; D015658:HIV Infections; D006801:Humans; D008297:Male; D064847:Multimodal Imaging; D012160:Retina; D012164:Retinal Diseases; D018805:Sepsis; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D013587:Syphilis; D016896:Treatment Outcome; D014786:Vision Disorders",
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"references": "28492430;26949365;29121358;26253239;29328066;28448725;28576230;26824952;24670628;26525563;26449198;25802752;26016486;24695061;28195616;25113611",
"title": "Acute subretinal abscess in Staphylococcus aureus septicaemia with endophthalmitis showcased by multimodal retinal imaging and with 2-year follow-up.",
"title_normalized": "acute subretinal abscess in staphylococcus aureus septicaemia with endophthalmitis showcased by multimodal retinal imaging and with 2 year follow up"
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"abstract": "Nocardia neocaledoniensis is an uncommon cause of human-infections. Few cases are reported in the literature. We describe the first case of bacteremia caused by N. neocaledoniensis. This article underlines the importance of mass spectrometry for easy and rapid identification of such bacterium.",
"affiliations": "Centre Hospitalier Régional Universitaire de Lille, Lille, France.;Centre Hospitalier de Roubaix, Roubaix, France.;Centre Hospitalier Régional Universitaire de Lille, Lille, France.;Centre Hospitalier de Roubaix, Roubaix, France.;Centre Hospitalier Régional Universitaire de Lille, Lille, France.;Centre Hospitalier Régional Universitaire de Lille, Lille, France.;Centre Hospitalier Régional Universitaire de Lille, Lille, France.",
"authors": "Regueme|Alexandre|A|;Vachee|Anne|A|;Duployez|Claire|C|;Petit|Anne-Emilie|AE|;Coulon|Pauline|P|;Wallet|Frédéric|F|;Loiez|Caroline|C|",
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"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30242-0\n10.1016/j.idcr.2020.e00934\ne00934\nArticle\nFirst case of fatal bacteremia due to Nocardia neocaledoniensis\nRegueme Alexandre alexandre.regueme@hotmail.fra Vachee Anne anne.vachee@ch-roubaix.frb Duployez Claire claire.duployez@chru-lille.fra Petit Anne-Emilie anne-emilie.petit@ch-roubaix.frb Coulon Pauline pauline.coulon@chru-lille.fra Wallet Frédéric frederic.wallet@chru-lille.fra Loiez Caroline caroline.loiez@chru-lille.fra⁎ a Centre Hospitalier Régional Universitaire de Lille, Lille, France\nb Centre Hospitalier de Roubaix, Roubaix, France\n⁎ Corresponding author at: Laboratoire de Bactériologie - Institut de Microbiologie, Centre de Biologie Pathologie, F-59037, Lille Cedex, France. caroline.loiez@chru-lille.fr\n22 8 2020 \n2020 \n22 8 2020 \n22 e009349 7 2020 20 8 2020 20 8 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• First case of bacteremia due to N.neocaledoniensis in an immunocompromised patient.\n\n• Mass spectrometry is a discriminant technique to identify rapidly N.neocaledoniensis.\n\n• Incubating culture media for a longer time helps to obtain definitive diagnosis and adapt antibiotics.\n\n\n\nNocardia neocaledoniensis is an uncommon cause of human-infections. Few cases are reported in the literature. We describe the first case of bacteremia caused by N. neocaledoniensis. This article underlines the importance of mass spectrometry for easy and rapid identification of such bacterium.\n\nKeywords\nNocardia neocaledoniensisBacteremiaMALDI-TOF\n==== Body\nIntroduction\nNocardia species are Gram-positive aerobic bacilli belonging to the order of Actinomycetales. These ubiquitous environnemental bacteria can be responsible for opportunistic infections, particularly in immunocompromised patients. Thanks to the developement of 16S rDNA sequencing and mass spectrometry, the number of Nocardia species has increased and more than 100 species are currently described [1,2]. Among them, Nocardia neocaledoniensis was first isolated from soil in New Caledonia and identified using 16S rDNA sequencing in 2004 [3]. Herein, we report the first case of bacteremia due to N. neocaledoniensis in an immunocompromised patient.\n\nCASE PRESENTATION\nAn 88-year-old man suffering from chronic lymphocytic leukemia was admitted to the geriatric unit for persistant febrile respiratory syndrome. He was treated with amoxicillin-clavulanic acid and ciprofloxacin for fifteen days without resolution.\n\nOn admission, physical examination revealed deterioration of his general condition with fever at 38 °C. The patient was conscious and oriented. A productive cough with clear sputum without respiratory distress was observed. Heart sounds were regular without heart murmur. Blood pressure was at 115/54 mmHg, pulse rate at 72/min and oxygen saturation at 95 %. Biological results indicated an elevated white blood cells (16.6 × 109/l with 9.6 × 109/l polymorphonuclear neutrophils) and an inflammatory syndrome with high level of C-reactive protein (27 mg/mL). Chest X-ray revealed after-effects of left basal pneumonia.\n\nThe influenza RT-PCR was negative. Urine soluble antigen testing for Streptococcus pneumoniae and Legionella pneumophila was not performed. Culture of sputum only showed an oro-pharyngeal flora. Two sets of blood cultures (BD BACTEC™ FX; Becton Dickinson, Franklin Lakes, New Jersey, United States) were positive after more than 72 h of culture. The direct examination of the blood culture showed a branched Gram-positive rod (Fig. 1). After 24 h of culture on blood agar plate, the culture showed cerebriform white colonies with sugary appearance, pitting into the agar. Identification was performed by MALDI-TOF spectrometry mass on the VITEK MS® (BioMérieux, Marcy l’Etoile, France) with an excellent confidence value (>99 %) for N. neocaledoniensis and was confirmed using 16S rDNA sequencing by the National Reference Center for nocardiosis.Fig. 1 Gram strain microscopic examination of Nocardia neocaledoniensis at magnification 1000 × . Presence of Gram-positive branched filamentous bacilli.\n\nFig. 1\n\nSusceptibility testing was performed using the CLSI-recommended method of broth microdilution [4]. The organism was susceptible to amikacin (MIC < 0.5 mg/L), imipenem (MIC = 0.5 mg/L), clarithromycin (MIC = 2 mg/L), linezolid (MIC = 2 mg/L), trimethoprim-sulfamethoxazole (MIC = 1 mg/L), and resistant to amoxicillin-clavulanic acid (MIC > 32 mg/L), cefotaxime (MIC = 32 mg/L), ciprofloxacin (MIC > 4 mg/L).\n\nUnfortunately, the respiratory and hemodynamic functions of our patient declined rapidly. He finally died five days after his admission from an acute respiratory distress syndrome.\n\nDiscussion\nThe review of the literature including key-words “Nocardia neocaledoniensis” and “human infection” related few cases caused by this bacterium. After its first description in 2004 from a hypermagnesian ultramafic soil, this species was isolated from milk samples of dairy cows with mastitis; its isolate identification was confirmed by 16S rDNA sequencing [5]. Since then, few human infections have been described. In 2007, Yin et al. identified three cases of conjunctivitis caused by N. neocaledoniensis out of 11 ocular infections, using hsp65 gene sequencing for species identification of Nocardia spp. [6]. In 2012, McGhie et al. described the first case of skin and soft tissue infection caused by N. neocaledoniensis in a 68-year-old man on immunosuppressive therapy for rheumatoid arthritis [7]. In 2020, Azadi et al. isolated N. neocaledoniensis from an abscess following a surgery in an immunocompetent patient [8].\n\nIn our case, we describe a fatal bacteremia due to N. neocaledoniensis identified using MALDI-TOF spectrometry mass. This technique allows a rapid and accurate identification of Nocardia species. Its performance was evaluated by Body et al. on a panel of 312 isolates representing 21 different Nocardia species. Of the 312 isolates, 3 % were incorrectly classified by this method, including 3 strains of N. asteroides which were misidentified as N. neocaledoniensis [9]. Concerning Nocardia bacteremia, the last study of Williams et al. reported more than 100 cases of invasive infections [10]. The most frequent species isolated were N. farcinica (33 %) followed by N. nova complex (10 %). In this study, 80 % of patients were immunocompromised, and the blood was the only site where Nocardia yielded in 38 % of cases, as described in our case. However, Nocardia species are slow-growing organisms: while incubation time of blood cultures is sufficient to detect them, media used for respiratory samples are conventionnally not looked for as long as. As in our study, it could have been underestimated in respiratory samples for this reason, while respiratory tract is the main entrance wound for these bacteria. The outcome of these patients was lethal in 40 % of the cases. Finally, the majority of strains were susceptible to linezolide (100 %), amikacin (98 %), imipenem (85 %) and trimethoprim-sulfamethoxazole (89 %) whereas 50 % of them were resistant to amoxicillin-clavulanic acid and ciprofloxacin. These data were confirmed in our case with the failure of the initial pneumonia treatment (amoxicillin-clavulanic acid and ciprofloxacin) and the secondary bacteremia. This case demonstrates the importance of quick detection and identification of Nocardia in clinical samples in order to prescribe an antibiotic deemed to be more effective (linezolide, imipenem, amikacin). Moreover, in case of persistant atypical pneumonia, physicians should consider requesting specifical Nocardia research to permit a long incubation of culture media. Although Nocardia may be isolated within 3–5 days of culture, prolonging the culture media incubation time to 2 weeks may be needed in cases with high clinical suspicion.\n\nAuthorship statement\nAll authors meet the ICMJE authorship criteria\n\nAR, CL and FW wrote the first draft of the article.\n\nAR, CD, AV, CL, FW and PC were responsible for biological analyses.\n\nAR, AV and AEP were responsible for collection of patients’ data.\n\nAll authors contributed to the writing and approved the final manuscript.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nThe authors have read and complied with the journal’s ethical consent policy. No specific ethical approval was required for this study.\n\nConsent\nStudies on patients or volunteers require ethics committee approval and fully informed written consent which should be documented in the paper.\n\nAuthors must obtain written and signed consent to publish the case report from the patient (or, where applicable, the patient's guardian or next of kin) prior to submission. We ask Authors to confirm as part of the submission process that such consent has been obtained, and the manuscript must include a statement to this effect in a consent section at the end of the manuscript, as follows: \"Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request”.\n\nPatients have a right to privacy. Patients’ and volunteers' names, initials, or hospital numbers should not be used. Images of patients or volunteers should not be used unless the information is essential for scientific purposes and explicit permission has been given as part of the consent. If such consent is made subject to any conditions, the Editor in Chief must be made aware of all such conditions. Even where consent has been given, identifying details should be omitted if they are not essential. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.\n\nDeclaration of Competing Interest\nThere are no conflicts of interest to declare.\n==== Refs\nReferences\n1 Kageyama A. Yazawa K. Ishikawa J. Hotta K. Nishimura K. Mikami Y. Nocardial infections in Japan from 1992 to 2001, including the first report of infection by Nocardia transvalensis Eur J Epidemiol 19 4 2004 383 389 15180109 \n2 Rahdar H.A. Azadi D. Shojaei H. Daei-Naser A. Molecular analysis and species diversity of Nocardia in the hospital environment in a developing country, a potential health hazard J Med Microbiol 66 3 2017 334 341 28100300 \n3 Saintpierre-Bonaccio D. Maldonado L.A. Amir H. Pineau R. Goodfellow M. Nocardia neocaledoniensis sp. nov., a novel actinomycete isolated from a New-Caledonian brown hypermagnesian ultramafic soil Int J Syst Evol Microbiol 54 2004 599 603 15023981 \n4 Clinical and Laboratory Standards Institute (CLSI) CLSIM24-A2: Susceptibility testing of Mycobacteria , Nocardiae and Other Aerobic Actinomycetes : Approved Standard 3rd ed. 2018 Clinical and Laboratory Standards Institute Villanova, PA \n5 Pisoni G. Locatelli C. Alborali L. Rosignoli C. Allodi S. Riccaboni P. Short communication: outbreak of Nocardia neocaledoniensis mastitis in an Italian dairy herd J Dairy Sci 91 1 2008 136 139 18096934 \n6 Yin X. Liang S. Sun X. Luo S. Wang Z. Li R. Ocular nocardiosis: HSP65 gene sequencing for species identification of Nocardia spp Am J Ophthalmol 144 4 2007 570 573 17698022 \n7 McGhie T. Fader R. Carpenter J. Brown-Elliott B.A. Vasireddy R. Wallace R.J. Nocardia neocaledoniensis [corrected] as a cause of skin and soft tissue infection J Clin Microbiol 50 9 2012 3139 3140 22785189 \n8 Azadi D. Motallebirad T. Ghaffari K. Shokri D. Rezaei F. Species Diversity, Molecular Characterization, and Antimicrobial Susceptibility of OpportunisticActinomycetes Isolated from Immunocompromised and Healthy Patients of Markazi Province of Iran Infect Drug Resist 13 2020 1 10 32021315 \n9 Body B.A. Beard M.A. Slechta E.S. Hanson K.E. Barker A.P. Babady N.E. Evaluation of the vitek MS v3.0 matrix-assisted laser desorption ionization-time of flight mass spectrometry system for identification of Mycobacterium and Nocardia species J Clin Microbiol 56 6 2018 e00237 18 29643203 \n10 Williams E. Jenney A.W. Spelman D.W. Nocardia bacteremia: a single-center retrospective review and a systematic review of the literature Int J Infect Dis 92 2020 197 207 31978577\n\n",
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"issn_linking": "2214-2509",
"issue": "22()",
"journal": "IDCases",
"keywords": "Bacteremia; MALDI-TOF; Nocardia neocaledoniensis",
"medline_ta": "IDCases",
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"nlm_unique_id": "101634540",
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"pages": "e00934",
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"pubdate": "2020",
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"title": "First case of fatal bacteremia due to Nocardia neocaledoniensis.",
"title_normalized": "first case of fatal bacteremia due to nocardia neocaledoniensis"
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"abstract": "Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.",
"affiliations": "Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Cambridge University Hospitals, NHS Foundation Trust, Cambridge, UK.;Department of Medicine III, Paracelsus Medical University, Salzburg, Austria.;Klinikum Schwabing, Academic Teaching Hospital of the University of Munich, Munich, Germany.;Klinikum Schwabing, Academic Teaching Hospital of the University of Munich, Munich, Germany.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.;Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.;Department of Medicine III, Paracelsus Medical University, Salzburg, Austria.;Klinikum Schwabing, Academic Teaching Hospital of the University of Munich, Munich, Germany.;Cambridge University Hospitals, NHS Foundation Trust, Cambridge, UK.;Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.;Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.;Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.",
"authors": "Kazianka|L|L|;Drucker|C|C|;Skrabs|C|C|;Thomas|W|W|;Melchardt|T|T|;Struve|S|S|;Bergmann|M|M|;Staber|P B|PB|;Porpaczy|E|E|;Einberger|C|C|;Heinz|M|M|;Hauswirth|A|A|;Raderer|M|M|;Pabinger|I|I|;Thalhammer|R|R|;Egle|A|A|0000-0003-0648-4416;Wendtner|C-M|CM|;Follows|G|G|;Hoermann|G|G|;Quehenberger|P|P|;Jilma|B|B|;Jaeger|U|U|",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012310:Ristocetin; C551803:ibrutinib; D000225:Adenine",
"country": "England",
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"doi": "10.1038/leu.2016.316",
"fulltext": "\n==== Front\nLeukemiaLeukemiaLeukemia0887-69241476-5551Nature Publishing Group leu201631610.1038/leu.2016.31627909342Original ArticleRistocetin-induced platelet aggregation for monitoring of bleeding tendency in CLL treated with ibrutinib Platelet function and ibrutinibKazianka L 12Drucker C 3Skrabs C 12Thomas W 4Melchardt T 5Struve S 6Bergmann M 6Staber P B 12Porpaczy E 12Einberger C 12Heinz M 12Hauswirth A 12Raderer M 27Pabinger I 12Thalhammer R 8Egle A 5http://orcid.org/0000-0003-0648-4416Wendtner C-M 6Follows G 4Hoermann G 8Quehenberger P 8Jilma B 3Jaeger U 12*1 Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria2 Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria3 Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria4 Cambridge University Hospitals, NHS Foundation Trust, Cambridge, UK5 Department of Medicine III, Paracelsus Medical University, Salzburg, Austria6 Klinikum Schwabing, Academic Teaching Hospital of the University of Munich, Munich, Germany7 Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria8 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria* Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna Austria. E-mail: ulrich.jaeger@meduniwien.ac.at05 2017 02 11 2016 02 12 2016 31 5 1117 1122 10 05 2016 28 09 2016 05 10 2016 Copyright © 2017 The Author(s)2017The Author(s)This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.\n==== Body\nIntroduction\nTargeting Bruton's tyrosine kinase (BTK) with the small-molecule ibrutinib has significantly improved progression-free and overall survival of patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma and is currently investigated in other B-cell lymphomas.1, 2, 3, 4, 5 The drug is now widely used in clinical routine. Its mechanism of action is based on the inhibition of BTK as part of the B-cell receptor signaling cascade.6, 7, 8, 9, 10 BTK is also expressed in other hematopoietic lineages, including platelets.11, 12, 13 Inhibition of this kinase may therefore result in relevant hematologic side effects. Indeed, bleeding episodes were observed in 44% of patients in the CLL registration trial1 and in up to 61% of patients after a longer observation period.14\n\nBleeding is usually mild (Common Toxicity Criteria (CTC) grades 1–2, corresponding to spontaneous bruising or petechiae), but more severe bleeding is observed in 8% of patients.14 CTC grade 3 or 4 bleeding occurs in ∼5% of patients after trauma.1, 4, 15\n\nBTK is a TEC family kinase and acts as a signaling molecule in von Willebrand factor (vWF)- and collagen-induced platelet activation.12 The corresponding receptors glycoprotein VI (GPVI, collagen receptor) and the glycoprotein Ib-IX-V complex (GPIb, vWF receptor) have previously been shown to be affected by BTK inhibition: in vitro binding of platelets from ibrutinib-treated patients to vWF matrix was significantly impaired16 as well as platelet response to collagen using light transmission aggregometry.11\n\nOf note, vWF antigen and activity in plasma remain within normal range.17 The dependency of GPIb-IX-V signaling on BTK has also been shown in vivo using a BTK-deficient mouse model.13 However, there is a possibility that TEC, another member of the TEC kinase family, compensates for the loss of BTK in platelets as it is indicated by the partially preserved response to collagen in human X-linked agammaglobulinemia patients.18 Nevertheless, the cysteine residue that is required for the covalent binding of ibrutinib to an adenosine triphosphate-binding site can also be found in TEC.12 Taken together, there is strong evidence that pharmacologic inhibition of BTK and other TEC kinases by ibrutinib results in impaired platelet function.\n\nProper management of bleeding complications is important because they may affect the length and intensity of ibrutinib treatment. In addition, up to 50% of CLL patients with cardiovascular comorbidities are under concomitant treatment with anticoagulants or platelet function inhibitors.19, 20\n\nWe used an easy to perform method for quantitative assessment of vWF/ristocetin-induced platelet aggregation (RIPA) in ibrutinib-treated CLL patients in order to (1) correlate the degree of impairment of platelet function with bleeding tendency and (2) monitor platelet aggregation during drug therapy and before interventions.\n\nSubjects and methods\nSubjects\nThis observational study included 64 CLL patients from 4 different centers in 3 countries (Cambridge, Munich, Salzburg and Vienna). Patients received ibrutinib at a target dose of 420 mg daily and were either included in the RESONATE study (28 patients), in the ibrutinib named patient program (12 patients) or received ibrutinib in routine clinical use according to the licensed indication in Europe (24 patients). Of the patients, 18% were previously untreated but had a 17p deletion or TP53 mutation, whereas 82% had relapsed or refractory CLL with or without 17p/TP53 aberrations. The study was approved by the ethics committee of the Medical University of Vienna (ethics committee Nr 1631/2012 and 11/2005) and informed consent was obtained. Eleven patients had multiple measurements before start and during ibrutinib therapy and 53 patients were investigated under stable ibrutinib intake.\n\nPatients were seen regularly (at least monthly) in their corresponding centers. Bleeding tendency was recorded at each time point by standardized questions including bruising, petechiae and epistaxis, and a physical examination was performed. Clinical information included clinical stage, genetics, lines of therapy and concomitant treatment, particularly therapy with antiplatelet agents or anticoagulants. Patient characteristics are shown in Table 1. Severity of bleeding was scored according to the CTC grading scale (version 4.03: 14 June 2010) used in the RESONATE protocol.\n\nControls included 13 CLL patients currently not on treatment, 11 patients receiving other treatments for CLL (4 with immunochemotherapy (rituximab plus fludarabine/cyclophosphamide or bendamustin) and 7 with phosphatidylinositol-3-kinase inhibitors (idelalisib, duvelisib)) as well as 1 patient with X-linked agammaglobulinemia and proven BTK protein deficiency.\n\nPlatelet function assessments\nFresh blood specimens (5 ml) for analysis of platelet function were drawn into hirudine containing tubes (Vacuette, Kremsmuenster, Austria) and analyzed within 3 h in a Multiplate Analyzer (Roche, Vienna, Austria) according to the manufacturer's recommendations. This whole blood platelet aggregometry measures the increase in electric resistance when platelets adhere and aggregate on electrodes. The in-house normal ranges of the performed aggregation tests were 44–176 U for RIPA and 22–110 U for collagen-induced platelet aggregation in healthy volunteers.21 The measured area under the curve allows quantification of platelet function. RIPA and collagen-induced platelet aggregation were performed for this study. Importantly, test results are dependent on platelet function and platelet count22, 23 and the assessment has to be performed on fresh whole blood locally.\n\nReproducibility\nVariability of the RIPA test was evaluated in Vienna in five healthy donors and six patients under ibrutinib. A total of 4–10 measurements were performed from the same time point and on consecutive days in healthy donors. In total, median values for healthy donors ranged from 81.9 to 133.0 U with an intraindividual coefficient of variation of 7.6 to 9.1%. Median values for the 6 patients were 4.1 to 37.5 U with a coefficient of variation from 11.2 to 15.6% in 5 patients. In one patient with very low values the results varied from 1 to 8 U (coefficient of variation 49.4%), but still stayed in the same range.\n\nIn addition, vWF antigen and activity were assessed by standard methods as described previously.24\n\nStatistical methods\nStatistical analysis was performed using JMP Statistics (SAS Corporation, Cary, NC, USA) software. Statistical methods comprised χ2 analysis or Fisher's exact test to compare baseline characteristics, and t-test or analysis of variance where applicable for RIPA analysis. Correlations were determined by Pearson's r. The P-values of <0.05 (two sided) were considered statistically significant.\n\nResults\nPatient characteristics and bleeding events\nThe study cohort consisted of a typical CLL cohort treated with ibrutinib with a median age of 71 (range: 40–92) years, 2 (range: 0–6) prior treatment lines and aberrations of TP53 (17p deletion and/or TP53 mutation) in 47.6%. The median observation period under ibrutinib was 10.9 months. Importantly, 28.1% were treated with concomitant antiplatelet (acetyl salicylic acid, clopidogrel, 18.8%) or anticoagulation therapy (coumarin, heparin, novel direct oral anticoagulants, 10.9%) or both (in 1 case).\n\nAt least one bleeding event was recorded in 39 of the 64 patients (60.9% Table 1). Bleeding was mild in most patients (CTC grade 1 or 2) and only two CTC grade 3 bleedings were observed. The total number of bleeding episodes was 87, again predominantly grade 1 or 2. None of the patients had a grade 4 or 5 bleeding event. Of note, 60 of the 64 patients (93.8%) were still responding and on ibrutinib after 10.9 months. Reasons for discontinuation or pause are shown in Table 1.\n\nBleeding tendency, platelet number and anticoagulation\nThe occurrence of bleeding events under ibrutinib was significantly associated with lower platelet counts (116.5 G/l, range: 38–303 vs 137 G/l, range: 51–328; P=0.0012; Supplementary Figure 1). Patients receiving antiplatelet therapy or anticoagulation (13/18, 72%) were more frequently affected than patients without concomitant treatment (26/46; 57%, P=0.25). Patients with anticoagulation had the highest frequency of bleeding (6 of 7 patients; Table 2). However, this was not statistically significant.\n\nImpairment of platelet aggregation during ibrutinib treatment\nIn total, 287 quantitative assessments were performed by RIPA (median: 3 per patient). CLL patients without current treatment (median 57 U, range: 8–111) or during immunochemotherapy (median 68.5 U, range: 27–94) had RIPA values close to normal, whereas patients under ibrutinib had considerably impaired RIPA values, although with a wide range (median 19.5 U, range: 0–199; Supplementary Figure 2).\n\nBleeding tendency and platelet function\nThe major goal of this study was to establish an association between bleeding and platelet function during ibrutinib treatment. The median RIPA measured at times of bleeding events under ibrutinib was significantly impaired (median 14 U, range: 0–76) compared with time points when no bleeding was observed (median 28 U, range: 0–199; P<0.0001; Figure 1a). Collagen-induced platelet aggregation testing confirmed the findings obtained by RIPA measurements. Platelet function showed significantly lower values at time points when bleeding occurred (P=0.0015; Supplementary Figure 3). We confirmed that RIPA values with this assay correlate with platelet numbers (P<0.0001; Supplementary Figure 4).23 However, low RIPA values were associated with bleeding regardless of platelet count (Figure 1b).\n\nEffect of concomitant anticoagulation\nRIPA was significantly impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005; Figure 2). This effect was seen regardless of platelet count, but more prominent when platelets were >100 G/l (Supplementary Figure 5). There was no difference between patients receiving antiplatelet or anticoagulant therapy (data not shown).\n\nBleeding severity and platelet function\nWe next analyzed platelet function in relation to the severity of the event expressed by CTC grade: a steady decline of median RIPA values was observed from time points without bleeding (28 U) to CTC grade 1 (14.5 U), grade 2 (12 U) and grade 3 (8.5 U) events (Figure 3). Importantly, no CTC grade 2 or 3 bleeding was observed with RIPA values of >36 U. These data indicate that impairment of platelet function is associated with severity of bleeding and that significant bleeding does not occur beyond a defined threshold.\n\nMonitoring of platelet function during ibrutinib therapy\nConsecutive samples before and after start of ibrutinib were available in 11 patients. A decline of platelet aggregation from 17 to 9 U was observed when therapy was initiated (P=0.019; Figure 4). The median interval between measurements was 13 days. When ibrutinib was paused or stopped (9 instances) the median RIPA values increased from 12 to 54 U (P=0.004; median interval 18 days; Figure 5a). Short-term RIPA kinetics were available in 5 patients (Figure 5b): some variability of platelet function recovery was observed with 4 of 5 patients crossing the imaginary threshold of 36 U within 7 days, whereas recovery was slow in 1 patient. These data indicate that quantitative assessment of RIPA may be used to monitor platelet function, for example, in the context of planned surgical interventions.\n\nPlatelet function with higher doses of ibrutinib and other BTK inhibitors\nWe also assessed RIPA in patients receiving higher doses of ibrutinib (560 mg daily) in mantle cell lymphoma patients (n=7). RIPA values were comparable to those in CLL patients (Figure 6). Ibrutinib also inhibits other kinases including TEC kinases that are also involved in the regulation of platelet function. Interestingly, patients under treatment with a different BTK inhibitor, CC292 (n=6), showed almost identical RIPA values (19.5 vs 23 U). Two different measurements in a patient with a hereditary BTK deficiency (X-linked agammaglobulinemia) showed less impairment of platelet function.\n\nDiscussion\nIbrutinib has become an integral part of the CLL treatment algorithm. The drug is well tolerated, but bleeding is a frequent side effect.14 Here we show that quantitative assessment of RIPA is a practical tool to monitor and manage bleeding tendency, and may thereby increase the safety of ibrutinib.\n\nThe theoretical basis for the impairment of platelet function has been well described by others13, 16, 18 (Supplementary Figure 6). BTK is an important component of the signaling cascades downstream of the GPIb and GPVI platelet receptors.13, 18 Therefore, ristocetin- as well as collagen-induced platelet aggregation are impaired and could both be used as diagnostic tools.16 Unfortunately, assessment of platelet function by light transmission aggregometry has turned out to be tedious, variable and operator dependent. Here we used an easy to perform whole blood aggregometry method that is frequently used in clinical routine. We chose the RIPA assay for our investigations because of its slightly better discriminatory power in preliminary experiments. However, similar results were obtained with collagen-induced platelet aggregation (Supplementary Figure 3). There are some uncertainties as to the contribution of BTK in comparison with other Tec kinases in impairing platelet function as ibrutinib inhibits several other kinases. However, the data obtained with a different BTK inhibitor, CC292, argue for a strong involvement of BTK in platelet function. It remains to be established whether this will translate into clinical bleeding tendency when other selective BTK inhibitors enter the clinic.25, 26\n\nThe major clinical finding of this study is that low RIPA values are strongly associated with bleeding tendency. This is supported by the following observations: (1) a decline in platelet aggregation was observed when ibrutinib is initiated; (2) platelet function was significantly impaired in CLL patients under stable ibrutinib therapy compared with CLL patients under immunochemotherapy or without current intervention; and (3) at times when bleeding events occurred, RIPA values were significantly lower (14 vs 28 U). This also is in line with previous observations made by other groups.11, 16, 17 Bleeding under ibrutinib is usually mild, but can be severe in 5 to 8% of patients.14, 16 A practical clinical implication of our study is that RIPA values decrease with the degree of bleeding. Thus, it seems possible to define a threshold (36 U in this study) above which no major bleeding events (CTC grade ⩾3) will occur. This will allow monitoring of bleeding tendency with RIPA tests before elective surgery or in cases of emergency, where platelet transfusions may be indicated.16 We note that the recommended washout period of 7 days before surgical interventions correlated well with the increase in RIPA above the threshold level of 36 U in most patients. However, this may be different in some patients in whom monitoring will add important information for clinical decisions.\n\nWe observed an association of platelet number with bleeding tendency confirming previous observations (Supplementary Figure 1), indicating that bleeding events were more frequent during the initial treatment phase of CLL patients, when platelets are still low.14 In addition, there was a strong correlation between RIPA and platelet number in the assay used for this study, as reported during the evaluation of the test (Supplementary Figure 4).23 However, the association of low RIPA values and bleeding under ibrutinib was still significant regardless of platelet counts (Figure 1b). In addition, the median platelet values were quite high with a median of 116.5 G/l in bleeding patients.\n\nIncreased bleeding tendency with concomitant antiplatelet or anticoagulation therapy has been reported and has led to the recommendation that warfarin should not be used together with ibrutinib.10 There was a trend for, but no significant association of, concomitant antiplatelet or anticoagulation treatment with bleeding in our study. This is probably because of low patient numbers. However, in our study low RIPA values were associated with both antiplatelet and anticoagulation therapy indicating a higher propensity for bleeding.\n\nThere are some limitations to this study. The RIPA impedance test has to be performed on site within a limited time frame with fresh samples. Frozen or shipped samples cannot be used. On the other hand, the analyzer used is now widely available in larger hospitals. In addition, similar and reliable results could be obtained in 4 different centers in 3 countries (median RIPA values were 26 U (range: 0–199; Vienna), 14 U (range: 1–148; Cambridge), 16 U (range: 2–76; Munich) and 25 U (range: 3–68; Salzburg)). Measurements under stable ibrutinib intake on consecutive visits showed little variability (Supplementary Figure 7). There was no significant statistical difference between centers. The test has a reasonably low intraindividual variation (coefficient of variation <10% in healthy donors and <16% in patients under ibrutinib) confirming its clinical reliability. The threshold for major bleeding events is currently only based on 64 CLL patients and 287 measurements. A more detailed and formal evaluation such as for other CLL diagnostic tests will be required for robust generalized diagnostics.27, 28 Reporting of bleeding events is dependent on thorough clinical evaluation of patients at any visit. We have therefore developed a questionnaire that can be used in the future. Last but not the least, further confirmation in larger studies is still needed.\n\nIt is important to note that 93.8% of our CLL patients were still responding to ibrutinib after 10.9 months and many will remain on the drug for much longer. Monitoring of bleeding tendency with platelet function tests may therefore contribute to enhance safety, adherence and the successful long-term use of ibrutinib.\n\nExpert assistance by Michaela Bronhagl and Bernadette Hilgarth is gratefully acknowledged. This study was in part supported by Grant SFB54-P04 (to BJ) from the Austrian Science Funds (FWF).\n\nSupplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)\n\nThis work has been presented in part at the 57th Annual Meeting of the American Society of Hematology in Orlando 2015.\n\nMB, PS, AE, C-MW and UJ received honoraria from Janssen. LK, CD, CS, WT, TM, SS, EP, CE, MH, AH, MR, IP, RT, GH, PQ and BJ declare no conflict of interest.\n\nSupplementary Material\nSupplementary Files Click here for additional data file.\n\n Figure 1 RIPA measurements in CLL patients during stable ibrutinib therapy. (a) RIPA measurements were significantly lower at the time when bleeding-related adverse events occurred (median 14 vs 28 U, P<0.0001). (b) When patients were grouped by platelet count, RIPA results remained impaired at the time of bleeding-related adverse events (P=0.003 and P<0.0001, respectively).\n\nFigure 2 RIPA in ibrutinib-treated CLL patients with concomitant antiplatelet and/or anticoagulant medication. Ibrutinib-treated CLL patients under concomitant antiplatelet and/or anticoagulant therapy showed reduced RIPA values (median 14 U, range: 0–118 U) when compared with patients without concomitant medication (median 25 U, range: 0–199 U; P=0.005).\n\nFigure 3 Relationship of RIPA with severity of bleeding. Results of RIPA measurements showed a median value of 28 U (range: 0–199 U) when no bleeding-related adverse event was reported, and decreased gradually from CTC grade 1 (median 14.5 U, range: 0–76 U) to CTC grade 2 (median 12 U, range: 0–36 U) and CTC grade 3 events (median 8.5 U, range: 2–15 U) dependent on adverse event severity.\n\nFigure 4 Dynamics of RIPA after initiation of ibrutinib therapy in CLL patients. Consecutive measurements were available in 11 CLL patients and showed a marked decrease (median 17 U, range: 3–70 U vs median 9 U, range: 0–19 U, P=0.019) after a median period of 13 days of ibrutinib therapy.\n\nFigure 5 Dynamics of RIPA measurements after pause/discontinuation of ibrutinib therapy in CLL patients. (a) Platelet function partly recovered (median 12 vs 54 U, P=0.004) after pause/discontinuation of ibrutinib therapy. The median time between measurements was 18 days in 9 patients. (b) In five patients, RIPA was measured in shorter intervals after discontinuation. The threshold of 36 U was reached within 7 days by 4/5 patients.\n\nFigure 6 Comparison of platelet function in ibrutinib-treated CLL (n=64), ibrutinib-treated mantle cell lymphoma (MCL; n=7), CC292-treated CLL (n=6), CLL control (n=13) and X-linked agammaglobulinemia (XLA; n=1) patients. Median RIPA values: ibrutinib/CLL (19.5 U, range: 0–199 U), ibrutinib/MCL (20.5 U, range: 9–97 U), CC292/CLL (23 U, range: 3–49 U), Control CLL (37 U, range: 6–94 U) and XLA (56 U, range 33–79 U).\n\nTable 1 Patient characteristics\nCharacteristic\tIbrutinib patients (n=64)\t\nMedian age, years (range)\t71 (40–92)\t\n ⩾70 Years\t56.3%\t\n ⩾75 Years\t29.7%\t\nMale, %\t64.1%\t\nMedian weight, kg (range)\t76 (44–114)\t\nMale\t80 (62–114)\t\nFemale\t58 (44–84)\t\nMedian number of prior therapies (range)\t2 (0–6)\t\n 0\t18%\t\n 1\t27.9%\t\n 2\t32.8%\t\n ⩾3\t21.3%\t\nDel17p or TP53 mutation, %\t47.6%\t\nMedian platelet count, G/l (range)\t114.5 (28–307)\t\nMedian observation period, months (range)\t10.9 (0.5–35.3)\t\nPatients with at least one bleeding event\t39/64 (60.9%)\t\n CTC grade 1 or 2\t37\t\n CTC grade 3\t2\t\nCTC grade 4 or more severe\tNone\t\nTotal number of bleeding events during follow-up\t87\t\n CTC grade 1 or 2\t85/87 (97.7%)\t\n CTC grade 3\t2/87 (2.3%)\t\n CTC grade 4 or more severe\tNone\t\nTotal number of patients in whom ibrutinib was paused or discontinued because of;\t11/64 (17.2%)\t\n Progression of disease/death\t2/64 (3.1%)\t\n Adverse event\t6/64 (9.4%)\t\n Planned surgery\t3/64 (4.7%)\t\nTotal number of patients still responding and on ibrutinib after a median of 10.9 months (0.5–35.3)\t60/64 (93.8%)\t\nAbbreviation: CTC, Common Toxicity Criteria.\n\nTable 2 Characteristics of bleeding and nonbleeding patients\nCharacteristic\tBleeding\tNo bleeding\tP-value\t\nTotal number (n=64)\t39/64 (60.9%)\t25/64 (39.1%)\tNA\t\nMedian body weight, kg (range)\t74 (48–108)\t69.5 (44–114)\t0.49\t\nMale, %\t64.1%\t64%\t0.99\t\nAntiplatelet or anticoagulant Tx\t13/39 (33.3%)\t5/25 (20%)\t0.25\t\nAntiplatelet therapy\t8/39 (20.5%)\t4/25 (16%)\t0.65\t\nOral AC/heparin\t6/39 (15.4%)\t1/25 (4%)\t0.15\t\nMedian platelet count, G/l (range)\t116.5 (38–303)\t137 (51–328)\t0.0012\t\nMedian hemoglobin, mg/dl (range)\t12.6 (9.2–16.7)\t12.1 (8.3–17.1)\t0.16\t\nMedian WBC, G/l (range)\t21.8 (4.3–347.8)\t16.0 (2.2–397)\t0.41\t\nAbbreviations: AC, anticoagulant; NA, not available; Tx, treatment; WBC, white blood cell count. Bold value indicates significant P-value.\n==== Refs\nByrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia . N Engl J Med \n2013 ; 369 : 32 –42.23782158 \nByrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM et al. Ibrutinib versus of atumumab in previously treated chronic lymphoid leukemia . N Engl J Med \n2014 ; 371 : 213 –223.24881631 \nWilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma . Nat Med \n2015 ; 21 : 922 –926.26193343 \nWang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma . N Engl J Med \n2013 ; 369 : 507 –516.23782157 \nWang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results . 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Leukemia \n2015 ; 29 : 783 –787.25138588 \nBerglof A, Hamasy A, Meinke S, Palma M, Krstic A, Mansson R et al. Targets for ibrutinib beyond B cell malignancies . Scand J Immunol \n2015 ; 82 : 208 –217.26111359 \nLiu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo . Blood \n2006 ; 108 : 2596 –2603.16788103 \nByrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib . Blood \n2015 ; 125 : 2497 –2506.25700432 \nAdvani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies . J Clin Oncol \n2013 ; 31 : 88 –94.23045577 \nLevade M, David E, Garcia C, Laurent PA, Cadot S, Michallet AS et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions . Blood \n2014 ; 124 : 3991 –3995.25305202 \nWiestner A. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia . Haematologica \n2015 ; 100 : 1495 –1507.26628631 \nAtkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk . Blood \n2003 ; 102 : 3592 –3599.12842985 \nGoede V, Bahlo J, Chataline V, Eichhorst B, Durig J, Stilgenbauer S et al. Evaluation of geriatric assessment in patients with chronic lymphocytic leukemia: Results of the CLL9 trial of the German CLL study group . Leuk Lymphoma \n2016 ; 57 : 789 –796.26377031 \nJones JA, Hillmen P, Coutre S, Tam C, Furman RR, Barr PM et al. Pattern of use of anticoagulation and/or antiplatelet agents in patients with chronic lymphocytic leukemia (CLL) treated with single-agent ibrutinib therapy . Blood \n2014 ; 124 : 1990 .\nSpiel AO, Bartko J, Schwameis M, Firbas C, Siller-Matula J, Schuetz M et al. Increased platelet aggregation and in vivo platelet activation after granulocyte colony-stimulating factor administration. A randomised controlled trial . Thromb Haemost \n2011 ; 105 : 655 –662.21301783 \nFemia EA, Scavone M, Lecchi A, Cattaneo M. Effect of platelet count on platelet aggregation measured with impedance aggregometry (Multiplate analyzer) and with light transmission aggregometry . J Thromb Haemost \n2013 ; 11 : 2193 –2196.24148217 \nHanke AA, Roberg K, Monaca E, Sellmann T, Weber CF, Rahe-Mayer N et al. Impact of platelet count on results obtained from multiple electrode platelet aggregometry (Multiplate) . Eur J Med Res \n2010 ; 15 : 214 –219.20562061 \nJilma-Stohlawetz P, Knobl P, Gilbert JC, Jilma B. The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease . Thrombosis Haemost \n2012 ; 108 : 284 –290.\nWalter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies . Blood \n2016 ; 127 : 411 –419.26542378 \nByrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia . N Engl J Med \n2016 ; 374 : 323 –332.26641137 \nRawstron AC, Fazi C, Agathangelidis A, Villamor N, Letestu R, Nomdedeu J et al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study . Leukemia \n2015 ; 30 : 929 –936.26639181 \nPospisilova S, Sutton LA, Malcikova J, Tausch E, Rossi D, Montserrat E et al. Innovation in the prognostication of chronic lymphocytic leukemia: how far beyond TP53 gene analysis can we go ? Haematologica \n2016 ; 101 : 263 –265.26928246\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0887-6924",
"issue": "31(5)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016903:Drug Monitoring; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D010974:Platelet Aggregation; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012310:Ristocetin",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1117-1122",
"pmc": null,
"pmid": "27909342",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "22875912;26193343;23782157;26639181;25305202;12842985;23045586;26928246;25138588;21301783;26059948;23656200;23782158;20562061;16788103;24111579;26542378;25700432;23045577;26377031;24881631;26111359;26641137;22740102;23296407;26628631;24148217",
"title": "Ristocetin-induced platelet aggregation for monitoring of bleeding tendency in CLL treated with ibrutinib.",
"title_normalized": "ristocetin induced platelet aggregation for monitoring of bleeding tendency in cll treated with ibrutinib"
} | [
{
"companynumb": "AT-JNJFOC-20170509493",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": null,
"... |
{
"abstract": "Heterozygous mutations in the genes encoding the proα1(I) or proα2(I) chains of type I procollagen (COL1A1 and COL1A2, respectively) account for most cases of osteogenesis imperfecta (OI), a disorder characterized by reduced bone strength and increased fracture risk. COL1A1 mutations can also cause rare cases of Ehlers-Danlos syndrome (EDS), a disorder that primarily affects connective tissue and often includes reduced bone mass. Here we present a kindred of three young siblings ages 1-4 years old whose mother has a history of mild type I OI. All three children are compound heterozygotes for COL1A1 mutations, with a novel frameshift mutation (c.2522delC; p.Pro841Leufs*266) from their mother and a known missense mutation (c.3196C>T; p.R1066C) from their clinically unaffected father, which has previously been described as causing a combined type I OI/EDS phenotype. The three children exhibit features of both COL1A1 mutations: early and frequent long bone fractures, joint hyperextensibility, and blue sclerae. We describe three siblings who are the first reported surviving subjects with biallelic pathogenic COL1A1 mutations. They have a more severe form of type I OI with features of EDS that represents their compound heterozygosity for two deleterious COL1A1 mutations. Their long-term outcomes are yet to be determined.",
"affiliations": "Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.",
"authors": "Ackermann|Amanda M|AM|http://orcid.org/0000-0002-5614-9790;Levine|Michael A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.38238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "173(7)",
"journal": "American journal of medical genetics. Part A",
"keywords": "Ehlers-Danlos syndrome; biallelic mutations; collagen; osteogenesis imperfecta",
"medline_ta": "Am J Med Genet A",
"mesh_terms": null,
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "1907-1912",
"pmc": null,
"pmid": "28436160",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Compound heterozygous mutations in COL1A1 associated with an atypical form of type I osteogenesis imperfecta.",
"title_normalized": "compound heterozygous mutations in col1a1 associated with an atypical form of type i osteogenesis imperfecta"
} | [
{
"companynumb": "PHHY2017US062833",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nThe consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) proposed by the European Network for Drug Allergy (ENDA) interest group (2011) was revised in 2013. We aimed to evaluate the usability of the latest NSAID hypersensitivity classification of ENDA.\n\n\nMETHODS\nA total of 370 patients with a history of hypersensitivity reactions to NSAIDs among the 1250 outpatients referred for suspected drug allergy between July 2013 and June 2014 were evaluated, and 308 patients who were confirmed as having NSAID hypersensitivity were included in this study. After confirming the diagnosis, a single-blind placebo-controlled drug provocation test was performed with aspirin or diclofenac to categorize the patients according to the ENDA classification. The reactions not meeting the ENDA classification criteria were grouped as blended reactions.\n\n\nRESULTS\nAmong the 308 patients (224 female, mean age 42.12 ± 13.24), the leading cause of hypersensitivity reactions was metamizol (30.5%) followed by aspirin (30.2%). The most common NSAID hypersensitivity subgroup was SNIUAA (46.4%) and the least common type was SNIDR (1.6%). Cross-reactivity was identified in 50.3% of the patients. In five patients (1.6%), the hypersensitivity reactions to NSAIDs did not meet the ENDA classification: Three patients experienced anaphylaxis with different NSAIDs, one patient encountered anaphylaxis with one NSAID and urticaria with other NSAIDs, and the last patient had angioedema with different NSAIDs.\n\n\nCONCLUSIONS\nThe latest ENDA classification for NSAID hypersensitivity is generally a practical and useful instrument for clinicians. We only point out that anaphylaxis with different NSAIDs can be seen in a small group of patients.",
"affiliations": "Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Demir|S|S|;Olgac|M|M|;Unal|D|D|;Gelincik|A|A|;Colakoglu|B|B|;Buyukozturk|S|S|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "Denmark",
"delete": false,
"doi": "10.1111/all.12689",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-4538",
"issue": "70(11)",
"journal": "Allergy",
"keywords": "classification; hypersensitivty reactions to NSAID",
"medline_ta": "Allergy",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000707:Anaphylaxis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003429:Cross Reactions; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012307:Risk Factors; D012882:Skin Tests; D055815:Young Adult",
"nlm_unique_id": "7804028",
"other_id": null,
"pages": "1461-7",
"pmc": null,
"pmid": "26173603",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs according to the latest classification.",
"title_normalized": "evaluation of hypersensitivity reactions to nonsteroidal anti inflammatory drugs according to the latest classification"
} | [
{
"companynumb": "PHHY2015TR148564",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
"d... |
{
"abstract": "Serotonin syndrome is a syndrome identified by a triad of altered mental status, neuromuscular overactivity, and autonomic instability caused by the overstimulation of serotonin in the central nervous system and periphery. Serotonin syndrome may be provoked with the addition or increase in serotonergic agents such as selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors as well as other agents with serotonergic properties. Some narcotics, including fentanyl and methadone, have these properties and may be associated with the development of serotonin syndrome when used in conjunction with other agents. Currently, there are no identified case reports of narcotics as the sole agent causing serotonin syndrome. This report provides a brief overview of serotonin syndrome, particularly with cases involving administration of narcotics such as fentanyl and methadone. The case described is the first report associated with fentanyl and methadone without the coadministration of other serotonergic agents, and a possible drug interaction with voriconazole is discussed. This raises awareness of using multiple serotonergic narcotics and the potential precipitation of serotonin syndrome.",
"affiliations": "Department of Pharmacy, The University of North Carolina Hospitals and Clinics, Chapel Hill, North Carolina.",
"authors": "Hillman|Ashley D|AD|;Witenko|Corey J|CJ|;Sultan|Said M|SM|;Gala|Gary|G|",
"chemical_list": "D000701:Analgesics, Opioid; D065819:Voriconazole; D008691:Methadone; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1528",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "35(1)",
"journal": "Pharmacotherapy",
"keywords": "drug interaction; fentanyl; methadone; narcotics; serotonin syndrome",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002056:Burns; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005283:Fentanyl; D006801:Humans; D008297:Male; D008691:Methadone; D020230:Serotonin Syndrome; D016896:Treatment Outcome; D065819:Voriconazole",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "112-7",
"pmc": null,
"pmid": "25615513",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonin syndrome caused by fentanyl and methadone in a burn injury.",
"title_normalized": "serotonin syndrome caused by fentanyl and methadone in a burn injury"
} | [
{
"companynumb": "US-ACTAVIS-2015-23589",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Despite significant recent advances in characterizing the molecular pathogenesis of undifferentiated round cell neoplasms, rare cases remain unclassified. Here, we report two distinctive undifferentiated round cell tumors occurring in young adults. One tumor presented intrabdominally and the other arose within the abdominal wall. One patient died of disease following local and distance recurrence, despite aggressive chemotherapy and radiotherapy. Morphologically, both tumors were similarly composed of primitive round to epithelioid cells arranged in nests, sheets, and trabecular patterns. The cytoplasm was scant and amphophilic, while the nuclei were round and uniform with brisk mitotic activity. Focal necrosis was present. Immunohistochemically, both tumors were variably positive for S100 and EMA, and one case focally expressed cytokeratin and TLE1. Targeted RNA sequencing revealed in both an identical SS18-POU5F1 fusion gene. Fluorescence in situ hybridization was performed which confirmed SS18 and POU5F1 gene rearrangements. Expression data, relative to over 200 other mesenchymal neoplasms that had undergone targeted RNA sequencing on the same platform, suggested the SS18-POU5F1 tumors cluster with EWSR1/FUS-POU5F1-positive myoepithelial tumors. In view of our limited sample size, additional studies are needed to characterize the breadth of clinical and pathologic findings in these neoplasms. In addition, further investigation is necessary to determine whether this entity represents a clinically aggressive and phenotypically undifferentiated variant of myoepithelial tumors, or perhaps an altogether novel category of undifferentiated round cell sarcoma.",
"affiliations": "Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.",
"authors": "Antonescu|Cristina R|CR|0000-0002-9717-8205;Agaram|Narasimhan P|NP|0000-0002-6991-2310;Sung|Yun-Shao|YS|;Zhang|Lei|L|;Dickson|Brendan C|BC|",
"chemical_list": "D050814:Octamer Transcription Factor-3; D015514:Oncogene Proteins, Fusion; C494173:POU5F1 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C093961:SS18 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1002/gcc.22879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1045-2257",
"issue": "59(11)",
"journal": "Genes, chromosomes & cancer",
"keywords": "POU5F1; SS18; fusion; myoepithelial tumor; sarcoma; synovial sarcoma",
"medline_ta": "Genes Chromosomes Cancer",
"mesh_terms": "D000008:Abdominal Neoplasms; D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D050814:Octamer Transcription Factor-3; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D012509:Sarcoma",
"nlm_unique_id": "9007329",
"other_id": null,
"pages": "620-626",
"pmc": null,
"pmid": "32557980",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25614489;20203285;31994243;26523541;32362012;29390927;9814708;29572501;29300189;20815032;25384085;11368913;7951320;31595587;18338330;15729702;27914109;10742100;29533464;22510762;28233365",
"title": "Undifferentiated round cell sarcomas with novel SS18-POU5F1 fusions.",
"title_normalized": "undifferentiated round cell sarcomas with novel ss18 pou5f1 fusions"
} | [
{
"companynumb": "US-009507513-2011USA004487",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAnti-tumor necrosis factor (TNF) drugs have improved the prognosis for juvenile idiopathic arthritis (JIA) significantly. However, evidence for individual treatment decisions based on serum anti-TNF drug levels and the presence of anti-drug antibodies (ADAbs) in children is scarce. We aimed to assess if anti-TNF drug levels and/or ADAbs influenced physician's treatment decisions in children with JIA.\n\n\nMETHODS\nPatients' records in our center were retrospectively screened for measurements of anti-TNF drug levels and ADAbs in children with JIA using etanercept, adalimumab or infliximab. Clinical characteristics and disease activity were retrieved from patient charts.\n\n\nRESULTS\nWe analyzed 142 measurements of anti-TNF drug levels in 65 children with JIA. Of these, ninety-seven (68.3%) were trough concentrations. N = 14/97 (14.4%) of these showed trough concentrations within the therapeutic drug range known for adults with RA and IBD. ADAbs against adalimumab were detected in seven patients and against infliximab in one patient. Seven (87,5%) of these ADAb-positive patients had non-detectable drug levels. A flowchart was made on decisions including rational dose escalation, stopping treatment in the presence of ADAbs and undetectable drug levels, showing that 45% of measurements influenced treatment decisions, which concerned 65% of patients (n = 42/65).\n\n\nCONCLUSIONS\nIn the majority of patients, measurement of anti-TNF drug levels led to changes in treatment. A wide variation of anti-TNF drug levels was found possibly due to differences in drug clearance in different age groups. There is need for determination of therapeutic drug ranges and pharmacokinetic curves for anti-TNF and other biologics in children with JIA.",
"affiliations": "Zaans Medical Center, Zaandam and Emma Children's Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands. a.nassar@amsterdamumc.nl.;Emma Children's Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands.;Emma Children's Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands.;Emma Children's Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands.;Department of Immunopathology, Sanquin Diagnostic Services Amsterdam, Amsterdam, The Netherlands.;Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.;Emma Children's Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands.;Department of Immunopathology, CLB Sanquin Amsterdam and Department of Rheumatology, Jan van Breemen Institute Amsterdam, Amsterdam, The Netherlands.;Emma Children's Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands.",
"authors": "Nassar-Sheikh Rashid|A|A|;Schonenberg-Meinema|D|D|;Bergkamp|S C|SC|;Bakhlakh|S|S|;de Vries|A|A|;Rispens|T|T|;Kuijpers|T W|TW|;Wolbink|G|G|;van den Berg|J M|JM|",
"chemical_list": "D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000079424:Tumor Necrosis Factor Inhibitors; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "England",
"delete": false,
"doi": "10.1186/s12969-021-00545-x",
"fulltext": "\n==== Front\nPediatr Rheumatol Online J\nPediatr Rheumatol Online J\nPediatric Rheumatology Online Journal\n1546-0096\nBioMed Central London\n\n545\n10.1186/s12969-021-00545-x\nResearch Article\nTherapeutic drug monitoring of anti-TNF drugs: an overview of applicability in daily clinical practice in the era of treatment with biologics in juvenile idiopathic arthritis (JIA)\nNassar-Sheikh Rashid A. a.nassar@amsterdamumc.nl\n\n1\nSchonenberg-Meinema D. d.schonenberg@amsterdamumc.nl\n\n2\nBergkamp S. C. s.c.bergkamp@amsterdamumc.nl\n\n2\nBakhlakh S. s.bakhlakh@amsterdamumc.nl\n\n2\nde Vries A. annick.devries@sanquin.nl\n\n3\nRispens T. t.rispens@sanquin.nl\n\n4\nKuijpers T. W. t.w.kuijpers@amsterdamumc.nl\n\n2\nWolbink G. wolbink@gmail.com\n\n5\nvan den Berg J. M. j.m.vandenberg@amsterdamumc.nl\n\n2\n1 grid.7177.6 0000000084992262 Zaans Medical Center, Zaandam and Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands\n2 grid.7177.6 0000000084992262 Emma Children’s Hospital, Amsterdam UMC, Pediatric Immunology, Rheumatology and Infectious Diseases, University of Amsterdam, Amsterdam, The Netherlands\n3 grid.417732.4 0000 0001 2234 6887 Department of Immunopathology, Sanquin Diagnostic Services Amsterdam, Amsterdam, The Netherlands\n4 grid.417732.4 0000 0001 2234 6887 Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands\n5 grid.418029.6 0000 0004 0624 3484 Department of Immunopathology, CLB Sanquin Amsterdam and Department of Rheumatology, Jan van Breemen Institute Amsterdam, Amsterdam, The Netherlands\n29 4 2021\n29 4 2021\n2021\n19 5926 1 2021\n14 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nAnti-tumor necrosis factor (TNF) drugs have improved the prognosis for juvenile idiopathic arthritis (JIA) significantly. However, evidence for individual treatment decisions based on serum anti-TNF drug levels and the presence of anti-drug antibodies (ADAbs) in children is scarce. We aimed to assess if anti-TNF drug levels and/or ADAbs influenced physician’s treatment decisions in children with JIA.\n\nMethods\n\nPatients’ records in our center were retrospectively screened for measurements of anti-TNF drug levels and ADAbs in children with JIA using etanercept, adalimumab or infliximab. Clinical characteristics and disease activity were retrieved from patient charts.\n\nResults\n\nWe analyzed 142 measurements of anti-TNF drug levels in 65 children with JIA. Of these, ninety-seven (68.3%) were trough concentrations. N = 14/97 (14.4%) of these showed trough concentrations within the therapeutic drug range known for adults with RA and IBD. ADAbs against adalimumab were detected in seven patients and against infliximab in one patient. Seven (87,5%) of these ADAb-positive patients had non-detectable drug levels. A flowchart was made on decisions including rational dose escalation, stopping treatment in the presence of ADAbs and undetectable drug levels, showing that 45% of measurements influenced treatment decisions, which concerned 65% of patients (n = 42/65).\n\nConclusions\n\nIn the majority of patients, measurement of anti-TNF drug levels led to changes in treatment. A wide variation of anti-TNF drug levels was found possibly due to differences in drug clearance in different age groups. There is need for determination of therapeutic drug ranges and pharmacokinetic curves for anti-TNF and other biologics in children with JIA.\n\nKeywords\n\nBiologics\nAnti-TNF drug trough levels\nAnti-drug antibodies\nChildren\nJuvenile idiopathic arthritis (JIA)\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nJuvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized by idiopathic chronic joint inflammation that persists for longer than 6 weeks, and has a disease onset before the age of 16 years. It is the most prevalent rheumatic disease in childhood [1]. Long term complications include chronic pain and joint damage causing physical disability and a decreased quality of life [2, 3]. In a substantial proportion of children with JIA, intermittently active disease persists into adulthood [4]. Since the introduction of biologicals, such as anti-tumor necrosis factor (TNF) drugs, treatment options have increased in children with JIA and its prognosis has improved significantly [1, 4]. Various anti-TNF drugs have been studied in children with JIA and are currently the mainstay of therapy in methotrexate-refractory JIA [5]. Biologics that are currently being used in JIA include anti-TNF drugs (etanercept, adalimumab, infliximab, golimumab and certolizumab pegol). This has changed the pediatric rheumatology landscape substantially, but improvements in the use of anti-TNF drugs are still needed, especially since anti-TNF drugs will be used earlier in the disease course when following recent international adaptations of JIA treat-to-target strategies [6].\n\nA relationship between drug concentrations and clinical outcome has been established in adults with RA, but anti-TNF drug concentrations varied widely between subjects [7–9]. One factor contributing to the variation in drug levels is the development of anti-drug antibodies (ADAbs), a response called “immunogenicity” [7, 8]. The presence of ADAbs can lead to a diminished half-life of the drug and thus decrease its efficacy. It may also lead to adverse effects, such as hypersensitivity reactions and anaphylaxis [10]. The clinical relevance of ADAbs has again been underlined in a recent systematic review by Swart et al. [11]. Several studies have shown that the risk for development of ADAbs is inversely related to the anti-TNF drug dose and these patients often have a subtherapeutic serum trough level [12, 13]. Increasing the dosage leads to higher drug concentrations and has been shown to subsequently lead to a decrease of ADAbs [14, 15]. Higher concentrations of adalimumab and infliximab in serum have been reported to correlate with clinical response not only in adults with RA, but also in adults with psoriasis [16] or IBD [17]. Several studies have been published on children with IBD receiving anti-TNF drug treatment showing a relationship between trough levels and disease activity [18, 19]. The therapeutic range is a pharmacologic term for the concentration range that provides efficacy without resulting in unacceptable toxicity [20, 21]. The therapeutic drug ranges for anti-TNF drugs in pediatric rheumatology are not yet defined [22]. In adults with RA and ankylosing spondylitis an etanercept concentration between 2 and 3 μg/mL is seen as therapeutic [23, 24]. To reach adequate clinical response in RA, adalimumab trough levels should be in a range of 5–8 μg/mL [7]. Studies in adults with inflammatory bowel disease (IBD) have described a therapeutic drug range of 3–7 μg/mL for infliximab [25]. In a recently published observational study of Naviglio et al. in children with IBD, infliximab concentrations > 3.11 μg/mL predicted sustained clinical remission and most cases of therapeutic failure were associated with low serum drug levels [19].\n\nPersonalized medicine, which is a model for tailoring the therapeutic strategy to the needs of the individual patient, is a promising approach in health care [26]. It maximizes efficacy and minimizes drug toxicity, and seems a very promising method to use in biologic treatment regimens as well [27]. Switching between biologics, increasing dosage when there is loss of response, or tapering the dosage after achieving inactive disease on medication are all examples of decisions pediatric rheumatologists now make based on clinical experience alone. Measuring serum trough levels of biologics and monitoring the presence of blocking ADAbs could be of use in practicing personalized medicine. Currently, there is a lack of data in the literature supporting this strategy in children with JIA. We hereby present an overview of children with JIA being treated with anti-TNF drugs in our tertiary center in whom serum (mostly trough) levels and -if applicable- ADAbs were measured. We aimed to assess if therapeutic drug monitoring (TDM) was of influence in treatment decisions in children with JIA.\n\nMethods\n\nWe conducted a retrospective study in children under the age of 18 years with a diagnosis of JIA (excluding systemic) fitting the ILAR criteria [28] that were treated with etanercept (Enbrel®), adalimumab (Humira®) and/or infliximab (Remicade®, Remsima®, Inflectra®) in our center. As golimumab (Simponi®) had just recently been approved for use in polyarticular JIA in the Netherlands, we did not have enough data on this drug to include in our overview. The patient data were retrieved from electronic patient records of the pediatric rheumatology department of the Emma Children’s Hospital (Amsterdam University Medicals Centers). All children that had been tested for anti-TNF drug levels in the time period of 2010 up to 2020 were included in this survey. Anti-TNF drug levels were determined using validated enzyme-linked immuno sorbent assays (ELISA) as described before [7, 23, 29]. In the etanercept and adalimumab groups, (trough) drug levels were measured at a regular visit at the outpatient clinic. The definition for ‘trough’ level is the lowest concentration reached by a drug before the next dose is administered. Trough levels were defined as a drug level 1–2 days before the next administration of injection for etancercept and adalimumab. Infliximab concentrations were all trough levels as all blood samples had been taken just minutes prior to the next infusion. Trough levels were separately analyzed as subgroup per frequency regime. Cut-off levels were based on adult data, as pediatric data on therapeutic drug levels for these drugs are not yet known. In this manuscript we defined the therapeutic drug range for etanercept based on available literature in adults with RA and ankylosing spondylitis (2–3 μg/mL) [23, 24], the therapeutic drug range for adalimumab in adults with RA (5–8 μg/mL) [7] and the therapeutic drug range for infliximab on adults with RA and inflammatory bowel disease (IBD) (3–7 μg/mL) [25, 30]. ADAbs [31] were determined in all patients with low drug concentrations of adalimumab and infliximab, because in the assays we used, free (neutralizing) ADAbs will not be detected if an excess of drug is present in the serum [32]. Sometimes ADAbs were determined routinely in patients at the physician’s discretion. ADAbs were not determined in patients on etanercept, as immunogenicity does not seem to be an issue in this drug. Several studies have shown no clinical significant antibody formation to etanercept [32, 33].\n\nThe following clinical variables were collected: age, sex, JIA subtype, current medication, reason for testing and decision effect of trough level and presence of ADAbs on therapy. Secondary loss of response was defined as a relapse of arthritis in a patient with JIA after an initial response to the drug, after excluding other causes for the relapse. Partial response was defined improvement of number of active joints and/or global assessment (PGA) or parent/patient Visual Analogue Scale (VAS) but no remission. No response was defined as no improvement or worsening of arthritis.\n\nData entry and management was carried out anonymously, hence informed consent was waved by the medical ethical committee. Microsoft Office Excel, 2007 (Microsoft Corp, Redmond, WA, USA®) was used for data collection. Statistical analyses were carried out using IBM SPSS software (version 26).\n\nResults\n\nA total of 142 serum samples from 65 patients with JIA were analyzed (characteristics shown in Table 1). The number of sera samples tested per individual patient ranged from 1 to 8 (median 2, IQR: 1–3) (Table 2). The different drug levels versus drug dose (per kg or m2) are plotted in Figs. 1, 2 and 3. Table 1 Patient characteristics (N = 65)\n\nAge, median (range)\t12.6 (2.4–17.8)\t\nIQR\t9.7–15.9\t\nSex (number and proportion)\t\n Male\t19 (29%)\t\n Female\t46 (71%)\t\nDiagnosis\t\n Oligo articular JIA, persistent\t7 (11%)\t\n Oligo articular JIA, extended\t6 (9%)\t\n Polyarticular JIA, RF negative\t29 (45%)\t\n Polyarticular JIA, RF positive\t9 (14%)\t\n Enthesitis-related JIA\t10 (15%)\t\n Psoriatic arthritis\t3 (5%)\t\n Undifferentiated\t1 (2%)\t\nNon-biologic DMARD usea\t\n Methotrexate\t57 (78%)\t\n Leflunomide\t2 (3%)\t\n Azathioprine\t4 (6%)\t\n Cellcept\t1 (1%)\t\n None\t10 (14%)\t\na some patients switched their non-biologic DMARD during treatment\n\nTable 2 Patient drug levels and anti-drug antibodies\n\n\tSubgroup analysis with trough levels\t\nAnti TNF, no. of drug levels/no. of patientsa\t\n Etanercept\t21/15\t6/6\t\n Adalimumab\t51/38\t22/21\t\n Infliximab\t70/28\t70/28\t\nDrug levels, median (range / IQR)\t\n Etanercept\t2.4 (0.0–8.1 / 1.8–3)\t2.2 (0.9–2.7 / 0.9–2.9)\t\n Adalimumab\t12 (0–49 / 4.8–15)\t10.2 (0–27 / 0.01–14)\t\n Infliximab\t16 (0–81 / 7.3–23)\t16 (0–81 / 7.3–23)\t\nTherapeutic drug levelsb (% per drug group)\t\n Etanercept\t\t3 (50%)\t\n Adalimumab\t\t0 (0%)\t\n Infliximab\t\t11 (16%)\t\nSubtherapeutic drug levelsb\t\n Etanercept\t\t2 (33%)\t\n Adalimumab\t\t9 (41%)\t\n Infliximab\t\t5 (7%)\t\nSupratherapeutic drug levelsb\t\n Etanercept\t\t1 (17%)\t\n Adalimumab\t\t13 (59%)\t\n Infliximab\t\t53 (77%)\t\nAntidrug antibodies (% of patients using that drug)\t\n Adalimumab\t7 (18.4%)\t\t\n Infliximab\t1 (4%)\t\t\na A few patients had received more than one anti-TNF drug on different time points\n\nb according to adult data in RA and IBD; therapeutic drug levels for JIA are not yet determined\n\nFig. 1 Dose vs. etanercept concentration\n\nFig. 2 Dose vs. adalimumab concentration. Red: ADA-positive patients. Green: frequency every 7 days. Blue: frequency every 14 days\n\nFig. 3 Dose vs. infliximab concentration. Red: ADA-positive patients. Blue: frequency every 4 weeks. Yellow: frequency every 6 weeks. Green: every 8 weeks\n\nLooking at trough levels, 14.4% (n = 14/97) were trough levels in the therapeutic drug ranges that are known for adults in RA and IBD (Table 2). Concentrations were measured for different reasons. These included primary or secondary loss of response (55%), remission (possibility to stop or taper treatment (15.5%), uveitis flare (12%), allergic reaction (1.4%), measurement after dosage change (6.3%) or unknown reason (not explained in patient file) (9.8%).\n\nTrough levels with influence of treatment decisions occurred in 45% (n = 64/142) of measurements which concerned 65% (n = 42/65) of patients. These treatment changes included dose/frequency increase, or stopping and switching treatment in the presence of ADAbs combined with undetectable drug levels. We have elaborated this process in a flowchart (Fig. 4). Fig. 4 Flow chart\n\nADAbs were detected in 18.4% (n = 7/38) of patients in the adalimumab group and in one patient (4%) in the infliximab group. All but one patient with ADAbs showed non-detectable drug trough levels. One ADA+ positive patient had antibodies against adalimumab and a subtherapeutic level. After changing to higher frequency of administration (weekly instead of every 14 days), the ADA against adalimumab could not be detected anymore. Treatment failure occurred in 87.5% (n = 7/8) of ADA-positive measurements. One ADA-positive patient developed an anaphylactic reaction during the second infusion of infliximab. ADA and drug level was tested 1–2 h after of this complicated infusion: ADA were 310 AE/ml and infliximab drug level was non-detectable. Four months later, this same rheumatoid-factor positive JIA-patient, developed ADA against adalimumab.\n\nDiscussion\n\nThis study shows that TDM has a role in standard follow-up of anti-TNF treatment of JIA. In the majority of patients in this study, TDM had influence on treatment decisions, even considering the fact that the therapeutic drug ranges for anti-TNF drugs in JIA are currently not established. Interpreting our data according to therapeutic drug ranges for adults with RA and IBD, only 15% would have drug levels in a therapeutic range. This implicates that there might be room for improvement in dosage regimes. One could argue that some children are undertreated, but a larger group is possibly over-treated based on the numbers of high serum levels (77% in infliximab). Another hypothesis is that therapeutic drug ranges differ from adult ranges and might be higher.\n\nThere seem to be opportunities to adapt anti-TNF drug dose to individual needs, also depending on drug clearance and treatment responses. This could potentially save costs if remission would be achieved sooner. For example, in non-responders, clinical remission could hypothetically be achieved sooner by using higher dosages or frequencies (guided by drug trough levels). This could lead to a decrease in unnecessary switching in biologics, which is relevant for children with a chronic disease in relation to future therapeutic choices and options. Switching therapy should be reserved for non-responders with high drug concentration or non-responders with low drug concentration combined with ADAbs. In case of remission (responders) and high drug levels, dosage or frequency could be tapered, which is equally important considering the high financial burden of anti-TNF drugs, but also diminishes the risk of developing side-effects. In responders with low drug concentration, stopping treatment should be considered.\n\nA wide variation in anti-TNF drug concentrations was found in our cohort, also in subgroups with comparable dosage per kg or BSA and comparable frequencies. We did not find any differences between the JIA subtypes. In the adalimumab and infliximab group, children with JIA-associated uveitis should be viewed differently, as it has been suggested that a higher dosage of anti-TNF drug is needed for penetration to obtain adequate drug levels in the eye [34]. In our study, 21% (n = 6/28) of studied infliximab patients had JIA-associated uveitis, of which three patients with active uveitis. Anti-TNF drug concentrations in adults can also vary widely between subjects, even with fixed dosages of anti-TNF drugs [7–9]. It is possible that this is due to different ages of patients and its influence on drug clearance [35]. Absorption, distribution, metabolism and excretion of the drug are factors influencing drug concentrations and differ in children compared to adults [35]. Adalimumab and infliximab are monoclonal antibodies (MAbs) structurally similar to endogenous IgG and share similar pharmacokinetic properties [36]. Due to their large size and poor membrane permeability, the distribution of these drugs is confined largely to the plasma and extracellular fluid [37]. The extracellular fluid volume fraction falls rapidly after birth, while plasma volumes rise gradually, leading to a higher total body volume available for distribution in small children than in adults. As compared to adults, it has been observed that children have faster weight-normalized plasma clearance of MAbs [36]. Lower concentrations of neonatal Fc receptor (FcRn) in vascular endothelial cells, which are responsible for recycling MAbs, lead to shorter half-lives of MAbs in small children. This implies that most drugs should be dosed relatively higher in children to achieve the same drug levels as in adults. Also, it has been postulated that levels of TNF in an individual patient may vary in time. That is: a high TNF level during active disease and a low level in inactive disease. This may in turn affect the level of anti-TNF drugs, resulting in higher serum concentration of anti-TNF drugs in inactive disease as compared to active disease in the same individual, without a change in the dose [38].\n\nAnti-TNF drugs have some degree of immunogenicity, even fully humanized ones. Etanercept seems to be an exception, as no clinical significant antibody formation to etanercept was seen in several studies [32]. High anti-infliximab antibody levels or low residual infliximab concentrations are strongly associated with acquired therapeutic resistance to infliximab in adult patients with rheumatoid arthritis [10]. Development of ADAbs can lead to a diminished half-life of all anti-TNF drugs. All but one patient in our cohort with ADAbs showed non-detectable serum trough levels, indicative of effect on pharmacokinetics of the drug. In these ADA-positive patients, the drug had clearly lost its efficacy, also indicative of a relevant pharmacodynamical effect. Treatment failure occurred in 87.5% (n = 7/8) of our ADA-positive patients. One ADA-positive patient developed a anaphylactic reaction during the second infusion of infliximab. Therefore, treatment failure could not (yet) be established but the drug needed to be switched due to severe allergy. When ADAbs are measured in high titers with a non-detectable drug trough level, this specific biologic has lost its therapeutic effect in this patient. The monitoring of serum trough levels and formation of ADAbs can therefore explain a (secondary) loss of therapeutic response to anti-TNF drugs. These measurements help with decisions for future treatments, either by increasing the dose or switching to another biologic when presence of ADAbs and non-detectable trough levels are found [10]. Higher starting doses of infliximab have been shown to correlate with lower incidence of ADAbs development and improved effectiveness of the drug in JIA and RA [14, 15]. This approach may also help in preventing the development of ADAbs. Another described preventive action against development of ADAbs is the concomitant use of non-biologic DMARDs, such as methotrexate or azathioprine [11, 15, 39, 40]. In our ADA-positive patients, this protective effect of non-biologic DMARD’s was not seen. ADA-positive patients concerned different JIA-subtypes, no subtype was outstanding (n = 1 artritis psoriatica, n = 1 oligo-extended JIA, n = 3 RF+ polyarticular JIA, n = 3 RF- polyarticular JIA). One of our patients had a serum through level of 0 without the development of ADAbs, but this patient was tapering the dose of etanercept. Therapeutic drug measurements could also be used in case of suspected non-compliance.\n\nLimitations of our study are sample size (especially for etanercept) and lack of JADAS disease activity scores. In adults with rheumatoid arthritis, psoriasis and IBD, correlations between concentration of TNF inhibitors and clinical response have been reported [9, 16, 17]. As this was not the aim of this retrospective study, we could not assess if there was a relationship between therapeutic drug level and clinical outcome in children. In current practice, JIA patients that are treated with biologics are monitored by the Juvenile Arthritis Disease Activity Score (JADAS) which represents physical examination (number of active joints), physician’s VAS (Visual Analog Scale), patient’s VAS of well-being, and ESR. These data were not available for all patients at important time-points and should be included in future prospective studies for assessment of therapeutic drug range(s) of biologics. Nevertheless, with our available data we think that the importance and relevance of TDM in treatment decisions for anti-TNF drugs in JIA can be shown.\n\nConclusion\n\nTDM of anti-TNF drugs is a valuable tool in making treatment decisions in JIA such as rational dose escalation and stopping treatment in the presence of ADAbs and undetectable drug levels. This paper shows that TDM in anti-TNF is useful in daily clinical practice but we need to determine the therapeutic drug ranges and pharmacokinetic curves of anti-TNF drugs in JIA.\n\nFuture perspective\n\nIn the era of biologics and personalized medicine there is a need for more studies on TDM in JIA treatment with biologics.\n\nNext steps in this research area are describing anti-TNF drug pharmacokinetics (PK) specifically for children and the concentration–effect relationship of anti-TNF drug using pharmacokinetic–pharmacodynamic (PK–PD) modelling in patients with JIA.\n\nAbbreviations\n\nADAbs Anti-drug antibodies\n\nDMARDs Disease Modifying Anti-Rheumatic Drugs\n\nELISA Enzyme-linked immuno sorbent assay\n\nFcRn Fc receptor\n\nFDA Food and Drug Administration\n\nIBD Inflammatory bowel disease\n\nIL-1 Interleukin-1\n\nIQR Interquartile ranges\n\nJADAS Juvenile Arthritis Disease Activity Score\n\nJIA Juvenile Idiopathic Arthritis\n\nMAbs Monoclonal antibodies\n\nNSAID Non-Steroidal Anti-Inflammatory Drug\n\nPK Pharmacokinetics\n\nPK-PD Pharmacokinetic–pharmacodynamic\n\nRA Rheumatoid arthritis\n\nTDM Therapeutic drug monitoring\n\nTNF Tumor necrosis factor\n\nVAS Visual Analog Scale\n\nNot applicable.\n\nAuthors’ contributions\n\nAll authors fulfil requirements for authorship and contributorship. All authors read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe Medical Research Involving Human Subjects Act (WMO) does not apply to this study and an official approval of this study was not required by the committee.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nTR reports grants and personal fees from Genmab, outside the submitted work.\n\nAll the other authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Ruperto N Lovell DJ Cuttica R Wilkinson N Woo P Espada G Wouters C Silverman ED Balogh Z Henrickson M Apaz MT Baildam E Fasth A Gerloni V Lahdenne P Prieur AM Ravelli A Saurenmann RK Gamir ML Wulffraat N Marodi L Petty RE Joos R Zulian F McCurdy D Myones BL Nagy K Reuman P Szer I Travers S Beutler A Keenan G Clark J Visvanathan S Fasanmade A Raychaudhuri A Mendelsohn A Martini A Giannini EH Paediatric Rheumatology International Trials OrganisationPediatric Rheumatology Collaborative Study Group A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis Arthritis Rheum 2007 56 9 3096 3106 10.1002/art.22838 17763439\n15. Maini RN Breedveld FC Kalden JR Smolen JS Davis D Macfarlane JD Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis Arthritis Rheum 1998 41 9 1552 1563 10.1002/1529-0131(199809)41:9<1552::AID-ART5>3.0.CO;2-W 9751087\n16. Carrascosa Carrilllo JM, Toro Montecinos M, Ballesca Lopez F, Teniente Serra A, Martinez Caceres E, Ferrandiz C. Correlation between trough serum levels of adalimumab and absolute PASI score in a series of patients with psoriasis. J Dermatolog Treat. 2018;29(2):140–4. 10.1080/09546634.2017.1341619. Epub 2017 Jul 6. PMID: 28604127.\n17. Steenholdt C Use of infliximab and anti-infliximab antibody measurements to evaluate and optimize efficacy and safety of infliximab maintenance therapy in Crohn’s disease Dan Med J 2013 60 4 B4616 23651723\n18. Hoekman DR Brandse JF de Meij TG Hummel TZ Lowenberg M Benninga MA The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease Scand J Gastroenterol 2015 50 9 1110 1117 10.3109/00365521.2015.1027264 25865965\n19. Naviglio S Lacorte D Lucafo M Cifu A Favretto D Cuzzoni E Causes of treatment failure in children with inflammatory bowel disease treated with infliximab: a pharmacokinetic study J Pediatr Gastroenterol Nutr 2019 68 1 37 44 10.1097/MPG.0000000000002112 30211845\n20. Stan K Bardal JEW Martin DS Applied Pharmacology 2011 3 16\n21. Papamichael K Cheifetz AS Use of anti-TNF drug levels to optimise patient management Front Gastroenterol 2016 7 4 289 300 10.1136/flgastro-2016-100685\n22. Murias S Magallares L Albizuri F Pascual-Salcedo D Dreesen E Mulleman D Current practices for therapeutic drug monitoring of biopharmaceuticals in pediatrics Ther Drug Monit 2017 39 4 370 378 10.1097/FTD.0000000000000423 28703718\n23. Kneepkens EL Krieckaert CL van der Kleij D Nurmohamed MT van der Horst-Bruinsma IE Rispens T Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up Ann Rheum Dis 2015 74 10 1825 1829 10.1136/annrheumdis-2014-205213 24812290\n24. Jamnitski A Krieckaert CL Nurmohamed MT Hart MH Dijkmans BA Aarden L Voskuyl AE Wolbink GJ Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients Ann Rheum Dis 2012 71 1 88 91 10.1136/annrheumdis-2011-200184 21914626\n25. Singh N Dubinsky MC Therapeutic drug monitoring in children and young adults with inflammatory bowel disease: a practical approach Gastroenterol Hepatol (N Y) 2015 11 1 48 55 27099572\n26. Personalized Medicine 2020 and beyond – Preparing Europe for leading the global way (PerMed).\n27. l'Ami MJ Krieckaert CL Nurmohamed MT van Vollenhoven RF Rispens T Boers M Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial Ann Rheum Dis 2018 77 4 484 487 10.1136/annrheumdis-2017-211781 28939629\n28. Petty RE Southwood TR Manners P Baum J Glass DN Goldenberg J He X Maldonado-Cocco J Orozco-Alcala J Prieur AM Suarez-Almazor ME Woo P International League of Associations for Rheumatology International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001 J Rheumatol 2004 31 2 390 392 14760812\n29. Vande Casteele N Buurman DJ Sturkenboom MG Kleibeuker JH Vermeire S Rispens T Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays Aliment Pharmacol Ther 2012 36 8 765 771 10.1111/apt.12030 22928581\n30. Wolbink GJ Vis M Lems W Voskuyl AE de Groot E Nurmohamed MT Stapel S Tak PP Aarden L Dijkmans B Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis Arthritis Rheum 2006 54 3 711 715 10.1002/art.21671 16508927\n31. Rispens T de Vrieze H de Groot E Wouters D Stapel S Wolbink GJ Aarden LA Antibodies to constant domains of therapeutic monoclonal antibodies: anti-hinge antibodies in immunogenicity testing J Immunol Methods 2012 375 1–2 93 99 10.1016/j.jim.2011.09.011 21986105\n32. Wolbink GJ Aarden LA Dijkmans BA Dealing with immunogenicity of biologicals: assessment and clinical relevance Curr Opin Rheumatol 2009 21 3 211 215 10.1097/BOR.0b013e328329ed8b 19399992\n33. Atiqi S Hooijberg F Loeff FC Rispens T Wolbink GJ Immunogenicity of TNF-inhibitors Front Immunol 2020 11 312 10.3389/fimmu.2020.00312 32174918\n34. Sukumaran S Marzan K Shaham B Reiff A High dose infliximab in the treatment of refractory uveitis: does dose matter? ISRN Rheumatol 2012 2012 765380 10.5402/2012/765380 22389806\n35. Batchelor HK Marriott JF Paediatric pharmacokinetics: key considerations Br J Clin Pharmacol 2015 79 3 395 404 10.1111/bcp.12267 25855821\n36. Malik P Edginton A Pediatric physiology in relation to the pharmacokinetics of monoclonal antibodies Expert Opin Drug Metab Toxicol 2018 14 6 585 599 10.1080/17425255.2018.1482278 29806953\n37. Wang W Wang EQ Balthasar JP Monoclonal antibody pharmacokinetics and pharmacodynamics Clin Pharmacol Ther 2008 84 5 548 558 10.1038/clpt.2008.170 18784655\n38. Strik AS Bots SJ D'Haens G Lowenberg M Optimization of anti-TNF therapy in patients with inflammatory bowel disease Expert Rev Clin Pharmacol 2016 9 3 429 439 10.1586/17512433.2016.1133288 26681400\n39. Jani M Barton A Warren RB Griffiths CE Chinoy H The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases Rheumatology (Oxford) 2014 53 2 213 222 10.1093/rheumatology/ket260 23946436\n40. Thomas SS Borazan N Barroso N Duan L Taroumian S Kretzmann B Bardales R Elashoff D Vangala S Furst DE Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. A Systematic Review and Meta-Analysis BioDrugs 2015 29 4 241 258 10.1007/s40259-015-0134-5 26280210\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1546-0096",
"issue": "19(1)",
"journal": "Pediatric rheumatology online journal",
"keywords": "Anti-TNF drug trough levels; Anti-drug antibodies; Biologics; Children; Juvenile idiopathic arthritis (JIA)",
"medline_ta": "Pediatr Rheumatol Online J",
"mesh_terms": "D000068879:Adalimumab; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D001171:Arthritis, Juvenile; D002648:Child; D000066491:Clinical Decision-Making; D004306:Dose-Response Relationship, Immunologic; D016903:Drug Monitoring; D000068800:Etanercept; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D054539:Medication Therapy Management; D018579:Patient Selection; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "101248897",
"other_id": null,
"pages": "59",
"pmc": null,
"pmid": "33926495",
"pubdate": "2021-04-29",
"publication_types": "D016428:Journal Article",
"references": "29701536;23946436;28939629;23950184;22928581;19770495;16508927;21914626;19399992;32174918;26280210;18784655;14760812;21986105;30809664;15485995;30211845;28604127;27484749;24326008;26681400;28839870;27099572;9751087;22179727;25865965;25855821;29806953;28703718;24812290;22389806;26268816;21131896;23651723;27752356;29643108;17763439",
"title": "Therapeutic drug monitoring of anti-TNF drugs: an overview of applicability in daily clinical practice in the era of treatment with biologics in juvenile idiopathic arthritis (JIA).",
"title_normalized": "therapeutic drug monitoring of anti tnf drugs an overview of applicability in daily clinical practice in the era of treatment with biologics in juvenile idiopathic arthritis jia"
} | [
{
"companynumb": "NL-CELLTRION INC.-2021NL010107",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Cancer is a leading cause of morbidity and deaths in solid organ transplant recipients. In immunocompetent patients, cancer prognosis has been dramatically improved with the development of immune checkpoint inhibitors (ICI), as programmed cell death protein 1/programmed death-ligand 1 and cytotoxic T lymphocyte-associated antigen 4 inhibitors, that increase antitumor immune responses. ICI has been developed outside of the scope of transplantation because of the theoretical risk of graft rejection, which has later been confirmed by the publication of several cases and small series. The use of ICI became unavoidable for treating advanced cancers including in organ transplant patients, but their management in this setting remains highly challenging, as to date no strategy to adapt the immunosuppression and to prevent graft rejection has been defined. In this article, we report a monocentric series of 5 solid organ transplant recipients treated with ICI and provide a comprehensive review of current knowledge of ICI management in the setting of solid organ transplantation. Strategies warranted to increase knowledge through collecting more exhaustive data are also discussed.",
"affiliations": "Department of Dermatology, AP-HP Hôpital Saint Louis, Université de Paris, INSERM U976, Team 1, HIPI, Paris, France.;Department of Nephrology and Kidney Transplantation, University Hospital Center (CHU) Necker, Université de Paris, Paris, France.;Department of Cardiac Surgery, AP-HP, Bichat-Claude Bernard University Hospital, Paris, France.;Department of Hepatology, AP-HP, Hôpital Saint-Antoine, UPMC University, Paris, France.;Department of Nephrology, AP-HP Hôpital Saint Louis, Université de Paris, Paris, France.;Department of Nephrology and Kidney Transplantation, University Hospital Center (CHU) Necker, Université de Paris, Paris, France.;Department of Dermatology, AP-HP Hôpital Saint Louis, Université de Paris, INSERM U976, Team 1, HIPI, Paris, France.",
"authors": "Delyon|Julie|J|;Zuber|Julien|J|;Dorent|Richard|R|;Poujol-Robert|Armelle|A|;Peraldi|Marie-Noelle|MN|;Anglicheau|Dany|D|;Lebbe|Celeste|C|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000003292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "105(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000368:Aged; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D016377:Organ Transplantation; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D059016:Tumor Microenvironment",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "67-78",
"pmc": null,
"pmid": "32355121",
"pubdate": "2021-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immune Checkpoint Inhibitors in Transplantation-A Case Series and Comprehensive Review of Current Knowledge.",
"title_normalized": "immune checkpoint inhibitors in transplantation a case series and comprehensive review of current knowledge"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1059783",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Hepatitis C is the most common indication for liver transplantation (LT) in the United States. Recurrence of hepatitis C virus (HCV) infection post-LT remains a problem for which there is no completely satisfactory treatment. The aim of the present study is to evaluate mycophenolate mofetil (MMF), which has both immunosuppressive and antiviral properties, to determine whether it is associated with a difference in the rate of HCV recurrence and also examine its impact on patient and graft survival. Between August 1995 and May 1998, a total of 106 patients who were HCV positive before LT were randomized to tacrolimus (TAC) and prednisone versus TAC, prednisone, and MMF therapy. The rate of recurrence of HCV, patient and graft survival, incidences of rejection, and histological findings were examined. Fifty six patients were randomized to TAC and steroid therapy (double [D] drug; group D), and 50 patients were randomized to TAC, steroid, and MMF therapy (triple [T] drug; group T). Liver biopsies were performed when liver function was abnormal; protocol liver biopsies were not performed. Mean follow-up was 4.3 +/- 0.8 years. Actuarial patient survivals at 4 years were 72.6% in group D and 73.8% in group T (P = not significant). Actuarial graft survivals at 4 years were 65.6% in group D and 65.4% in group T. One patient in group D and 2 patients in group T underwent a second LT for recurrent HCV. One patient in each group died of recurrent HCV without re-LT. Twenty-six patients in group D (46.4%) and 23 patients in group T (46.0%) showed signs of recurrent HCV. Mean hepatitis activity index (HAI) scores were 7.4 +/- 2.7 in group D and 7.0 +/- 3.4 in group T, and mean fibrosis scores were 2.9 +/- 1.7 in group D and 2.6 +/- 1.1 in group T. The rate of rejection was 0.57/patient in each group for the entire follow-up period. None of these values reached statistical significance. Rates of HCV recurrence, graft loss or death from recurrent HCV, and 4-year actuarial patient and graft survival were not different between the groups. In liver transplant recipients with HCV, MMF has no impact on patient survival, graft survival, rejection, or rate of HCV recurrence based on biochemical changes and histological findings. In addition, there was no difference in HAI or fibrosis score between the two groups. Either MMF has no anti-HCV effect or its immunosuppressive properties overwhelm its antiviral effect in the clinical setting.",
"affiliations": "Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. jainab@msx.upmc.edu",
"authors": "Jain|Ashok|A|;Kashyap|Randeep|R|;Demetris|Anthony J|AJ|;Eghstesad|Bijan|B|;Pokharna|Renu|R|;Fung|John J|JJ|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1053/jlts.2002.29763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "8(1)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000328:Adult; D000368:Aged; D002423:Cause of Death; D005260:Female; D006084:Graft Rejection; D006526:Hepatitis C; D006801:Humans; D007166:Immunosuppressive Agents; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011183:Postoperative Complications; D011446:Prospective Studies; D055502:Secondary Prevention; D016559:Tacrolimus",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "40-6",
"pmc": null,
"pmid": "11799484",
"pubdate": "2002-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C.",
"title_normalized": "a prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis c"
} | [
{
"companynumb": "US-ROCHE-2009418",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nCOVID-19 patients, especially the patients requiring hospitalisation, have a high risk of several complications such as opportunistic bacterial and fungal infections. Mucormycosis is a rare and opportunistic fungal infection that mainly affects diabetic and immunocompromised patients. An increase has been observed in the number of rhino-orbital mucormycosis in patients with COVID-19 admitted to Imam Khomeini Hospital, Kermanshah, Iran, since October 2020. This is a report of the frequency, risk factors, clinical manifestations, treatment and prognosis of COVID-19 associated with mucormycosis infection.\n\n\nMETHODS\nThe medical records of COVID-19 patients with rhino-orbital mucormycosis who were diagnosed in an educational therapeutic hospital in Kermanshah, west of Iran were surveyed. Several parameters were analysed including demographic, clinical, therapeutic and laboratory characteristics.\n\n\nRESULTS\nTwelve patients with COVID-19-associated rhino-orbital mucormycosis were identified from 12 October to 18 November 2020. All cases reported as proven mucormycosis had a history of hospitalisation due to COVID-19. Comorbidities mainly included diabetes mellitus (83.33%) and hypertension (58.33%). Seventy-five per cent of patients received corticosteroids for COVID- 19 treatment. The sites of involvement were rhino-sino-orbital (83%) and rhino-sino (17%). Amphotericin B/liposomal amphotericin B alone or in combination with surgical debridement or orbital exenteration was used as the first-line therapy. The overall mortality rate was 66.7% (8/12).\n\n\nCONCLUSIONS\nWe found a high incidence of mucormycosis among COVID-19 patients. Diabetes mellitus and corticosteroid use were the dominant predisposing factor of mucormycosis. Mucormycosis is a life-threatening and opportunistic infection; therefore, physicians should know the signs and symptoms of the disease so that a timely diagnosis and therapy can be performed.",
"affiliations": "Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Ophthalmology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Pathology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Ophthalmology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Anesthesiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Ophthalmology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Interna, Medicine, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Imam Khomeini and Mohamad Kermanshahi Clinical Research Development Unit, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Otorhinolaryngology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Infectious Diseases Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.",
"authors": "Avatef Fazeli|Manouchehr|M|;Rezaei|Leila|L|;Javadirad|Etrat|E|;Iranfar|Khosro|K|;Khosravi|Abbas|A|;Amini Saman|Javad|J|;Poursabbagh|Pardis|P|;Ghadami|Mohammad Rasoul|MR|;Parandin|Mohammad Mehdi|MM|;Dehghani|Amrollah|A|;Ahmadi Jouybari|Touraj|T|;Mahdavian|Behzad|B|;Eivazi|Nastaran|N|;Rezaei|Sohbat|S|;Rezaei|Alireza|A|;Emami|Bashir|B|;Haqgou|Mohadeseh|M|;Bozorgomid|Arezoo|A|https://orcid.org/0000-0003-2093-9317;Sayad|Babak|B|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.13351",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "64(11)",
"journal": "Mycoses",
"keywords": "COVID-19; Iran; SARS-CoV-2; co-infection; mucormycosis",
"medline_ta": "Mycoses",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000086382:COVID-19; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D015994:Incidence; D007492:Iran; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D009916:Orbital Diseases; D012189:Retrospective Studies; D012220:Rhinitis",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "1366-1377",
"pmc": null,
"pmid": "34252988",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Increased incidence of rhino-orbital mucormycosis in an educational therapeutic hospital during the COVID-19 pandemic in western Iran: An observational study.",
"title_normalized": "increased incidence of rhino orbital mucormycosis in an educational therapeutic hospital during the covid 19 pandemic in western iran an observational study"
} | [
{
"companynumb": "IR-PFIZER INC-202200248719",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"dru... |
{
"abstract": "BACKGROUND\nPrimary central nervous system lymphoma (PCNSL) is a rare disease with a dismal prognosis compared to its systemic large B-cell lymphoma counterpart. Real world data are limited, when considering a uniform backbone treatment.\n\n\nMETHODS\nA retrospective study of all adult patients treated sequentially with a high-dose methotrexate (HD MTX)-based regimen in a single tertiary medical center between 2003 and 2019.\n\n\nRESULTS\nThe 2015-2019 period differed from its predecessor in that most patients were treated with an HD MTX-based polychemotherapy regimen as opposed to HD MTX monotherapy (81% vs. 13%, P < .001), rituximab was given as standard of care (100% vs. 56%, P < .01), and most induction-responsive patients received consolidation treatment (70% vs. 18%, P = .01). The median progression-free and overall survival (OS) for the entire cohort (n = 73, mean age 64 years) was 9.9 and 29.8 months, respectively. Patients diagnosed between 2015 and 2019 had superior OS (P = .03) compared to those treated earlier. An interim partial response (PR) state, documented after two cycles of chemotherapy, was associated with increased incidence of progression, with only 33% of those patients achieving end-of-induction complete response. Twenty-three percent of patients developed thrombotic events and 44% developed grade 3-4 infections. HD MTX-based polychemotherapy induction was associated with both increase in thrombotic and infection incidence.\n\n\nCONCLUSIONS\nContemporary HD MTX-based combination therapies suggestively improved the outcomes for PCNSL, but at a cost of increased incidence of toxicity. Patients who achieve an interim PR status are at a high risk for treatment failure.",
"affiliations": "Department of Hematology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 6423906, Tel Aviv, Israel. nadavsarid@gmail.com.;Division of Oncology, Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Division of Oncology, Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Clinical Operation Research and Quality Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Department of Hematology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 6423906, Tel Aviv, Israel.;Department of Hematology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 6423906, Tel Aviv, Israel.;Department of Hematology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 6423906, Tel Aviv, Israel.;Department of Hematology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 6423906, Tel Aviv, Israel.",
"authors": "Sarid|Nadav|N|http://orcid.org/0000-0002-5388-7392;Bokstein|Felix|F|;Blumenthal|Deborah T|DT|;Weiss-Meilik|Ahuva|A|;Gibstein|Lili|L|;Avivi|Irit|I|;Perry|Chava|C|;Ram|Ron|R|",
"chemical_list": "D003561:Cytarabine; D000069283:Rituximab; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-020-03654-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "151(2)",
"journal": "Journal of neuro-oncology",
"keywords": "High-dose methotrexate; Primary central nervous system lymphoma; Prognosis; Toxicity",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D003561:Cytarabine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008223:Lymphoma; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D012189:Retrospective Studies; D000069283:Rituximab; D015996:Survival Rate; D054556:Venous Thromboembolism",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "211-220",
"pmc": null,
"pmid": "33099747",
"pubdate": "2021-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
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"title": "Impact of contemporary regimens on the outcomes and toxicity of primary CNS lymphoma: a single-center retrospective analysis of 73 patients.",
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"abstract": "Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.",
"affiliations": "Department of Rheumatology and Immunology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.;Department of Rheumatology and Immunology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.;Department of Rheumatology and Immunology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.;Department of Rheumatology and Immunology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.;Department of Rheumatology and Immunology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.",
"authors": "Chen|Cuihong|C|;Chen|Yulan|Y|;Huang|Qin|Q|;Hu|Qiu|Q|;Hong|Xiaoping|X|",
"chemical_list": "D000911:Antibodies, Monoclonal; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1",
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"doi": "10.3389/fimmu.2021.625495",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.625495\nImmunology\nCase Report\nCase Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis\nChen Cuihong †\n\nChen Yulan †\nHuang Qin\nHu Qiu\nHong Xiaoping *\n\nDepartment of Rheumatology and Immunology, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China\nEdited by: Marie-Agnes Dragon-Durey, Université Paris Descartes, France\n\nReviewed by: Tomoki Origuchi, Nagasaki University, Japan; Dana P. Ascherman, University of Pittsburgh, United States\n\n*Correspondence: Xiaoping Hong, hong_xiaoping@hotmail.com\n†These authors have contributed equally to this work\n\nThis article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology\n\n25 2 2021\n2021\n12 62549503 11 2020\n11 1 2021\nCopyright © 2021 Chen, Chen, Huang, Hu and Hong\n2021\nChen, Chen, Huang, Hu and Hong\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.\nDermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors’ knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.\n\nclinically amyopathic dermatomyositis\nanti-melanoma differentiation-associated gene 5\nrapidly progressive interstitial lung disease\npregnancy\ntreatment\n==== Body\nIntroduction\n\nDermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.\n\nCase Presentation\n\nA 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.\n\nFigure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.\n\nPhysical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.\n\nTable 1 Laboratory findings on admission.\n\nParameter\tValue\tReference range\t\nLeukocytes (109/L)\t3.6\t4–10\t\nErythrocytes (1012/L)\t4.76\t3.5–5\t\nHemoglobin (g/L)\t129\t110–150\t\nPlatelets (109/L)\t251\t100–300\t\nGlucose (mmol/L)\t4.89\t3.9–6.1\t\nCholesterol (mmol/L)\t3.46\t3.4–6.5\t\nHDL (mmol/L)\t0.94\t0.9–1.91\t\nLDL (mmol/L)\t1.69\t2.08–4.14\t\nAST (U/L)\t50\t0–40\t\nALT (U/L)\t48\t0–45\t\nALP (U/L)\t61\t15–121\t\nCK (U/L)\t171\t25–192\t\nLDH (U/L)\t441\t110–240\t\nUrea nitrogen (mmol/L)\t2.79\t2.5–7.5\t\nCreatinie (µmol/L)\t64\t44–133\t\nIgG (g/L)\t10.21\t8–18\t\nFerritin level (µg/L)\t167.3\t11.0–306.8\t\n24-h urine protein (g/24 h)\t0.216\t0.028–0.141\t\nESR (mm/h)\t53\t0–20\t\nCRP (mg/L)\t30.94\t<5\t\nPCT (ng/ml)\t<0.05\t<0.05\t\nC3 (g/L)\t1.28\t0.80–1.81\t\nC4 (g/L)\t0.32\t0.15–0.57\t\nCoombs’ test\tNegative\tNegative\t\nRF (IU/mL)\t7.3\t<25\t\nAnti-CCP\tNegative\tNegative\t\ncANCA\tNegative\tNegative\t\nanti-PR3\tNegative\tNegative\t\npANCA\tNegative\tNegative\t\nanti-MPO\tNegative\tNegative\t\nANA\tNegative\tNegative\t\nAnti-centromere\tNegative\tNegative\t\nAnti-dsDNA\tNegative\tNegative\t\nAnti-SS-A\tNegative\tNegative\t\nAnti-SS-B\tNegative\tNegative\t\nAnti-MDA5\tStrongly positive\tNegative\t\nAnti-tRNA synthase autoantibody panel\tNegative\tNegative\t\nHDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.\n\nFurther tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.\n\nFigure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.\n\nBecause of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .\n\nFigure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.\n\nDiscussion\n\nInflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).\n\nThe onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).\n\nThere are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.\n\nIn view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).\n\nExamples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.\n\nCertain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.\n\nConcluding Remarks\n\nThe present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nCC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThe research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nThe authors wish to thank the patient in this study.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Callander J Robson Y Ingram J Piguet V . Treatment of clinically amyopathic dermatomyositis in adults: a systematic review. Br J Dermatol (2018) 179 :1248–55. 10.1111/bjd.14726\n2 Han B Guo Q . Clinically Amyopathic Dermatomyositis Caused by a Tattoo. Case Rep Rheumatol (2018) 2018 :7384681. 10.1155/2018/7384681 30515341\n3 Chen Z Cao M Plana MN Liang J Cai H Kuwana M . 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Impact of obesity on hospitalizations and mortality, due to COVID-19: A systematic review. Obes Res Clin Pract (2020) 14 :398–403. 10.1016/j.orcp.2020.07.005 32736969\n23 Cai Q Chen F Wang T Luo F Liu X Wu Q . Obesity and COVID-19 Severity in a Designated Hospital in Shenzhen, China. Diabetes Care (2020) 43 :1392–8. 10.2337/dc20-0576\n24 Akalin T Akkaya H Buke B Kocak I . A Case of New-Onset Dermatomyositis in the Second Trimester of Pregnancy: A Case Report and Review of the Literature. Case Rep Obstet Gynecol (2016) 2016 :6430156. 10.1155/2016/6430156 27478664\n25 Zhong Z Lin F Yang J Zhang F Zeng X You X . Pregnancy in polymyositis or dermatomyositis: retrospective results from a tertiary centre in China. Rheumatology (Oxford) (2017) 56 :1272–5. 10.1093/rheumatology/kex070\n26 Okada R Miyabe YS Kasai S Hashimoto K Yamauchi S Yoshikawa M . Successful treatment of interstitial pneumonia and pneumomediastinum associated with polymyositis during pregnancy with a combination of cyclophosphamide and tacrolimus: A case report. Nihon Rinsho Meneki Gakkai Kaishi (2010) 33 :142–8. 10.2177/jsci.33.142\n27 Mayu S Isojima S Miura Y Nishimi S Hatano M Tokunaga T . Polymyositis-Dermatomyositis and Interstitial Lung Disease in Pregnant Woman Successfully Treated with Cyclosporine and Tapered Steroid Therapy. Case Rep Rheumatol (2019) 2019 :4914631. 10.1155/2019/4914631 30984438\n28 Ochiai M Sato E Tanaka E Tochihara M Shimizu Y Osawa H . Successful delivery in a patient with clinically amyopathic dermatomyositis during pregnancy despite first-trimester acute exacerbation of interstitial lung disease. Mod Rheumatol (2017) 27 :364–8. 10.3109/14397595.2014.975906\n29 Sato Y Otsuka K Tamai K Ono Y Hamaguchi Y Tomii K . An Atypical Clinical Course of Anti-MDA5 Antibody-positive Interstitial Lung Disease in a Patient with Three Deteriorations in 9 years. Intern Med (2017) 56 :341–6. 10.2169/internalmedicine.56.6856\n30 Yamada K Asai K Okamoto A Watanabe T Kanazawa H Ohata M . Correlation between disease activity and serum ferritin in clinically amyopathic dermatomyositis with rapidly-progressive interstitial lung disease: a case report. BMC Res Notes (2018) 11 :34. 10.1186/s13104-018-3146-7 29338781\n31 Lian X Zou J Guo Q Chen S Lu L Wang R . Mortality Risk Prediction in Amyopathic Dermatomyositis Associated With Interstitial Lung Disease: The FLAIR Model. Chest (2020) 158 :1535–45. 10.1016/j.chest.2020.04.057\n32 Shu E Kanoh H Murakami A Seishima M . Potential inhibition of development of rapidly progressive interstitial lung disease by prompt and sufficient immunosuppressive treatment in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis. J Dermatol (2017) 44 :e91–2. 10.1111/1346-8138.13659\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "12()",
"journal": "Frontiers in immunology",
"keywords": "anti-melanoma differentiation-associated gene 5; clinically amyopathic dermatomyositis; pregnancy; rapidly progressive interstitial lung disease; treatment",
"medline_ta": "Front Immunol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D003882:Dermatomyositis; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D000072640:Interferon-Induced Helicase, IFIH1; D017563:Lung Diseases, Interstitial; D010257:Paraneoplastic Syndromes; D011247:Pregnancy; D011248:Pregnancy Complications; D012074:Remission Induction; D012131:Respiratory Insufficiency",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "625495",
"pmc": null,
"pmid": "33717138",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "20601834;27081322;28387857;29464127;30984438;29865091;27774665;16754626;25619281;15880816;24739327;31249780;32736969;28154280;30515341;23908005;17033833;28842784;27279944;16546580;26651481;29065773;10673212;27167896;32409502;28752606;29338781;22589330;32428508;27478664",
"title": "Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.",
"title_normalized": "case report rapidly progressive interstitial lung disease in a pregnant patient with anti melanoma differentiation associated gene 5 antibody positive dermatomyositis"
} | [
{
"companynumb": "CN-BAYER-2021-115396",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
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... |
{
"abstract": "An intensive \"5 + 1\" regimen, which included bolus high dose cytarabine (HiDAC) at 3 g/m2 once daily over 3 hours on days 1-5 and high dose mitoxantrone (HDM) 80 mg/m2 on day 2, was evaluated in 101 consecutively treated newly diagnosed acute myeloid leukemia (AML) patients at a single center since 2009. The median age was 65 (range 18-90) years. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%), respectively. The overall response (complete remission [CR] + CRi) was 76.2% (77/101). The median overall survival (OS) stratified by age group <60, 60-69 and ≥70 years were 56, 31 and 9 months respectively (log-rank, P = 0.02). 51.7% (45/84) of patients with intermediate/adverse risk category proceeded to allogeneic stem cell transplants. Among these 84 patients, the percentage of patients able to proceed to transplant in age groups <60, 60-69, and ≥ 70 years were 75% (18/24), 60.7% (17/28), and 31.2% (10/32), respectively. In conclusion, HDM-based chemotherapy regimen produces high CR rates, is well tolerated and more patients can undergo curative postremission therapy including stem cell transplant.",
"affiliations": "Division of Bone Marrow Transplantation, UMass Memorial Medical Center, Worcester, Massachusetts.;Division of Bone Marrow Transplantation, UMass Memorial Medical Center, Worcester, Massachusetts.;Department of Internal Medicine, UMass Memorial Medical Center, Worcester, Massachusetts.;Albany Medical College, New York.;Lahey Cancer Center and Clinic, Massachusetts.;Division of Bone Marrow Transplantation, UMass Memorial Medical Center, Worcester, Massachusetts.;Department of Internal Medicine, UMass Memorial Medical Center, Worcester, Massachusetts.;Division of Bone Marrow Transplantation, UMass Memorial Medical Center, Worcester, Massachusetts.;Division of Bone Marrow Transplantation, UMass Memorial Medical Center, Worcester, Massachusetts.;UMass Memorial Medical Center Cytogenetics Director, Quest Diagnostics.;Division of Bone Marrow Transplantation, UMass Memorial Medical Center, Worcester, Massachusetts.;Division of Bone Marrow Transplantation, UMass Memorial Medical Center, Worcester, Massachusetts.;Banner MD Anderson Cancer Center, Phoenix, Gilbert, Arizona.",
"authors": "Saini|Neeraj Y|NY|0000-0001-7435-0933;Cerny|Jan|J|;Furtado|Vanessa F|VF|;Desmond|Angela|A|;Zhou|Zheng|Z|;Raffel|Glen|G|;Puthawala|Imran|I|;Bednarik|Jayde|J|;Shanahan|Lindsey|L|;Miron|Patricia M|PM|;Woda|Bruce|B|;Ramanathan|Muthalagu|M|;Nath|Rajneesh|R|",
"chemical_list": "D008942:Mitoxantrone",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.25347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "94(2)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D012074:Remission Induction; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "209-215",
"pmc": null,
"pmid": "30417942",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Elderly do benefit from induction chemotherapy: High dose mitoxantrone-based (\"5 + 1\") induction chemotherapy regimen in newly diagnosed acute myeloid leukemia.",
"title_normalized": "elderly do benefit from induction chemotherapy high dose mitoxantrone based 5 1 induction chemotherapy regimen in newly diagnosed acute myeloid leukemia"
} | [
{
"companynumb": "US-PFIZER INC-2018471360",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYTARABINE"
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"drugadditional": null,
... |
{
"abstract": "We report the case of a 61 year-old male who underwent heart transplantation eight months before developing a systemic condition with central nervous system, lung, kidney, colonic, cutaneous, and hematologic involvement, found to be secondary to a systemic toxoplasmosis despite co-trimoxazole prophylaxis in a previous-to-transplant seronegative patient receiving a heart from a seropositive donor. A review of prophylactic options in our environment is discussed.",
"affiliations": "Servicio de Enfermedades Infecciosas, Clínica Cardio VID, Medellín, Colombia. victoria15_davila@hotmail.com.",
"authors": "Dávila|Victoria|V|;Roncancio-Villamil|Gustavo|G|;Correa|Luis Alfonso|LA|;Restrepo|Catalina|C|;Madrid|Camilo Alberto|CA|;González|Javier Mauricio|JM|",
"chemical_list": "D000913:Antibodies, Protozoan; D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Colombia",
"delete": false,
"doi": "10.7705/biomedica.v37i3.3189",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0120-4157",
"issue": "37(3)",
"journal": "Biomedica : revista del Instituto Nacional de Salud",
"keywords": "Toxoplasmosis; heart transplantation; immune tolerance; seroconversion",
"medline_ta": "Biomedica",
"mesh_terms": "D000913:Antibodies, Protozoan; D000998:Antiviral Agents; D003131:Combined Modality Therapy; D003586:Cytomegalovirus Infections; D018450:Disease Progression; D016027:Heart Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D011183:Postoperative Complications; D012008:Recurrence; D000069078:Seroconversion; D014019:Tissue Donors; D014123:Toxoplasmosis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014766:Viremia",
"nlm_unique_id": "8205605",
"other_id": null,
"pages": "303-307",
"pmc": null,
"pmid": "28968006",
"pubdate": "2017-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated toxoplasmosis in a heart transplant patient despite co-trimoxazole prophylaxis: A case report.",
"title_normalized": "disseminated toxoplasmosis in a heart transplant patient despite co trimoxazole prophylaxis a case report"
} | [
{
"companynumb": "CO-EDENBRIDGE PHARMACEUTICALS, LLC-CO-2018EDE000242",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Zoledronic acid, a potent bisphosphonate, is commonly administered to patients with bone metastases to reduce the risk of skeletal-related events (SREs). However, there have been concerns regarding its long-term monthly administration.\nTo examine whether zoledronic acid every 12 weeks was noninferior to zoledronic acid every 4 weeks in patients with metastatic breast cancer that involved the bone who had previously received a standard dosing regimen of zoledronic acid and/or pamidronate disodium.\nOPTIMIZE-2 was a prospective, randomized, double-blind, multicenter phase 3 trial of intention-to-treat (full analysis set), evaluable (per protocol), and safety populations. Patients were randomized (1:1) to receive 4.0 mg of intravenous zoledronic acid every 4 or every 12 weeks with placebo for interim infusions for 1 year. The study was conducted at 102 clinical trial centers in the United States from March 3, 2006, to July 25, 2013. Data analysis was performed from October 7, 2013, to March 24, 2014. The study randomized 416 women (≥18 years old) with bone metastases from breast cancer who previously received 9 or more doses of zoledronic acid and/or pamidronate during the first 10 to 15 months of therapy.\nThe primary end point was the proportion of patients with 1 or more SRE on study (SRE rate). The key secondary end points included time to first SRE and skeletal morbidity rate (SMR).\nA total of 416 women were randomized: 200 patients received zoledronic acid every 4 weeks (mean [SD] age, 59.2 [11.1] years; 173 were white [86.5%]), 203 patients received zoledronic acid every 12 weeks (mean [SD] age, 58.6 [11.2] years; 178 were white [87.7%]), and 13 patients received placebo (mean [SD] age, 60.8 [12.2] years; 13 were white [100%]). Baseline characteristics were similar in both zoledronic acid treatment arms. After 1 year of follow-up, SREs occurred in 44 patients (22.0%) in the zoledronic acid every 4 weeks group and 47 patients (23.2%) in the zoledronic acid every 12 weeks group (proportional difference of -1.2%; 1-sided 97.5% CI bound of the difference in SRE rate between arms, -9.8%; noninferiority P = .02). The time to first SRE between treatment groups was not statistically significantly different (hazard ratio [HR], 1.06; 95% CI, 0.70-1.60; P = .79). The mean (SD) SMR was 0.46 (1.06) vs 0.50 (1.50) events per year in the every 4 weeks vs every 12 weeks groups (P = .85). The safety profiles of the every 4 weeks and every 12 weeks groups were comparable, with 189 patients (95.5%) in the every 4 weeks group having at least 1 adverse event compared with 189 (93.5%) in the every 12 weeks group.\nThe every 12 weeks regimen of zoledronic acid was noninferior to the every 4 weeks regimen for the proportion of patients experiencing 1 or more SRE. These results may have a substantial influence on current clinical practice for treatment of patients with bone metastasis from breast cancer.\nclinicaltrials.gov Identifier: NCT00320710.",
"affiliations": "Department of Breast Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston.;Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor.;Utah Cancer Specialists, Salt Lake City, Utah.;Department of Medicine-Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.;Department of Internal Medicine-Hematology/Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California.;Department of Hematology/Oncology, Cancer Center of Kansas, Wichita.;Department of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas.;Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey.;Consultant, AstraZeneca, London, England10Consultant, BeyondSpring Pharmaceuticals, New York, New York.;Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey.;Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania.",
"authors": "Hortobagyi|Gabriel N|GN|;Van Poznak|Catherine|C|;Harker|W Graydon|WG|;Gradishar|William J|WJ|;Chew|Helen|H|;Dakhil|Shaker R|SR|;Haley|Barbara B|BB|;Sauter|Nicholas|N|;Mohanlal|Ramon|R|;Zheng|Ming|M|;Lipton|Allan|A|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2016.6316",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2437",
"issue": "3(7)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D004164:Diphosphonates; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005598:Fractures, Spontaneous; D006801:Humans; D007093:Imidazoles; D008875:Middle Aged; D016896:Treatment Outcome; D000077211:Zoledronic Acid",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "906-912",
"pmc": null,
"pmid": "28125763",
"pubdate": "2017-07-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "25935860;9362426;8053405;14734954;16059626;15084698;21343561;18728715;20857339;25332877;15983391;14692023;18338493;24141714;16046206;7160191;17763372;19190592;23684411;11417967",
"title": "Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial.",
"title_normalized": "continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone the optimize 2 randomized clinical trial"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US01591",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
},
"drugadditional": null,
... |
{
"abstract": "Proton pump inhibitors (PPI)-induced acute interstitial nephritis and autoimmune hemolytic anemia can occur concomitantly, which should prompt discontinuation of PPI. PPI should wisely be prescribed and discontinued when no longer needed.",
"affiliations": "School of Medicine Oakland University Rochester MI USA.;Graduate Medical Education Department of Internal Medicine Ascension Macomb-Oakland Hospital Warren MI USA.;School of Medicine Wayne State University Detroit MI USA.",
"authors": "Sharma|Neetu|N|;Ip|Randy|R|;Hadid|Tarik|T|https://orcid.org/0000-0002-5423-4211",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2661",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2661\nCCR32661\nCase Report\nCase Reports\nConcomitant acute interstitial nephritis and autoimmune hemolytic anemia induced by omeprazole\nSHARMA et al.Sharma Neetu MD\n1\n Ip Randy MD\n2\n Hadid Tarik MD, MPH, MShttps://orcid.org/0000-0002-5423-4211\n3\nthadid@wayne.edu \n1 \nSchool of Medicine\nOakland University\nRochester\nMI\nUSA\n\n\n2 \nGraduate Medical Education\nDepartment of Internal Medicine\nAscension Macomb‐Oakland Hospital\nWarren\nMI\nUSA\n\n\n3 \nSchool of Medicine\nWayne State University\nDetroit\nMI\nUSA\n\n* Correspondence\n\nTarik Hadid, Wayne State University, School of Medicine, 540 E Canfield Street, Detroit, MI 48201, USA.\n\nEmail: thadid@wayne.edu\n\n15 1 2020 \n2 2020 \n8 2 10.1002/ccr3.v8.2379 382\n09 11 2019 16 12 2019 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nProton pump inhibitors (PPI)—induced acute interstitial nephritis and autoimmune hemolytic anemia can occur concomitantly, which should prompt discontinuation of PPI. PPI should wisely be prescribed and discontinued when no longer needed.\n\nProton pump inhibitors (PPI)—induced acute interstitial nephritis and autoimmune hemolytic anemia can occur concomitantly, which should prompt discontinuation of PPI. PPI should wisely be prescribed and discontinued when no longer needed.\n\n\nacute interstitial nephritishemolytic anemiaomeprazoleproton pump inhibitors source-schema-version-number2.0cover-dateFebruary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.6.1 mode:remove_FC converted:26.02.2020\n\n\nSharma \nN \n, \nIp \nR \n, \nHadid \nT \n. Concomitant acute interstitial nephritis and autoimmune hemolytic anemia induced by omeprazole\n. Clin Case Rep . 2020 ;8 :379 –382\n. 10.1002/ccr3.2661\n==== Body\n1 INTRODUCTION\nProton pump inhibitors (PPI) are commonly prescribed worldwide. PPI are rarely associated with acute interstitial nephritis (AIN) and autoimmune hemolytic anemia (AIHA). We report a unique patient who simultaneously developed AIN and AIHA with complete recovery with PPI discontinuation. PPI should wisely be prescribed and discontinued when no longer needed.\n\nProton pump inhibitors (PPI) are widely used for the prevention and treatment of peptic ulcer disease (PUD), erosive and nonerosive esophagitis and Zollinger‐Ellison syndrome.1 Omeprazole is the prototype of PPI. In the United States, multiple PPI such as lansoprazole, and esomeprazole and omeprazole magnesium are available over the counter. PPI inhibit the H+/K+‐ATPase pumps on the surface of the parietal cells, the final step in the hydrochloric acid (HCL) secretary process, resulting in marked decrease in HCL production. PPI are effective and safe with only limited side effects such as increased risk for osteoporosis, hip fractures, Salmonella, Campylobacter jejuni, and Clostridium difficile infections, vitamin B12 deficiency, and electrolytes imbalance.2 Serious and life‐threatening adverse effects of PPI such as Steven‐Johnson syndrome and toxic epidermal necrolysis are extremely uncommon and only reported sporadically in the literature.3\n\n\nRenal and hematologic toxicities of PPI are exceedingly rare. We report a patient who concomitantly developed autoimmune hemolytic anemia (AIHA) and acute interstitial nephritis (AIN) along with acute tubular necrosis (ATN) due to use of PPI.\n\n2 CASE REPORT\nA 43‐year‐old previously healthy woman presented with generalized weakness and fatigue. She reported no shortness of breath, palpitation, chest pain, or clinical symptoms of bleeding. Physical examination was unremarkable except for conjunctival pallor. Complete blood counts revealed hemoglobin of 5.7 gm/dL, white blood cells 3200/µL, platelet count 295 000/µL, mean corpuscular volume 55.7 fL, ferritin 3 mg/mL, and iron saturation 2.5%. She received 2 units of packed red blood cells, intravenous famotidine, and a short course of intravenous ferrous gluconate. She was subsequently discharged on oral ferrous sulfate and omeprazole for empiric treatment of PUD and recommended for outpatient endoscopic examination. Her hemoglobin at the day of discharge was 8.5 gm/dL.\n\nThe patient returned to the emergency department 9 days later with worsening weakness, intractable nausea and vomiting and decreased oral intake for a few days. She denies consumption of nonsteroidal anti‐inflammatory drugs. Her medications were limited to ferrous sulfate, omeprazole, and ergocalciferol. Upon presentation, she was found to have severe anemia with hemoglobin of 7.4 gm/dL which subsequently further declined to 6.2 gm/dL. She was also found to have acute kidney injury with creatinine of 5.17 mg/dL, which further progressed to peak at 15.09 mg/dL. Laboratory studies revealed improving iron parameters with normal vitamin B12 and folic acid levels. Due to concern about hemolysis, lactic dehydrogenase was checked and found to be elevated at 1155 IU/L, which then further progressed to peak at 1769 IU/L. Haptoglobin was <10 mg/dL, and plasma free hemoglobin was detected at 9 mg/dL. Coomb's test was negative, but super‐Coombs was positive. Paroxysmal nocturnal hemoglobinuria panel and glucose‐6‐phosphate dehydrogenase levels were normal. Peripheral blood smear showed no schistocytes making the diagnosis of microangiopathic hemolytic anemia unlikely. Antinuclear antibody was weakly positive with a titer of 1:80. Anti‐smith antibody, antideoxynucleic acid antibody, C3, C4, and serum immunofixation studies were all unremarkable. Cytoplasmic‐neutrophil cytoplasmic antibodies (C‐ANCA) was weakly positive with a titer of 1:40. Serologic testing for human immunodeficiency virus and hepatitis B and C were negative. The patient was diagnosed with autoimmune hemolytic anemia (AIHA) and was initiated on intravenous methylprednisolone 1000 mg daily for 3 days along with plasmapheresis. Bone marrow aspiration and biopsy were performed to assess for possible lymphoproliferative disorder, which was negative. Renal biopsy was performed which revealed acute tubular injury with necrosis with eosinophilic granular casts, patchy, mild‐focally moderate lymphocytic interstitial infiltrate and interstitial edema. No global glomerulosclerosis with only minimal to mild interstitial fibrosis, tubular atrophy, and mild arteriosclerosis. Myoglobin immunostain and immunofluorescence of light chains were negative without evidence of active vasculitis or thrombotic microangiopathy (Figures 1 and 2). These findings are consistent with concomitant diagnosis of AIN and ATN most likely induced by omeprazole.\n\nFigure 1 A myoglobin immunostain on kidney biopsy fails to stain granular casts, ruling out myoglobin nephropathy. There is mild interstitial fibrosis and minimal tubular atrophy (left) with normal glomeruli (right)\n\nFigure 2 The renal interstitium contains focally moderate lymphocytic and eosinophilic cellular infiltrates with associated edema and chronic inflammation (arrows)\n\nThe patient was continued on 3‐month tapered course of prednisone. Omeprazole was permanently discontinued. Two weeks later, kidney function improved and hemoglobin stabilized. Outpatient follow‐up confirmed complete hematologic and renal recovery.\n\n3 DISCUSSION\nPPI have been widely prescribed for the management of gastroesophageal reflux symptoms since their discovery in 1980s. Omeprazole was introduced as the first effective PPI in 1989.2 Most studies have supported a mild side effect profile ranging from headaches and dizziness to abdominal pain and diarrhea. Hemolytic anemia and AIN are considered rare side effects of PPI with only few case reports described patients with PPI‐induced hemolytic anemia and a few others reported patients with PPI‐induced AIN.2, 4\n\n\nDrug‐induced autoimmune hemolytic anemia is commonly associated with the use of antibiotics. Drug‐induced AIHA is believed to be significantly underestimated likely due to underdiagnosis. There are two types of antibodies that have been associated with drug‐induced AIHA; drug‐independent antibody that can be detected in vitro without the addition of the drug and drug‐dependent antibody that reacts in vitro only in the presence of the drug.5 Interestingly, it remains unclear why and how certain drugs can induce RBC autoantibody formation without necessarily causing a hemolytic anemia.6 However, there is a universally accepted mechanism through which drug‐dependent hemolytic anemia develops. Certain drugs can bind to RBC surface proteins covalently, and at high enough concentrations, the RBC will be coated with the drug. While this is typically a benign process, some patients may develop IgG autoantibodies that can bind to the drug‐RBC protein surfaces leading to complexes that are targeted by the immune system for destruction and ultimately hemolysis.5 This theory explains why these patients usually develop Coombs positive AIHA. Our patient had AIHA with positive super‐Coombs test and responded well to steroids, which strongly suggests autoimmune mechanism of hemolysis most likely triggered by the use of omeprazole.\n\nPPI‐induced AIN is rarely reported in literature.7, 8 Of the reported cases, the majority were linked to the use of omeprazole possibly due to its longer availability for clinical use and its inherent immunogenicity.2 The largest series to date was reported by Geevasinga et al who described 18 cases of biopsy‐proven PPI‐induced AIN diagnosed over 10 years in two large Australian hospitals, which represent 64% of all biopsy‐proven AIN cases within this period. Among these patients, 11 were induced by omeprazole, 3 by pantoprazole, 3 by esmeprazole, and 1 by rabeprazole. AIN developed at a mean of 11 weeks following initiation of PPI.4 The presentation of PPI‐induced AIN is variable. While 10% of reported cases in literature have classical hypersensitivity triad of fever, rash, and eosinophilia, the majority of patients, however, had nonspecific complaints including weakness, fatigue, nausea, and vomiting as in our patient.9 Diagnosis of PPI‐induced AIN is suspected based on history but should be confirmed with renal biopsy given the variability of clinical presentation. Renal biopsy typically shows interstitial infiltrates with or without tubular injury and tubulitis. Cellular infiltrates in the interstitium consist mostly of eosinophils and lymphocytes. Glomeruli in most cases are normal. Management of PPI‐induced AIN and hemolytic anemia relies mainly on discontinuation of the offending drug. However, early initiation of steroids may hasten renal recovery and improve hemolysis.10\n\n\nAlthough PPI‐induced AIHA and AIN were individually reported in the literature,2, 4, 7, 8 to our knowledge, this is the first case to report these two entities occurring concomitantly. Fortunately, the offending drug was promptly discontinued, and the patient achieved complete recovery.\n\n4 CONCLUSION\nWhile PPI are often safe, they can cause serious complications such as AIN and AIHA. Rarely, more than one PPI‐induced complications can simultaneously occur. Therefore, PPI should judiciously be prescribed. Early diagnosis of PPI‐induced adverse effects is essential to prompt discontinuation of PPI and initiation of supportive therapy to improve clinical outcomes.\n\nCONFLICT OF INTEREST\nAll authors disclose that they have no conflict of interests related to this manuscript. All authors contributed to this manuscript.\n\nAUTHOR CONTRIBUTIONS\nNeetu Sharma, MD: extensively reconstructed, edited, and reviewed the details of this manuscript. Randy Ip, MD: wrote the initial manuscript, which was then further edited and reviewed by the other authors. Tarik Hadid, MD, MPH, MS: provided the final review and edit of this manuscript and formatted it in its final form.\n\nCONSENT\nThe patient has provided written informed consent for publication.\n\nACKNOWLEDGMENTS\nNot applicable.\n==== Refs\nREFERENCES\n1 \n\nMarks \nDR \n, \nJoy \nJV \n, \nBonheim \nNA \n. Hemolytic anemia associated with the use of omeprazole\n. Am J Gastroenterol . 1991 ; 86 (2 ): 217 ‐218\n. e‐pub ahead of print 1991/02/01.1992636 \n2 \n\nStrand \nDS \n, \nKim \nD \n, \nPeura \nDA \n. 25 years of proton pump inhibitors: a comprehensive review\n. Gut and Liver . 2017 ;11 (1 ):27 ‐37\n.27840364 \n3 \n\nFracaroli \nTS \n, \nMiranda \nLQ \n, \nSodré \nJL \n, \nChaves \nM \n, \nGripp \nA \n. Toxic epidermal necrolysis induced by lansoprazole\n. An Bras Dermatol . 2013 ;88 (1 ):117 ‐120\n.23539016 \n4 \n\nGeevasinga \nN \n, \nColeman \nPL \n, \nWebster \nAC \n, \nRoger \nSD \n. Proton pump inhibitors and acute interstitial nephritis\n. Clin Gastroenterol Hepatol . 2006 ;4 (5 ):597 ‐604\n. e‐pub ahead of print 2006/04/25.16630752 \n5 \n\nGarratty \nG \n. Drug‐induced immune hemolytic anemia\n. Hematology Am Soc Hematol Educ Program . 2009 ;2009 (1 ):73 ‐79\n. e‐pub ahead of print 2009/12/17.\n6 \n\nPetz \nLD \n, \nGarratty \nG \n. Drug‐induced haemolytic anemia\n. Clin Haematol . 1975 ; 4 (1 ): 181 ‐197\n. e‐pub ahead of print 1975/02/01.126834 \n7 \n\nSampathkumar \nK \n, \nRamalingam \nR \n, \nPrabakar \nA \n, \nAbraham \nA \n. Acute interstitial nephritis due to proton pump inhibitors\n. Indian J Nephrol . 2013 ;23 (4 ):304 ‐307\n.23960351 \n8 \n\nRay \nS \n, \nDelaney \nM \n, \nMuller \nAF \n. Proton pump inhibitors and acute interstitial nephritis\n. BMJ . 2010 ;341 :c4412 .20861097 \n9 \n\nButt \nMI \n, \nSajid \nS \n, \nSobolewski \nS \n. Autoimmune haemolytic anaemia due to Omeprazole\n. Irish Med J . 2007 ; 100 (2 ): 372 . e‐pub ahead of print 2007/04/17.\n10 \n\nPusey \nCD \n, \nSaltissi \nD \n, \nBloodworth \nL \n, \nRainford \nDJ \n, \nChristie \nJL \n. Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy\n. Q J Med . 1983 ; 52 (206 ): 194 ‐211\n. e‐pub ahead of print 1983/01/01.6604293\n\n",
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"keywords": "acute interstitial nephritis; hemolytic anemia; omeprazole; proton pump inhibitors",
"medline_ta": "Clin Case Rep",
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"title": "Concomitant acute interstitial nephritis and autoimmune hemolytic anemia induced by omeprazole.",
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"abstract": "Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the JC virus under an immunosuppressed state. This condition carries a high risk of cryptococcal meningitis. We herein report a 65-year-old woman who simultaneously developed PML and cryptococcal meningitis and presented with bilateral sixth nerve palsy. She had been treated with methotrexate and infliximab for rheumatoid arthritis. Her symptoms improved with antifungal drug treatment and discontinuation of immunosuppression therapy. Although concurrent PML and cryptococcal meningitis is rare, it should be considered in immunosuppressed patients.",
"affiliations": "Department of Neurology, Toyohashi Municipal Hospital, Japan.;Department of Neurology, Toyohashi Municipal Hospital, Japan.;Department of Neurology, Toyohashi Municipal Hospital, Japan.;Department of Neurology, Toyohashi Municipal Hospital, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Japan.;Department of Virology 1, National Institute of Infectious Diseases, Japan.;Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan.;Department of Neurology, Toyohashi Municipal Hospital, Japan.",
"authors": "Nosaki|Yasunobu|Y|;Ohyama|Ken|K|;Watanabe|Maki|M|;Yokoi|Takamasa|T|;Nakamichi|Kazuo|K|;Saijo|Masayuki|M|;Miura|Yoshiharu|Y|;Iwai|Katsushige|K|",
"chemical_list": "D000935:Antifungal Agents; D018501:Antirheumatic Agents; D000069285:Infliximab; D008727:Methotrexate",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3152736910.2169/internalmedicine.2570-18Case ReportSimultaneous Development of Progressive Multifocal Leukoencephalopathy and Cryptococcal Meningitis during Methotrexate and Infliximab Treatment Nosaki Yasunobu 1Ohyama Ken 1Watanabe Maki 1Yokoi Takamasa 1Nakamichi Kazuo 2Saijo Masayuki 2Miura Yoshiharu 3Iwai Katsushige 1\n1 Department of Neurology, Toyohashi Municipal Hospital, Japan\n2 Department of Virology 1, National Institute of Infectious Diseases, Japan\n3 Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, JapanCorrespondence to Dr. Yasunobu Nosaki, nozaki-yasunobu@toyohashi-mh.jp\n\n15 9 2019 58 18 2703 2709 25 12 2018 24 3 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the JC virus under an immunosuppressed state. This condition carries a high risk of cryptococcal meningitis. We herein report a 65-year-old woman who simultaneously developed PML and cryptococcal meningitis and presented with bilateral sixth nerve palsy. She had been treated with methotrexate and infliximab for rheumatoid arthritis. Her symptoms improved with antifungal drug treatment and discontinuation of immunosuppression therapy. Although concurrent PML and cryptococcal meningitis is rare, it should be considered in immunosuppressed patients. \n\nprogressive multifocal leukoencephalopathycryptococcal meningitisinfliximabmethotrexateJC virus\n==== Body\nIntroduction\nProgressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of the JC virus (JCV). PML often occurs in patients who are immunosuppressed or who are receiving immunosuppression therapy (1). Cryptococcal meningitis is another condition that occurs in immunosuppressed conditions and remains a major cause of human immunodeficiency virus (HIV)-related mortality worldwide (2). Given the recent increase in the use of immunosuppression therapy for rheumatologic conditions, oncology, and organ transplantation, the incidence of PML and cryptococcal meningitis is increasing (3-7).\n\nTwo commonly used immunosuppressive drugs are methotrexate (MTX) and infliximab. MTX is an analogue of the B vitamin folic acid that is used as first-line immunosuppression therapy for patients with rheumatoid arthritis (8). Infliximab is a monoclonal chimeric antibody directed against soluble and membrane-bound tumor necrosis factor alpha (TNFα) that prevents receptor binding and blocks gene transcription (9). Although these agents are effective for rheumatoid arthritis, they may increase the risk of opportunistic infections.\n\nWe herein report a patient diagnosed with concurrent PML and cryptococcal meningitis while receiving infliximab and methotrexate treatment for rheumatoid arthritis.\n\nCase Report\nA 65-year-old woman was admitted to our hospital because of transient acute right upper limb weakness and gait disturbance. Her medical history revealed that she had been diagnosed with rheumatoid arthritis at 57 years of age and started on 3 mg/day prednisolone and weekly oral methotrexate (6 mg). At 61 years of age, infliximab had been administered every 8 weeks, and prednisolone was reduced to 2 mg/day. Because of remission, prednisolone had been reduced to 1 mg/day and oral methotrexate to 4 mg. At 64 years of age, prednisolone was discontinued due to remission of symptoms. Until admission, remission of arthritis symptoms had been maintained with oral methotrexate (4 mg) and infliximab (3 mg/kg). She had no history of diabetes mellitus during the treatment period.\n\nOn admission, she was 151 cm tall and weighed 52.2 kg. She was alert and well oriented. Her cranial nerve function was intact. Slight weakness of the right upper and lower limbs was noted. Although there was no objective sensory loss, she complained of numbness of the right fingers. Her cognitive function was normal, her Revised Hasegawa's Dementia Scale (HDS-R) score was 28 points, and her mini mental state examination score was 30. Brain computed tomography (CT) showed no hemorrhagic changes. Brain magnetic resonance imaging (MRI) showed no abnormal intensity areas on diffusion-weighted imaging (DWI). Nonspecific lesions were seen on fluid-attenuated inversion recovery (FLAIR) images (Fig. 1A). A neurological examination was normal on the second hospital day, and a transient ischemic attack (TIA) was diagnosed. The patient was discharged four days later as there was no recurrence of limb palsy or TIA symptoms.\n\nFigure 1. Changes in brain magnetic resonance imaging (MRI) over time. Fluid-attenuated inversion recovery (FLAIR) scans at first admission (A) and two months (B), three months (C), and six months (D) after the first admission. (A) shows nonspecific changes. (B) shows focal lesions in the white matter of the bilateral frontal and temporal lobes. (C) shows that the lesions in the white matter on FLAIR grew. (D) shows that the lesions gradually disappeared, and no new lesions developed.\n\nAfter discharge, the patient reported onset of headache and general fatigue. Eight weeks later, she was readmitted with headache, nausea, dizziness, weight loss, and double vision. At that time, her weight was 45 kg, her cognitive function was mildly disturbed, and her HDS-R score was 16 points. A neurological examination revealed a drowsy state and bilateral sixth nerve palsy. Other cranial nerve functions and muscle strength of the extremities were normal. There were no meningeal signs, such as neck stiffness or Kernig's sign. The finger-to-nose and heel-to-knee tests showed no abnormalities. Deep tendon reflexes were slightly increased in the upper and lower extremities. The patient could not walk without assistance due to headache, dizziness, and double vision.\n\nBlood tests showed a normal white blood cell count (5,400 cells/μL; reference 3,300-8,600 cells/μL) with decreased lymphocytes (4.0%; reference 21.3-50.2%). Blood chemistry demonstrated normal C-reactive protein and β-D-glucan levels, and the HIV antibody test were negative. In addition, blood glucose levels were normal (143 mg/dL; reference 60-160 mg/dL). A cerebrospinal fluid examination (CSF) revealed an elevated white blood cell count (23 cells/μL, monocyte 22 cells/μL, polymorphonuclear count 1 cell/μL; reference 5 or less cells/μL) with an opening pressure of over 30 cmH2O. The protein concentration in the CSF was increased (199 mg/dL; reference 10-45 mg/dL). The glucose level in the CSF was 22 mg/dL, and the ratio of the CSF/blood glucose was decreased (0.15; reference >0.4). Cryptococcal antigen was detected in the CSF and serum. A direct examination with India ink staining of the CSF and CSF culture identified Cryptococcus neoformans.\n\nBrain MRI revealed focal lesions in the white matter of the bilateral frontal and temporal lobes (Fig. 1B). These lesions appeared hyperintense on T2-weighted and FLAIR images and hypointense and devoid of contrast enhancement on T1-weighted images.\n\nThe clinical course is summarized in Fig. 2. We diagnosed the patient with cryptococcal meningitis based on the results of the CSF examination. MTX and infliximab were discontinued, and treatment with amphotericin B intravenously in combination with flucytosine was started. After six weeks, induction therapy succeeded, and fluconazole was started for maintenance therapy. Three weeks after starting antifungal therapy, polymerase chain reaction (PCR) targeting the JCV large T gene in CSF revealed the presence of JCV-DNA showing 479 copies/mL (reference <50 copies/mL). The JCV genome in CSF showed a mutation characteristic of the PML-type virus identified in the non-coding control region (NCCR) using multiplex real-time PCR (10). Based on MRI findings and PCR test results for JCV in CSF, we diagnosed her with probable PML. Antifungal therapy was continued without restarting MTX and infliximab, and no other alternative immunosuppressive agents were started. The patient's clinical symptoms gradually improved without recurrence of rheumatoid arthritis. Follow-up MRI performed one month after readmission showed enlargement of some lesions and the appearance of new lesions (Fig. 1C). At that time, DWI showed slight hyperintensity of the lesions and a partial low signal on the apparent diffusion coefficient map.\n\nFigure 2. Summary of the clinical course. Methotrexate and infliximab were discontinued, and antifungal therapy was initiated at readmission. The patient symptoms improved over 10 weeks, and there was no recurrence >24 weeks after the first admission.\n\nGiven the lack of focal neurological symptoms, we closely monitored the patient's condition without treatment, other than antifungal therapy. Eight weeks after readmission, she was discharged with improvement in double vision. Her cognitive function became normal, and her HDS-R score was 28. Two months after discharge, JCV DNA in CSF was negative, and MRI findings showed slight improvement (Fig. 1D). At the time of writing, the patient had been stable for over six months.\n\nDiscussion\nThe patient in the present case was diagnosed with PML and cryptococcal meningitis. Brain imaging and CSF examinations at the time of secondary admission revealed Cryptococcus neoformans infection and JCV reactivation. Clinical symptoms of headache, nausea, dizziness, bilateral sixth nerve palsy, and cognitive dysfunction were observed. These symptoms are frequently observed in cryptococcal meningitis (6), and they gradually improve after starting antifungal therapy without the improvement of MRI findings. Therefore, we considered the symptoms of secondary admission to have been caused by cryptococcal meningitis.\n\nPCR of the patient's CSF DNA was positive for JCV, which had the mutation within the NCCR of the viral genome. JCV infection is common in humans and JCV DNA (archetype) is usually found in the blood or urine in non-PML patients. However, JCV variants with NCCR mutations (PML-type) were detected in PML patients (10). Brain MRI revealed focal lesions in the white matter of the bilateral frontal and temporal lobes. PML and cryptococcal meningitis were therefore simultaneously diagnosed. To our knowledge, there have been only three cases of PML concurrent with cryptococcal meningitis (11-13; Table). Cases 1 and 2 were diagnosed PML at an autopsy. Prednisone had been used as an immunosuppressive agent in Cases 2 and 3, whereas biologic agents were administered in our case. Antifungal therapy without antiviral drugs was administered as treatment in all cases; however, only our patient survived. Compared with these previous three cases, the patient in the present case had a short disease duration prior to the diagnosis of cryptococcal meningitis and PML as well as an early administration of antifungal therapy with the discontinuation of immunosuppressive therapy. We suspect that these factors contributed to her good prognosis.\n\nTable. Known Cases of PML Concurrent with Cryptococcal Meningitis.\n\nCase\tAge (years)/\nSex\tUnderlying diseases\tImmunosuppressive agents\tCryptococcal meningitis identified\tPML identified\tTreatment/\nAntiviral drugs\tOutcome (interval)\t\n1\t49/M\n(Mathews 1977)\tSarcoidosis\tNone\tCSF\tAutopsy\tAntifungal therapy and corticosteroids/\nnone\tDeclined and died \n(60 months)\t\n2\t36/F \n(Malas 1977)\tSLE, Thymoma, Aplastic anemia\tPrednisone, Oxymetholone, Azathioprine, and Radiotherapy for thymoma\tCSF\tAutopsy\tAntifungal therapy/\nnone\tDied \n(5 months)\t\n3\t61/M \n(Weitzman 1978)\tPoorly differentiated lymphocytic lymphoma\tCyclophosphamide, Vincristine, and Prednisone\tCSF\tCT, Biopsy\tAntifungal therapy/\nnone\tDied \n(7 months)\t\nPresent case\t65/F\tRheumatoid arthritis\tMethotrexate and Infliximab\tCSF\tMRI, JC virus PCR\tAntifungal therapy/\nnone\tSurvived, stable \n(6 months)\t\nSLE: systemic lupus erythematosus, CSF: cerebrospinal fluid, PML: progressive multifocal leukoencephalopathy, CT: computed tomography, MRI: magnetic resonance imaging, PCR: polymerase chain reaction\n\nCases 1, 2, and 3 are from previously published reports (11-13).\n\nIn our case, brain MRI over time showed gradual changes (Fig. 1). In HIV-positive patients with cryptococcal meningitis, MRI findings show leptomeningeal enhancement with or without a micronodular pattern, microcystic prominence involving the temporal lobes or basal ganglia, ventriculomegaly, and brain abscess (14). In non-HIV patients with cryptococcal meningitis, Virchow-Robin dilatation, hydrocephalus, intracerebral nodules, and pseudocysts are typically present (15). The MRI findings for our patient differed from those in previous cases of cryptococcal meningitis in all therapy periods. Specifically, PML lesions were seen as a single or multiple hyperintense areas in T2-weighted images with variable shapes and size. Typically, bilateral, asymmetric, multifocal white matter plaque-like lesions that are T1 hypointense do not show enhancement. There is no edema or mass effect, either. On DWI, the advancing edge of the demyelination is strongly hyperintense. For drug-associated PML, lesions are typically localized supratentorially and not infratentorially, especially in the frontal and parietal lobes. Although atypical MRI findings are common, MRI may still be useful for detecting lesions at an early stage of PML (16, 17). In the present case, brain MRI at the initial admission did not show obvious PML lesions. However, the second MRI scan revealed multiple lesions on T2-weighted images and FLAIR hyperintense areas compatible with PML. In addition, the lesions of the bilateral frontal and temporal lobes changed throughout the clinical course.\n\nCryptococcal meningitis is one of the most important opportunistic infections among immunocompromised hosts, and infection in patients treated with infliximab or MTX has been previously reported (18-21). PML has been reported in patients receiving biologic agents, such as natalizumab, efalizumab, rituximab, and infliximab (5, 7). Such biologic immunosuppressive agents are known to have a strong association with drug-induced PML (3). These immunosuppressants are classified into three categories (22-24): Class 1 drugs, including natalizumab, are associated with the highest risk of PML. Class 2 drugs, including rituximab and non-biologic drugs, such as MTX, are recognized to be associated with a lower risk of PML than class 1 agents. Infliximab and other TNF-α inhibitors are class 3 drugs. The risk of developing PML with class 3 drugs remains uncertain, with one report suggesting that a relationship between PML and treatment with anti-TNF agents is unlikely (25). However, several reports have described an association with PML (5, 26, 27). In the present case, the blood cell count showed decreased lymphocyte numbers due to immunosuppression therapy with MTX and infliximab. The decreased T lymphocyte numbers impaired cell-mediated immunity, leading to the breakdown of the prevention of JCV reactivation and cryptococcal infection (6, 7, 27). Therefore, PML should be considered in patients receiving combination therapy with class 2 and 3 agents. In addition, TNF-α inhibitors are known to induce CNS demyelination (28). Although the mechanism is not fully understood, MRI findings from patients treated with TNF-α inhibitors show CNS demyelination as white matter changes on T2-weighted and FLAIR images. This characteristic is similar to PML findings, and we should consider the possibility of PML when changes in MRI findings are noted for patients receiving TNF-α inhibitors.\n\nThe recommended approach for drug-induced PML is to exclude suspicious drug use and perform plasma exchange (17). Although several reports have shown some effectiveness of zidovudine, interferon alpha, foscavir, cidofovir, mitazapine, mefloquine, and comptochecin (29-31), the most effective treatment for PML has not been determined. Therefore, many targeted therapies against PML are presently under study. In our patient, we diagnosed probable PML concurrent with cryptococcal meningitis. After starting antifungal therapy and stopping infliximab and MTX, the clinical symptoms and CSF cell count gradually improved. Plasma exchange and drug treatment for PML were not performed in our patient due to her clinical improvement. MRI findings from long-term survivors of PML show leukomalacia and subcortical atrophy (32), whereas the white matter lesions on MRI in our patient gradually disappeared. Our patient received only an antifungal drug and remained stable over the long term with gradual improvement in MRI findings.\n\nRecently, the occurrence of immune reconstitution inflammatory syndrome (IRIS) has been recognized in association with the treatment of cryptococcal meningitis and PML. IRIS is characterized by a tissue-destructive inflammatory response after initiating highly active antiretroviral therapy (HAART) for HIV or tapering or discontinuing immunosuppressive drugs. IRIS should be considered when clinical symptoms develop and atypical imaging findings are noted despite adequate treatment. IRIS can manifest as cryptococcal meningitis or PML, which is known as cryptococcal meningitis-IRIS or PML-IRIS, respectively. The risk factors of IRIS are pre-treatment HIV or a severe immunosuppressive state with very low CD4 counts and increasing CD4 counts after the initiation of therapy (33). In the present case, IRIS was not observed after the discontinuation of immunosuppressive agents. The patient did not have HIV, and the recovery of her immune function was slow, as the lymphocyte and CD4 cell counts had been decreased for 17 and >24 weeks, respectively. We suspected the occurrence of IRIS was prevented by these characteristics.\n\nWe also evaluated JCV with mutation within the NCCR of the viral genome. Many kinds of rearranged NCCR of JCV variants (PML-type) have been reported, and the frequent NCCR typing changed in accordance with either the vial load or therapeutic intervention. The NCCR of JCV variants can be used to evaluate PML progression, and changes in NCCR typing can be used as a biomarker of PML treatment in the future (34).\n\nIn summary, we encountered a case of simultaneous development of PML and cryptococcal meningitis in a patient receiving MTX and infliximab. All patients treated with immunosuppressive therapy, including monoclonal antibodies, require careful monitoring, and if neurological symptoms are noted, CNS infection should be considered. In particular, multiple infections should be considered in immunosuppressed patients.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThis work was supported in part by JSPS KAKENHI (Grant Number 17K09768) and a Grant-in-Aid for the Research Committee of Prion Disease and Slow Virus Infection, Research on Policy Planning and Evaluation for Rare and Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan (Grant Number H29-Nanchitou (Nan)-Ippan-036).\n==== Refs\n1. \nNakamichi K , Mizusawa H , Yamada M , et al \nCharacteristics of progressive multifocal leukoencephalopathy clarified through internet-assisted laboratory surveillance in Japan . BMC Neurol \n12 : 121 , 2012 .23066763 \n2. \nPark BJ , Wannemuehler KA , Marston BJ , Govender N , Pappas PG , Chiller TM \nEstimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS . AIDS \n23 : 525 -530 , 2009 .19182676 \n3. \nPiccinni C , Sacripanti C , Poluzzi E , et al \nStronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents . Eur J Clin Pharmacol \n66 : 199 -206 , 2010 .19838692 \n4. \nPyrgos V , Seitz AE , Steiner CA , Prevots DR , Williamson PR \nEpidemiology of cryptococcal meningitis in the US: 1997-2009 . Plos One \n8 : 390 -396 , 2013 .\n5. \nSammut L , Wallis D , Holroyd C \nProgressive multifocal leukoencephalopathy associated with infliximab . J R Coll Physicians Edinb \n46 : 163 -165 , 2016 .27959350 \n6. \nQu J , Zhou T , Zhong C , Deng R , Lü X \nComparison of clinical features and prognostic factors in HIV-negative adults with cryptococcal meningitis and tuberculous meningitis: a retrospective study . BMC Infect Dis \n17 : 51 , 2017 .28068915 \n7. \nBohra C , Sokol L , Dalia S \nProgressive multifocal leukoencephalopathy and monoclonal antibodies: a review . Cancer Control \n24 : 1 -9 , 2017 .\n8. \nSmolen JS , Landewé R , Bijlsma J , et al \nEULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update . Ann Rheum Dis \n76 : 960 -977 , 2017 .28264816 \n9. \nMaini RN , Feldmann M \nHow does infliximab work in rheumatoid arthritis? \nArthritis Res \n4 : S22 -S28 , 2002 .12110154 \n10. \nRyschkewitsch CF , Jensen PN , Major EO \nMultiplex qPCR assay for ultra sensitive detection of JCV DNA with simultaneous identification of genotypes that discriminates non-virulent from virulent variants . J Clin Virol \n57 : 243 -248 , 2013 .23619054 \n11. \nMathews T , Wisotzkey H , Moossy J \nMultiple central nervous system infections in progressive multifocal leukoencephalopathy . Neurology \n26 : 9 -14 , 1976 .942775 \n12. \nMalas D , Weiss S \nProgressive multifocal leukoencephalopathy and cryptococcal meningitis with systemic lupus erythematosus and thymoma . Ann Neurol \n1 : 188 -191 , 1977 .889304 \n13. \nWeitzman S , Kaufman S , Wolpow E , Hinton RC , Richardson EP Jr \nCase report. Simultaneous fungal and viral infection of the central nervous system . Am J Med Sci \n276 : 127 -132 , 1978 .581533 \n14. \nSarkis RA , Mays M , Isada C , Ahmed M \nMRI findings in cryptococcal meningitis of the non-HIV population . Neurologist \n19 : 40 -45 , 2015 .25607331 \n15. \nZhong Y , Zhou Z , Fang X , Peng F , Zhang W \nMagnetic resonance imaging study of cryptococcal neuroradiological lesions in HIV-negative cryptococcal meningitis . Eur J Clin Microbiol Infect Dis \n36 : 1367 -1372 , 2017 .28247152 \n16. \nSahraian MA , Radue EW , Eshaghi A , Besliu S , Minagar A \nProgressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis . Eur J Neurol \n19 : 1060 -1069 , 2012 .22136455 \n17. \nWilliamson EML , Berger JR \nDiagnosis and treatment of progressive multifocal leukoencephalopathy associated with multiple sclerosis therapies . Neurotherapeutics \n14 : 961 -973 , 2017 .28913726 \n18. \nBaughman RP , Lower EE \nFungal infections as a complication of therapy for sarcoidosis . QJM \n98 : 451 -456 , 2005 .15879444 \n19. \nKluger N , Poirier P , Guilpain P , Baixench MT , Cohen P , Paugam A \nCryptococcal meningitis in a patient treated with infliximab and mycophenolate mofetil for Behçet's disease . Int J Infect Dis \n13 : e325 , 2009 .19157948 \n20. \nTrillos RF , Fernández-Ávila DG , Díaz MC , Gutiérrez JM \nCryptococcal meningoencephalitis in a patient with rheumatoid arthritis treated with methotrexate and prednisone . Reumatol Clin \n10 : 346 -347 , 2014 .24746915 \n21. \nVasant DH , Limdi JK , Borg-Bartolo SP , Bonington A , George R \nPosterior reversible encephalopathy syndrome and fatal cryptococcal meningitis after immunosuppression in a patient with elderly onset inflammatory bowel disease . ACG Case Rep J \n3 : e98 , 2016 .27807560 \n22. \nZaheer F , Berger JR \nTreatment-related progressive multifocal leukoencephalopathy: current understanding and future steps . Ther Adv Drug Saf \n3 : 227 -239 , 2012 .25083238 \n23. \nCalabrese LH , Molloy E , Berger J \nSorting out the risks in progressive multifocal leukoencephalopathy . Nat Rev Rheumatol \n11 : 119 -123 , 2015 .25314016 \n24. \nClavel G , Moulignier A , Semerano L \nProgressive multifocal leukoencephalopathy and rheumatoid arthritis treatments . Joint Bone Spine \n84 : 671 -675 , 2017 .28323224 \n25. \nMolloy ES , Calabrese LH \nProgressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies . Arthritis Rheum \n64 : 3043 -3051 , 2012 .22422012 \n26. \nKumar D , Bouldin TW , Berger RG \nA case of progressive multifocal leukoencephalopathy in a patient treated with infliximab . Arthritis Rheum \n62 : 3191 -3195 , 2010 .20722036 \n27. \nKeene DL , Legare C , Taylor E , Gallivan J , Cawthorn GM , Vu D \nMonoclonal antibodies and progressive multifocal leukoencephalopathy . Can J Neurol Sci \n38 : 565 -571 , 2011 .21672696 \n28. \nSolomon AJ , Spain RI , Kruer MC , Bourdette D \nInflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors . Mult Scler \n17 : 1472 -1487 , 2011 .21816758 \n29. \nKishida S , Tanaka K \nMefloquine treatment in a patient suffering from progressive multifocal leukoencephalopathy after umbilical cord blood transplant . Intern Med \n49 : 2509 -2513 , 2010 .21088359 \n30. \nSano Y , Nakano Y , Omoto M , et al \nRituximab-associated progressive multifocal leukoencephalopathy derived from non-Hodgkin lymphoma: neuropathological findings and results of mefloquine treatment . Intern Med \n54 : 965 -970 , 2015 .25876582 \n31. \nPavlovic D , Patera AC , Nyberg F , Gerber M , Liu M , Progressive Multifocal Leukeoncephalopathy Consortium \nProgressive multifocal leukoencephalopathy: current treatment options and future perspectives . Ther Adv Neurol Disord \n8 : 255 -273 , 2015 .26600871 \n32. \nLima MA , Bernal-Cano F , Clifford DB , Gandhi RT , Koralnik IJ \nClinical outcome of long-term survivors of progressive multifocal leukoencephalopathy . J Neurol Neurosurg Psychiatry \n81 : 1288 -1291 , 2010 .20710013 \n33. \nPost MJ , Thurnher MM , Clifford DB , et al \nCNS-immune reconstitution inflammatory syndrome in the setting of HIV infection, part 1: overview and discussion of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome and cryptococcal-immune reconstitution inflammatory syndrome . AJNR Am J Neuroradiol \n34 : 1297 -1307 , 2013 .22790246 \n34. \nNakamichi K , Kishida S , Tanaka K , et al \nSequential changes in the non-coding control region sequences of JC polyomaviruses from the cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy . Arch Virol \n158 : 639 -650 , 2013 .23138154\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(18)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "JC virus; cryptococcal meningitis; infliximab; methotrexate; progressive multifocal leukoencephalopathy",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D000069285:Infliximab; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D016919:Meningitis, Cryptococcal; D008727:Methotrexate; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2703-2709",
"pmc": null,
"pmid": "31527369",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25607331;28975841;889304;21672696;25314016;581533;28913726;942775;23066763;21816758;23619054;26600871;27959350;23138154;22790246;23457543;20710013;24746915;28068915;25876582;20722036;27807560;28264816;15879444;22422012;22136455;25083238;28247152;12110154;19838692;19157948;28323224;21088359;19182676",
"title": "Simultaneous Development of Progressive Multifocal Leukoencephalopathy and Cryptococcal Meningitis during Methotrexate and Infliximab Treatment.",
"title_normalized": "simultaneous development of progressive multifocal leukoencephalopathy and cryptococcal meningitis during methotrexate and infliximab treatment"
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"abstract": "Levetiracetam is well-tolerated and commonly used as a broad spectrum antiepileptic in both partial and generalized seizures. Few cases of levetiracetam-induced psychosis in children are reported in the literature. The present case of levetiracetam-induced acute psychosis highlights the adverse effect of this drug and also emphasizes the need for close monitoring of children on levetiracetam.",
"affiliations": "Department of Pediatrics, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, Maharashtra, India.;Department of Pediatrics, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, Maharashtra, India.",
"authors": "Zaki|Syed Ahmed|SA|;Gupta|Saurabh|S|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
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"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-46-34110.4103/0253-7613.132195Drug WatchLevetiracetam-induced acute psychosis in a child Zaki Syed Ahmed Gupta Saurabh Department of Pediatrics, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, Maharashtra, IndiaCorrespondence to: Dr. Syed Ahmed Zaki, E-mail: drzakisyed@gmail.comMay-Jun 2014 46 3 341 342 20 5 2013 28 8 2013 20 3 2014 Copyright: © Indian Journal of Pharmacology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Levetiracetam is well-tolerated and commonly used as a broad spectrum antiepileptic in both partial and generalized seizures. Few cases of levetiracetam-induced psychosis in children are reported in the literature. The present case of levetiracetam-induced acute psychosis highlights the adverse effect of this drug and also emphasizes the need for close monitoring of children on levetiracetam.\n\nKEY WORDS\nAntiepileptic drugchildrenlevetiracetampsychosis\n==== Body\nIntroduction\nLevetiracetam is an antiepileptic drug, which has a safe and proven efficacy in complex partial seizures, generalized tonic clonic seizures and myoclonic seizures. It is widely used as add-on therapy in patients with epileptic disorders.[1] Though generally well-tolerated, it may cause some mild adverse reactions.[1] However, psychosis associated with its use in children has rarely been reported.[23] We report a case of an 11-year-old girl who developed levetiracetam-induced psychosis.\n\nCase Report\nAn 11-year-old girl was brought to the outpatient department with the complaints of restlessness and “talking to herself” for 1 day. She described hallucinations of either seeing a ghost or of snakes crawling all over her body. She had a history of generalized tonic convulsions 8 days ago for which she was started on tablet levetiracetam by a private practitioner. The convulsion had lasted for 2 min and she recovered after the convulsion. She had been was advised half tablet (500 mg) levetiracetam twice a day (20 mg/kg/day). However, her mother misunderstood the dose and started with one tablet twice a day (40 mg/kg/day). There was no history of fever, vomiting, headache, abdominal pain, or urinary complaints. There was no history of other drug ingestion, contact with tuberculosis or head injury, or history of psychiatric illness in past or in other family members. There was no preceding stressful event at home or in school. Developmentally, the child was normal. She was studying in 5th grade had good academic performance. Birth and family history were insignificant.\n\nOn examination, the child was afebrile and her vitals were normal. There was no icterus, pallor or rash. Central nervous system examination revealed a restless child with uninhibited behavior. She spoke excessively, but speech was not slurred. No other abnormalities were detected on systemic examination. Laboratory investigations, e.g., complete blood count, liver function, renal function tests, urine analysis and serum electrolytes, thyroid function tests and antinuclear antibody test were normal. Magnetic resonance imaging of brain and electroencephalography were also normal. Measurement of drug levels in blood facility is not available in our institution hence drug levels were not measured. Levetiracetam was stopped and oral olanzapine was started. The patient recovered from her psychotic symptoms within 72 h and was discharged. Olanzapine was stopped 10 days after the discharge. This type A class of adverse drug reaction was evaluated for causality and was found to have a probable/likely causal relationship with levetiracetam as per Naranjo algorithm.[4]\n\nDiscussion\nLevetiracetam, a piracetam analog, is a water-soluble pyrrolidone derivative ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) with a novel chemical structure and unique mechanism of action. It exerts its antiepileptic effects by specifically binding to synaptic vesicle protein 2A (a 90-kDa-membrane protein), inhibiting calcium release from intra-neuronal stores, opposing the activity of negative modulators of gamma-amino butyric acid- and glycine-gated currents and inhibiting excessive synchronized activity between neurons.[56] It also blocks zinc and beta-carbolines from interrupting chloride influx in the GABA and glycine receptors.[5] And inhibits N-type calcium channels.[6] It is absorbed through gastrointestinal tract with high oral bioavailability and is excreted unchanged through the kidneys. It is not associated with clinically significant pharmacokinetic interactions with other drugs, including other antiepileptic drugs.[6]\n\nThe usual effective dose is between 20 and 60 mg/kg/day. One can start at 20 mg/kg in two doses and increase every 1-2 weeks till 60 mg/kg/day. Though generally well-tolerated, it may cause some adverse reactions such as asthenia, ataxia, diplopia, dizziness, dysarthria, fatigue, headache, light-headedness, nystagmus, paresthesias, somnolence, and tremors. These are usually either dose related or transient. Behavioral effects including agitation, anxiety, depression, emotional lability, hallucinations, and psychosis also observed.[256] Psychiatric side-effects are seen in up to 13.3% in adults and 37.6% in pediatric patients. Of these, severe symptoms such as depression, agitation, or hostility, and psychotic behavior are observed in 0.7% of patients.[7] Factors like young age, history of febrile convulsions, status epilepticus, previous history of seizure, poorly controlled seizures, previous psychiatric history or cognitive problems, sensory deprivation and rapid increase in the dose of levetiracetam can increase risk of adverse reactions.[1258] Lamotrigine co-therapy has been shown to have a protective effect against psychosis.[8] Although, there is evidence that the drug may trigger behavioral disorders, there are reports that it may reduce hyperactivity, impulsivity, mood instability and aggression in autistic children.[9] Levetiracetam-induced psychosis normally occurs about 1 week after the start of treatment. However, it has also been reported after long term treatment.[10] Table 1 documents some reported cases of levetiracetam-induced psychosis. Most of the patients had certain predisposing risk factors. In the present case, young age and high dose of levetiracetam at the onset were the two risk factors predisposing to psychosis.\n\nTable 1 Reports of levetiracetam-induced psychosis and associated rise factors in literature\n\nHence, the authors suggest that children prescribed this drug should be monitored particularly with regard to psychiatric adverse effects. Titration of medication over a period of days or weeks rather than administration of full dose since the beginning may be practiced minimizes these adverse effects.\n\nAcknowledgment\nWe would like to thank the Dean for permitting us to publish this manuscript.\n\nSource of Support: Nil\n\nConflict Interest: No\n==== Refs\n1 Aggarwal A Sharma DD Sharma RC Kumar R Probable psychosis associated with levetiracetam: A case report J Neuropsychiatry Clin Neurosci 2011 23 E19 20 \n2 Youroukos S Lazopoulou D Michelakou D Karagianni J Acute psychosis associated with levetiracetam Epileptic Disord 2003 5 117 9 12875956 \n3 Kossoff EH Bergey GK Freeman JM Vining EP Levetiracetam psychosis in children with epilepsy Epilepsia 2001 42 1611 3 11879376 \n4 Zaki SA Adverse drug reaction and causality assessment scales Lung India 2011 28 152 3 21712934 \n5 Dannaram S Borra D Pulluri M Jindal P Sharma A Levetiracetam-induced acute psychotic episode Innov Clin Neurosci 2012 9 10 2 23198271 \n6 Shakya DR Dutta A Gautam R Hallucination in a seizure patient using levetiracetam: A case report Case Rep Med 2012 2012 706243 \n7 Delanty N Jones J Tonner F Adjunctive levetiracetam in children, adolescents, and adults with primary generalized seizures: Open-label, noncomparative, multicenter, long-term follow-up study Epilepsia 2012 53 111 9 22050371 \n8 Mula M Trimble MR Yuen A Liu RS Sander JW Psychiatric adverse events during levetiracetam therapy Neurology 2003 61 704 6 12963770 \n9 Rugino TA Samsock TC Levetiracetam in autistic children: An open-label study J Dev Behav Pediatr 2002 23 225 30 12177568 \n10 Bayerlein K Frieling H Beyer B Kornhuber J Bleich S Drug-induced psychosis after long-term treatment with levetiracetam Can J Psychiatry 2004 49 868 15679219\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "46(3)",
"journal": "Indian journal of pharmacology",
"keywords": "Antiepileptic drug; children; levetiracetam; psychosis",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D010889:Piracetam; D011605:Psychoses, Substance-Induced; D012640:Seizures",
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"pages": "341-2",
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"title": "Levetiracetam-induced acute psychosis in a child.",
"title_normalized": "levetiracetam induced acute psychosis in a child"
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"abstract": "Bedaquiline, a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB), is recommended for a duration of 24 weeks. There are scarce data on patients treated with this drug outside clinical trials.All MDR-TB patients who started treatment from January 1, 2011 to December 31, 2013 and received ≥30 days of bedaquiline were included in a multicentre observational cohort.Among 45 MDR-TB patients, 53% harboured isolates resistant to both fluoroquinolones and second-line injectables, and 38% harboured isolates resistant to one of these drug classes. Median bedaquiline treatment duration was 361 days and 33 patients (73%) received prolonged (>190 days) bedaquiline treatment. Overall, 36 patients (80%) had favourable outcome, five were lost to follow-up, three died, and one failed and acquired bedaquiline resistance. No cases of recurrence were reported. Severe and serious adverse events were recorded in 60% and 18% of patients, respectively. Values of Fridericia-corrected QT interval (QTcF) >500 ms were recorded in 11% of patients, but neither arrhythmias nor symptomatic cardiac side-effects occurred. Bedaquiline was discontinued in three patients following QTcF prolongation. No significant differences in outcomes or adverse events rates were observed between patients receiving standard and prolonged bedaquiline treatment.Bedaquiline-containing regimens achieved favourable outcomes in a large proportion of patients. Prolonged bedaquiline treatment was overall well tolerated in this cohort.",
"affiliations": "Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France lorenzo.guglielmetti@gmail.com.;AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.;Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France.;AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, Paris, France.;Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France.;Sorbonne Université, UPMC Université Paris 06, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Paris, France.;Sorbonne Université, UPMC Université Paris 06, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Paris, France.;Sorbonne Université, UPMC Université Paris 06, CR7, INSERM, U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI, Team E13 (Bactériologie), Paris, France.;AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, Paris, France.;AP-HP, Service des Maladies Infectieuses et Tropicales, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France.;Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, France.",
"authors": "Guglielmetti|Lorenzo|L|0000-0003-0886-9635;Jaspard|Marie|M|;Le Dû|Damien|D|;Lachâtre|Marie|M|;Marigot-Outtandy|Dhiba|D|;Bernard|Christine|C|;Veziris|Nicolas|N|;Robert|Jérôme|J|;Yazdanpanah|Yazdan|Y|;Caumes|Eric|E|;Fréchet-Jachym|Mathilde|M|;|||",
"chemical_list": "D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline",
"country": "England",
"delete": false,
"doi": "10.1183/13993003.01799-2016",
"fulltext": null,
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"issn_linking": "0903-1936",
"issue": "49(3)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D064687:Diarylquinolines; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005602:France; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D009169:Mycobacterium tuberculosis; D012189:Retrospective Studies; D013183:Sputum; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28182570",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis.",
"title_normalized": "long term outcome and safety of prolonged bedaquiline treatment for multidrug resistant tuberculosis"
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{
"companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2019-03140",
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{
"abstract": "BACKGROUND\nPatients with Fontan circulation are known to be at high risk for developing atrial tachyarrhythmias (AAs). Our objective was to examine the efficacy and safety of amiodarone in the management of ATs in adult Fontan patients.\n\n\nMETHODS\nPrimary outcomes of this single-centre, retrospective study included freedom from AAs and incidence of adverse effects of amiodarone on Fontan patients. Heart failure (HF) events and composite outcomes of death from any cause, Fontan revision and heart transplantation were evaluated as secondary outcomes. Predictors of HF and discontinuing amiodarone were also evaluated.\n\n\nRESULTS\nA total of 61 patients (mean age 31.6±11.3 years, 40.9% female), who were treated with amiodarone in between 1995 and 2018, were included. AAs free survival at 1, 3 and 5 years were 76.2%, 56.9% and 30.6%, respectively. During a median follow-up of 50.5 months, 34 (55.7%) patients developed side effects, and 20 (32.8%) patients discontinued amiodarone due to side effects. Thyroid dysfunction was the most common side effect (n=26, 76.5%), amiodarone-induced thyrotoxicosis (AIT) (n=16, 27.1%) being most common thyroid dysfunction. Young age (age <28.5 years) was associated with discontinuing amiodarone (HR 5.50, 95% CI 1.19 to 25.4, p=0.029). AIT significantly increased risk of HF (HR 4.82, 95% CI 1.71 to 13.6, p=0.003).\n\n\nCONCLUSIONS\nShort-term efficacy of amiodarone in Fontan physiology is acceptable. However, long-term administration is associated with a reduction of efficacy and a significant prevalence of non-cardiac side effects. AIT is associated with exacerbation of HF. The judicious use of amiodarone administration should be considered in this population.",
"affiliations": "Electrophysiology department, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.;Electrophysiology department, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Electrophysiology department, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.;Electrophysiology department, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.;Electrophysiology department, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.;Electrophysiology Service and Adult Congenital Heart Disease, Department of Medicine, Montreal Heart Instiutue, Montreal, Quebec, Canada.;Electrophysiology Service and Adult Congenital Heart Disease, Department of Medicine, Montreal Heart Instiutue, Montreal, Quebec, Canada.;Electrophysiology department, Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada Krishnakumar.Nair@uhn.ca.",
"authors": "Kawada|Satoshi|S|http://orcid.org/0000-0002-0948-6460;Chakraborty|Praloy|P|http://orcid.org/0000-0002-5054-9136;Roche|Lucy|L|;Oechslin|Erwin N|EN|;Silversides|Candice|C|;Wald|Rachel M|RM|;Downar|Eugene|E|;Harris|Louise|L|;Swan|Lorna|L|;Alonso-Gonzalez|Rafael|R|;Thorne|Sara|S|;Yamamura|Kenichiro|K|;Nanthakumar|Kumaraswamy|K|;Mondésert|Blandine|B|;Khairy|Paul|P|;Nair|Krishnakumar|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/heartjnl-2020-317378",
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"fulltext_license": null,
"issn_linking": "1355-6037",
"issue": null,
"journal": "Heart (British Cardiac Society)",
"keywords": "atrial flutter; drug monitoring; fontan physiology",
"medline_ta": "Heart",
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"nlm_unique_id": "9602087",
"other_id": null,
"pages": null,
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"pmid": "33115764",
"pubdate": "2020-10-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Role of amiodarone in the management of atrial arrhythmias in adult Fontan patients.",
"title_normalized": "role of amiodarone in the management of atrial arrhythmias in adult fontan patients"
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{
"abstract": "We report the successful use of daptomycin in a child with methicillin-resistant Staphylococcus aureus endocarditis with persistent bacteremia and clinical deterioration, despite treatment with vancomycin and rifampicin. She had acute kidney injury, requiring daptomycin dosage adjustment.",
"affiliations": "From the *Department of Pediatric Critical Care, †Department of Infectious Disease, and †Department of Pediatric Cardiology, Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India.",
"authors": "Prabhudesai|Sumant|S|;Kanjani|Amruta|A|;Nambi|P Senthur|PS|;Gnanasambandam|S|S|;Ramachandran|Bala|B|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D017576:Daptomycin; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000000958",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "35(5)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002675:Child, Preschool; D017576:Daptomycin; D004697:Endocarditis, Bacterial; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D012293:Rifampin; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "517-8",
"pmc": null,
"pmid": "27074655",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Successful Use of High-dose Daptomycin in a Child With Staphylococcus aureus Endocarditis.",
"title_normalized": "successful use of high dose daptomycin in a child with staphylococcus aureus endocarditis"
} | [
{
"companynumb": "IN-SA-2016SA103764",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizati... |
{
"abstract": "OBJECTIVE\nIn this post hoc analysis, we assessed whether guanfacine extended-release (GXR) adjunctive to a psychostimulant resulted in greater response and remission rates than placebo + psychostimulant in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).\n\n\nMETHODS\nIn this 9-week, double-blind, placebo-controlled dose-optimization study, participants (N = 461) aged 6 to 17 years with suboptimal response to psychostimulants were randomized to GXR on awakening (AM) + psychostimulant, GXR at bedtime (PM) + psychostimulant, or placebo + psychostimulant.\n\n\nRESULTS\nAt the final on-treatment assessment, more participants in both GXR + psychostimulant groups versus the placebo + psychostimulant group achieved response as assessed by 2 criteria: reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score (1) ≥40% (GXR AM + psychostimulant = 69.8%, GXR PM + psychostimulant = 70.3%, versus placebo + psychostimulant = 57.9%; p = .032 and p = .026, respectively), or (2) ≥50% (63.1%, 64.9%, versus 43.4%; p <.001 for both). Results were similar for symptomatic remission (ADHD-RS-IV total score ≤18; 61.1%, 62.2%, versus 46.1%; p = .010 and p = .005, respectively) and syndromal remission (symptomatic remission plus Clinical Global Impressions of Severity of Illness score ≤2). The most common treatment-emergent adverse events in participants receiving GXR + psychostimulant were headache (21.2%) and somnolence (13.6%).\n\n\nCONCLUSIONS\nGXR + psychostimulant treatment resulted in a greater percentage of participants meeting stringent criteria for response and remission compared with placebo + psychostimulant. The adverse event profile of adjunctive therapy was consistent with known effects of either treatment alone. Clinical trial registration information-Efficacy and Safety of SPD503 in Combination With Psychostimulants; http://clinicaltrials.gov/; NCT00734578.",
"affiliations": "Florida Clinical Research Center, LLC, Bradenton, FL and University of Florida, Gainesville, FL. Electronic address: acutler@flcrc.com.;Baylor College of Medicine, Houston.;DePelchin Children's Center, Houston and Baylor College of Medicine.;Washington University School of Medicine, St. Charles, MO.;University of California, San Francisco, San Francisco.;Shire Pharmaceutical Development Ltd, Basingstoke, UK.;Alcobra Inc., Plymouth Meeting, PA.",
"authors": "Cutler|Andrew J|AJ|;Brams|Matthew|M|;Bukstein|Oscar|O|;Mattingly|Gregory|G|;McBurnett|Keith|K|;White|Carla|C|;Rubin|Jonathan|J|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D000697:Central Nervous System Stimulants; D016316:Guanfacine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-8567",
"issue": "53(10)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": "ADHD; guanfacine XR; remission; response; α(2A)-agonist",
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D000293:Adolescent; D058647:Adrenergic alpha-2 Receptor Agonists; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D016316:Guanfacine; D006801:Humans; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "1092-101",
"pmc": null,
"pmid": "25245353",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Response/remission with guanfacine extended-release and psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder.",
"title_normalized": "response remission with guanfacine extended release and psychostimulants in children and adolescents with attention deficit hyperactivity disorder"
} | [
{
"companynumb": "US-JNJFOC-20141014633",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "To study the frequency of vertically acquired occult hepatitis B virus (HBV) infection (OBI).\n\n\n\nWe investigated 44 children born to hepatitis B surface antigen (HBsAg) positive mothers. They received HBV vaccine directly after birth and at 2, 6 and 52 weeks of age; eight with HBeAg-positive mothers also received hepatitis B immunoglobulin (HBIG). HBV DNA was analyzed in blood collected at 6 weeks and 12 months of age, and HBV antibodies at 12 and 18 months of age.\n\n\n\nHBV DNA, but not HBsAg or anti-HBc, was detected at 12 months of age in three children. The viral sequences were almost identical with HBV DNA from their mothers who all were HBeAg-positive and had received tenofovir during pregnancy. Follow-up at 5-7 years age showed that one of the three children had become seropositive for HBsAg and anti-HBc. This child and one of the other two had detectable HBV DNA at the follow-up, with whole genome sequences identical to those in HBV from their mothers.\n\n\n\nMothers-to-child transmission of HBV can, despite adequate prophylaxis, lead to OBI which may later develop into overt HBV infection. Whether such infections are of clinical importance needs to be further investigated.",
"affiliations": "Department of Infectious Diseases, University of Gothenburg, 413 46 Gothenburg, Sweden. Electronic address: anders.eilard@gu.se.;Department of Infectious Diseases, University of Gothenburg, 413 46 Gothenburg, Sweden.;Department of Infectious Diseases, University of Gothenburg, 413 46 Gothenburg, Sweden.;Department of Infectious Diseases, University of Gothenburg, 413 46 Gothenburg, Sweden.;Department of Infectious Diseases, University of Gothenburg, 413 46 Gothenburg, Sweden.;Department of Infectious Diseases, University of Gothenburg, 413 46 Gothenburg, Sweden. Electronic address: magnus.lindh@microbio.gu.se.",
"authors": "Eilard|Anders|A|;Andersson|Maria|M|;Ringlander|Johan|J|;Wejstål|Rune|R|;Norkrans|Gunnar|G|;Lindh|Magnus|M|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D006513:Hepatitis B e Antigens; D007136:Immunoglobulins; D000068698:Tenofovir; C045213:hepatitis B hyperimmune globulin",
"country": "England",
"delete": false,
"doi": "10.1016/j.jinf.2019.01.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4453",
"issue": "78(3)",
"journal": "The Journal of infection",
"keywords": "Hepatitis B virus; Mother-to-child; OBI; Occult",
"medline_ta": "J Infect",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral; D005260:Female; D005500:Follow-Up Studies; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D006513:Hepatitis B e Antigens; D006515:Hepatitis B virus; D006801:Humans; D007136:Immunoglobulins; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D011446:Prospective Studies; D013548:Sweden; D000068698:Tenofovir; D055815:Young Adult",
"nlm_unique_id": "7908424",
"other_id": null,
"pages": "226-231",
"pmc": null,
"pmid": "30658081",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Vertically acquired occult hepatitis B virus infection may become overt after several years.",
"title_normalized": "vertically acquired occult hepatitis b virus infection may become overt after several years"
} | [
{
"companynumb": "SE-MYLANLABS-2019M1086912",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TENOFOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Auditory hallucinations (AHs) are one of the most distressing symptoms of schizophrenia (SZ) and are often resistant to medication. Imaging studies of individuals with SZ show hyperactivation of the default mode network (DMN) and the superior temporal gyrus (STG). Studies in SZ show DMN hyperconnectivity and reduced anticorrelation between DMN and the central executive network (CEN). DMN hyperconnectivity has been associated with positive symptoms such as AHs while reduced DMN anticorrelations with cognitive impairment. Using real-time fMRI neurofeedback (rt-fMRI-NFB) we trained SZ patients to modulate DMN and CEN networks. Meditation is effective in reducing AHs in SZ and to modulate brain network integration and increase DMN anticorrelations. Consequently, patients were provided with meditation strategies to enhance their abilities to modulate DMN/CEN. Results show a reduction of DMN hyperconnectivity and increase in DMNCEN anticorrelation. Furthermore, the change in individual DMN connectivity significantly correlated with reductions in AHs. This is the first time that meditation enhanced through rt-fMRI-NFB is used to reduce AHs in SZ. Moreover, it provides the first empirical evidence for a direct causal relation between meditation enhanced rt-fMRI-NFB modulation of DMNCEN activity and post-intervention modulation of resting state networks ensuing in reductions in frequency and severity of AHs.",
"affiliations": "Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology. Cambridge, MA 02139, USA; Northeastern University, Boston, MA 02139, USA. Electronic address: cccbauer@mit.edu.;Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology. Cambridge, MA 02139, USA.;Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology. Cambridge, MA 02139, USA.;Northeastern University, Boston, MA 02139, USA.;Northeastern University, Boston, MA 02139, USA; Medical Image Analysis Laboratory (LAIMBIO), Rey Juan Carlos University, Madrid, Spain.;Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology. Cambridge, MA 02139, USA.;Harvard Medical School. Boston, MA 02115, USA; Boston VA Healthcare System. Boston, MA 02130, USA; University of Massachusetts, Boston, Boston MA 02215, USA.;Harvard Medical School. Boston, MA 02115, USA; Boston VA Healthcare System. Boston, MA 02130, USA; Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.;Mind, Brain Imaging and Neuroethics Research Unit, The Royal's Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada.;Harvard Medical School. Boston, MA 02115, USA; Boston VA Healthcare System. Boston, MA 02130, USA; Beth Israel Deaconess Medical Center. Boston, MA 02215, USA.;Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology. Cambridge, MA 02139, USA; Northeastern University, Boston, MA 02139, USA.",
"authors": "Bauer|Clemens C C|CCC|;Okano|Kana|K|;Ghosh|Satrajit S|SS|;Lee|Yoon Ji|YJ|;Melero|Helena|H|;Angeles|Carlo de Los|CL|;Nestor|Paul G|PG|;Del Re|Elisabetta C|EC|;Northoff|Georg|G|;Niznikiewicz|Margaret A|MA|;Whitfield-Gabrieli|Susan|S|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.psychres.2020.112770",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-1781",
"issue": "284()",
"journal": "Psychiatry research",
"keywords": "Auditory hallucinations; Default mode network; Mindfulness meditation; Real-time neurofeedback; Schizophrenia",
"medline_ta": "Psychiatry Res",
"mesh_terms": "D000328:Adult; D001921:Brain; D001931:Brain Mapping; D005260:Female; D006212:Hallucinations; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D019122:Meditation; D008875:Middle Aged; D009415:Nerve Net; D058765:Neurofeedback; D000075082:Proof of Concept Study; D012146:Rest; D012559:Schizophrenia",
"nlm_unique_id": "7911385",
"other_id": null,
"pages": "112770",
"pmc": null,
"pmid": "32004893",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21872614;11259662;17560126;30264927;28315577;23954146;15852468;19198666;23519021;18976716;16781167;27531135;21146961;31103786;22535908;9460087;22883428;17234951;21654735;16767087;22403536;22452556;20015455;28545945;14613682;14964560;22432927;17585307;21350845;31694816;28663069;12167262;11849614;12135971;24535033;18329323;21147519;28823723;22224834;23932148;21111832;15528092;24135553;25598821;24033306;28293180;20932348;20952459;24248372;22226903;29430009;21979382;11209064;15976020;20409665;30477401;22642651;22536289;30953836;26937312;29660081;19164577;16466680;20682350;27890810;17919929;21889994;5146491;12729491;12511172;31832347;15936729;18219617;27091719;25956256;27109713;25468173;22114193;18400922;21144498;19427258;12506194;15784441;30703519;19727302;23426796;19206103;19930254;21653723;22287947;21126181;25562175;24443396",
"title": "Real-time fMRI neurofeedback reduces auditory hallucinations and modulates resting state connectivity of involved brain regions: Part 2: Default mode network -preliminary evidence.",
"title_normalized": "real time fmri neurofeedback reduces auditory hallucinations and modulates resting state connectivity of involved brain regions part 2 default mode network preliminary evidence"
} | [
{
"companynumb": "US-OTSUKA-2020_011271",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "A 58-year-old man presented with recurrence of chronic myeloid leukemia (CML) after complete molecular remission in the setting of non-compliance with imatinib. He was restarted on imatinib and was also noted to have IgG kappa monoclonal gammopathy of undetermined significance (MGUS). The patient re-achieved molecular remission after resumption of imatinib, but his MGUS progressed to smoldering myeloma and he was eventually diagnosed with multiple myeloma (MM) and initiated on treatment for MM with thalidomide, bortezomib and dexamethasone. He has responded well to treatment of the myeloma and continues concurrent maintenance imatinib treatment for CML and is being evaluated for bone marrow transplant. The association of two concurrent hematological malignancies, CML and MM, is very rare and has been infrequently reported in literature. The pathophysiology of this has not yet been fully understood. This case report reviews the various theories to explain this and discusses the potential challenges of simultaneous treatment of MM and CML.",
"affiliations": "Department of Internal Medicine, Albert Einstein Medical Center, Philadelphia, PA, 19141, USA.;Department of Hematology, Albert Einstein Medical Center, Philadelphia, PA, 19141, USA.;Department of Hematology, Albert Einstein Medical Center, Philadelphia, PA, 19141, USA.",
"authors": "Swaminathan|Neeraja|N|0000-0002-9043-0420;Gupta|Sorab|S|;Dourado|Claudia|C|",
"chemical_list": "D007074:Immunoglobulin G; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.12688/f1000research.24086.2",
"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\nF1000Research\n2046-1402 F1000 Research Limited London, UK \n\n10.12688/f1000research.24086.2\nCase Report\nArticles\nCase Report: IgG multiple myeloma and chronic myeloid leukemia in a single patient\n[version 2; peer review: 2 approved]\n\nSwaminathan Neeraja Writing – Original Draft PreparationWriting – Review & Editinghttps://orcid.org/0000-0002-9043-0420a1 Gupta Sorab SupervisionWriting – Review & Editing2 Dourado Claudia Supervision2 \n1 Department of Internal Medicine, Albert Einstein Medical Center, Philadelphia, PA, 19141, USA\n\n2 Department of Hematology, Albert Einstein Medical Center, Philadelphia, PA, 19141, USA\na neeraja1991@yahoo.co.inNo competing interests were disclosed.\n\n\n23 9 2020 \n2020 \n9 48817 9 2020 Copyright: © 2020 Swaminathan N et al.2020This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 58-year-old man presented with recurrence of chronic myeloid leukemia (CML) after complete molecular remission in the setting of non-compliance with imatinib. He was restarted on imatinib and was also noted to have IgG kappa monoclonal gammopathy of undetermined significance (MGUS). The patient re-achieved molecular remission after resumption of imatinib, but his MGUS progressed to smoldering myeloma and he was eventually diagnosed with multiple myeloma (MM) and initiated on treatment for MM with thalidomide, bortezomib and dexamethasone. He has responded well to treatment of the myeloma and continues concurrent maintenance imatinib treatment for CML and is being evaluated for bone marrow transplant. The association of two concurrent hematological malignancies, CML and MM, is very rare and has been infrequently reported in literature. The pathophysiology of this has not yet been fully understood. This case report reviews the various theories to explain this and discusses the potential challenges of simultaneous treatment of MM and CML.\n\nmultiple myelomaMGUSCMLchronic myeloid leukemiaThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\nThis submission clarifies a few aspects in the presentation and clinical course of this patient. 1.The transcripts at the time of diagnosis of CML were typical. 2. At the time of CML relapse, patient was in chronic phase as evidenced by peripheral smear showing only rare blasts but bone marrow biopsy was not done 3. Prior to diagnosis of MGUS, bone marrow biopsy confirmed < 10% plasma cells 4. Side-effects of concurrent myeloma treatment and imatinib seen in this patient are described in more detail.\n==== Body\nIntroduction\nChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of pluripotent hematopoietic stem cells. It results from a translocation t (9;22) (q34q11) known as the Philadelphia chromosome creating a BCR-ABL fusion gene, which is transcribed into proteins with abnormal tyrosine kinase activity that drives abnormal white blood cell (WBC) proliferation\n1. Multiple myeloma (MM) is a monoclonal disorder of plasma cells which have differentiated from lymphoid B cells. Therefore, the abnormal cell types in CML and MM are distinctly different. The instances of both MM and CML in the same patient occurring in a synchronous or metachronous manner are extremely rare. There are several factors that have been postulated to be related to this occurrence. These include age, gender, race, exposure to environmental carcinogens or radiation, epigenetic upregulation/downregulation, as a result of progression or treatment of one malignancy potentiating the development of malignant cells (which acquire antiapoptotic ability) and mechanisms to evade immune surveillance, chronic antigenic stimulation, genetic polymorphisms. At present there are multiple theories but insufficient data to make any definite conclusions about the mechanism of co-existence of CML and MM. With the advent of novel therapies and improving survival in patients with CML and MM, there is value in further investigation regarding the pathophysiology and clinical characteristics of such cases\n2,\n3. Additionally, the occurrence of more than one hematological malignancy in the same patient presents treatment challenges because it can lead to the possibilities of drug-drug interactions and medication toxicities. Analysis of the treatment protocols of these patients and their follow-up will be required to assess the risks and benefits of different treatment options. At this time, due to paucity of data, the management is tailored according to the patient’s individual risk factors and clinician’s judgement.\n\nThis is a rare case of the occurrence of IgG MM and CML in a single patient and reviews the management of these diseases.\n\nCase report\nA 58-year-old man with history of CML presented in December 2015 for re-establishment of care after being lost to follow-up. He was first diagnosed in December 2007 with CML and was treated with imatinib (400mg daily). He achieved complete molecular remission but was unfortunately lost to follow-up after 2012. The patient stated that he had stopped taking imatinib in September 2015 due to family issues and stressors. When he presented in December 2015, he had no specific complaints. He was noted to have mild pallor on exam, but no lymphadenopathy or hepatosplenomegaly. Labs were significant for leukocytosis and blasts noted on peripheral smear. BCR-ABL FISH/PCR was also positive indicating relapse of CML and the transcripts at the time of diagnosis were typical. His peripheral smear showed only rare blasts (< 10 %) and the patient appeared to be in the chronic phase of CML. A bone marrow biopsy was not repeated at this time.\n\nThe patient was re-initiated on treatment with imatinib 400mg daily. Within 2 weeks of resuming treatment he was noted to have an improvement in WBC count. However, he was incidentally detected to have an elevated total protein level. In view of this serum protein, electrophoresis was ordered and the patient was found to have an IgG kappa monoclonal gammopathy of undetermined significance (MGUS). This diagnosis was established because the total M protein spike was <3g/dL, bone marrow biopsy showed < 10% plasma cells and the patient had no evidence of end organ damage. Skeletal survey was done which showed no lytic lesions. Imatinib was continued for CML and he was monitored closely for progression of plasma cell dyscrasia.\n\nWith regard to the patient’s CML, he achieved molecular remission in November 2016 with 3 log reduction in the 3 tested transcripts b2a2, b3a2, e1a2 and without detectable Philadelphia chromosome. However, he had a steady increase in the paraprotein level from December 2015 to April 2019 without any symptoms. He did not develop myeloma defining events such as hypercalcemia (>1mg/dL over the upper limit of normal OR >11mg/dL), renal insufficiency (creatinine clearance <40mL/min or serum creatinine >2mg/dL), anemia (Hemoglobin > 2g/dL below lower limit of normal or <10g/dL) or bony pain/lytic lesions (on skeletal radiography/CT/PET). These are together referred to as the CRAB phenomenon. His serum free light chain ratio remained at <100mg/L.\n\nIn May 2019, the patient had further rise in creatinine and paraprotein level and had an increase in serum free light chain ratio. Therefore, he underwent a PET CT in June 2019. This showed increased uptake in the left 4\nth rib, left and right ischium, and a lesion in the second lumbar (L2) vertebra. He also underwent a bone marrow biopsy in July 2019, which showed 50% plasma cells expressing CD 38, CD 138, dim/partial CD 117, CD 56 and kappa light chain restriction. No BCR ABL gene rearrangement was noted. Thus, it confirmed the diagnosis of MM.\n\nMM interphase fluorescence in situ hybridization (FISH) panel analysis of CD138+ enriched plasma cells was positive for three CCND1 signals consistent with trisomy 11 and for extra signals for chromosomes 7, 9 and 15. There were no cells with FGFR3-IGH, CCND1-IGH, or IGH-MAF fusions. Results for 1p/1q, 13q and TP53 were normal. Extra signals for probes targeting the chromosomes reported above suggest the presence of a hyperdiploid clone. Thus, the patient’s cytogenetic testing was negative for high risk factors.\n\nThe trends of serum protein electrophoresis are seen in\nTable 1, and\nFigure 1 and\nFigure 2. Trends of WBC count, hemoglobin, platelet count, and creatinine are seen in\nFigure 3–\nFigure 6, respectively.\n\nTable 1. Serum electrophoresis results.\n\tA/G\n\nratio\talpha 1\n\nglobulin\talpha 2\n\nglobulin\tbeta\n\nglobulin\tgamma\n\nglobulin\tM\n\nspike\tkappa\n\nlambda\n\nratio\tIgG\tIgA\tIgM\tbeta 2\n\nmicroglobin\tLactate\n\ndehydrogenase\t\n\nDec-15\n\t1.1\t0.2\t0.6\t0.8\t2.1\t0.8\t\t\t\t\t\t\t\n\nNov-16\n\t0.9\t0.2\t0.5\t0.7\t4.1\t1.8\t6.89\t3103\t<5\t27\t\t\t\n\nApr-17\n\t0.8\t0.2\t0.6\t0.8\t3.2\t2.3\t\t3239\t<5\t19\t\t\t\n\nAug-17\n\t0.8\t0.1\t0.5\t0.8\t3.3\t2.6\t10.3\t3770\t<5\t17\t\t233\t\n\nDec-17\n\t\t\t\t\t\t\t10.84\t3826\t<5\t16\t\t\t\n\nJul-18\n\t0.7\t0.2\t0.6\t0.9\t3.7\t2.9\t\t3931\t<5\t13\t\t\t\n\nOct-18\n\t0.8\t0.1\t0.5\t0.7\t3.7\t3.2\t14.5\t3871\t<5\t14\t\t\t\n\nApr-19\n\t0.7\t0.2\t0.6\t0.8\t4.1\t3.5\t24.35\t\t\t\t\t\t\n\nMay-19\n\t0.7\t0.2\t0.6\t0.8\t4.1\t3.6\t20.91\t4456\t<5\t11\t4.2\t\t\n\nSep-19\n\t0.6\t0.2\t0.7\t0.8\t4.5\t4\t25.47\t5367\t<5\t9\t4\t169\t\n\nOct-19\n\t0.8\t0.2\t0.6\t0.7\t2.5\t2.3\t15.48\t\t\t\t\t175\t\n\nNov-19\n\t1.1\t0.2\t0.7\t0.8\t1.1\t0.8\t1.75\t1176\t<5\t26\t\t377\t\n\nDec-19\n\t1.4\t0.2\t0.6\t0.8\t0.8\t0.3\t1.43\t\t\t\t\t\t\n\nJan-20\n\t1.6\t0.2\t0.6\t0.7\t0.7\tfaint\t1.35\t\t\t\t\t\t\nAbbreviations used: A/G ratio- albumin/globulin ratio, M spike- monoclonal spike, Ig- immunoglobulin, LDH-lactate dehydrogenase.\n\nFigure 1. Graphical trend of M spike.\nFigure 2. Graphical trend of kappa/lambda ratio.\nFigure 3. Graphical trend of white blood cell (WBC) count, lymphocytes and basophils.\nFigure 4. Graphical trend of hemoglobin.\nFigure 5. Graphical trend of platelet count.\nFigure 6. Graphical trend of creatinine.\nThe patient was started on treatment for ISS stage II standard risk myeloma with thalidomide (50mg/day daily for 21 days followed by 7 days off), weekly bortezomib (1.3mg/m\n2) and dexamethasone (40mg/day once a week) in September 2019. This regimen was preferred over the VRd (lenalidomide, bortezomib and dexamethasone) due to the concern for increased risk of pancytopenia with concurrent use of imatinib and lenalidomide.\n\nAfter cycle 2 of the myeloma treatment, this patient developed a morbilliform pruritic rash over trunk and bilateral upper extremities which has been described as a side effect of thalidomide. He was managed with a short course of steroids. After cycle 5, he had recurrence of above described rash and also developed conjunctival injection bilaterally. He was seen by ophthalmology and diagnosed to have meibomian gland dysfunction. Due to the rash and ocular symptoms, there were delays in his myeloma treatment but these were not dose-limiting toxicities. His symptoms improved with supportive care (oral steroids and steroid eye drops) and resolved completely. Thus far he has completed 6 cycles of treatment for myeloma with concurrent imatinib and has been referred to a transplant center to assess his eligibility for the same.\n\nDiscussion\nThe occurrence of CML and MM together is very rare. There are multiple explanations that have been suggested for co-existence of more than one hematological malignancy. One of the theories is that there is a common progenitor stem cell. The Philadelphia chromosome is observed not only in granulocytes but also in cells of the monocytic, erythroid, megakaryocytic and lymphoid series. This finding supports the concept of a common pluripotent progenitor cell. The transformation to lymphoid cells in the blast phase of the CML also suggests a relationship between the myeloid and lymphoid lineage\n4.\n\nThe role of imatinib in promoting development of MM is debatable. There is some evidence from Pandiella\net al.\n5 that imatinib inhibits MM cell proliferation\nin vitro. On the contrary, it has been reported that imatinib has a stimulatory effect on MM cells through activation of Erk1 and Erk2 mitogen activated protein kinases (MAP kinases). There have also been reports of MM developing in non CML patients such as those with gastrointestinal stromal tumors treated with imatinib\n6 Carulli\net al.\n7 looked at the possible interference of imatinib with plasma cell phenotype. Their study looked at 30 patients and found that 70% of these patients had an abnormal plasma cell phenotype, which they defined as plasma cells which lack CD 19. Some of these cells showed additional aberrations such as expression of CD 56. Although this cannot establish a causal relationship between imatinib and MM, it merits further investigation.\n\nImatinib mesylate is a tyrosine kinase inhibitor, which is the standard of care for CML as a first line agent. It has activity against different genes involved in cellular transformation such as BCR-ABL1, c-KIT, PGFR-α and β and Jak 2. Imatinib in CML acts by competing with ATP to bind to the BCR ABL1 tyrosine kinase and thereby inhibiting the WBC proliferation that it effects\n7.\n\nTreatment of MM is based on whether the patient has standard or high-risk disease, which in turn is determined by cytogenetic analysis. High risk features constitute t (14;16), t (4;20), del17p13, t (4;14) and 1q gain. Additionally, patients should be assessed for eligibility to receive an autologous stem cell transplant. In standard risk patients such as ours the standard first line treatment is RVd regimen, which comprises lenalidomide, bortezomib and dexamethasone. Post induction therapy, if patients are eligible for hematopoietic cell transplant (HCT), they may choose either an early HCT or delayed HCT strategy. Autologous HCT is the mainstay, although allogenic HCT is still largely investigational. Post-transplant patients need maintenance therapy as well. Transplant in eligible patients receive either a two/three drug induction regimen followed by maintenance therapy. Melphalan, cyclophosphamide and thalidomide are also part of first line treatment options for myeloma. In patients with relapse, several of the newer agents are being used, which include the new proteasome inhibitor (carfilzomib), immunomodulatory drugs (like pomalidomide), inhibitors of NF-κB, MAPK and AKT, histone deacetylase inhibitors (like vorinostat and panobinostat), and monoclonal antibodies (such as daratumumab, elotuzumab and siltuximab)\n8.\n\nDue to the rarity of coexistence of more than one hematological malignancy in the same patient, we do not have robust data on treatment regimens. Current treatment is based on factoring in the patient’s individual risk factors and the physician’s judgement and experience. Even though there is concern for imatinib being associated with MGUS and myeloma, co-administration of imatinib with myeloma treatment seems to be reasonable. Myeloma treatment both for high risk and standard risk group patients involves a proteasome inhibitor, such as bortezomib. Both bortezomib and imatinib are metabolized by microsomal enzyme CYP3A4. However, imatinib is a potent inhibitor of CYP3A4, while bortezomib is only a weaker inhibitor. Reduction of bortezomib dosing to once weekly instead of twice seems to be associated with less adverse effects when used in conjunction with imatinib\n9.\n\nAdditionally, bisphosphonates, which are used as supportive treatment in myeloma, have also been shown to inhibit CML cell lines and induce apoptosis synergistically with imatinib through the inhibition of prenylation of Ras and Ras-related proteins\n10\n\n\nThis case report presents an experience with a CML patient who over time progressed to develop the entire spectrum of myeloma, starting with MGUS followed by smoldering myeloma and ultimately MM requiring treatment. At this point it is difficult to say if this association is coincidental or related to some other mechanism and this is a subject that requires further research.\n\nConclusion\nThe most essential take-home points from this case are as follows:\n\n1. MM can be diagnosed in patients with one of the following: >10% plasma cells in bone marrow OR biopsy proven bony/extramedullary plasmacytoma and any one of the CRAB phenomenon OR any of the following- >/= 60% plasma cells in bone marrow OR serum free light chain ratio >/= 100 OR >1 focal lesion on MRI studies.\n\n2. Both MGUS and smoldering myeloma are characterized by an absence of myeloma defining events. In MGUS: paraprotein level <3g/dL, bone marrow plasma cells <10%; while in smoldering myeloma: paraprotein level >3g/dL or urinary monoclonal protein >/= 500mg in 24 hours and/or clonal bone marrow plasma cells 10 to 60%\n\n3. Co-existence of CML and MM is very rare. Etiology is probably multifactorial but there is a possibility that this is because CML and MM share a common pluripotent progenitor stem cell which can differentiate into both lymphoid and myeloid lines.\n\n4. There is concern that the imatinib may lead to alteration of the plasma cell phenotype and it may be worthwhile to monitor serum electrophoresis and protein levels in patients who have received imatinib treatment.\n\n5. Co-administration of bortezomib and imatinib is feasible. Since CYP3A4 is important for metabolism of both drugs, administration of bortezomib as weekly instead of twice weekly may help to reduce adverse effects of bortezomib.\n\nData availability\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nConsent\nWritten informed consent for the publication of the case report and any associated images was obtained from the patient.\n\n10.5256/f1000research.28094.r71881\nReviewer response for version 2\nSwaminathan Mahesh 1Refereehttps://orcid.org/0000-0001-5959-397X \n1 Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA\n\nCompeting interests: No competing interests were disclosed.\n\n\n30 9 2020 \nCopyright: © 2020 Swaminathan M2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 2recommendationapproveNo further comments.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nMyeloid leukemias, clinical trials, Genetic syndromes in leukemia.\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.26569.r65599\nReviewer response for version 1\nBhattacharyya Pritish K. 12Refereehttps://orcid.org/0000-0001-6000-030X \n1 Department of Pathology, Hackensack University Medical Center, Hackensack, NJ, USA\n\n2 Rutgers New Jersey Medical School, Newark, NJ, USA\n\nCompeting interests: No competing interests were disclosed.\n\n\n9 7 2020 \nCopyright: © 2020 Bhattacharyya PK2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapproveThis is an uncommon case presentation of two apparently unrelated hematopoietic malignancies.\n\n Association of Multiple myeloma following CLL or other low grade B cell lymphoma may be related to terminal changes of B cell to Plasma cells (Jaffe\net al., NIH)\n\n We had published a similar case in 2014 in a patient of CML with t9:22) along with JAK2 mutation and Myeloma (Maerki\net al., 2014\n1). We suggested another potential theory of multiple simultaneous malignancies includes the sharing of a common malignant pluripotent progenitor stem cell which may allow further transformation of both lymphoid and myeloid differentiations.\n\n It has been proposed that plasma cell myeloma and CML may evolve from the same hematopoietic stem cell [1, 8, 12]. There have been multiple accounts in which plasma cell neoplasms, including plasma cell leukemia and multiple myeloma, have been seen in coexistence with or arising in the background of CML [37–39]. It is suggested that the simultaneous occurrence of CML and multiple myeloma is analogous to acute lymphoblastic leukemia arising in the blastic phase of CML [5, 6, 8, 12, 15]. This reveals the capability of CML in differentiating into either myeloid lineage or lymphoid lineage. Furthermore, the Philadelphia chromosome (Ph) has been linked to increased cell survival, proliferation, and malignant transformation [1, 40] and has been found in all hematopoietic cell lineages including erythropoietic cells, megakaryocytes, macrophages, and B-lymphocytes [1,12, 41].\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nLeukemia, Lymphoma, Myeloma with molecular genetic applications\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.26569.r64202\nReviewer response for version 1\nSwaminathan Mahesh 1Refereehttps://orcid.org/0000-0001-5959-397X \n1 Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA\n\nCompeting interests: No competing interests were disclosed.\n\n\n8 6 2020 \nCopyright: © 2020 Swaminathan M2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapprove-with-reservationsIn this case report, the authors have discussed a patient with chronic myeloid leukemia and metachronous IgG multiple myeloma. The clinical presentation and disease course are well described and discussed. \n\n Adding the following details would add more clarity to the case and help readers:\nPlease mention the transcripts at diagnosis (as knowing typical versus atypical transcripts is important for follow up, the latter might not be detectable in routine PCR and warrants RT-PCR).\n\nAt CML disease relapse, please indicate if the patient was still in the chronic phase. Was there a bone marrow biopsy done at that time, if so what was the percentage of plasma cells. \n\nAs the diagnosis of MGUS requires BMBx? Please indicate if the clonal plasma cells were <10% facilitating the diagnosis of MGUS.\n\nPlease indicate if the x-axis in Figure 1-2 denotes months?\n\nIt will be interesting to know the most common Grade >3 AEs experienced by the patient (to know if there were any specific side effects that were more common with concomitant imatinib and myeloma therapy.\n\n\n\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nMyeloid leukemias, clinical trials, Genetic syndromes in leukemia.\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\nSwaminathan Neeraja Albert Einstein Medical Center, USA\n \nCompeting interests: none\n\n\n13 6 2020 \nThank you for the feedback and comments provided. \n\n \nYes, the transcripts at the time of diagnosis were also typical.\n\nAt the time of relapse, the patient was in the chronic phase. Only rare blasts were seen on peripheral blood smear. There were fewer than 10% blast cells in the blood and a bone marrow biopsy was not performed.\n\nWhen patient was noted to have an abnormal M-protein spike on serum electrophoresis, a bone marrow biopsy was repeated which showed < 10% plasma cells. The total M protein spike was <3g/dL and the patient had no evidence of end organ damage. All of this helped establish the diagnosis of MGUS and he was monitored clinically and with labs until May-June 2019 when he developed an increase in creatinine and eventually had a bone marrow biopsy which confirmed the diagnosis of multiple myeloma.\n\nYes, the x-axis in figures 1 and 2 denotes time in months.\n\nThis patient developed a morbilliform pruritic rash over trunk and bilateral upper extremities which has been described as a side effect of thalidomide. This occurred after cycle 2 and was managed with short course of steroids. After cycle 5, he had recurrence of above described rash and also developed conjunctival injection bilaterally. He was seen by ophthalmology and diagnosed to have meibomian gland dysfunction. In view of these symptoms, there was a delay in his myeloma treatment but his symptoms improved with supportive care (oral steroids and steroid eye drops) and resolved completely. He has now completed 6 cycles of treatment for myeloma and is being evaluated for bone marrow transplant. He has had no other side effects. \n\n\n\n\nSwaminathan Mahesh Roswell Park Cancer Institute, USA\n \nCompeting interests: None\n\n\n14 7 2020 \nThanks for updating.\n\n Please make necessary inclusions of those comments in the manuscript.\n==== Refs\n1 \nHehlmann R Hochhaus A Baccarani M :\n“Chronic myeloid leukaemia”\n\nLancet. \n2007 ;370 (9584 ):342 –350\n.\n10.1016/S0140-6736(07)61165-9 \n17662883 \n2 \nAli N Pickens PV Auerbach HE :\nImmunoglobulin D multiple myeloma, plasma cell leukemia and chronic myelogenous leukemia in a single patient treated simultaneously with lenalidomide, bortezomib, dexamethasone and imatinib.\n\nHematol Rep. \n2016 ;8 (1 ):6295 .\n10.4081/hr.2016.6295 \n\n27103978 \n3 \nMaerki J Katava G Siegel D :\nUnusual Case of Simultaneous Presentation of Plasma Cell Myeloma, Chronic Myelogenous Leukemia, and a Jak2 Positive Myeloproliferative Disorder.\n\nCase Rep Hematol. \n2014 ;2014 :738428 .\n10.1155/2014/738428 \n\n25386371 \n4 \nKlenn PJ Hyun BH Lee YH :\nMultiple myeloma and chronic myelogenous leukemia: a case report with literature review.\n\nYonsei Med J. \n1993 ;34 (3 ):293 –300\n.\n10.3349/ymj.1993.34.3.293 \n8259707 \n5 \nPandiella A Carvajal-Vergara X Tabera S :\nImatinib mesylate (STI571) inhibits multiple myeloma cell proliferation and potentiates the effect of common antimyeloma agents.\n\nBr J Haematol. \n2003 ;123 (5 ):858 –868\n.\n10.1046/j.1365-2141.2003.04706.x \n14632777 \n6 \nIde M Kuwahara N Matsuishi E :\nUncommon case of chronic myeloid leukemia with multiple myeloma.\n\nInt J Hematol. \n2010 ;91 (4 ):699 –704\n.\n10.1007/s12185-010-0546-4 \n20352382 \n7 \nCarulli G Cannizzo E Ottaviano V :\nAbnormal phenotype of bone marrow plasma cells in patients with chronic myeloid leukemia undergoing therapy with Imatinib.\n\nLeuk Res. \n2010 ;34 (10 ):1336 –1339\n.\n10.1016/j.leukres.2010.01.012 \n20149455 \n8 \nRajkumar SV :\nMultiple myeloma: Every year a new standard?\n\nHematol Oncol. \n2019 ;37 Suppl 1 (Suppl 1 ):62 –65\n.\n10.1002/hon.2586 \n\n31187526 \n9 \nMaral S Bakanay SM Yikilmaz AS :\nDevelopment of plasma cell leukemia in a patient with chronic myeloid leukemia while on treatment with imatinib mesylate.\n\nJ Cancer Res Ther. \n2018 ;14 (6 ):1431 –33\n.\n10.4103/0973-1482.192762 \n30488870 \n10 \nChuah C Barnes DJ Kwok M :\nZolendronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells.\n\nLeukemia. \n2005 ;19 (11 ):1896 –1904\n.\n10.1038/sj.leu.2403949 \n16167056\n\n",
"fulltext_license": "CC BY",
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"keywords": "CML; MGUS; chronic myeloid leukemia; multiple myeloma",
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"mesh_terms": "D000069286:Bortezomib; D003907:Dexamethasone; D006801:Humans; D000068877:Imatinib Mesylate; D007074:Immunoglobulin G; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance; D009101:Multiple Myeloma; D013792:Thalidomide",
"nlm_unique_id": "101594320",
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"pmid": "33042520",
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"title": "Case Report: IgG multiple myeloma and chronic myeloid leukemia in a single patient.",
"title_normalized": "case report igg multiple myeloma and chronic myeloid leukemia in a single patient"
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"abstract": "Invasive mucormycosis infections occur in less than 1% of recipients of orthotopic heart transplants. Given the angioinvasive nature of these infections, the mortality rate is high. Little literature exists regarding the presentation and management of these infections. We present a case of a patient who developed an infection after orthotopic heart transplant, describe the successful multidisciplinary management surrounding his care, and review the available literature regarding mucormycosis infections in heart transplant recipients.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.;Department of Cardiovascular and Thoracic Surgery, Mayo Clinic, Scottsdale, Arizona, USA.;Department of Pharmacy, Mayo Clinic, Scottsdale, Arizona, USA.;Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona, USA.;Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona, USA.;Department of Pulmonary Medicine, Mayo Clinic, Scottsdale, Arizona, USA.;Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona, USA.;Department of Cardiovascular and Thoracic Surgery, Mayo Clinic, Scottsdale, Arizona, USA.",
"authors": "Nokes|Brandon T|BT|;Pajaro|Octavio|O|;Stephen|Jenise|J|;DeValeria|Patrick|P|;Scott|Robert|R|;Shah|Sadia|S|;Steidley|Eric|E|;Jahanyar|Jama|J|",
"chemical_list": "D000935:Antifungal Agents",
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"issue": "21(2)",
"journal": "The heart surgery forum",
"keywords": "antifungal therapy; heart transplantation; immunosuppression; mucormycosis",
"medline_ta": "Heart Surg Forum",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D005500:Follow-Up Studies; D006333:Heart Failure; D016027:Heart Transplantation; D006801:Humans; D008168:Lung; D008172:Lung Diseases, Fungal; D008297:Male; D009091:Mucormycosis; D011013:Pneumonectomy; D011183:Postoperative Complications; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients",
"nlm_unique_id": "100891112",
"other_id": null,
"pages": "E072-E074",
"pmc": null,
"pmid": "29658861",
"pubdate": "2018-03-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Monster Lung Cavity in a Heart Transplant Recipient.",
"title_normalized": "monster lung cavity in a heart transplant recipient"
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"abstract": "Recently, there have been reports suggesting that intracameral vancomycin has been associated with retinal vasculitis; some have described this phenomenon as postoperative hemorrhagic occlusive retinal vasculitis. We present a case of a 65-year-old woman who underwent uncomplicated phacoemulsification and posterior chamber intraocular lens implantation followed by intracameral antibiotic prophylaxis. Unlike prior reports, this report demonstrates a case of mild visual reduction and minimal inflammation with subtle but complete unilateral peripheral retinal ischemia associated with cataract surgery and intracameral vancomycin, suggesting a spectrum of toxicity that may be underrecognized.",
"affiliations": "Department of Ophthalmology & Visual Sciences, University of Iowa Hospitals & Clinics, Iowa City, IA 52240, USA.;Department of Ophthalmology & Visual Sciences, University of Iowa Hospitals & Clinics, Iowa City, IA 52240, USA.;Department of Ophthalmology & Visual Sciences, University of Iowa Hospitals & Clinics, Iowa City, IA 52240, USA.;Department of Ophthalmology & Visual Sciences, University of Iowa Hospitals & Clinics, Iowa City, IA 52240, USA.;Vitreoretinal Surgery, PA, 7760 France Avenue S., Minneapolis, MN 55435, USA.",
"authors": "Lenci|Lucas T|LT|;Chin|Eric K|EK|;Carter|Christi|C|;Russell|Stephen R|SR|;Almeida|David R P|DR|",
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"doi": "10.1155/2015/683194",
"fulltext": "\n==== Front\nCase Rep Ophthalmol MedCase Rep Ophthalmol MedCRIOPMCase Reports in Ophthalmological Medicine2090-67222090-6730Hindawi Publishing Corporation 10.1155/2015/683194Case ReportIschemic Retinal Vasculitis Associated with Cataract Surgery and Intracameral Vancomycin Lenci Lucas T. \n1\n\n*\nChin Eric K. \n1\nCarter Christi \n1\nRussell Stephen R. \n1\nAlmeida David R. P. \n2\n1Department of Ophthalmology & Visual Sciences, University of Iowa Hospitals & Clinics, Iowa City, IA 52240, USA2Vitreoretinal Surgery, PA, 7760 France Avenue S., Minneapolis, MN 55435, USA*Lucas T. Lenci: lucas-lenci@uiowa.eduAcademic Editor: Cristiano Giusti\n\n2015 5 11 2015 2015 6831946 8 2015 6 10 2015 12 10 2015 Copyright © 2015 Lucas T. Lenci et al.2015This 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.Recently, there have been reports suggesting that intracameral vancomycin has been associated with retinal vasculitis; some have described this phenomenon as postoperative hemorrhagic occlusive retinal vasculitis. We present a case of a 65-year-old woman who underwent uncomplicated phacoemulsification and posterior chamber intraocular lens implantation followed by intracameral antibiotic prophylaxis. Unlike prior reports, this report demonstrates a case of mild visual reduction and minimal inflammation with subtle but complete unilateral peripheral retinal ischemia associated with cataract surgery and intracameral vancomycin, suggesting a spectrum of toxicity that may be underrecognized.\n==== Body\n1. Introduction\nCataract surgery may be associated with postoperative inflammatory or infectious complications, such as toxic anterior segment syndrome (TASS) or endophthalmitis. Typically, TASS or endophthalmitis is heralded by a disproportionate reduction in vision or increase in inflammation. Prior cases reported to be retinal vasculitis associated with cataract surgery and intracameral vancomycin injection showed similar reduction in vision with marked inflammation [1, 2]. In this report, we present a case of mild visual reduction and minimal inflammation with subtle but complete unilateral peripheral retinal ischemia associated with cataract surgery and intracameral vancomycin, suggesting a spectrum of toxicity that may be underrecognized.\n\n2. Case Report\nA 65-year-old woman with a past medical history of hypertension underwent uncomplicated phacoemulsification cataract extraction with implantation of a posterior chamber intraocular lens (PCIOL) in her right eye (OD) that concluded with injection of intracameral vancomycin (Hospira, NDC# 00409-4332-01, Lot# 396158E02, expiration 3/1/2016, concentration 1.0 mg/0.1 cc) as routine infection prophylaxis. Ofloxacin and prednisolone acetate 1% were postoperatively prescribed. On postoperative day 1, her vision was 20/20; however, this decreased two days later to 20/400. There was a 0.9–1.2 log unit relative afferent papillary defect (RAPD) OD. Intraocular pressure (IOP) was 18 mmHg OD. Slit-lamp examination of the right eye revealed mild conjunctival injection, trace corneal edema, deep anterior chamber with trace cell and flare but no hypopyon or fibrin, and a PCIOL in the capsular bag with no pigment or inflammatory deposits on the lens. The vitreous was quiet with no cells. On dilated examination, the optic nerve was normal with no disc edema or disc hemorrhage and a cup-to-disc ratio of 0.3. The retinal vessels were attenuated with box-carring and areas of arteriolar nonperfusion with distal branch retinal artery occlusions and scattered dot-blot hemorrhages in the periphery (Figure 1(a)). The left eye was normal with no abnormal findings except moderate nuclear sclerosis. The patient was cognizant of a paracentral scotoma that was confirmed by Goldmann visual field (GVF) (Figure 1(b)). Optical coherence tomography (OCT) showed preservation of all posterior retinal layers (Figure 1(c)). Fluorescein angiogram showed delayed retinal and choroidal filling with numerous peripheral branch retinal artery occlusions and scattered areas of vessel wall hyperfluorescence (Figures 1(d)–1(f)). Wide-field montages of mid- and late-phase angiograms showed the border of ischemia to be nearly equidistant about the posterior pole.\n\nGiven the evidence of retinal ischemic vasculitis and lack of signs of endophthalmitis or TASS, the patient was observed closely maintaining her ofloxacin and prednisolone drops and an inflammatory workup initiated. The procedure was uncomplicated and the patient did not have any hypertensive episodes. Her blood pressure was 150/67 and she continued being on her normal antihypertensive regimen. On postoperative day 4, her vision improved to 20/40 with unchanged mild inflammation. On day 5, her vision further improved to 20/25 OD and, at this time, the anterior chamber was quiet and the pupillary response partially normalized to a 0.3–0.6 log unit RAPD. Posterior segment examination revealed stable attenuation of retinal vessels with areas of arteriolar nonperfusion. Two months later, her vision returned to 20/20 with no RAPD (<0.3 log units). The right eye showed arteriolar sheathing and peripheral attenuation with collateral vessel formation in the temporal mid periphery (Figure 2(a)); GVF scotoma had resolved (Figure 2(b)). The left eye was normal and unchanged. The patient had no prior history of hypercoagulability or thromboses. All systemic investigations were negative including complete blood count, erythrocyte sedimentation rate, C-reactive protein, syphilis serology, tuberculosis quantiferon gold, anti-nuclear antibody, rheumatoid factor, and anti-neutrophil cytoplasmic antibodies.\n\n3. Discussion\nWe present a case of ischemic retinal vasculitis associated with intraoperative intracameral vancomycin during cataract surgery. In the literature, there is one report of two cases of retinal vasculitis after cataract surgery with vancomycin and one more recent case series which described this sequela as postoperative hemorrhagic occlusive retinal vasculitis [1, 2]. In contrast to the prior reported cases that had severe anterior chamber and vitreous inflammatory reactions with profound irreversible vision loss, our case had minimal inflammatory reaction and significant retinal vasculitis with multiple arterial occlusions in a circular distribution about the posterior pole. The present case demonstrated rapid resolution when treated with a short course of topical medications.\n\nAlthough it is impossible to confirm the relationship of this disease to vancomycin exposure, we believe that it is unlikely to be related to an underlying systemic process or autoimmune disease. The patient had no history of hypertensive episodes or history of thrombosis. This contention is also supported by the abrupt onset, rapid resolution, temporal and ipsilateral association to vancomycin and the lack of prior symptoms or signs of uveitis, and negative laboratory workup. Although we believe the etiology is unlikely to be TASS (there were no other affected cases at the same surgery center on that day and our case had minimal anterior chamber reaction), the most provocative finding was the rapid normalization of the afferent pupillary defect and vision.\n\nVancomycin has been recommended for widespread prophylactic use in cataract surgery [3, 4]. Vancomycin is also widely used as an intravitreal injection for endophthalmitis [5]. Vancomycin retinal toxicity has been demonstrated in rabbits receiving intravitreal injections of vancomycin in silicone-filled eyes but human toxicity has not been suggested until recently [1, 6]. If this case represents the mild end of a spectrum of vancomycin toxicity, we believe that prospective evaluation will be needed to determine the incidence of the transitory and variable nature of the visual impact of widespread vancomycin surgical prophylaxis.\n\nEthical Approval \nThe authors fully adhered to the Declaration of Helsinki and all Federal and State laws.\n\nConflict of Interests\nThe authors have no financial or conflict of interests to disclose.\n\nAuthors' Contribution\nDavid R. P. Almeida had full access to all the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. All authors were responsible for design and conduct of the study. Collection, management, analysis, and interpretation of the data were the responsibility of all authors. Preparation, review, and approval of the paper were done by all authors. Decision to submit the paper for publication was made by all authors.\n\nFigure 1 Presentation of ischemic hemorrhagic retinal vasculitis after cataract surgery with intracameral vancomycin. Color fundus montage photograph displays attenuated retinal vessels with arteriolar nonperfusion and distal branch retinal artery occlusions (a). Goldmann visual field shows enlargement of the blind spot to the I4e isopter, paracentral scotoma to the I4e isopter, and central constriction of the I1e and I2e isopters (b). Optical coherence tomography illustrates adequate representation of all retinal layers (c). Fluorescein angiography with delayed retinal and choroidal filling in the mid frame (d). Late frames show numerous peripheral branch retinal artery occlusions (e) and scattered areas of vessel wall hyperfluorescence (f). The left eye was normal with no abnormal findings except moderate nuclear sclerosis.\n\nFigure 2 Resolution of ischemic retinal vasculitis after eight weeks. Color fundus montage photograph shows posterior pole arteriolar sheathing with attenuation in the retinal periphery (a). Goldmann visual field shows resolution of previous visual field defects (b). Optical coherence tomography is stable compared to previous with adequate representation of all retinal layers (c). The left eye was never affected.\n==== Refs\n1 Nicholson L. B. Kim B. T. Jardón J. Severe bilateral ischemic retinal vasculitis following cataract surgery Ophthalmic Surgery, Lasers and Imaging Retina 2014 45 4 338 342 10.3928/23258160-20140605-01 \n2 Witkin A. J. Shah A. R. Engstrom R. E. Postoperative hemorrhagic occlusive retinal vasculitis: expanding the clinical spectrum and possible association with vancomycin Ophthalmology 2015 122 7 1438 1451 10.1016/j.ophtha.2015.03.016 25886796 \n3 Anijeet D. R. Palimar P. Peckar C. O. Intracameral vancomycin following cataract surgery: an eleven-year study Clinical Ophthalmology 2010 4 1 321 326 2-s2.0-77953402392 20463800 \n4 Gore D. M. Angunawela R. I. Little B. C. United Kingdom survey of antibiotic prophylaxis practice after publication of the ESCRS Endophthalmitis Study Journal of Cataract and Refractive Surgery 2009 35 4 770 773 10.1016/j.jcrs.2009.01.004 2-s2.0-62349089222 19304103 \n5 Lemley C. A. Han D. P. Endophthalmitis: a review of current evaluation and management Retina 2007 27 6 662 680 10.1097/iae.0b013e3180323f96 2-s2.0-34447305200 17621174 \n6 Hegazy H. M. Kivilcim M. Peyman G. A. Evaluation of toxicity of intravitreal ceftazidime, vancomycin, and ganciclovir in a silicone oil-filled eye Retina 1999 19 6 553 557 10.1097/00006982-199911000-00013 2-s2.0-0033507203 10606458\n\n",
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"title": "Ischemic Retinal Vasculitis Associated with Cataract Surgery and Intracameral Vancomycin.",
"title_normalized": "ischemic retinal vasculitis associated with cataract surgery and intracameral vancomycin"
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"abstract": "OBJECTIVE\nTo report a case of warfarinization involving a patient who developed nasal bleeding and an elevated prothrombin time-international normalized ratio (PT-INR) after taking 15 mg of mirtazapine.\n\n\nMETHODS\nA 70-year-old Japanese man with anxiety and irritation was admitted to the ER of our hospital with nasal bleeding. His medical history included atrial fibrillation, treated with warfarin at 3.0 mg a day, hypertension, and diabetus mellitus. He had also been taking mirtazapine at 15 mg. He experienced nasal bleeding 4 days after the initiation of therapy with mirtazapine. His PT-INR markedly elevated from 1.21 before therapy to 7.93 after therapy. Both mirtazapine and warfarin were immediately discontinued by his cardiologist. One week later, PT-INR had normalized (1.00) and the nasal bleeding had resolved.\n\n\nCONCLUSIONS\nThe metabolism of warfarin involves several cytochrome P450 isoenzymes, including CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Mirtazapine is metabolized primarily by CYP2D6 and CYP3A4, with lesser contributions by CYP1A2. A competitive enzyme inhibition may occur, with CYP3A4 metabolizing the two drugs. No drug interaction was seen with his other medications.\n\n\nCONCLUSIONS\nThe coadministration of mirtazapine and warfarin can result in an increase in the anticoagulant effect of warfarin. This case shows the need to closely monitor potential drug interactions in the elderly, especially those taking mirtazapine and warfarin.",
"affiliations": null,
"authors": "Nishimura|Hiroshi|H|;Kawakami|Masanori|M|",
"chemical_list": "D000925:Anticoagulants; D008803:Mianserin; D014859:Warfarin; D011516:Prothrombin; D000078785:Mirtazapine",
"country": "Japan",
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"journal": "Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica",
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"medline_ta": "Seishin Shinkeigaku Zasshi",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D004347:Drug Interactions; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008803:Mianserin; D000078785:Mirtazapine; D011516:Prothrombin; D014859:Warfarin",
"nlm_unique_id": "9801787",
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"title": "A Case with the Increased PT-INR after the Addition of Mirtazapine to Warfarin Therapy.",
"title_normalized": "a case with the increased pt inr after the addition of mirtazapine to warfarin therapy"
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"abstract": "Patients with malignancy may present with significant thromboembolic complications including deep vein thrombosis (DVT), pulmonary embolism, arterial thrombosis, nonbacterial thrombotic endocarditis, and stroke due to abnormal coagulation cascades. Although these events are typically recognized later in the disease process, complications of a hypercoagulable state can rarely present as the first manifestation of an occult malignancy. We report a case of a young male who was ultimately found to have an aggressive form of lung adenocarcinoma after the initial presentation of multiple thromboembolic events. DVT and stroke as an initial presentation of an active lung adenocarcinoma in a young patient is extremely rare as patients presenting in a hypercoagulable state usually are older. Though testing for a hypercoagulable state is not recommended for the first unprovoked DVT, clinicians should be prompted to screen for malignancy in the setting of cryptogenic strokes, especially in younger patients with no prior risk factors.",
"affiliations": "Mount Sinai Medical Center, Miami Beach, FL, USA.;Mount Sinai Medical Center, Miami Beach, FL, USA.;Mount Sinai Medical Center, Miami Beach, FL, USA.;University of South Florida, Tampa, FL, USA.",
"authors": "Galarza Fortuna|Gliceida M|GM|0000-0002-1084-953X;Singh|Anita|A|;Jacobs|Adam|A|0000-0002-9732-9771;Ugalde|Israel|I|",
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"doi": "10.1177/2324709620969482",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n33138640\n10.1177/2324709620969482\n10.1177_2324709620969482\nCase Report\nLung Adenocarcinoma Presenting as Multiple Thromboembolic\nEvents: A Case Report and Review of the Literature\nhttps://orcid.org/0000-0002-1084-953XGalarza Fortuna Gliceida M. MD1 Singh Anita DO, MBA1 https://orcid.org/0000-0002-9732-9771Jacobs Adam DO1 Ugalde Israel DO2 1 Mount Sinai Medical Center, Miami\nBeach, FL, USA\n2 University of South Florida,\nTampa, FL, USA\nGliceida M. Galarza Fortuna, MD,\nDepartment of Internal Medicine, Mount Sinai Medical Center, 4300\nAlton Road, Miami Beach, FL 33140, USA. Email:\ngliceida.galarza@gmail.com\n2 11 2020 \nJan-Dec 2020 \n8 23247096209694823 7 2020 1 10 2020 3 10 2020 © 2020 American Federation for Medical\nResearch2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative\nCommons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/)\nwhich permits non-commercial use, reproduction and distribution\nof the work without further permission provided the original\nwork is attributed as specified on the SAGE and Open Access page\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Patients with malignancy may present with significant thromboembolic\ncomplications including deep vein thrombosis (DVT), pulmonary\nembolism, arterial thrombosis, nonbacterial thrombotic endocarditis,\nand stroke due to abnormal coagulation cascades. Although these events\nare typically recognized later in the disease process, complications\nof a hypercoagulable state can rarely present as the first\nmanifestation of an occult malignancy. We report a case of a young\nmale who was ultimately found to have an aggressive form of lung\nadenocarcinoma after the initial presentation of multiple\nthromboembolic events. DVT and stroke as an initial presentation of an\nactive lung adenocarcinoma in a young patient is extremely rare as\npatients presenting in a hypercoagulable state usually are older.\nThough testing for a hypercoagulable state is not recommended for the\nfirst unprovoked DVT, clinicians should be prompted to screen for\nmalignancy in the setting of cryptogenic strokes, especially in\nyounger patients with no prior risk factors.\n\nlung cancerthromboembolic eventsmalignancy-associated hypercoagulable statecover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThromboembolic events such as deep vein thrombosis (DVT), pulmonary embolism\n(PE), arterial thrombosis, nonbacterial thrombotic endocarditis, and\nischemic strokes can be the initial event leading to the diagnosis of an\nunderlying malignancy; this is due to abnormalities in the coagulation\ncascade that often accompanies many oncologic diseases. However, these\nevents are typically recognized later in the disease process and rarely\npresent as the first manifestation of an occult malignancy. We report a case\nof a young male who was ultimately found to have an aggressive form of lung\nadenocarcinoma after the initial presentation of multiple thromboembolic\nevents.\n\nCase Presentation\nA 36-year-old male truck driver with a history of tobacco abuse initially\npresented to the emergency department with a chief complaint of right lower\nleg swelling and pain. Lower extremity ultrasound revealed a DVT of the\nright popliteal and right posterior tibial vein. Initial laboratory\nexaminations showed normal complete blood count—hemoglobin 13.1 g/dL,\nhematocrit 40.7%, white blood cells 7.91 × 103/µL, platelet count\n155 × 103/µL, and normal coagulation studies— activated partial\nthromboplastin time 29.9 seconds, activated partial thromboplastin time\nratio 1.09, prothrombin time 14.1 seconds, and international normalized\nratio 1.1. He was discharged home with rivaroxaban, a factor Xa\ninhibitor.\n\nHe returned to the hospital 1 day later complaining of facial droop, slurred\nspeech, and right upper extremity weakness. Imaging studies revealed\nmultiple infarctions in the bilateral cerebral hemispheres with perfusion\ndefect most significant in the left middle cerebral artery (MCA; Figure 1). Given the\nischemic strokes were suggestive of an embolic event, a transesophageal\nechocardiogram was performed, which resulted negative for patent foramen\novale, valvular disease, and arrhythmias. Initial hypercoagulable workup\nshowed decreased protein S activity (65% of normal), normal protein C\nactivity (95% of normal), normal antithrombin III levels (97% of normal),\nnegative lupus anticoagulant (lupus anticoagulant not detected; dRVVT ≤45\nseconds, negative hexagonal phase phospholipid neutralization, decreased\nfactor VIII (36% of normal), and factor V (Leiden) mutation was not\ndetected. Other pertinent diagnostic studies included negative ANA, ANCA,\nand anticardiolipin IgG/IgM. During the hospital stay the patient was\nanticoagulated with enoxaparin 1 mg/kg and once discharged rivaroxaban was\nresumed.\n\nFigure 1. Computed tomography scan of the head showing multiple infarctions\nin the bilateral cerebral hemispheres—marked by arrows—with\nperfusion defect most significant in the left middle cerebral\nartery. Bilateral cerebral infarctions are more often seen as\nthe result of thromboembolic events rather than atherosclerotic\ndisease.\n\nTwo weeks later, the patient returned to the emergency department with a sudden\nepisode of headache, chest pain, and confusion. Computed tomography (CT)\nscan of the brain revealed a small subarachnoid hemorrhage in the right\nposterior parietal and left frontal lobe (Figure 2). Emergent cerebral\nangiography revealed a total occlusion of the M2 branch of the right MCA.\nRepeat echocardiogram revealed a mobile mass attached to the anterior mitral\nvalve leaflet on its atrial side, suspicious for a thrombus. During this\nadmission, the patient developed multiple thromboembolic strokes in the left\nMCA and bilateral posterior cerebellar arteries. Repeat lower extremity\nultrasound showed an acute DVT within the left deep femoral artery. CT\nangiogram of the chest revealed a PE, multilevel supraclavicular,\nmediastinal, hilar lymphadenopathy, and a bilobed pulmonary nodule opacity\nat the posterior basal segment of the left lower lung (Figure 3).\n\nFigure 2. Computed tomography scan of the brain revealed a small subarachnoid\nhemorrhage in the right posterior parietal and left frontal\nlobe—marked by arrows.\n\nFigure 3. Computed tomography angiogram of the chest revealed a pulmonary\nembolism (PE), multilevel supraclavicular, mediastinal, hilar\nlymphadenopathy, and a bilobed pulmonary nodule opacity at the\nposterior basal segment of the left lower lung.\n\nCT-guided biopsy of a right supraclavicular lymph node showed metastatic\ncarcinoma. Immunohistochemical stains for CK7 and napsin A were positive;\nCK20 and TTF were focally positive, while CD45, S-100, and SOX-10 were\nnegative, suggesting a lung primary malignancy. Follow-up stains showed\nPDL-1 expression by immunohistochemistry (high expression at 50%) and\nALK/ROS1 gene rearrangement by fluorescence in situ hybridization was\npositive for ROS1 gene rearrangement. EGFR mutation was also negative. Given\nhis aggressive hypercoagulable state, he was restarted on rivaroxaban.\nTreatment with crizotonib was initiated as he was a poor candidate for\nplatinum-based chemotherapy. Repeat CT of chest showed improvement in the\nsize of the pulmonary nodule and lymphadenopathy 6 weeks later (Figure 3). The\npatient remained ventilator dependent with poor neurological status and\nrequired bilateral below the knee amputations due to lower extremity\ngangrene. Given the lack of neurological responsiveness and poor prognosis,\nhospice was offered; however, his family insisted the patient continue\nchemotherapy. The patient remained in the hospital for a total of 6 months\nand ultimately died of cardiac arrest.\n\nDiscussion\nProvoked Versus Unprovoked DVT\nThe association between thromboembolic events and underlying malignancies\nhas been known for many years. The most common thromboembolic events\nseen in these patients include DVT and PE; other less frequently seen\ncomplications include arterial events, such as vascular cerebral\nevents or strokes, and myocardial infarctions. These complications\nhave been linked to an increased mortality in cancer patients. In a\nstudy by Khorana,1 cancer patients were noted to have a 47-fold elevation of death\nsecondary to venous thromboembolism (VTE; both arterial and venous),\nbeing the most common cause of non–cancer-related death, along with\ninfections. Similarly, in their study, cancer patients had a 2.7-fold\nelevation on the annualized death rate for arterial thrombosis.\nHowever, these complications are often seen later in the course of\ncancer and seldom lead to the initial diagnosis as it was the case\nwith the patient described here.\n\nMoreover, VTEs are often classified into provoked versus unprovoked\naccording to the underlying risk factors present on the patient under\nstudy. Risk factors can be transient, such as immobilization after a\nsurgical procedure or persistent such as active cancer. When no\ntransient or persistent provoking risk factors are found in the\npatient’s history, the VTE is determined to be unprovoked.2 Inherited thrombophilia, a genetic tendency to thrombotic\ncomplications in the setting of an imbalance in hemostasis of the\ncoagulation cascade, such as antithrombin deficiency, antithrombin\nresistance, protein C deficiency, protein S deficiency, and factor V\nLeiden mutation are commonly associated with the development of VTE.3 These conditions should be investigated in patients to assess\nthe likelihood of recurrence. The population that often benefits from\ntesting are young patients, those with family history of thrombotic\nevents, pregnant females, patients with VTE in unusual sites, and\nyoung patients presenting with arterial ischemia and right-to-left\nshunt. However, the timing of testing is of crucial importance;\ntesting should be performed at least 1 month after the finalizing\nanticoagulation treatment or 3 months after the initial thrombotic\nevent. On the contrary, common acquired causes of thrombophilia\ninclude age more than 65 years, body mass index more than 30\nkg/m2, and the presence of antiphospholipid\nantibodies and lupus anticoagulant.3 Our patient satisfied at least 2 conditions which indicated\ntesting, including age less than 50 years and an arterial event\n(ischemic stroke of the left MCA). However, the patient’s initial\nworkup was done while inpatient, 2 days after presentation and after 2\ndoses of rivaroxaban. The above-mentioned caveats could explain why\nthe patient’s protein S activity was below the normal range as active\nthrombosis can lower the levels of free protein S and therefore lead\nto an erroneous diagnosis.4\n\nInitial Treatment of Provoked Versus Unprovoked DVTs\nThe mainstream treatment for VTE consists of anticoagulation. The\navailable choices of anticoagulation consists of vitamin K antagonists\n(VKAs) such as a warfarin, unfractionated heparin (UFH),\nlow-molecular-weight heparin (LMWH), the indirect factor Xa inhibitor\nfondaparinux, and direct oral anticoagulants Xa inhibitors, and direct\nthrombin inhibitors (DOACs) such as apixaban, endoxaban, dabigatran,\nand rivaroxaban.5,6 Additionally, the use of DOACs for VTE has many\nadvantages, including its availability in oral form, the lack of\nprothrombin time/international normalized ratio monitoring, rapid\nonset of action, short half-life, and the lack of prior bridging (with\nthe exception of dabigatran and endoxaban, which require treatment\noverlap with a parenteral anticoagulant).5 Because of the above-mentioned characteristics, DOACs are not\nonly the gold standard for the treatment of VTE in noncancer patients\nbut are also among the first options for cancer patients who are\ndetermined to have a low risk of bleeding.7 Our patient was appropriately treated with a DOAC, rivaroxaban,\nhowever, presented shortly after with an arterial thrombosis, an event\nthat should immediately lead to the initiation of a thrombophilia\nscreening.\n\nHypercoagulable States Workup After DVT/PEs\nThe most common causes of thrombophilia that are typically tested include\ngenetic conditions such as deficiency of protein C, protein S,\nantithrombin, or the genetic mutation of factor V Leiden. Other\ninherited causes of thrombophilia include hyperhomocysteinemia,\ndysfibrinogenemia, and certain blood groups such as non–O blood\ngroups, mostly blood group B.8,9 Moreover, those patients younger than 50 years\nwith no obvious identified risk factors for the development of a\nthromboembolic event should be considered for screening of occult\ncancer, paroxysmal nocturnal hemolysis, and autoimmune conditions as\nthe underlying cause of their hypercoagulable state.8\n\nThe current data indicate that patients who are diagnosed with a first\nnonprovoked VTE in whom cancer screening is determined to be\nappropriate, a limited screening strategy that includes a complete\nhistory, physical examination, basic blood testing, chest radiograph,\nand age-/sex-specific cancer screening are appropriate. The addition\nof further imaging studies such as CT scan of the abdomen and pelvis\ndo not lead to a clinical significant increase in the detection rate\nof underlying malignancy in patients.10,11 However, the detection rate of occult cancer\nafter 1 year of the diagnosis of an unprovoked VTE is 1 in 20 patients.10 In those patients in whom cancer was diagnosed during screening\nfollowing an unprovoked VTE, colon cancer was the most common\nmalignancy, found in 17% of the patients, followed by lung cancer and\npancreatic cancer with 15% and 11%, respectively.10\n\nMalignancy as a Hypercoagulable State\nMalignancies are associated with a 4% to 20% increase in VTE and 2% to 5%\nincrease in arterial thrombosis.12 Many pathways have been implicated in the development of venous\nthrombosis in cancer patients. In a review article by Hisada and Mackman,12 the authors describe the main pathways and biomarkers\nassociated with venous thrombosis in cancer patients. Leukocytosis is\npresent in approximately 30% of cancer patients and the cancer\nsubtypes in which the most frequently seen include colon and lung cancer.12 Neutrophils and monocytes are the cell lines with the greatest\ncontribution to the development of thrombosis. Neutrophils increase\nthe likelihood of thrombotic events by generating neutrophils\nextracellular traps, which have prothrombotic quality,13 while monocytes have been shown to be procoagulant by the\nexpression of tissue factor.12,14 Similarly, thrombocytosis is often found in\nlaboratory examination of cancer patients. Thrombocytosis is present\nin approximately 21.6% of patients with lung cancer, and it is most\noften seen in patients with advance cancer stages.15 Additionally, platelets are of extreme importance in the\ndevelopment of arterial thrombosis and also play a significant role\nthe development of VTE in cancer patients.12\n\nLung Cancer and VTE\nLung cancer is associated with an increased prevalence of VTE. In\npatients with newly diagnosed lung cancer, Zhang and colleagues16 described that 13.2% of patients with recently diagnosed lung\ncancer developed a VTE either within 1 week from admission or 3 months\nprior to admission. In this study, 6.2% of the patients developed DVT\nonly, 4.9% developed PE only, and 2.1% of patients were found to have\nboth DVT and PE.16 Similarly, Ruiz-Artacho and colleagues17 described that the development of VTE in lung cancer patients\ntypically occurs earlier in the disease course. Fifty percent of the\npatients in their cohort of lung cancer patients with diagnosed VTE\ndeveloped the thromboembolic complication within less than 3 months\nafter diagnosis and 32% within the first 30 days.17 Interestingly, elevated CEA levels has been associated with an\nincreased risk for the development of PE.16,18 Of the histologic variants, lung adenocarcinoma\nis the lung cancer histopathology most associated with the later\ndevelopment of VTE.16 Other important risk factors that were associated with\nincreased prevalence of VTE in patients with lung cancer were the\npresence of distant metastasis, leukocytosis, and younger age.16\n\nROS-1 Rearranged Non–Small Cell Lung Cancer (NSCLC) and\nThromboembolic Events\nThe incidence of venous thromboembolic events in patients with non–small\ncell cancer has been established to be approximately 14% during the\ncourse of disease.19 In addition to the adenocarcinoma histologic subtype of lung\ncancer being associated with a higher incidence of lung cancer, the\ndifferent genetic mutations often seen in NSCLC, such as EGFR\nmutation, KRAS mutation, ALK rearrangement, and ROS1 rearrangement,\nhave been associated with and specific incidence of VTE. ROS1\nrearrangement occurs approximately in 2% of patients with NSCLC.20 Of the different above-mentioned genetic mutations associated\nwith NSCLC, patients with ROS1 rearrangement NSCLC have been noted to\nhave 3- to 5-fold higher risk of developing VTEs soon before or after\nthe initial diagnosis, with most patients developing the\nthromboembolic events within 1.8 months of diagnosis.20 The exact mechanism through which this occurs is not completely\nunderstood. Some research suggest an increased incidence of inherited\nthrombophilia in patients with this specific genetic alteration.20\n\nLung Cancer and Strokes\nAn increased incidence of strokes, both ischemic and hemorrhagic, has\nbeen described in patients with underlying cancer. Graus and colleagues21 initially described that cerebrovascular disease (CVD) was\npresent in 14.6% of patients with cancer. In patients with underlying\ncarcinomas, ischemic strokes were more commonly observed than\nhemorrhagic strokes, although both have been described.21 The most common underlying etiologies of ischemic/embolic\nstrokes in this population are hypercoagulopathy and other coagulation\ndisorders. Cardioembolic strokes, atherosclerosis, small vessel\nocclusion, and nonbacterial thrombotic endocarditis has also been\nmentioned in the literature although in a lesser frequency.22,23 Among the\nunderlying cancers that have been more frequently observed in patients\nwith CVD are pancreas, gastric, and lung cancer.24\n\nIn patients with lung cancer, biomarkers such as elevated CEA levels,\nCA155, and CA199 were independently associated with and increased risk\nof stroke in patients with no other typical risk factors for the\ndevelopment of CVD such as dyslipidemia or atrial fibrillation.\nSimilar to the timeline of our patient described in this case report,\nstrokes are typically seen within the first 4 months after diagnosis\nof lung cancer and the distribution of the lesions often involves\nmultiple arterial territories of the brain consistent with a\ncryptogenic stroke.25 Moreover, the development of CVD in patients with cancer\ncarries an increased mortality rate of approximately 25%.23\n\nLung Cancer and Nonbacterial Endocarditis\nNonbacterial thrombotic endocarditis (NBTE) is defined as the presence of\nvegetation on a valvular cardiac structure, consisting of fibrin and\nplatelet deposition in the absence of bacterial colonization or inflammation.26 This entity has an estimated incidence of 0.3% to 9.3% and is\nmore often found in patients with advanced stage malignancy. Recurrent\nembolization is frequently observed and approximately 50% of the\npatients with nonbacterial thrombotic endocarditis develop emboli to\ndifferent organs, most important, the brain, kidneys, and spleen.26 These lesions occur given the interaction between macrophages\nand malignant cells, which release cytokines leading to the damage of\nthe valvular endothelium, which promotes the further deposition of\nplatelets and subsequent thrombus formation.27 As with any other thromboembolic complications, NBTE is most\ncommonly observed in patients with lung, pancreas, or gastric cancer,\nadenocarcinoma being the histology most commonly associated with this entity.27\n\nTeaching Points\nRecurrent thromboembolic events in young patients with no known\nunderlying medical conditions should prompt clinicians to\ninvestigate known causes of VTEs such as malignancy.\n\nLung cancer, in particular, lung adenocarcinoma, is highly\nassociated with multiple hypercoagulable conditions such as DVT,\nPE, CVD, and NBTE.\n\nThe development of DVT, PE, CVD, and NBTE in patients with\nunderlying malignancy is often associated with a poor prognosis\nand is frequently seen in late stages of the disease\nprocess.\n\nROS-1 rearrangement associated NSCLC have an increased risk of VTE\nwhen compared with other genetic profiles.\n\nFurther research is needed to understand the pathophysiologic\nprocess behind the hypercoagulable state associated with\nhematological and solid malignancies and regarding possible\npreventive strategies for patients with newly diagnosed\ndisease.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to\nthe research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship,\nand/or publication of this article.\n\nEthical Approval: Our institution does not require ethical approval for reporting\nindividual cases or case series.\n\nInformed consent: Informed consent for patient information to be published in this article\nwas not obtained because it was not required by our institution.\n\nORCID iDs: Gliceida M. Galarza Fortuna \nhttps://orcid.org/0000-0002-1084-953X\n\nAdam Jacobs \nhttps://orcid.org/0000-0002-9732-9771\n==== Refs\nReferences\n1 \nKhorana AA \nVenous thromboembolism and prognosis\nin cancer\n. Thromb Res .\n2010 ;125 :490 -493\n.20097409 \n2 \nKearon C Ageno W Cannegieter SC Cosmi B Geersing GJ Kyrle PA ; Subcommittees on Control of Anticoagulation,\nand Predictive and Diagnostic Variables in Thrombotic\nDisease . Categorization of patients as\nhaving provoked or unprovoked venous thromboembolism: guidance\nfrom the SSC of ISTH\n. J Thromb\nHaemost .\n2016 ;14 :1480 -1483\n.27428935 \n3 \nColucci G Tsakiris DA \nThrombophilia screening: universal,\nselected, or neither?\n\nClin Appl Thromb Hemost .\n2017 ;23 :893 -899\n.28049358 \n4 \nD’Angelo A Vigano-D’Angelo S Esmon CT Comp PC \nAcquired deficiencies of protein S.\nProtein S activity during oral anticoagulation, in liver\ndisease, and in disseminated intravascular\ncoagulation\n. J Clin Invest .\n1988 ;81 :1445 -1454\n.3284913 \n5 \nBartholomew JR \nUpdate on the management of venous\nthromboembolism\n. Cleve Clin J\nMed .\n2017 ;84 :39 -46\n.29257737 \n6 \nSerhal M Barnes GD \nVenous thromboembolism: a clinician\nupdate\n. Vasc Med .\n2019 ;24 :122 -131\n.30950331 \n7 \nAntunes LF \nNew oral anticoagulants (NOACs) are\nthe gold standard invenous thromboembolism\n.\nRev Port Cir Cardiotorac Vasc .\n2020 ;27 :33 -37\n.32239823 \n8 \nColucci G Tsakiris DA \nThrombophilia screening revisited: an\nissue of personalized medicine\n. J Thromb\nThrombolysis .\n2020 ;49 :618 -629\n.\ndoi:10.1007/s11239-020-02090-y 32248336 \n9 \nBaudouy D Moceri P Chiche O , et al\nB blood group: a\nstrong risk factor for venous thromboembolism\nrecurrence\n. Thromb Res .\n2015 ;136 :107 -111\n.25981188 \n10 \nVan Es N Le Gal G Otten HM , et al\nScreening for\noccult cancer in patients with unprovoked venous\nthromboembolism\n. Ann Intern\nMed .\n2017 ;167 :410 -417\n.28828492 \n11 \nCarrier M Lazo-Langner A Shivakumar S , et al; SOME\nInvestigators . Screening for occult\ncancer in unprovoked venous thromboembolism\n.\nN Engl J Med .\n2015 ;373 :697 -704\n.26095467 \n12 \nHisada Y Mackman N \nCancer-associated pathways and\nbiomarkers of venous thrombosis\n.\nBlood .\n2017 ;130 :1499 -1506\n.28807983 \n13 \nBrinkmann V Reichard U Goosmann C , et al\nNeutrophil\nextracellular traps kill bacteria\n.\nScience .\n2004 ;303 :1532 -1535\n.15001782 \n14 \nGregory SA Morrissey JH Edgington TS \nRegulation of tissue factor gene\nexpression in the monocyte procoagulant response to\nendotoxin\n. Mol Cell Biol .\n1989 ;9 :2752 -2755\n.2503712 \n15 \nMaráz A Furák J Varga Z Kahan Z Tiszlavicz L Hideghety K \nThrombocytosis has a negative\nprognostic value in lung cancer\n.\nAnticancer Res .\n2013 ;33 :1725 -1729\n.23564823 \n16 \nZhang Y Yang Y Chen W , et al\nPrevalence and\nassociations of VTE in patients with newly diagnosed lung\ncancer\n. Chest .\n2014 ;146 :650 -658\n.24676401 \n17 \nRuiz-Artacho P Trujillo-Santos J López-Jiménez L , et al; RIETE\nInvestigators . Clinical characteristics\nand outcomes of patients with lung cancer and venous\nthromboembolism\n. TH Open .\n2018 ;2 :e210 -e217\n.31249944 \n18 \nGuo J Deng QF Xiong W , et al\nComparison among\ndifferent presentations of venous thromboembolism because of\nlung cancer\n. Clin Respir J .\n2019 ;13 :574 -582\n.31306554 \n19 \nChiari R Ricciuti B Landi L , et al\nROS1-rearranged\nnon–small-cell lung cancer is associated with a high rate of\nvenous thromboembolism: analysis from a phase II, prospective,\nmulticenter, two-arms trial (METROS)\n.\nClin Lung Cancer .\n2020 ;21 :15 -20\n.31607443 \n20 \nAlexander M Pavlakis N John T , et al\nA multicenter\nstudy of thromboembolic events among patients diagnosed with\nROS1-rearranged non-small cell lung cancer\n.\nLung Cancer .\n2020 ;142 :34 -40\n.32087434 \n21 \nGraus F Rogers LR Posner JB \nCerebrovascular complications in\npatients with cancer\n. Medicine\n(Baltimore) .\n1985 ;64 :16 -35\n.3965856 \n22 \nDardiotis E Aloizou AM Markoula S , et al\nCancer-associated\nstroke: pathophysiology, detection and\nmanagement\n. Int J Oncol .\n2019 ;54 :779 -796\n.30628661 \n23 \nGrazioli S Paciaroni M Agnelli G , et al\nCancer-associated\nischemic stroke: a retrospective multicentre cohort\nstudy\n. Thromb Res .\n2018 ;165 :33 -37\n.29558659 \n24 \nNavi BB Iadecola C \nIschemic stroke in cancer patients: a\nreview of an underappreciated pathology\n.\nAnn Neurol .\n2018 ;83 :873 -883\n.29633334 \n25 \nXie X Chen L Zeng J , et al\nClinical features\nand biological markers of lung cancer-associated\nstroke\n. J Int Med Res .\n2016 ;\n44 :1483 -1491\n.28322105 \n26 \nAsopa S Patel A Khan OA Sharma R Ohri SK \nNon-bacterial thrombotic\nendocarditis\n. Eur J Cardiothorac\nSurg .\n2007 ;32 :696 -701\n.17881239 \n27 \nel-Shami K Griffiths E Streiff M \nNonbacterial thrombotic endocarditis\nin cancer patients: pathogenesis, diagnosis, and\ntreatment\n. Oncologist .\n2007 ;12 :518 -523\n.17522239\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "lung cancer; malignancy-associated hypercoagulable state; thromboembolic events",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000328:Adult; D017809:Fatal Outcome; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D011655:Pulmonary Embolism; D020521:Stroke; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709620969482",
"pmc": null,
"pmid": "33138640",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "29257737;20097409;24676401;15001782;28807983;31249944;30628661;28049358;26095467;31306554;28322105;29558659;28828492;30950331;27428935;3965856;31607443;2503712;17881239;3284913;32248336;32087434;32239823;17522239;29633334;23564823;25981188",
"title": "Lung Adenocarcinoma Presenting as Multiple Thromboembolic Events: A Case Report and Review of the Literature.",
"title_normalized": "lung adenocarcinoma presenting as multiple thromboembolic events a case report and review of the literature"
} | [
{
"companynumb": "US-JNJFOC-20201148898",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "3",
... |
{
"abstract": "Coccidioidomycosis infections result from inhalation of the dimorphic fungus Coccidiodes immitis. Coccidioidomycosis typically is benign, but its extremely rare disseminated form can result in significant morbidity and mortality. Dissemination of the fungus to the spine is difficult to control and usually requires an aggressive combination approach (surgical/medical). In this article, we report the case of a 27-year-old Indonesian man with vertebral osteomyelitis caused by disseminated coccidioidomycosis. We outline the case management (includes 30-month follow-up) and review the treatment recommendations. The patient presented with an unstable C5 pathologic fracture caused by C immitis. After corpectomy and stabilization of the cervical spine along with antifungal therapy with amphotericin B and oral fluconazole, he developed multiple complications. This case illustrates some of the potential pitfalls in managing spinal osteomyelitis caused by C immitis and the need for continuous medical therapy after surgical treatment.",
"affiliations": "Department of Orthopaedic Surgery, University of Toldedo Medical Center, Toledo, OH. helgafy@aol.com.",
"authors": "Elgafy|Hossein|H|;Miller|Jacob|J|;Meyers|Stephanie|S|;Assaly|Ragheb|R|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-4519",
"issue": "43(8)",
"journal": "American journal of orthopedics (Belle Mead, N.J.)",
"keywords": null,
"medline_ta": "Am J Orthop (Belle Mead NJ)",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D002574:Cervical Vertebrae; D003047:Coccidioidomycosis; D015725:Fluconazole; D006801:Humans; D008297:Male; D010019:Osteomyelitis; D016103:Spinal Fractures; D013123:Spinal Fusion; D016896:Treatment Outcome",
"nlm_unique_id": "9502918",
"other_id": null,
"pages": "E181-4",
"pmc": null,
"pmid": "25136876",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated coccidioidomycosis of the spine in an immunocompetent patient.",
"title_normalized": "disseminated coccidioidomycosis of the spine in an immunocompetent patient"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0043015",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to investigate possible functional and structural ocular changes caused by chronic sildenafil therapy to treat pulmonary arterial hypertension (PAH).\n\n\nMETHODS\nCase-control study included patients with pulmonary arterial hypertension: chronically using sildenafil and without sildenafil treatment. A comprehensive ophthalmologic exam including ectoscopy, extrinsic ocular motility, logMAR visual acuity measurement, contrast sensitivity test, color test, anterior segment biomicroscopy, Schirmer test 1, intraocular pressure, fundus exam under pupil dilation, fundus pictures, time domain and spectral domain optical coherence tomography, ocular Doppler ultrasound were performed. Full-field electroretinography (ERG) was tested for each eye in a subgroup of sildenafil-treated patients.\n\n\nRESULTS\nTwenty patients from each group were tested. Bilateral severe keratitis was found in seven (35 %) patients under sildenafil therapy. Lacrimal film break-up time (BUT) was significantly reduced (p = 0.006 respectively) and Doppler ultrasound showed a reduced resistance index of the central retinal artery in the group of sildenafil users (p = 0.019). No diffuse retinal functional abnormalities were found in ERG in treated patients. Visual acuity, contrast sensitivity and color discrimination were normal in both groups. No abnormalities were found in both time-domain and spectral-domain OCT for retinal parameters.\n\n\nCONCLUSIONS\nOne-third of the treated PAH group showed severe bilateral keratitis. This finding could be related to connective tissue abnormalities usually present in patients with this condition that might be exacerbated with the sildenafil usage. The resistance index of the central retinal artery was diminished in the chronic users group and it could be associated to the vasodilation caused by the medication in the choroidal vessels. An ophthalmic assessment for these patients is recommended to diagnose and treat possible ocular surface and choroidal blood flow abnormalities caused by sildenafil.",
"affiliations": "Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil. liciamatieli@gmail.com.;Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil.;Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil.;Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil.;Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil.;Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil.;Divisão de Pneumologia, Departamento de Clínica Médica, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, São Paulo, SP, Brasil.;Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil.;Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo - UNIFESP, Hospital São Paulo, Rua Botucatu, 822 - Vila Clementino, São Paulo, 04023-062, SP, Brasil.",
"authors": "Matieli|Licia|L|;Berezovsky|Adriana|A|;Salomão|Solange Rios|SR|;Allemann|Norma|N|;Martins|Elisabeth Nogueira|EN|;Hirai|Flavio E|FE|;Ota-Arakaki|Jaquelina|J|;Morales|Maira S A|MS|;de Freitas|Denise|D|",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-016-3352-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "254(6)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": "Eye; Keratitis; Pulmonary Hypertension; Sildenafil; Toxicity",
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001783:Blood Flow Velocity; D016022:Case-Control Studies; D004596:Electroretinography; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007634:Keratitis; D007766:Lacrimal Apparatus Diseases; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors; D012161:Retinal Artery; D012164:Retinal Diseases; D000068677:Sildenafil Citrate; D018615:Ultrasonography, Doppler, Color; D014792:Visual Acuity",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "1167-74",
"pmc": null,
"pmid": "27094700",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "12462670;16291984;19132801;14711156;19030905;15948790;18818963;10908271;14973526;15063421;14661900;20975620;25922708;11944862;12566892;25502644;15502501;10541153;20965396;11183578;22354598;24464938;18639219;19365010;24757559;11767027;10206581",
"title": "Ocular toxicity assessment of chronic sildenafil therapy for pulmonary arterial hypertension.",
"title_normalized": "ocular toxicity assessment of chronic sildenafil therapy for pulmonary arterial hypertension"
} | [
{
"companynumb": "BR-PFIZER INC-2016251072",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SILDENAFIL CITRATE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nOne of the major goals of pemphigus therapy is to reduce the patient's cumulative exposure to systemic corticosteroids. To investigate the efficacy of enteric-coated mycophenolate sodium (EC-MPS), 10 patients with active, refractory pemphigus vulgaris (PV) or foliaceous (PF) were treated with EC-MPS (1440 mg daily) and prednisone (75 mg daily) over 18 months.\n\n\nMETHODS\nFollowing EC-MPS/prednisone therapy, disease progression was inhibited between days 30 and 45 in 9/10 patients (8 PV; 1 PF). At 18 months, 8/9 PV patients had clinically quiescent disease; EC-MPS therapy was no longer required in two patients as a result of disease remission. The remaining PV patient showed no response to treatment. The PF patient also had clinically quiescent disease but with high levels of anti-desmoglein-1. ECMPS dose was reduced to 720 mg daily in 4/9 patients by month 6. Average daily prednisone requirement decreased to 25 mg at 6 months and to 15 mg at 18 months. Three adverse events were reported: headache (two cases; one mild and one moderate) and significant increase in blood glucose (one case; moderate).\n\n\nCONCLUSIONS\nEnteric-coated mycophenolate sodium is effective and safe as an adjuvant therapy in patients with refractory pemphigus and may be effective even in patients whose disease is unresponsive to azathioprine.",
"affiliations": "Department of Dermatology, University of Palermo, Palermo, Italy. istderm@unipa.it",
"authors": "Bongiorno|Maria Rita|MR|;Pistone|Giuseppe|G|;Doukaki|Spyridoula|S|;Aricò|Mario|M|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D009173:Mycophenolic Acid; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-4632.2009.04291.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "49(6)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D010392:Pemphigus; D011241:Prednisone; D013608:Tablets, Enteric-Coated; D016896:Treatment Outcome",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "693-9",
"pmc": null,
"pmid": "20618478",
"pubdate": "2010-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Enteric-coated mycophenolate sodium in the treatment of refractory pemphigus.",
"title_normalized": "enteric coated mycophenolate sodium in the treatment of refractory pemphigus"
} | [
{
"companynumb": "IT-STRIDES ARCOLAB LIMITED-2016SP017730",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drug... |
{
"abstract": "Valproic acid (VPA) is widely used for the treatment of epilepsy, migraine, and a variety of psychiatric symptoms, including bipolar disorder, borderline personality disorder, and alcohol withdrawal. Valproate is associated with severe idiosyncratic adverse effects, the most notable being valproate-induced hyperammonemic encephalopathy (VHE). Topiramate is also a broad-spectrum anticonvulsant that is also extensively used for migraine prophylaxis, as a mood stabilizer, and for alcohol dependency. There is increased occurrence of VHE when valproate is used with other medications like phenytoin, phenobarbital, and topiramate. Our case report is on a young patient who was on valproic acid and topiramate and developed metabolic encephalopathy with hypoxic respiratory failure. We reviewed the causes and management of the hyperammonemic encephalopathy. We believe that clinicians should be aware of possible hyperammonemic encephalopathy in any patient who is taking valproic acid and presenting with impaired consciousness and cognitive decline. We also underline the importance of early recognition and high index of suspicion of encephalopathy related to hyperammonemia.",
"affiliations": "Department of Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, USA.;Pulmonary and Critical Care Medicine, Department of Internal Medicine Marshall University Joan C. Edwards School of Medicine, Huntington, WV, USA.",
"authors": "Raru|Yonas|Y|;Zeid|Fuad|F|",
"chemical_list": null,
"country": "England",
"delete": false,
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30140-010.1016/j.rmcr.2018.05.026Case ReportHypoxic respiratory failure due to hyperammonemic encephalopathy induced by concurrent use of valproic acid and topiramate, a case report and review of the literature Raru Yonas raru@marshall.edua∗Zeid Fuad zeid@marshall.eduba Department of Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, USAb Pulmonary and Critical Care Medicine, Department of Internal Medicine Marshall University Joan C. Edwards School of Medicine, Huntington, WV, USA∗ Corresponding author. raru@marshall.edu30 5 2018 2018 30 5 2018 25 1 3 16 5 2018 26 5 2018 26 5 2018 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Valproic acid (VPA) is widely used for the treatment of epilepsy, migraine, and a variety of psychiatric symptoms, including bipolar disorder, borderline personality disorder, and alcohol withdrawal. Valproate is associated with severe idiosyncratic adverse effects, the most notable being valproate-induced hyperammonemic encephalopathy (VHE). Topiramate is also a broad-spectrum anticonvulsant that is also extensively used for migraine prophylaxis, as a mood stabilizer, and for alcohol dependency. There is increased occurrence of VHE when valproate is used with other medications like phenytoin, phenobarbital, and topiramate. Our case report is on a young patient who was on valproic acid and topiramate and developed metabolic encephalopathy with hypoxic respiratory failure. We reviewed the causes and management of the hyperammonemic encephalopathy. We believe that clinicians should be aware of possible hyperammonemic encephalopathy in any patient who is taking valproic acid and presenting with impaired consciousness and cognitive decline. We also underline the importance of early recognition and high index of suspicion of encephalopathy related to hyperammonemia.\n==== Body\n1 Introduction\nValproic acid is a broad-spectrum antiepileptic drug that inhibits degradation, and promotes postsynaptic transmission of gamma-aminobutyric acid (GABA) [1]. Valproic acid (VPA) is widely used for the treatment of epilepsy, migraine, and a variety of psychiatric symptoms, including bipolar disorder, borderline personality disorder, and alcohol withdrawal. VPA has been used effectively to reduce agitation and aggression in both acute and post-acute traumatic brain injury patients, as well as a variety of other neuropsychiatric syndromes, including dementia and mental retardation [[2], [3], [4]]. Valproate is associated with severe idiosyncratic adverse effects, the most notable being valproate-induced hyperammonemic encephalopathy (VHE), which is seen in up to 0.9% of patients taking valproate [5]. Topiramate is also a broad-spectrum anticonvulsant that is also extensively used for migraine prophylaxis, as a mood stabilizer, and for alcohol dependency. There are studies in the literature which has shown an increased occurrence of VHE when valproate is used with other medications like phenytoin, phenobarbital, and topiramate [6].\n\nThe combined antiepileptic valproate and topiramate therapy causes reduction of topiramate metabolism through cytochrome P 450 pathway and topiramate decreases levels of valproate by increasing its metabolism [7].\n\nVHE causes metabolic encephalopathy which is defined as a diffuse cerebral dysfunction, typically manifesting as changes in cortical functions and as disorders of consciousness, ranging from confusion to coma [8].\n\nRecognition of VHE requires a high level of clinical suspicion, as clinical presentation is nonspecific and correlates poorly with dosage, blood levels, or duration of treatment [9].\n\nThe development of hyperammonemia, the consequences of which are difficult to differentiate from the pathology itself and that can be misdiagnosed as therapeutic failure instead of an adverse drug reaction related to the use of VPA [10].\n\nThis case report illustrates the importance high clinical suspicion and early recognition of VHE and its management.\n\n2 Case report\nOur patient is a 21-year-old female patient with past medical history of medically refractory epilepsy, hypothyroidism and mood disorder came with altered mental status. She started to have seizure disorder from childhood and she was not eating and drinking because of her clinical condition. She was also not taking her medications for the last 3 days. She underwent vagal nerve stimulation procedure for her epilepsy and she was on Levetiracetam, Valproic acid and topiramate. She still had seizures even if she is on these treatments but her mood disorder was well controlled. Last seizure episode happened a month ago. She was also having cough and mild shortness of breath but no fever or chills. She is not a smoker and lives with her mother who takes care of her. In the emergency room, she was found to be tachycardic and hypoxic with a PH of 7.37, PCO2 of 39 and PO2 of 56 on arterial blood gas. CT chest performed there showed bilateral lung infiltrates suggestive of pneumonia. On physical examination, blood pressure was 124/86, heart rate was 107 beats per minute, respiratory rate was 19 breaths per minute and temperature was 99.2-degree fahrenheit. Well developed, well-nourished but limited spontaneous speech, mild confusion. Scattered soft crepitations in the lower posterior chest bilaterally and has regular rate and rhythm of the pulse with no murmur and no gallop. She didn't have any edema. On neurologic examination, she was alert, follows some specific commands and names simple objects. She had no gaze preference and facial strength and sensation were intact and symmetric. Neck was supple with no neck stiffness. Hearing was grossly intact and symmetric. Strength was 5/5 in all 4 extremities without evidence of pronator drift. She had intact sensation to light touch and pin prick sensation in all her extremity without evidence of asymmetry. She had no evidence of dysmetria with finger to nose bilaterally. She was admitted to a step-down unit and she was started on broad spectrum antibiotics and maintenance intravenous fluids. Her antiepileptic medications were also restarted at the same dose that she was getting at home. Her procalcitonin and lactic acid levels were found to be with in normal range. Atypicals and viral panel were found to be negative and blood and sputum culture were negative. Antibiotics were deescalated accordingly. On the next day of admission, patient was still having mild confusion and ammonia level was ordered and it was found to be elevated at 102 μg/deciliter (mcg/dl). Her valproic acid level in the same day was 77 mcg/dl (normal 50–125 mcg/dl). Her TSH level was within the normal limit. At this point, metabolic encephalopathy due to hyperammonemia was considered and she was started on l-carnitine and Lactulose. Patient's clinical condition stayed the same with this treatment.\n\nHer ammonia level increased to 126 mcg/dl. EEG was performed and reported to show intermittent generalized slowing consistent with a mild encephalopathy but there were no electroencephalographic seizures or any interictal epileptiform activity. The cause of the hyperammonemia was thought to be related to valproic acid. Her epilepsy was relatively well controlled by her seizure medications and there was a reluctance to stop any of her medications from the primary team.\n\nNeurology evaluation suggested decreasing the dose of topiramate as it was a relatively new medication. Her topiramate dose was halved and was continued with l- Carnitine and lactulose but her confusion stayed the same and her ammonia level on the next day increased to 162. Her repeat valproic acid level was 77 mcg/dl. Since there was no clinical improvement with the treatment, valproic acid was stopped. The clinical condition of the patient improved day by day after that and her ammonia level was trended daily and it came down from 161 to 115 mcg/dl at first and within 3 days it went down to 52 mcg/dl. Five days after valproic acid was stopped, patient's clinical condition stabilized and her seizure medications were changed to Levetiracetam and lacosamide. She was not having any seizure activity and her mood disorder stayed stable and her general condition got back to her baseline.\n\n3 Discussion\nIn one report, it is estimated that up to 50% of patients taking valproate develop hyperammonemia. Most of these patients have elevations of ammonia with normal liver function and are asymptomatic [11,12]. There is also no clear correlation between blood ammonia levels and the severity of encephalopathy, suggesting that mechanisms other than those involving ammonia contribute to the neurological dysfunction [1]. Approximately 0.9% of patients using valproate develop hyperammonemic encephalopathy. This number could be higher if patients are taking sedatives and other antiepileptic medications like lamotrigine, topiramate and risperidone [13]. Carnitine deficiency and urea cycle enzyme abnormalities also expose patients for valproate and topiramate induced hyperammonemic encephalopathy [[2], [3], [4]]. Our patient was on topiramate in addition to the valproic acid but she was not checked for carnitine deficiency or urea cycle enzyme defect. Topiramate was originally synthesized as a potential hypoglycemic agent even if it was found not to have that effect and it was later found out that it is an important medication for seizure, migraine prophylaxis and mood disorder due to its effect in the CNS and sodium and calcium channels [5,6]. The presence of pneumonia in our patient might be responsible for her deterioration and presentation to us but her clinical response with the decrease in the level of the ammonia supports the fact that the hyperammonemia is responsible for her deterioration.\n\nThe mechanism by which valproate causes hyperammonemia is not clear but hepatic and renal metabolic pathways have been proposed. Propionate, a metabolite of valproate reduces hepatic N-acetylglutamate concentration, which is an obligatory activator of carbamoyl phosphate synthetase 1 (CPS-1), the first enzyme of the urea cycle. Decline in CPS-1 activity results in defective ammonia utilization and accumulation of ammonia. Another mechanism thought to play a role is reduction of hepatic carnitine levels by valproate. This results in decreased beta-oxidation of fatty acids, which in turn results in reduced levels of Acetyl Co-A. This decrease in Acetyl Co-A ultimately disrupts the urea cycle resulting in ammonia accumulation [2]. The less common mechanism is that valproic acid stimulates kidney tubule glutaminase that subsequently enhances glutamine uptake into renal cortical cell mitochondria. The conversion of glutamine ultimately leads to increased ammonia production [4]. The cytosolic ammonia accumulated within astrocytes and neuronal cells which is conjugated with glutamine by glutamine synthetase is responsible for the oxidative stress and subsequently leads to mitochondrial swelling and cytosolic edema [2,14]. Availability of electroencephalogram recordings may help improve diagnostic validity, but it is unlikely to facilitate differentiation of VPA from other causes of encephalopathy [13].\n\nWe have EEG recordings done in our patient which showed intermittent generalized slowing consistent with a mild encephalopathy but there were no electroencephalographic seizures or any interictal epileptiform activity. Our patient could possibly have a non-convulsive seizure due to drug withdrawal with subsequent deterioration since she was not taking her medications for 3 days before presentation. This is very difficult to prove as we only have EEG 2 days after her presentation.\n\nThe mainstay of VHE treatment is discontinuation of VPA, which leads to complete recovery in most patients [[1], [2], [3], [4]]. We decreased the dose of both valproate and topiramate in our patient but patient's clinical condition didn't improve. So, both medications were stopped and she was started on l-carnitine. Persistence of VHE despite reduction or discontinuation of VPA is an indication for additional ammonia-depleting agents such as lactulose, charcoal, neomycin, rifaximin, or l-carnitine [2,3]. We have used l-carnitine and lactulose in our patient since discontinuation of the medications didn't completely improve her clinical condition. l-carnitine is an amino acid derivative and important nutrient involved in fat metabolism. Up to 75% of l-carnitine is provided by diet, particularly red meat and dairy products. It is also biosynthesized endogenously from dietary amino acids (methionine, lysine), especially in the liver and in the kidneys. Carnitine is responsible for 2 metabolic functions. It eases the fatty acyl-group transport into mitochondria and it also preserves the ratio of acyl-CoA to free CoA in the mitochondria.\n\nAs VPA-induced hyperammonemia and VHE could be mediated at least in part by carnitine deficiency, it has been hypothesized that l-carnitine supplementation may prevent, correct, or attenuate these adverse effects [[5], [6], [7], [8], [9]]. l-carnitine should be given intravenously because of the low bioavailability of enteral l-carnitine [7]. There is also a literature on the use of arginine supplementation for treatment of hyperammonemic encephalopathy even if we haven't used it in our patient. Arginine supplementation tends to normalize elevated plasma ammonia concentrations. Arginine plays a critical role in ammonia detoxification, as ammonia is detoxified via its metabolism into urea. On the one hand, it has been accepted that arginine is an activator of N-acetyl glutamate synthetase (NAGS) via agmatine; on the other hand, arginine entering the liver via the portal vein is metabolized to provide ornithine for citrulline and aspartate synthesis and for the priming of the urea cycle [6,10]. The clinical response of our patient was correlated with the decrease in the serum ammonia level but literature has shown that serum levels of ammonium do not correlate with the severity of valproate-induced encephalopathy and there is no conclusive evidence of a major causative role of hyperammonemia on encephalopathy in human clinical studies [[1], [2], [3]]. Because of that it is suggested to follow patients clinically rather than monitor the level of serum ammonia once the diagnosis of hyperammonemic encephalopathy was made and the right treatment started. The valproic acid level of our patient stayed in the normal range the whole time in our patient but still there is no concordance with respect to a direct relationship between the development of VHE and serum valproic acid levels [[2], [3], [4], [5]].\n\n4 Conclusion\nMetabolic encephalopathy represents a serious problem that needs to be addressed in a multidisciplinary approach as there could be complications related to the respiratory and central nervous system. We need to have a high index of suspicion for diagnosing VHE in patients receiving valproate presenting with impaired consciousness and acute cognitive decline. Serum ammonia level is a useful test to guide in diagnosing VHE but it is very important to know that its level does not correlate with the severity of VHE. Increased familiarity with the diagnosis and appropriate treatment of VHE is also essential. Resolution or prevention of hyperammonemia may be enhanced with the administration of intravenous l-carnitine as the oral form has low bioavailability.\n==== Refs\nReferences\n1 Adeva, MM. et al. Ammonium metabolism in humans metabolism - Clin. Exp., Volume 61, Issue 11, 1495–1511.\n2 Tantikittichaikul S. Johnson J. Topiramate-induced hyperammonemic encephalopathy in a patient with mental retardation: a case report and review of the literature Epilepsy Behav. Case Rep. 4 2015 84 85 26543812 \n3 Walker, Valerie. Severe hyperammonemia in adults not explained by liver disease. Ann. Clin. Biochem.. Vol 49, Issue 3, pp. 214–228.\n4 Chopra A. Kolla B.P. Mansukhani M.P. Netzel P. Frye M.A. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management Gen. Hosp. Psychiatr. 34 03 2012 290 298 \n5 Laish Ido Noncirrhotic hyperammonaemic encephalopathy Liver International 31 9 October 2011 1259 1270 21745294 \n6 Cheng, Minfeng et al. Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012. Compr. Psychiatr., Volume 54, Issue 5, 562–567.\n7 Lewis, Chandani et al. Valproate-induced hyperammonemic encephalopathy in general hospital patients with one or more psychiatric disorders. Psychosomatics, Volume 58, Issue 4, 415–420.\n8 Maldonado C., Guevara N, et al. L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: a case report J. Int. Med. Res.: Vol 45, Issue 3, pp. 1268–1272.\n9 Vázquez M. Fagiolino P. Maldonado C. Hyperammonemia associated with valproic acid concentrations BioMed Res. Int. 2014 2014 217269 7 pages \n10 Cattaneo C.I. Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: essential review of the literature and case report Medicine 96 39 2017 e8117 28953637 \n11 Yeung G. Chau K.W. A fatal case of valproate-induced hyperammonemic encephalopathy: an update on proposed pathogenic mechanisms and treatment options Int. J. Epilepsy 04 02 2017 181 183 \n12 Tseng Y.L. Huang C.-R. Lin C.H. Lu Y.T. Lu C.H. Chen N.C. Chuang Y.C. Risk factors of hyperammonemia in patients with epilepsy under valproic acid therapy Medicine 93 11 2014 e66 25192484 \n13 Berisavac II How to recognize and treat metabolic encephalopathy in Neurology intensive care unit Neurol. India 65 2017 123 128 28084256 \n14 Sousa C. Valproic acid-induced hyperammonemic encephalopathy − a potentially fatal adverse drug reaction SpringerPlus 2 01 2013 13 23451336\n\n",
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"title": "Hypoxic respiratory failure due to hyperammonemic encephalopathy induced by concurrent use of valproic acid and topiramate, a case report and review of the literature.",
"title_normalized": "hypoxic respiratory failure due to hyperammonemic encephalopathy induced by concurrent use of valproic acid and topiramate a case report and review of the literature"
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"abstract": "BACKGROUND\nAlthough squamous cell anal carcinomas are relatively rare, their incidence has been increasing steadily. Because of the limited data, treatment of metastatic disease is a major therapeutic challenge. In this study, we report the safety and efficacy of epidermal growth factor receptor (EGFR) inhibitors in patients with advanced squamous cell anal carcinomas.\n\n\nMETHODS\nA retrospective analysis was conducted using the Moffitt Cancer Tumor Registry from January 2009 to January 2014. Eligible patients had diagnosis of advanced squamous cell anal carcinomas and received an EGFR inhibitor as part of their treatment.\n\n\nRESULTS\nA total of 13 patients were identified for analysis. All of them received concurrent chemoradiation as initial treatment and subsequently had recurrence. Five patients received single agent cetuximab or panitumumab, and the others received cetuximab or panitumumab with irinotecan or FOLFIRI. The objective response rate was 30.8% including 1 complete response, and the disease control rate was 46.2%. With a median follow-up of 9.6 months, the median progression-free survival and median overall survival were 4.4 months and 11.4 months, respectively.\n\n\nCONCLUSIONS\nOur analysis suggests that EGFR inhibitors have potential efficacy and are reasonably well tolerated in patients with squamous cell anal carcinomas. These findings warrant further evaluation in a large prospective trial.",
"affiliations": "Department of Gastrointestinal Oncology, Moffit Cancer Center, Tampa, FL, USA.",
"authors": "Kim|Dae Won|DW|;Byer|Jennifer|J|;Kothari|Nishi|N|;Mahipal|Amit|A|;Chang|Yound Doo|YD|;Kim|Richard D|RD|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D002166:Camptothecin; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D059248:Chemoradiotherapy; D066246:ErbB Receptors; D005260:Female; D005431:Florida; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077544:Panitumumab; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "EGFR Inhibitors in Patients with Advanced Squamous Cell Anal Carcinomas: A Single-Institution Experience.",
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"abstract": "BACKGROUND\nCytomegalovirus (CMV)-seronegative kidney transplant (KTx) recipients of organs from CMV-seropositive donors (D+/R-) are at increased risk for CMV infection. Despite valganciclovir (VGCV) prophylaxis (900 mg daily for 200 days), late-onset CMV (LO-CMV) occurs at excessive rates. VGCV-associated cost and toxicities remain problematic.\n\n\nMETHODS\nWe retrospectively evaluated 50 D+/R- adult KTx recipients from August 2008 to August 2014 who received low-dose VGCV (450 mg daily) prophylaxis for an extended duration. The primary outcome was occurrence of CMV disease.\n\n\nRESULTS\nAll patients received depletion induction and underwent ABO-compatible KTx. Mean prophylaxis and follow-up durations were 22.8 and 40.7 months, respectively. Eight patients developed CMV: 5 breakthrough cases (1 case of colitis [2%] and 4 cases of infection [8%]) and 3 cases of LO-CMV (1 syndrome [2.9%] and 2 cases of infection [5.7%]). On logistic regression, longer duration of VGCV prophylaxis was protective against CMV infection or disease (P = .044; odds ratio, 1.12 [95% confidence interval, 1.03-1.29]). None of 19 recipients with prophylaxis for ≥12 months developed LO-CMV compared with 3 of 16 recipients with prophylaxis for <12 months (18.8%) (P = .086). Four patients had recurrence of CMV, and 1 patient developed resistance. CMV was not responsible for graft or patient loss and did not affect survival.\n\n\nCONCLUSIONS\nLow-dose VGCV is an effective prophylaxis for D+/R- KTx recipients despite depleting induction. Longer prophylaxis is more protective, and receiving VGCV for ≥12 months nearly eradicated LO-CMV without increasing antiviral resistance.",
"affiliations": "Transplant Surgery, Fort Worth Transplant Institute, Plaza Medical Center, Fort Worth, Texas; Department of Surgery, Faculty of Medicine, Cairo University, Cairo Egypt; Rush University Medical Center, Chicago, Illinois, USA. Electronic address: sfayek@ppghealthcare.com.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.;Rush University Medical Center, Chicago, Illinois, USA.",
"authors": "Fayek|S A|SA|;Beshears|E|E|;Lieber|R|R|;Alvey|N|N|;Sauer|A|A|;Poirier|J|J|;Hollinger|E F|EF|;Olaitan|O K|OK|;Jensik|S|S|;Geyston|J|J|;Brokhof|M M|MM|;Hodowanec|A C|AC|;Hertl|M|M|;Simon|D M|DM|",
"chemical_list": "D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D000077562:Valganciclovir; D015774:Ganciclovir",
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"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D003692:Delayed-Action Preparations; D024882:Drug Resistance, Viral; D005260:Female; D015774:Ganciclovir; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014019:Tissue Donors; D066027:Transplant Recipients; D000077562:Valganciclovir",
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"title": "Extended Low-Dose Valganciclovir Is Effective Prophylaxis Against Cytomegalovirus in High-Risk Kidney Transplant Recipients With Near-Complete Eradication of Late-Onset Disease.",
"title_normalized": "extended low dose valganciclovir is effective prophylaxis against cytomegalovirus in high risk kidney transplant recipients with near complete eradication of late onset disease"
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"abstract": "To analyse the volume and content of tweets in relation to biological treatments for chronic inflammatory arthropathies.\nA Twitter analysis was carried out during one month using the following keywords: 'rheumatoid arthritis', 'ankylosing spondylitis', 'psoriatic arthritis' and their biological therapies: 'abatacept', 'adalimumab', 'certolizumab', 'etanercept', 'golimumab', 'infliximab' and 'tocilizumab'. Tweets were hand-coded and filtered for content.\n25 441 tweets contained at least one of the keywords. After filtering, 2480 tweets were included in the analysis. Regarding the 983 tweets about therapies, the most frequently mentioned biologics were 'adalimumab' (n=359), 'infliximab' (n= 278) and 'etanercept' (n= 205). In the 1497 tweets about diseases, the term 'rheumatoid arthritis' (n= 1109) was used more frequently than 'psoriatic arthritis' (n= 233) and 'ankylosing spondylitis' (n= 155). The most commonly addressed subjects in the tweets in relation to biological therapies were related to safety/adverse events (136 of 983 (13.8%)) and to administration, particularly drug infusion (60 of 983 (6.1%)) and self-administration (57 of 983 (5.8%)). Regarding diseases, the most commonly addressed subjects were non-pharmacological recommendations such as alternative therapies (145 of 1497 (9.7%)), nutrition (128 of 1497 (8.5%)) and exercise (91 of 1497 (6.1%)).\nTwitter is widely used to search for information about biological treatments for chronic athropathies. Learning more about the subjects dealt with in the tweets will enable us to improve our understanding of the areas of greater interest and concern among patients. This could help hospital pharmacists establish patient-focused strategies addressing the needs of the patients.",
"affiliations": "Department of Pharmacy, EOXI, Vigo, Spain.;Department of Pharmacy, EOXI, Vigo, Spain.;Department of Pharmacy, EOXI, Vigo, Spain.;Department of Pharmacy, EOXI, Vigo, Spain.;Department of Pharmacy, EOXI, Vigo, Spain.;Group of Investigation in Rheumatology and Immune-Mediated Diseases, Instituto de Investigacion Sanitaria Galicia Sur, EOXI, Vigo, Spain.",
"authors": "Martínez-López De Castro|Noemí|N|;Samartín-Ucha|Marisol|M|;Martín-Vila|Alicia|A|;Álvarez-Payero|Miriam|M|;Piñeiro-Corrales|Guadalupe|G|;Pego-Reigosa|José M|JM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/ejhpharm-2017-001402",
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"issue": "26(3)",
"journal": "European journal of hospital pharmacy : science and practice",
"keywords": "ankylosing spondylitis; biological treatment; content analysis; patients opinions; psoriatic arthritis; rheumatoid arthritis; twitter",
"medline_ta": "Eur J Hosp Pharm",
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"nlm_unique_id": "101578294",
"other_id": null,
"pages": "124-128",
"pmc": null,
"pmid": "31428318",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "11276800;17425798;19519924;23945732;24325434;24867458;25520780;25653505;25991101;26099267;27680322",
"title": "Content analysis of Twitter in relation to biological treatments for chronic inflammatory arthropathies: an exploratory study.",
"title_normalized": "content analysis of twitter in relation to biological treatments for chronic inflammatory arthropathies an exploratory study"
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"abstract": "OBJECTIVE\nWe sought to identify the antecedents and correlates of visual field deficits (VFDs) at age 2 years among infants born before the 28th week of gestation.\n\n\nMETHODS\nThe visual fields of 1023 infants were assessed by confrontation at age 2 years. We compared the ante-and postnatal characteristics and exposures of the 65 infants with a VFD to their peers who did not have a VFD. We used time-oriented logistic regression risk models to assess the associations of potential antecedents and correlates with a VFD.\n\n\nRESULTS\nIn the final regression model, VFD was associated with maternal consumption of aspirin during the current pregnancy, recurring/persistent acidemia during the first 3 postnatal days, cerebral ventriculomegaly seen on neonatal ultrasound, prethreshold retinopathy of prematurity (ROP), and supplemental oxygen and ventilator dependence at 36 weeks post-menstrual age. Birth before the 27th week was also associated with increased risk, but its significance was diminished by the addition of postnatal variables.\n\n\nCONCLUSIONS\nIn this sample of extremely preterm born infants, antenatal as well as early and late postnatal characteristics and exposures are associated with an increased risk of having a VFD. Our study adds to our knowledge about the complex etiology of visual deficits of prematurity, and supports a multifactorial cause of these deficits.",
"affiliations": "Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, N-7489 Trondheim, Norway; Department of Public Health and Community Medicine, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA. Electronic address: mari.holm@ntnu.no.;Department of Pediatrics, Section of Developmental and Behavioral Pediatrics and JP Kennedy Research Center on Intellectual and Developmental Disabilities, University of Chicago Comer Children's Hospital, 5721 S. Maryland Avenue, Chicago, IL 60637, USA. Electronic address: mmsall@peds.bsd.uchicago.edu.;Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, N-7489 Trondheim, Norway. Electronic address: jon.skranes@ntnu.no.;Department of Public Health and Community Medicine, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA; Neuroepidemiology Unit, Hannover School of Medicine, Hannover, Germany. Electronic address: olaf.dammann@tufts.edu.;Neurology Departments, Boston Children's Hospital, and Harvard Medical School, Au-414 300 Longwood Avenue, Boston, MA 02115-5724, USA. Electronic address: lizard@hsph.harvard.edu.;Neurology Departments, Boston Children's Hospital, and Harvard Medical School, Au-414 300 Longwood Avenue, Boston, MA 02115-5724, USA. Electronic address: alan.leviton@childrens.harvard.edu.",
"authors": "Holm|Mari|M|;Msall|Michael E|ME|;Skranes|Jon|J|;Dammann|Olaf|O|;Allred|Elizabeth|E|;Leviton|Alan|A|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1090-3798",
"issue": "19(1)",
"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Brain development; Prematurity; Preterm birth; ROP; Ventriculomegaly; Visual field deficits",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000138:Acidosis; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D002552:Cerebral Ventricles; D002657:Child Development; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D008297:Male; D010102:Oxygen Inhalation Therapy; D010920:Placenta; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D012044:Regression Analysis; D012178:Retinopathy of Prematurity; D014463:Ultrasonography; D012122:Ventilators, Mechanical; D014786:Vision Disorders; D058609:Visual Field Tests; D014794:Visual Fields",
"nlm_unique_id": "9715169",
"other_id": null,
"pages": "56-63",
"pmc": null,
"pmid": "25455711",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17914431;17901950;18166321;18237241;18446627;18534210;18756014;18430596;19620203;19765918;20026499;20032809;20477841;20800392;20807736;20736416;20689332;20733333;21320954;21775664;21995985;21796662;21455777;22712803;22939723;11533356;15534127;14974834;15060229;6547831;3816638;2064531;17542439;17765331;1951265;7612557;8888047;22773283;23148992;23657712;24204040;24496539;24310059;24924276;24579723;11002433;11061766;11148519;11483077;12324867;12509599;9112965;14974075;16417880;16704698;16581321;17305728",
"title": "Antecedents and correlates of visual field deficits in children born extremely preterm.",
"title_normalized": "antecedents and correlates of visual field deficits in children born extremely preterm"
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"abstract": "Periodic limb movement disorder (PLMD) is characterized by pathological periodic limb movements during sleep, insomnia and/or diurnal sleepiness, and the absence of another primary sleep disorder. We report a patient with complex partial seizures who developed PLMD while taking topiramate (TPM). He had no evidence of metabolic and/or other conditions inducing PLMD. He also had fragmented sleep and disruptive PLMS on polysomnography, and PLMS subsided with change of antiepileptic drug. Topiramate may modulate the dopaminergic pathway by inhibition of glutamate release, thereby inducing PLMD as observed in our patient. Although a single case does not allow any generalization, PLMD should be considered in patients complaining of insomnia and treated with TPM.",
"affiliations": "IRCCS Neuromed, Via Atinense 18, Pozzilli, IS, Italy ; University of Rome Tor Vergata, Neurophysiopathology Department, Sleep & Epilepsy Center, University General Hospital, Rome, Italy.;IRCCS Neuromed, Via Atinense 18, Pozzilli, IS, Italy.;IRCCS Neuromed, Via Atinense 18, Pozzilli, IS, Italy.;IRCCS Neuromed, Via Atinense 18, Pozzilli, IS, Italy.",
"authors": "Romigi|Andrea|A|;Vitrani|Giuseppe|G|;D'Aniello|Alfredo|A|;Di Gennaro|Giancarlo|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ebcr.2014.04.002",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(14)00026-710.1016/j.ebcr.2014.04.002Case ReportTopiramate-induced periodic limb movement disorder in a patient affected by focal epilepsy Romigi Andrea a_romigi@inwind.itab⁎Vitrani Giuseppe aD'Aniello Alfredo aDi Gennaro Giancarlo aa IRCCS Neuromed, Via Atinense 18, Pozzilli, IS, Italyb University of Rome Tor Vergata, Neurophysiopathology Department, Sleep & Epilepsy Center, University General Hospital, Rome, Italy⁎ Corresponding author at: Sleep Medicine Centre, IRCCS Neuromed, Via Atinense 18, Pozzilli, IS, Italy. Tel.: + 39 0865 929154; fax: + 39 06 97655221. a_romigi@inwind.it21 5 2014 2014 21 5 2014 2 121 123 9 4 2014 10 4 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Periodic limb movement disorder (PLMD) is characterized by pathological periodic limb movements during sleep, insomnia and/or diurnal sleepiness, and the absence of another primary sleep disorder. We report a patient with complex partial seizures who developed PLMD while taking topiramate (TPM). He had no evidence of metabolic and/or other conditions inducing PLMD. He also had fragmented sleep and disruptive PLMS on polysomnography, and PLMS subsided with change of antiepileptic drug. Topiramate may modulate the dopaminergic pathway by inhibition of glutamate release, thereby inducing PLMD as observed in our patient. Although a single case does not allow any generalization, PLMD should be considered in patients complaining of insomnia and treated with TPM.\n\nKeywords\nTopiramateFocal epilepsyPLMDSleepSleepinessCyclic alternating pattern\n==== Body\n1 Introduction\nPeriodic limb movement disorder (PLMD) is diagnosed when there are periodic limb movements during sleep (PLMS) exceeding norms for age, clinical sleep disturbance, and the absence of another primary sleep disorder or reason for the PLMS [1]. Pathological periodic limb movement index (PLMI) is defined as > 15 movements/h in adults [1]. Periodic limb movement disorder is rarer than restless legs syndrome (RLS), which is characterized by the sensory motor symptoms frequently associated with PLMS, usually occurring at night and leading to disrupted sleep and daytime fatigue as in neuromuscular disorders [2]. Several medications are known to induce and/or to worsen PLMD (i.e., antidepressants, antihistamines, and antipsychotics) [3]. Although alternative RLS/PLMD treatments include antiepileptic drugs (AEDs) [4], in contrast, topiramate (TPM)-induced RLS also associated with PLMS was described in four patients affected by epilepsy [5], [6]. We report a case of TPM-induced PLMD in a patient affected by cryptogenic temporal lobe epilepsy lacking a history of previous sleep disorders.\n\n2 Case report\nA 34-year-old male affected by cryptogenic temporal lobe epilepsy previously treated with carbamazepine (up to 1200 mg per day) manifested monthly complex partial seizures. Topiramate slowly titrated up to 250 mg per day induced seizure freedom and, afterward, carbamazepine was discontinued. Concurrently, he complained of insomnia, nonrestorative sleep, and daytime sleepiness (Epworth Sleepiness Scale (ESS) score: 16). In addition, his wife reported the appearance of frequent nocturnal leg movements that were never previously observed. The patient also denied having had prior similar symptoms. Serum examination (blood count, electrolytes, liver and renal function, thyroid hormones, and iron and ferritin levels) was unremarkable. Therefore, our patient underwent a full polysomnography (PSG) that showed a severe PLMD (PLMI: 62.7/h) associated with high PLM arousal index (PLMAI: 11.9/h); low sleep efficiency; high sleep latency, wakefulness after sleep onset, and number of awakenings; high percentage of light sleep (N2); and low percentage of slow-wave sleep (N3) (see Table 1). Periodic limb movements during sleep were strictly associated with periodic electroencephalographic arousals and cyclic alternating pattern (CAP). In particular, CAP oscillations were triggered by PLM with higher presence of CAP subtypes A2 and A3 (see Fig. 1). These CAP subtypes represent an arousal phenomenon that likely leads to clinical correlates of disturbed sleep. Respiratory disturbance index and oxygen desaturation index were normal. Therefore, because of the progressive impairment of insomnia and daytime dysfunction, TPM was slowly discontinued and switched to valproate up to 900 mg per day. During TPM discontinuation and after complete withdrawal, the patient underwent full PSG (TPM: 50 mg per day). Periodic limb movement index and periodic limb movement arousal index showed a significant improvement and, after TPM discontinuation, reached a normal value (PLMI < 15/h). Polysomnography variables and ESS scores showed remarkable amelioration (see Table 1). In addition, the CAP rate exhibited a slight reduction, an increase of CAP phase A1 and a parallel reduction of phases A2 and A3. All PSG data are summarized in Table 1. In order to evaluate the association between TPM and PLMD, the Naranjo probability scale [7] documented a probable association (Naranjo score: 8/13) between PLMD and TPM intake.\n\n3 Discussion\nThis is the first publication, to our knowledge, to describe TPM-induced PLMD in a patient affected by cryptogenic temporal lobe epilepsy previously not complaining of sleep disorders. Although there is a high night-to-night variability of PLMI in PLMD/RLS that may influence our results, this issue is still controversial, and the nocturnal pattern of PLM occurrence was highly reliable across nights, suggesting that a single-night study may be sufficiently sensitive to confirm diagnosis and associated sleep disturbances [8]. Therefore, we can state that PLMD was probably induced by TPM in our patient.\n\nIn addition, RLS and PLMD pathophysiology is highly debated; a common central dysregulation of dopaminergic system seems to be implicated [9]. This hypothesis is supported by the efficacy of dopaminergic treatment for both sleep disorders. Several drugs with a dopamine-modulating profile may provoke RLS and/or PLMD [3]. Although such AEDs may be effective treatments for RLS and PLMD, TPM-induced RLS was previously described in a few cases [5], [6]. Topiramate shows multiple mechanisms of action. Topiramate enhances GABA function and inhibits AMPA and kainate glutamate pathways, inducing an extracellular modulation of dopamine release in the mesocorticolimbic dopamine system [10]. These experimental lines of evidence are confirmed by its efficacy against alcohol, nicotine, and cocaine addictions [11], [12]. Therefore, we can hypothesize that TPM may modulate the dopaminergic pathway, thereby inducing PLMD in subjects with specific individual susceptibility.\n\nOn the other hand, the clinical significance of PLMS lacking RLS symptoms is still debated. Patients showing PLMS may complain of insomnia and daytime dysfunction. High levels of EEG arousals and/or CAP sequences prior to leg movements confirm the presence of sleep impairment in these patients [13], [14]. Periodic limb movements are short movements that can be entrained by central pattern generators in reciprocal oscillatory coupling. Specifically, CAP phases A2 and A3 that represent arousal phenomena are more probably associated with disturbed sleep [14] as also demonstrated polygraphically in our patient (Fig. 1). The patients are typically not aware of these limb movements, but quality of sleep may be compromised, and the bed partners might recognize PLMS. Even though the literature failed to document a clear correlation between PLMS severity and sleep disruption [13], Haba-Rubio et al. [15] found a correlation between PLMS and tiredness, sleep efficiency, and psychological well-being.\n\nPeriodic limb movement disorder, insomnia, and diurnal symptoms promptly recovered after drug discontinuation in our patient suggesting a probable association with TPM. We are aware that, regarding the mutual interactions between sleep and epilepsy, not only sleep deprivation and daytime sleepiness but also abnormal sleep per se represent well-known potential triggers for seizures and are themselves influenced by epilepsy in a sort of reciprocal effect. Notwithstanding, comorbidities and pharmacological treatment are other commonly accepted major factors that influence this interplay. Therefore, an accurate clinical history and PSG study in selected cases could be useful in order to recognize potential drug-induced sleep disorders.\n\nConflict of interests\nOn behalf of all authors, the corresponding author states that there is no conflict of interest.\n\nFig. 1 Two-minute segment of full polysomnography (TPM: 250 mg per day) showing periodic limb movement during NREM sleep (N2). The muscle contractions of the anterior tibialis (RTib and LTib) and of the chin (EMG) occur after the onset of the A phase (A2 and A3) of the cyclic alternating pattern and follow the same cyclic recurrence. The TPM withdrawal induced the progressive reduction of PLMS and CAP rate, particularly phases A2 and A3, considered a marker of sleep instability.\n\nTable 1 PSG data during TPM treatment (250 mg and 50 mg) and after TPM discontinuation.\n\nSleep variables\tTPM\n(250 mg)\tTPM\n(50 mg)\tNo TPM\t\nTST, total sleep time (min)\t399\t510\t495\t\nSleep efficiency (%)\t81.5%\t93.1%\t97.2%\t\nSleep latency (min)\t22\t12\t13\t\nn awakenings\t29 (4.4/h)\t17 (2/h)\t4 (0.1/h)\t\nn REM periods\t3\t4\t5\t\nREM latency (min)\t80.5\t92\t80\t\nWASO (min)\t68\t43\t14.1\t\n% N1\t2.3\t6.2\t0.4\t\n% N2\t62.8\t32\t49.7\t\n% N3\t21.5\t42.2\t23.3\t\n% REM\t13.5\t19.5\t16.6\t\nRDI\t0.7/h\t1.7/h\t1.2/h\t\nCAP rate (%)\t66.3\t47.7\t45.1\t\nA1 (%)\t23.7\t33.4\t42.5\t\nA2 (%)\t41.8\t44.5\t27.7\t\nA3 (%)\t34.5\t22.1\t29.8\t\nODI\t0.8/h\t1.4/h\t0.7/h\t\nPLMI\t62.7/h\t21.5/h\t11.6/h\t\nPLMAI\t11.9/h\t3.4/h\t0.9/h\t\nPLMW\t50.2/h\t5.2/h\t6.7/h\t\nESS score\t16\t11\t10\t\nRDI, respiratory disturbance index; ODI, oxygen desaturation index; PLMI, periodic limb movement index; PLMAI, periodic limb movement arousal index; PLMW, periodic limb movements during wakefulness; CAP, cyclic alternating pattern; A1, CAP phase A1; A2, CAP phase A2; A3, CAP phase A3; ESS score, Epworth Sleepiness Scale score.\n==== Refs\nReferences\n1 American Academy of Sleep Medicine The International Classification of Sleep Disorders: Diagnostic and Coding Manual 2nd ed. 2005 American Academy of Sleep Medicine Westchester, Ill. \n2 Romigi A. Izzi F. Pisani V. Placidi F. Pisani L.R. Marciani M.G. Sleep disorders in adult-onset myotonic dystrophy type 1: a controlled polysomnographic study Eur J Neurol 18 9 2011 1139 1145 21338442 \n3 Lesage S. Hening W.A. The restless legs syndrome and periodic limb movement disorder: a review of management Semin Neurol 24 3 2004 249 259 15449218 \n4 Lee Y.A. Huynh P. Neher J.O. Safranek S. Clinical inquiry. What drugs are effective for periodic limb movement disorder? J Fam Pract 61 5 2012 296 298 22577635 \n5 Romigi A. Izzi F. Placidi F. Sperli F. Cervellino A. Marciani M.G. Topiramate-induced restless legs syndrome: a report of two cases J Neurol 254 8 2007 1120 1121 17473947 \n6 Bermejo P.E. Restless legs syndrome induced by topiramate: two more cases J Neurol 256 4 2009 662 663 19444538 \n7 Naranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 30 2 1981 239 245 7249508 \n8 Sforza E. Haba-Rubio J. Night-to-night variability in periodic leg movements in patients with restless legs syndrome Sleep Med 6 3 May 2005 259 267 15854857 \n9 Siddiqui F. Strus J. Sun Y.J. Walters A.S. No significant difference in cytokine levels in patients with restless legs syndrome versus controls — preliminary data Sleep Med 8 1 2007 98 99 17174153 \n10 Shank R.P. Gardocki J.F. Streeter A.J. Maryanoff B.E. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action Epilepsia 41 Suppl. 1 2000 S3 S9 10768292 \n11 Johnson B.A. Ait-Daoud N. Wang X.Q. Penberthy J.K. Javors M.A. Seneviratne C. Topiramate for the treatment of cocaine addiction: a randomized clinical trial JAMA Psychiatry 70 12 2013 1338 1346 24132249 \n12 Kampman K.M. Pettinati H.M. Lynch K.G. Spratt K. Wierzbicki M.R. O'Brien C.P. A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence Drug Alcohol Depend 133 1 2013 94 99 23810644 \n13 Karadeniz D. Ondze B. Besset A. Billiard M. Are periodic leg movements during sleep (PLMS) responsible for sleep disruption in insomnia patients? Eur J Neurol 7 3 2000 331 336 10886318 \n14 Parrino L. Boselli M. Buccino G.P. Spaggiari M.C. Di Giovanni G. Terzano M.G. The cyclic alternating pattern plays a gate-control on periodic limb movements during non-rapid eye movement sleep J Clin Neurophysiol 13 4 1996 Jul 314 323 8858493 \n15 Haba-Rubio J. Staner L. Krieger J. Macher J.P. What is the clinical significance of periodic limb movements during sleep? Neurophysiol Clin 34 6 2004 293 300 15890162\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-3232",
"issue": "2()",
"journal": "Epilepsy & behavior case reports",
"keywords": "Cyclic alternating pattern; Focal epilepsy; PLMD; Sleep; Sleepiness; Topiramate",
"medline_ta": "Epilepsy Behav Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101614202",
"other_id": null,
"pages": "121-3",
"pmc": null,
"pmid": "25667887",
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"title": "Topiramate-induced periodic limb movement disorder in a patient affected by focal epilepsy.",
"title_normalized": "topiramate induced periodic limb movement disorder in a patient affected by focal epilepsy"
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"abstract": "Animal studies have shown that Listeria monocytogenes can probably access the brain through a peripheral intraneural route, and it has been suggested that a similar process may occur in humans. However, thus far, its spreading through the central nervous system (CNS) has not been completely elucidated. The authors present a case of multiple L. monocytogenes cerebral abscesses characterized by a pattern of distribution that suggested spread along white matter fiber tracts and reviewed the literature to identify other cases for analysis. They elected to include only those cases with 3 or more cerebral abscesses to make sure that the distribution was not random, but rather followed a pattern. In addition, they included those cases with abscesses in both the brainstem and the cerebral hemispheres, but excluded cases in which abscesses were located solely in the brainstem. Of 77 cases of L. monocytogenes CNS abscesses found in the literature, 17 involved multiple abscesses. Of those, 6 were excluded for lack of imaging and 3 because they involved only the brainstem. Of the 8 remaining cases from the literature, one was a case of bilateral abscesses that did not follow a fiber tract; another was also bilateral, but with lesions appearing to follow fiber tracts on one side; and in the remaining 6, to which the authors added their own case for a total of 7, all the abscesses were located exclusively in the same hemisphere and distributed along white matter fiber tracts. The findings suggest that after entering the CNS, L. monocytogenes travels within the axons, resulting in a characteristic pattern of distribution of multiple abscesses along the white matter fiber tracts in the brain. This report is the first description suggesting intraaxonal CNS spread of L. monocytogenes infection in humans following its entry into the brain. This distinct pattern is clearly seen on imaging and its recognition may be valuable in the diagnosis of listeriosis. This finding may allow for earlier diagnosis, which may improve outcome.",
"affiliations": "Divisions of 1 Neurosurgery and.;Divisions of 1 Neurosurgery and.;Divisions of 1 Neurosurgery and.;Divisions of 1 Neurosurgery and.;Divisions of 1 Neurosurgery and.;Neuroradiology, Hôpital Notre Dame, Montréal, Quebec, Canada; and.",
"authors": "Bojanowski|Michel W|MW|;Seizeur|Romuald|R|;Effendi|Khaled|K|;Bourgouin|Patrick|P|;Magro|Elsa|E|;Letourneau-Guillon|Laurent|L|",
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"issue": "123(6)",
"journal": "Journal of neurosurgery",
"keywords": "CNS = central nervous system; DTI = diffusion tensor imaging; Listeria monocytogenes; SWI = susceptibility-weighted imaging; bacterial neural invasion; brain abscesses; diagnosis; fiber tracts; infection; neuroradiology",
"medline_ta": "J Neurosurg",
"mesh_terms": "D000368:Aged; D001922:Brain Abscess; D005260:Female; D006801:Humans; D008089:Listeria monocytogenes; D008088:Listeriosis; D009434:Neural Pathways",
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"title": "Spreading of multiple Listeria monocytogenes abscesses via central nervous system fiber tracts: case report.",
"title_normalized": "spreading of multiple listeria monocytogenes abscesses via central nervous system fiber tracts case report"
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"abstract": "Pembrolizumab is an effective therapy for patients with metastatic melanoma. However, not all patients derive benefit. It is postulated that an increase in regulatory T cells in melanoma patients can impair the response to immunotherapies. Continuous low-dose temozolomide has shown to cause immunomodulatory effects resulting in CD4 + lymphopenia due to which Treg population can also decrease significantly. Herein, we present a case series of three patients with metastatic melanoma who after progression on pembrolizumab showed a radiological response after just one cycle of metronomic temozolomide (75 mg/m daily for 6 weeks on 8-week cycle). This suggests that temozolomide may be a useful alternative for patients with metastatic melanoma after disease progression on pembrolizumab. Further studies with biomarkers are warranted to elucidate which patients will derive benefit from this strategy.",
"affiliations": "Departments of Hematology, Oncology, and Blood and Marrow Transplantation.;Departments of Hematology, Oncology, and Blood and Marrow Transplantation.;Departments of Hematology, Oncology, and Blood and Marrow Transplantation.;Pathology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.;Pathology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.;Departments of Hematology, Oncology, and Blood and Marrow Transplantation.;Departments of Hematology, Oncology, and Blood and Marrow Transplantation.",
"authors": "Swami|Umang|U|;Monga|Varun|V|;Freesmeier|Michele|M|;Zhang|Weizhou|W|;Bossler|Aaron D|AD|;Zakharia|Yousef|Y|;Milhem|Mohammed|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018906:Antineoplastic Agents, Alkylating; C582435:pembrolizumab; D000077204:Temozolomide",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000592",
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"issue": "29(6)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018906:Antineoplastic Agents, Alkylating; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma; D012878:Skin Neoplasms; D016019:Survival Analysis; D000077204:Temozolomide",
"nlm_unique_id": "9109623",
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"pages": "643-647",
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"pubdate": "2019-12",
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"references": "28187290;18720480;18467721;27471721;22122467;28822576;19221744;30238891;17957190;20564393;25806780;28612140;14726505;27951441;20930514",
"title": "Exceptional responses with sequential metronomic temozolomide after pembrolizumab failure in patients with metastatic melanoma.",
"title_normalized": "exceptional responses with sequential metronomic temozolomide after pembrolizumab failure in patients with metastatic melanoma"
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... |
{
"abstract": "BACKGROUND\nInvasive Aspergillus infection (IA) in lung transplantation can result in poor outcomes. Itraconazole has been shown to be effective for fungal prophylaxis in lung transplant recipients. However, IA remains a major cause of death after lung transplantation. Therefore, we aimed to clarify the risk factors for IA on itraconazole prophylaxis.\n\n\nMETHODS\nWe examined 120 recipients to uncover their IA epidemiology, clinical characteristics, and outcomes. In addition, a case-control study was performed to identify risk factors of IA.\n\n\nRESULTS\nOf the 120 patients, 12 developed IA under itraconazole prophylaxis. The patient demographics and clinical characteristics were compared among the following two groups: IA group, 12 patients, and control group, 108 patients. Significant differences were observed in age (p = 0.004), history of interstitial pneumonia (p = 0.032), and CMV infection (p < 0.001) between the groups. Before the onset of IA, 92% (11/12) of the patients received itraconazole with trough concentrations above the therapeutic range. IA developed at 272.9 ± 114.1 days after lung transplantation. Of the 12 patients who developed IA, 66.7% (8/12) had early cessation of cytomegalovirus (CMV) prophylaxis due to toxicity of valganciclovir, as follows: leukocytopenia in 4 patients, and renal dysfunction in 4 patients. Of the 8 patients who stopped valganciclovir, 75% (6/8) developed CMV infection subsequently.\n\n\nCONCLUSIONS\nThis study suggests that older age, history of interstitial pneumonia, and CMV infection may be important risk factors for IA on itraconazole prophylaxis. These results may help clinicians optimize prophylactic strategies for IA.",
"affiliations": "Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan; Department of Infection Control and Prevention, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Infection Control and Prevention, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan; Department of Clinical Laboratory Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan; Department of Infection Control and Prevention, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan; Department of Pharmacy, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.;Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Shogoin- Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. Electronic address: teradat@kuhp.kyoto-u.ac.jp.",
"authors": "Katada|Yoshiki|Y|;Nakagawa|Shunsaku|S|;Nagao|Miki|M|;Yoshida|Yuko|Y|;Matsuda|Yuya|Y|;Yamamoto|Yuki|Y|;Itohara|Kotaro|K|;Imai|Satoshi|S|;Yonezawa|Atsushi|A|;Nakagawa|Takayuki|T|;Matsubara|Kazuo|K|;Tanaka|Satona|S|;Nakajima|Daisuke|D|;Date|Hiroshi|H|;Terada|Tomohiro|T|",
"chemical_list": "D000998:Antiviral Agents; D017964:Itraconazole; D015774:Ganciclovir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2021.09.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "28(1)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "6): invasive Aspergillus infection; Breakthrough aspergillosis; Itraconazole; Lung transplantation; Prophylaxis; Risk factor",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D001228:Aspergillosis; D016022:Case-Control Studies; D015774:Ganciclovir; D006801:Humans; D017964:Itraconazole; D008168:Lung; D012189:Retrospective Studies; D012307:Risk Factors; D066027:Transplant Recipients",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "54-60",
"pmc": null,
"pmid": "34649759",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk factors of breakthrough aspergillosis in lung transplant recipients receiving itraconazole prophylaxis.",
"title_normalized": "risk factors of breakthrough aspergillosis in lung transplant recipients receiving itraconazole prophylaxis"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-336600",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"... |
{
"abstract": "OBJECTIVE\nTo explore the prevention and management of human cytomegalovirus (HCMV) infection accompanied with acute pancreatitis after kidney transplantation.\n\n\nRESULTS\nA retrospective analysis of 5 patients with acute pancreatitis after kidney transplantation was conducted. The incidence of acute pancreatitis after kidney transplantation was 2.3% (5/217). All the 5 cases were complicated by active HCMV infection, 3 of which had hyperlipemia and 2 had liver dysfunction. Three cases were finally cured while the other 2 died, one of which was due to respiration failure arising from HCMV interstitial pneumonia accompanied with hemorrhagic necrotizing pancreatitis, and the other due to fulminating liver function failure because of active HCMV infection accompanied with hemorrhagic necrotizing pancreatitis.\n\n\nCONCLUSIONS\nActive HCMV infection is the most important factor responsible for acute pancreatitis, and early diagnosis and treatment are crucial to lower mortality rate.",
"affiliations": "Department of Kidney Transplantation, Second People's Hospital of Guangdong Province, Guangzhou 510317, China.",
"authors": "Liu|Dong|D|;Tang|Bin|B|;Wu|Jia-qing|JQ|;Li|Cheng|C|;Meng|Shan-dong|SD|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1000-2588",
"issue": "25(8)",
"journal": "Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA",
"keywords": null,
"medline_ta": "Di Yi Jun Yi Da Xue Xue Bao",
"mesh_terms": "D000328:Adult; D003586:Cytomegalovirus Infections; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D019283:Pancreatitis, Acute Necrotizing; D012189:Retrospective Studies",
"nlm_unique_id": "9426110",
"other_id": null,
"pages": "1049-50",
"pmc": null,
"pmid": "16109575",
"pubdate": "2005-08",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus infection accompanied with acute pancreatitis after kidney transplantation.",
"title_normalized": "cytomegalovirus infection accompanied with acute pancreatitis after kidney transplantation"
} | [
{
"companynumb": "CN-ROCHE-2451398",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "We present the autopsy findings and differential diagnosis of a 37-year-old immunocompetent male patient who presented primarily with extensive cerebral vein thrombosis and was found to have a rare association with JAK2V617F mutation positivity.",
"affiliations": "Department of Pathology, Command Hospital Air Force, Bengaluru, Karnataka, India.;Department of Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India.;Department of Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India.;Department of Pathology, Command Hospital Air Force, Bengaluru, Karnataka, India.;Department of Pathology, Command Hospital Air Force, Bengaluru, Karnataka, India.;Department of Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India.",
"authors": "Mutreja|Deepti|D|;Saxena|Rajeev|R|;K Tilak|T V S V G|TVSVG|;Tewari|Vanmalini|V|;Moorchung|Nikhil|N|;Nandi|Bhaskar|B|",
"chemical_list": "C507924:JAK2 protein, human; D053614:Janus Kinase 2",
"country": "India",
"delete": false,
"doi": "10.4103/IJPM.IJPM_232_17",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0377-4929",
"issue": "61(2)",
"journal": "Indian journal of pathology & microbiology",
"keywords": "Autopsy; Burkitt lymphoma; extensive cerebral vein thrombosis",
"medline_ta": "Indian J Pathol Microbiol",
"mesh_terms": "D000328:Adult; D001921:Brain; D002051:Burkitt Lymphoma; D006801:Humans; D020767:Intracranial Thrombosis; D053614:Janus Kinase 2; D008279:Magnetic Resonance Imaging; D008297:Male; D020246:Venous Thrombosis",
"nlm_unique_id": "7605904",
"other_id": null,
"pages": "219-224",
"pmc": null,
"pmid": "29676361",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 37-year-old male with extensive cerebral venous thrombosis: Clinicopathological correlation of a rare case.",
"title_normalized": "a 37 year old male with extensive cerebral venous thrombosis clinicopathological correlation of a rare case"
} | [
{
"companynumb": "IN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-026221",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Visual disturbance following non-ophthalmologic surgery under general anesthesia is rare but can be devastating both socially and medicolegally. Immediate salvage intervention as well as prevention is of utmost importance since this can be a serious blow to patient's functional outcome postoperatively. We experienced a case of temporary but significant visual disturbance right after transperitoneal laparoscopic radical prostatectomy for localized prostate cancer. We need to raise our levels of vigilance to this condition since it can be avoided and prevented with immediate therapeutic intervention and decent clinical awareness.",
"affiliations": "Department of Urology, The Jikei University School of Medicine.;Department of Ophthalmology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.;Department of Ophthalmology, The Jikei University School of Medicine.;Department of Urology, The Jikei University School of Medicine.",
"authors": "Yamamoto|Toshihiro|T|;Komatsu|Koji|K|;Matsuura|Taishi|T|;Shimada|Hayato|H|;Kimura|Shoji|S|;Koike|Yusuke|Y|;Sasaki|Hiroshi|H|;Miki|Jun|J|;Yamada|Hiroki|H|;Kimura|Takahiro|T|;Miki|Kenta|K|;Sakai|Tsutomu|T|;Egawa|Shin|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5980/jpnjurol.109.156",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5287",
"issue": "109(3)",
"journal": "Nihon Hinyokika Gakkai zasshi. The japanese journal of urology",
"keywords": "prostate cancer; radical prostatectomy; visual loss",
"medline_ta": "Nihon Hinyokika Gakkai Zasshi",
"mesh_terms": null,
"nlm_unique_id": "2984841R",
"other_id": null,
"pages": "156-159",
"pmc": null,
"pmid": "31327857",
"pubdate": "2018",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "SIGNIFICANT, TRANSIENT VISUAL DISTURBANCE AFTER LAPAROSCOPIC RADICAL PROSTATECTOMY.",
"title_normalized": "significant transient visual disturbance after laparoscopic radical prostatectomy"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2018-098946",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Extra-renal noncerebral rhabdoid tumors (ERRTs) are highly aggressive and often lethal. An optimal chemotherapy regimen for ERRT remains undetermined. We report on three pediatric patients successfully treated with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). Two of our patients who had metastatic or refractory disease have survived more than 2 years, one disease free without myeloablative megatherapy. The treatment with high-dose alkylator therapy is reported to have a beneficial effect on survival. A VIDE regimen containing high-dose ifosfamide is feasible and appears to prolong the survival of patients with ERRT. This regimen may be a promising option for ERRT treatment without myeloablative megatherapy.",
"affiliations": "Division of Pediatric Oncology, National Cancer Center Hospital East.;Division of Pathology and Clinical Laboratories, National Cancer Center Hospital.;Division of Musculoskeletal Oncology, National Cancer Center Hospital.;Division of Musculoskeletal Oncology, National Cancer Center Hospital.;Division of Pediatric Oncology, National Cancer Center Hospital East.",
"authors": "Yasui|Naoko|N|;Yoshida|Akihiko|A|;Kobayashi|Eisuke|E|;Nakatani|Fumihiko|F|;Kawamoto|Hiroshi|H|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25777",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(2)",
"journal": "Pediatric blood & cancer",
"keywords": "VIDE; chemotherapy; malignant rhabdoid tumor",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D018335:Rhabdoid Tumor; D014750:Vincristine",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "352-4",
"pmc": null,
"pmid": "26469354",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Extra-Renal Noncerebral Rhabdoid Tumors with VIDE.",
"title_normalized": "successful treatment of extra renal noncerebral rhabdoid tumors with vide"
} | [
{
"companynumb": "JP-ACCORD-050663",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nWe aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson's disease (PD).\n\n\nMETHODS\nWe retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline.\n\n\nRESULTS\nn = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: -6 ± 5.10 at 1 month and -7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson's Disease Rating Scale (UPDRS-II): -2.51 ± 6.30 and -2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: -3.58 ± 8.68 and -4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: -0.61 ± 2.61 and -0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported.\n\n\nCONCLUSIONS\nSafinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.",
"affiliations": "Neurology Department, Hospital La Moraleja, 28050 Madrid, Spain.;Neurology Department, Hospital Infanta Sofía, 28703 Madrid, Spain.;Neurology Department, Hospital Infanta Sofía, 28703 Madrid, Spain.;Neurology Department, Hospital Ramón y Cajal, 28034 Madrid, Spain.;Neurology Department, Hospital Ramón y Cajal, 28034 Madrid, Spain.;Neurology Department, Hospital Ramón y Cajal, 28034 Madrid, Spain.;Neurology Department, Hospital La Princesa, 28006 Madrid, Spain.;Neurology Department, Complejo Hospitalario Ruber Juan Bravo, 28006 Madrid, Spain.;Neurology Department, Hospital Infanta Leonor, 28031 Madrid, Spain.;Neurology Department, Hospital Infanta Leonor, 28031 Madrid, Spain.;Neurology Department, Hospital Quironsalud Madrid, 28223 Madrid, Spain.;Neurology Department, Clínica del Rosario, 28006 Madrid, Spain.",
"authors": "Peña|Esteban|E|;Borrué|Carmen|C|;Mata|Marina|M|;Martínez-Castrillo|Juan Carlos|JC|0000-0001-7744-6850;Alonso-Canovas|Araceli|A|;Chico|Juan Luis|JL|0000-0001-6557-912X;López-Manzanares|Lydia|L|;Llanero|Marcos|M|;Herreros-Rodríguez|Jaime|J|;Esquivel|Alberto|A|;Maycas-Cepeda|Teresa|T|;Ruíz-Huete|Cristina|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/brainsci11020232",
"fulltext": "\n==== Front\nBrain Sci\nBrain Sci\nbrainsci\nBrain Sciences\n2076-3425\nMDPI\n\n10.3390/brainsci11020232\nbrainsci-11-00232\nArticle\nImpact of SAfinamide on Depressive Symptoms in Parkinson’s Disease Patients (SADness-PD Study): A Multicenter Retrospective Study\nPeña Esteban 1*\nBorrué Carmen 2\nMata Marina 2\nhttps://orcid.org/0000-0001-7744-6850\nMartínez-Castrillo Juan Carlos 3\nAlonso-Canovas Araceli 3\nhttps://orcid.org/0000-0001-6557-912X\nChico Juan Luis 3\nLópez-Manzanares Lydia 4\nLlanero Marcos 5\nHerreros-Rodríguez Jaime 6\nEsquivel Alberto 6\nMaycas-Cepeda Teresa 7\nRuíz-Huete Cristina 8\nRicciardi Lucia Academic Editor\n1 Neurology Department, Hospital La Moraleja, 28050 Madrid, Spain\n2 Neurology Department, Hospital Infanta Sofía, 28703 Madrid, Spain; carmenborrue@hotmail.com (C.B.); mmataal@yahoo.es (M.M.)\n3 Neurology Department, Hospital Ramón y Cajal, 28034 Madrid, Spain; jcmcastrillo@gmail.com (J.C.M.-C.); aracelialcan@yahoo.es (A.A.-C.); juanluis.chico.garcia@gmail.com (J.L.C.)\n4 Neurology Department, Hospital La Princesa, 28006 Madrid, Spain; lydialopez@hotmail.com\n5 Neurology Department, Complejo Hospitalario Ruber Juan Bravo, 28006 Madrid, Spain; mllanero@gmail.com\n6 Neurology Department, Hospital Infanta Leonor, 28031 Madrid, Spain; hrinvest@hotmail.com (J.H.-R.); alberto.esquivel@salud.madrid.org (A.E.)\n7 Neurology Department, Hospital Quironsalud Madrid, 28223 Madrid, Spain; tmaycas@gmail.com\n8 Neurology Department, Clínica del Rosario, 28006 Madrid, Spain; ruizhuete@yahoo.es\n* Correspondence: epenal.pex@sanitas.es\n13 2 2021\n2 2021\n11 2 23209 1 2021\n10 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/).\nBackground: We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson’s disease (PD). Methods: We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline. Results: n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: −6 ± 5.10 at 1 month and −7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson’s Disease Rating Scale (UPDRS-II): −2.51 ± 6.30 and −2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: −3.58 ± 8.68 and −4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: −0.61 ± 2.61 and −0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported. Conclusions: Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.\n\nParkinson’s disease\ndepression\nserotonin syndrome\nantidepressants\nsafinamide\nmotor symptoms\n==== Body\n1. Introduction\n\nSafinamide is a reversible and selective monoamine oxidase B inhibitor (MAOIB) and glutamate release modulator [1]. Several trials have demonstrated that in advanced Parkinson’s disease (PD), safinamide significantly improves “ON” time without causing troublesome dyskinesia, reduces “OFF” time, and improves scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), improving quality of life [2,3,4,5,6]. Thus, it is approved for the treatment of mid-to-late fluctuating PD patients as an add-on therapy alongside stable doses of levodopa alone or in combination with others drugs. However, few studies have evaluated the role of safinamide in real clinical practice [7].\n\nDepression is not only one of the most common non-motor symptoms in PD, with a prevalence around 30–35%, but it is also the main determinant of quality of life [8,9]. Although the pathophysiology of depression in PD is complex, dopamine and glutamate disorders could be involved [8,10]. Accordingly, it has been demonstrated that dopaminergic therapy, including MAOIBs, can improve depressive symptoms in PD patients [11,12,13,14]. In fact, some authors recommend that in Parkinson’s disease patients with depression, it could be useful to modify dopaminergic therapy before to add antidepressants [8]. Furthermore, drugs that inhibit abnormal presynaptic glutamate release such as lamotrigine or riluzole are considered mood stabilizers [15]. Thus, considering the dual mechanism of action of safinamide as a glutamatergic modulator and dopaminergic stimulator, we hypothesized that safinamide could be useful for improving depression in PD.\n\nConcerns exist regarding the safety of combining MAOBIs with antidepressants, because of the risk of the potentially fatal serotonin syndrome, although serotonin syndrome is rarely induced by MAOBIs such as selegiline and rasagiline [16,17,18,19,20]. However, there are no studies assessing serotonin syndrome in patients concomitantly treated with safinamide and antidepressants.\n\nThe aim of this study was to assess the effect of safinamide on depression in PD patients. The secondary goals were to assess the tolerability of safinamide in real clinical practice, with a special focus on serotonin syndrome in PD patients concomitantly treated with safinamide and antidepressants, and to assess the effect of safinamide on motor symptoms, motor complications, and daily life activities for PD patients in real clinical practice.\n\n2. Materials and Methods\n\n2.1. Study Design and Population\n\nThis was a multicenter, observational, retrospective study based on real clinical practice. Up to March 2020, researchers from the movement disorder units of 13 different hospitals selected PD patients from medical history databases fulfilling the following inclusion criteria: aged over 18 years, with a PD diagnosis (according to MDS clinical diagnostic criteria [21]) and depression diagnosis (a Hamilton Depression Rating Scale based on 17 items, HAMD-17, >14 [22]), and being treated with safinamide within labeled use (according to the terms of the marketing authorization), with full clinical assessments at baseline, one month (when available) and three months after the onset of safinamide treatment. The clinical data required were demographic data, HAMD-17 scores, Patient Global Impression of Improvement Scale (PGI-I) scores with respect to depressive symptoms, UPDRS scores, concomitant treatment with antidepressants and other anti-Parkinsonian drugs, and registered adverse events, with a special focus on serotonin syndrome symptoms. The main exclusion criteria were PD-associated dementia and patients who underwent other major changes in antidepressant or anti-Parkinsonian drug treatments during the follow-up period.\n\nThe sample was divided according to safinamide dose into 50 and 100 mg/day groups and also according to antidepressant use (safinamide-only vs. safinamide-plus-antidepressants group) to assess potential serotonergic adverse events.\n\nThe primary outcome measure for the antidepressant effect was the HAMD-17 scores at 1 and 3 months. The PGI-I scores related to depressive symptoms were considered as the secondary outcome measure.\n\nAs for daily life activities, motor symptoms, and motor complications, changes in UPDRS Parts II, III, and IV at 1 and 3 months (from baseline) were compared. PD patients were assessed in ON-medication states.\n\nTo test for serotonin syndrome, we followed previously reported methods [18]. Patients of both the safinamide-only and safinamide-plus-antidepressants groups were compared for 15 symptoms linked to serotonin toxicity: (a) major symptoms: confusion, emotional lability, fever, sweating, and myoclonus; (b) minor symptoms: agitation, sleep disorders, nervousness, tachycardia, hyperventilation, dyspnea, diarrhea, hypertension, hypotension, and ataxia. These symptoms were registered whenever present, regardless of whether the investigator considered them to be drug related or not. Serotonin syndrome was diagnosed in patients who had combinations of at least 3 major symptoms. We chose this definition because it was considered more inclusive than those definitions where minor symptoms were included [18].\n\nLevodopa equivalent daily dose (LEDD) was calculated according to previous reports [23,24].\n\n2.2. Statistical Analyzsis\n\nThe demographic and clinical data are shown as means (standard deviations), ranges, or relative frequencies. The PGI-I scores are shown as relative frequencies. Comparisons between baseline and 1 and 3 months for the variables HAMD-17 and UPDRS were conducted using the Student’s t-test for paired data. The frequencies of serotonin syndrome symptoms were compared between the safinamide-only and safinamide-plus-antidepressants groups with the Fisher’s exact test. p values < 0.05 were considered statistically significant.\n\n3. Results\n\nWe enrolled 82 patients with a minimum follow-up period of 3 months; 78 of them had available data at 1 and 3 months. Twenty-two patients (26.8%) were treated with 50 mg of safinamide, and sixty (73.2%) were treated with 100 mg. Of the 82 patients recruited, 44 (53.7%) received concomitant treatment with antidepressants. The demographic and clinical data at baseline are shown in Table 1.\n\nThe doses of anti-Parkinsonian drugs remained largely stable throughout the study: LEDDs were 810.2 (368.45) mg at baseline, +26,07 (424.10) mg at 1 month, p = 0.3763 (Student’s t-test for paired data), and −4.13 (376,11) mg at 3 months (p = 0.3763, Student’s t-test for paired data). Furthermore, in the group of patients concomitantly treated with safinamide and antidepressants, the doses of antidepressant drugs did not change during the follow-up period. The antidepressants prescribed and their doses are listed in Table 2.\n\n3.1. Effect of Safinamide on Depression in PD Patients\n\nThe primary outcome measure for the antidepressant effect (the HAMD-17 score) showed significant improvements of −6 (5.10) points at 1 month and −7.27 (5.10) points at 3 months (p < 0.0001). Furthermore, there was a significant fall in the HAMD-17 scores at 1 and 3 months for both doses, although a tendency toward greater reductions with 100 vs. 50 mg was observed (Table 3). In the same line, 60.3% of patients at 1 month and 69.5% at 3 months reported some improvement in their depressive symptoms according to the PGI-I scale (Figure 1). Overall, the perception of improvement according to the PGI-I scale was higher with 100 than 50 mg of safinamide (see Figure 1).\n\n3.2. Safinamide on Motor Symptoms, Motor Complications, and Daily Life Activities in Real Clinical Practice\n\nIn the analysis of the complete cohort, we observed a significant improvement in UPDRS Part II (−2.51 (6.30) and −2.47 (6.11) points at 1 and 3 months respectively, p < 0.0001, Table 3) and UPDRS part III (−3.58 (8,68) and −4.03 (8,95) points at 1 and 3 months, respectively, p < 0.0001, see Table 3). UPDRS Part IV also showed mild but significant improvements of −0.61 (2.61) and −0.8 (2.53) points at 1 and 3 months, p < 0.0001 (Table 3). However, only 100 mg of safinamide significantly improved UPDRS Parts II, III, and IV (see Table 3).\n\n3.3. Serotonin Syndrome in Patients Concomitantly Treated with Antidepressant Drugs: Other Adverse Events\n\nThe relative frequencies of the symptoms related to serotonin syndrome in the patients concomitantly treated with safinamide and antidepressants vs. the patients only treated with safinamide are shown in Table 4. Overall, these symptoms were present in a low proportion of patients in both groups. Only “sleep disorders” (16.7% vs. 5.1% at 1 month, p = 0.053, and 15.9% vs. 4.9% at 3 months, p = 0.054) and “nervousness” (19.2% vs. 5.1% at 1 month, p < 0.05, and 15.9% vs. 6.1% at 3 month, p = 0.108), both minor symptoms, were notably more frequent in the safinamide + antidepressant group, although significant differences were only found in “nervousness” at 1 month (Table 4). According to the established criteria, there were no patients with serotonin syndrome in our cohort. However, in two patients, serotonin toxicity symptoms, although not severe, led to discontinuation of the drug (in one case, safinamide; in another, duloxetine). The first patient was a 68-year-old man treated with safinamide at 50 mg/day plus sertraline at 50 mg/day who developed confusion, sleep disorders, and diarrhea, and the symptoms improved upon the withdrawal of safinamide. The second patient was a 90-year-old woman with a complex condition of advanced PD and chronic pain. She was treated with safinamide at 50 mg/day and duloxetine at 30 mg/day, developing confusion, myoclonus, sleep disorders, and nervousness. These symptoms improved with the withdrawal of duloxetine. Importantly, this patient was concomitantly treated with tramadol at 37.5 mg/day, since some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, which increases the serotonergic effect.\n\nFinally, 7.31% of the patients developed other safinamide-related adverse events not associated with serotonin syndrome at 1 month, and 8.53% did so at 3 months. These were nausea (two patients, 2.43%), dyskinesia (one patient, 1.21%), fatigue (one patient, 1.21%), dizziness (one patient, 1.21%), and blurred vision (one patient, 1.21%). None were judged as severe.\n\n4. Discussion\n\nSafinamide, with a dual effect as a glutamatergic modulator and dopaminergic stimulator, could theoretically be useful in the treatment of depression in PD patients. However, heterogeneous results have been reported from clinical trials. In a study with early PD patients (study 015), safinamide (in 100 or 200 mg doses) did not improve Hamilton scale scores compared with placebo [25]. Additionally, in studies on mid-to-late PD patients such as 016 and SETTLE, neither 50 nor 100 mg of safinamide resulted in significant changes in Hamilton score vs. placebo [2,4]. However, these results were not conclusive, considering that patients with depression were excluded from studies 015, 016, and SETTLE, meaning that the baseline Hamilton scale scores were low in those studies [2,4,25]. By contrast, statistically significant differences in GRID Hamilton Rating Scale for Depression (GRID-HAM-D) scores were realized with 100 mg doses of safinamide in an 18-month extension of study 16 (study 018) [3]. In addition, the pooled analysis of studies 016 and 018 showed significant long-term improvements in the safinamide (100 mg/day) group vs. placebo, in terms of both the GRID-HAM-D and the “Emotional well-being” domain of the PDQ-39 as well as the proportions of patients reporting depression as an adverse event [26]. In the same line, an observational study showed that 100 mg/day of safinamide significantly improved scores on the non-motor symptoms scale for PD domains related to mood [27]. In agreement with these findings, our real clinical experience showed objective and subjective improvements in depression according to the HAMD-17 and PGI-I scales in PD patients. Note that by definition, the baseline HAMD-17 scores in our cohort were greater than 14, in contrast to the much lower baseline Hamilton scale scores of the studies 015, 016, and SETTLE [2,4,25]. Therefore, we suggest that safinamide could be useful in the treatment of depression in PD.\n\nAlthough robust improvements in depression in our cohort were observed with both doses, 100 mg seems to be more effective. MAOB has been shown to be almost completely inhibited by 50 mg/day of safinamide [28], so the extra benefit observed with 100 mg/day may be mostly due to nondopaminergic mechanisms. Therefore, the enhanced benefit for depressive symptoms observed in our study with 100 mg of safinamide not only supports a nondopaminergic role in the improvement of depression in PD patients but also implies an interesting difference between safinamide and other dopaminergic drugs that lack these nondopaminergic effects. Nevertheless, the potential biases and insufficient sample size in the 50 mg safinamide group, as discussed below, preclude definite conclusions in this regard.\n\nBased on the UPDRS analysis, our real clinical practice study confirms that safinamide may improve motor symptoms, motor complications, and daily life activities in PD patients, which is in agreement with previous reports [2,3,4,5,29,30]. Supporting these findings, a recent meta-analysis that evaluated both motor function and the activities of daily life in PD patients treated with safinamide suggested that the drug not only improves scores for UPDRS Parts II and III over placebo [31] but also improves motor function, motor fluctuations, and quality of life in PD [31]. However, we found important differences between the 100 and 50 mg doses of safinamide: 100 mg led to significant improvements in UPDRS Parts II, III, and IV, while 50 mg did not result in any significant differences. In previous studies, safinamide at 50 mg/day also did not lead to significant differences in UPDRS II and IV [2,3,5], although an improvement in UPDRS Part III was observed [2,3,5,7], which is in contrast with our results. This difference may be related to the low number of patients in our 50 mg safinamide group (n = 22, 26.8%) and, possibly, a selection bias for patients kept on a low dose of safinamide in the medium term; for most patients, it is only a titration dose used for a short period. Regardless, other studies have more often observed benefits from safinamide at 100 mg than 50 mg/day doses [2,6].\n\nWe found safinamide to be well tolerated in real conditions, even when co-administered with antidepressants, which is in consonance with previous reports [30,32]. Overall, the relative frequencies of major and minor symptoms associated with serotonin syndrome were low, without significant differences between the safinamide-only and safinamide + antidepressants groups. Only, “sleep disorders” and “nervousness” were notably more frequent in the safinamide + antidepressant group, but significant differences were only observed in “nervousness” at 1 month. Furthermore, these were minor symptoms, not serious, and potentially linked to the depression and antidepressants themselves. These findings are similar to previous reports on rasagiline [18]. Finally, according to the established criteria, no patient in our cohort developed serotonin syndrome, which is similar to in previous studies with rasagiline and safinamide [17,30]. However, two patients withdrew from the treatment due to major symptoms, although they were not severe. Even though safinamide is safe in patients older than 75 years [30], an advanced age and concomitant treatment with opioids are likely to have played a role in these cases. It is important to explain here that some opioids such as tramadol can inhibit the reuptake of serotonin by inhibiting the serotonin transporter, and therefore, they should also be considered serotonergic drugs [33]. Thus, our experience suggests that the co-administration of safinamide and antidepressants is safe, although caution is warranted, especially for the elderly, for whom we recommend avoiding other serotonergic drugs, for instance, opioids as tramadol, using doses as low as possible, and closely monitoring for adverse events [20].\n\nWe must acknowledge several limitations of our study. First, it was an observational retrospective study where comparisons were made with respect to baseline, so it lacked a control cohort without safinamide treatment, and there was a possible selection bias related to non-controlled withdrawals, which could have led to the overestimation of the results with respect to the population. This bias is frequent in retrospective designs. Second, the observation period established in the design was short, and the final sample size was small; both of these were due to difficulties in obtaining the required data in a retrospective manner. Third, for reasons explained above, we could not draw definitive conclusions regarding the differential effects of safinamide at 50 mg on motor and non-motor symptoms. Future prospective studies or clinical trials with control groups could overcome these limitations.\n\n5. Conclusions\n\nSafinamide could be useful for the treatment of depression in PD. In real clinical conditions, safinamide seems to be efficacious in improving motor symptoms, motor complications and daily life activities. Greater benefits for both depression and motor symptoms appear to be realized with 100 mg/day doses. Safinamide seems to be well tolerated in real clinical practice, even when co-administered with antidepressant drugs, but it should still be used with caution.\n\nAcknowledgments\n\nThis is a collaborative study of the movement disorders group of the Asociación Madrileña de Neurología (AMN). Authors thank to AMN their support.\n\nAuthor Contributions\n\nConceptualization, E.P.; Data curation, E.P.; Formal analysis, E.P.; Funding acquisition, E.P.; Investigation, E.P., C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H.; Methodology, E.P.; Writing – original draft, E.P.; Writing – review & editing, C.B., M.M., J.C.M.-C., A.A.-C., J.L.C., L.L.-M., M.L., J.H.-R., A.E., T.M.-C. and C.R.-H. All authors contributed to the study conception and design. Data collection was performed by all authors. Material preparation and data analysis were performed by E.P. The first draft of the manuscript was written by E.P. and all authors commented on previous versions of the manu-script. All authors read and approved the final manuscript.\n\nFunding\n\nThis study was funded by Zambon.\n\nInstitutional Review Board Statement\n\nEthical approval was waived by the local ethics committee of the Hospital La Princesa in view of the retrospective nature of the study; all the procedures being performed were part of routine care.\n\nInformed Consent Statement\n\nInformed consent was obtained from all the individual participants included in the study. The patients signed informed consent regarding the publishing of their data.\n\nData Availability Statement\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nConflicts of Interest\n\nEsteban Peña has received grants, honoraria as a member of advisory boards, speaker honoraria, research funding and travel support from Zambon, Bial and Exeltis. Juan Carlos Martínez-Castrillo has received honoraria as a speaker from AbbVie, Allergan, Bial, Boehringer, GSK, Krka, Merz, Ipsen, Italfarmaco, Lundbeck, Medtronic, TEVA, UCB and Zambon; travel grants from AbbVie, Allergan, Bial, Italfarmaco, TEVA, UCB, Merz, Krka and Zambón; and research grants from AbbVie, Allergan, Merz, Italfarmaco, Lundbeck, UCB and Zambon; and participated in the advisory boards of AbbVie, Allergan, GSK, Bial, Merz, Merck, Boehringer, Ipsen, Italfarmaco, Lundbeck, Orion, UCB, and Zambon. Araceli Alonso-Canovas has received lecture honoraria from Abbvie and Zambon, honoraria as a member of advisory boards from Abbvie, Zambon and Bial and travel grants from Abbvie and Zambon. Lydia López-Manzanares reports compensated advisory services, consulting, research grant support, and speaker honoraria from AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. Jaime Herreros-Rodríguez has received speaker honoraria from Zambon. Teresa Maycas-Cepeda has received personal compensation as an advisory board member from Zambon. Marcos Llanero has received honoraria as a speaker from Bial, Krka, Novartis, Pfizer and Zambon and travel grants from Bial, Teva, UCB, KrKa and Zambon The rest of the authors do not declare any conflicts of interest.\n\nFigure 1 Patient Global Impression of Improvement Scale scores at 1 and 3 months.\n\nbrainsci-11-00232-t001_Table 1 Table 1 Demographic and clinical data at baseline (n = 82).\n\nn\tn (%)\tComplete cohort\t82\t\nSafinamide-only group\t38 (46.3%)\t\nSafinamide + antidepressants group\t44 (53.7%)\t\nAge (years)\tMean (SD) [range]\tComplete cohort\t68.33 (11.41) [41–90]\t\nSsafinamide-only group\t70.13 (9.83) [41–87]\t\nSafinamide + antidepressants group\t66.77 (12.51) [42–90]\t\nGender (male/female)\tn (%)/n (%)\tComplete cohort\t37 (45.1%)/45 (54.9%)\t\nSafinamide-only group\t21 (55.3%)/17 (44.7%)\t\nSafinamide + antidepressants group\t16 (36.4%)/28 (63.6%)\t\nDisease duration (years)\tMean (SD)\tComplete cohort\t8.67 (8.55)\t\nSafinamide-only group\t7.84 (9.65)\t\nSafinamide + antidepressants group\t9.39 (7.51)\t\nUPDRS\t\t\t\t\nI\tMean (SD)\tComplete cohort\t4.56 (1.82)\t\nSafinamide-only group\t3.82 (1.90)\t\nSafinamide + antidepressants group\t5.20 (1.49)\t\nII\tMean (SD)\tComplete cohort\t13.59 (6.67)\t\nSafinamide-only group\t13.55 (7.07)\t\nSafinamide + antidepressants group\t13.61 (6.38)\t\nIII\tMean (SD)\tComplete cohort\t22.91 (8.68)\t\nSafinamide-only group\t22.47 (9.90)\t\nSafinamide + antidepressants group\t23.30 (7.57)\t\nIV\tMean (SD)\tComplete cohort\t3.51 (2.83)\t\nSafinamide-only group\t2.61 (2.52)\t\nSafinamide + antidepressants group\t4.30 (2.87)\t\nHAMD-17\tMean (SD)\tComplete cohort\t19.49 (4.03)\t\nSafinamide-only group\t18.39 (3.58)\t\nSafinamide + antidepressants group\t20.43 (4.20)\t\nLEDD (mg)\tMean (SD)\tComplete cohort\t810.26 (368.45)\t\nSafinamide-only group\t681.25 (218.15)\t\nSafinamide + antidepressants group\t921.68 (432.86)\t\nUPDRS: Unified Parkinson’s Disease Rating Scale. HAMD-17: Hamilton Depression Rating Scale based on 17 items. LEDD: Levodopa equivalent daily dose. SD: Standard deviation.\n\nbrainsci-11-00232-t002_Table 2 Table 2 List of antidepressants concomitantly prescribed with safinamide.\n\nAntidepressant Drug\tRange of Doses (mg/day)\tn (%)\t\nDULOXETINE\t30–120\t11 (25.0%)\t\nESCITALOPRAM\t5–15\t7 (15.9%)\t\nMIRTAZAPINE\t15–30\t5 (11.4%)\t\nSERTRALINE\t50–100\t5 (11.4%)\t\nVENLAFAXINE\t75–150\t5 (11.4%)\t\nTRAZODONE\t50–100\t4 (9.1%)\t\nAMITRIPTILINE\t25\t1 (2.3%)\t\nCLORIMIPRAMINE\t25\t1 (2.3%)\t\nBUPROPION\t150\t1 (2.3%)\t\nCITALOPRAM\t20\t1 (2.3%)\t\nPAROXETINE + AMITRIPTILINE\t10 + 25\t1 (2.3%)\t\nVENLAFAXINE + MIRTAZAPINE\t75 + 15\t1 (2.3%)\t\nVORTIOXETINE\t10\t1 (2.3%)\t\n\nbrainsci-11-00232-t003_Table 3 Table 3 Changes in Hamilton Depression Rating Scale based on 17 items and Unified Parkinson’s Disease Rating Scale scores at 1 and 3 months vs. baseline.\n\n\t\tBaseline\nMean (SD)\t1 Month\nMean Difference from Baseline (SD)\tp-Value\t3 Months\nMean Difference from Baseline (SD)\tp-Value\t\nHAMD-17\tComplete cohort\t19.49 (4.03)\nn = 82\t−6 (5.10)\nn = 78\tp < 0.0001\t−7.27 (5.48)\nn = 82\tp < 0.0001\t\nSafinamide 50 mg\t18.50 (2.69)\nn = 22\t−3.32 (4.54)\nn = 22\tp = 0.0003\t−4.73 (4.49)\nn = 22\tp < 0.0001\t\nSafinamide 100 mg\t19.85 (4.39)\nn = 60\t−7.03 (5.19)\nn = 56\tp < 0.0001\t−8.02 (5.73)\nn = 60\tp < 0.0001\t\nUPDRS I\tComplete cohort\t4.56 (1.82)\nn = 82\t−1.32 (1.99)\nn = 78\tp < 0.0001\t−1.5 (2.03)\nn = 82\tp < 0.0001\t\nSafinamide 50 mg\t4.59 (1.47)\nn = 22\t−0.64 (1.91)\nn = 22\tp = 0.0157\t−0.91 (1.76)\nn = 22\tp = 0.0045\t\nSafinamide 100 mg\t4.55 (1.94)\nn = 60\t−1.59 (1.97)\nn = 56\tp < 0.0001\t−1.72 (2.08)\nn = 60\tp < 0.0001\t\nUPDRS II\tComplete cohort\t13.59 (6.67)\nn = 82\t−2.51 (6.30)\nn = 78\tp < 0.0001\t−2.47 (6.11)\nn = 82\tp < 0.0001\t\nSafinamide 50 mg\t11.50 (5.20)\nn = 22\t−0.36 (5.44)\nn = 22\tp = 0.4064\t−0.23 (5.23)\nn = 22\tp = 0.4966\t\nSafinamide 100 mg\t14.35 (7.02)\nn = 60\t−3.30 (6.65)\nn = 56\tp < 0.0001\t−3.28 (6.45)\nn = 60\tp < 0.0001\t\nUPDRS III\tComplete cohort\t22.91 (8.68)\nn = 82\t−3.58 (8.56)\nn = 78\tp < 0.0001\t−4.03 (8.95)\nn = 82\tp < 0.0001\t\nSafinamide 50 mg\t22.00 (8.12)\nn = 22\t−0.41 (8.88)\nn = 22\tp = 0.7722\t+0.50 (9.42)\nn = 22\tp = 0.6723\t\nSafinamide 100 mg\t23.25 (8.92)\nn = 60\t−4.8 (8.34)\nn= 56\tp < 0.0001\t−5.70 (8.47)\nn = 60\tp < 0.0001\t\nUPDRS IV\tComplete cohort\t3.51 (2.83)\nn = 82\t−0.61 (2.61)\nn = 78\tp = 0.0003\t−0.8 (2.53)\nn = 82\tp < 0.0001\t\nSafinamide 50 mg\t4.64 (2.59)\nn = 22\t−0.32 (2.38)\nn = 22\tp = 0.1839\t−0.28 (2.50)\nn = 22\tp = 0.2482\t\nSafinamide 100 mg\t3.10 (2.82)\nn = 60\t−0.76 (2.50)\nn = 56\tp = 0.0007\t−1.00 (2.28)\nn = 60\tp < 0.0001\t\nHAMD-17: Hamilton Depression Rating Scale based on 17 items. UPDRS: Unified Parkinson’s Disease Rating Scale. SD: Standard deviation. Comparisons were made using the Student’s t-test for paired data. p values < 0.05 were considered statistically significant.\n\nbrainsci-11-00232-t004_Table 4 Table 4 Symptoms related to serotonin syndrome in safinamide-only group vs. safinamide-plus-antidepressants group at 1 and 3 months.\n\n\t\t\t1 Month\t3 Months\t\n\t\t\tSafinamide + Antidepressants Group\nn = 42\tSafinamide-only Group\nn = 36\tp-Value\tSafinamide + Antidepressants Group\nn = 44\tSafinamide-only Group\nn = 38\tp-Value\t\nMajor symptoms\tConfusion\tn (%)\t2 (2.6%)\t0 (0%)\tp = 0.564\t1 (1.2%)\t0 (0%)\tp = 1.251\t\nEmotional lability\t2 (2.6%)\t1 (1.3%)\tp = 1.021\t3 (3.7%)\t1 (1.2%)\tp = 0.627\t\nFever\t0 (0%)\t0 (0%)\t-\t0 (0%)\t0 (0%)\t-\t\nSweating\t3 (3.8%)\t1 (1.3%)\tp = 0.627\t3 (3.7%)\t0 (0%)\tp = 0.266\t\nMyoclonus\t0 (0%)\t0 (0%)\t-\t2 (2.4%)\t0 (0%)\tp = 0.565\t\nMinor symptoms\tAgitation\tn (%)\t2 (2.6%)\t1 (1.3%)\tp = 1.021\t1 (1.2%)\t0 (0%)\tp = 1.251\t\nSleep disorders\t13 (16.7%)\t4 (5.1%)\tp = 0.053\t13 (15.9%)\t4 (4.9%)\tp = 0.054\t\nNervousness\t15 (19.2%)\t4 (5.1%)\tp = 0.017\t13 (15.9%)\t5 (6.1%)\tp = 0.108\t\nTachycardia\t2 (2.6%)\t1 (1.3%)\tp = 1.021\t3 (3.7%)\t0 (0%)\tp = 0.266\t\nHyperventilation\t0 (0%)\t1 (1.3%)\tp = 0.897\t0 (0%)\t1 (1.2%)\tp = 0.894\t\nDyspnea\t1 (1.3%)\t2 (2.6%)\tp = 0.642\t2 (2.4%)\t3 (3.7%)\tp = 0.666\t\nDiarrhea\t0 (0%)\t1 (1.3%)\tp = 0.897\t1 (1.2%)\t0 (0%)\tp = 1.251\t\nHypertension\t0 (0%)\t1 (1.3%)\tp = 0.897\t0 (0%)\t1 (1.2%)\tp = 0.894\t\nHypotension\t0 (0%)\t0 (0%)\t-\t0 (0%)\t0 (0%)\t-\t\nAtaxia\t0 (0%)\t1 (1.3%)\tp = 0.897\t0 (0%)\t1 (1.2%)\tp = 0.894\t\nData were compared using the Fisher’s exact test. p values < 0.05 were considered statistically significant.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Stocchi F. Torti M. Adjuvant therapies for Parkinson’s disease: Critical evaluation of safinamide Drug. Des. Dev. Ther. 2016 10 609 618 10.2147/DDDT.S77749\n2. Borgohain R. Szasz J. Stanzione P. Meshram C. Bhatt M. Chirilineau D. Stocchi F. Lucini V. Iuliani R. Forrest E. Study 016 Investigators. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations Mov. Disord. 2014 29 229 237 10.1002/mds.25751 24323641\n3. Borgohain R. Szasz J. Stanzione P. Meshram C. Bhatt M.H. Chirilineau D. Stocchi F. Lucini V. Giuliani R. Forrest E. Study 018 Investigators. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease Mov. Disord. 2014 29 1273 1280 10.1002/mds.25961 25044402\n4. Schapira A.H. Fox S.H. Hauser R.A. Jankovic J. Jost W.H. Kenney C. Kulisevsky J. Pahwa R. Poewe W. Anand R. Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial JAMA Neurol. 2017 74 216 224 10.1001/jamaneurol.2016.4467 27942720\n5. Hattori N. Tsuboi Y. Yamamoto A. Sasagawa Y. Nomoto M. Efficacy and safety of safinamide as an add-on therapy to L-DOPA for patients with Parkinson’s disease: A randomized, double-blind, placebo-controlled, phase II/III study Parkinsonism Relat. Disord. 2020 75 17 23 10.1016/j.parkreldis.2020.04.012 32446176\n6. Tsuboi Y. Hattori N. Yamamoto A. Sasagawa Y. Nomoto M. Long-term safety and efficacy of safinamide as add-on therapy in levodopa-treated Japanese patients with Parkinson’s disease with wearing-off: Results of an open-label study J. Neurol. Sci. 2020 416 117012 10.1016/j.jns.2020.117012 32673884\n7. Mancini F. Di Fonzo A. Lazzeri G. Borellini L. Silani V. Lacerenza M. Comi C. Real life evaluation of safinamide effectiveness in Parkinson’s disease Neurol. Sci. 2020 39 733 739 10.1007/s10072-018-3272-y\n8. Aarsland D. Påhlhagen S. Ballard C.G. Ehrt U. Svenningsso P. Depression in Parkinson disease-epidemiology, mechanisms, and management Nat. Rev. Neurol. 2020 8 35 47 10.1038/nrneurol.2011.189\n9. Carod-Artal F.J. Ziomkowski S. Mourão Mesquita H. Martínez-Martin P. Anxiety and depression: Main determinants of health-related quality of life in Brazilian patients with Parkinson’s disease Parkinsonism Relat. Disord. 2008 14 102 108 10.1016/j.parkreldis.2007.06.011 17719828\n10. Machado-Vieira R. Manji H.K. Zarate C.A. The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders Neuroscientist 2009 15 525 539 10.1177/1073858409336093 19471044\n11. Allain H. Pollak P. Neukirch H.C. Symptomatic effect of selegiline in de novo parkinsonian patients. The French Selegiline Multicenter Trial Mov. Disord. 1993 8 Suppl. S1 S36 S40 10.1002/mds.870080508 8302306\n12. Barone P. Poewe W. Albrecht S. Debieuvre C. Massey D. Rascol O. Tolosa E. Weintraub D. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: A randomised, double-blind, placebo-controlled trial Lancet Neurol. 2010 9 573 580 10.1016/S1474-4422(10)70106-X 20452823\n13. Rektorova I. Balaz M. Svatova J. Zarubova K. Honig I. Dostal V. Sedlackova S. Nestrasil I. Mastik J. Bares M. Effects of ropinirole on nonmotor symptoms of Parkinson disease: A prospective multicenter study Clin. Neuropharmacol. 2008 31 261 266 10.1097/WNF.0b013e31815d25ce 18836343\n14. Korchounov A. Winter Y. Rössy W. Combined beneficial effect of rasagiline on motor function and depression in de novo PD Clin. Neuropharmacol. 2012 35 121 124 10.1097/WNF.0b013e31823b1da8 22561875\n15. Zarate C. Machado-Vieira R. Henter I. Ibrahim L. Diazgranados N. Salvatore G. Glutamatergic modulators: The future of treating mood disorders? Harv. Rev. Psychiatry 2010 18 293 303 10.3109/10673229.2010.511059 20825266\n16. Richard I.H. Kurlan R. Tanner C. Factor S. Hubble J. Suchowersky O. Waters C. Parkinson Study Group Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease Neurology 1997 48 1070 1077 10.1212/WNL.48.4.1070 9109902\n17. Panisset M. Chen J.J. Rhyee S.H. Conner J. Mathena J. The STACCATO study investigators Serotonin Toxicity Association with Concomitant Antidepressants and Rasagiline Treatment: Retrospective study (STACCATO) Pharmacotherapy 2014 34 1250 1258 10.1002/phar.1500 25314256\n18. Panisset M. Schwied S. Ondo W. Fitzer-Attas C. Chen J.J. Safety of concomitant therapy with rasagiline and antidepressants in Parkinson’s diesease Mov. Disord. 2007 22 Suppl. S16 S104 10.1002/mds.21535\n19. Smith K.M. Eyal E. Weintraub D. for the ADAGIO Investigators Combined rasagiline and antidepressant use in Parkinson disease in the ADAGIO study. Effects on nonmotor symptoms and tolerability JAMA Neurol. 2015 72 88 95 10.1001/jamaneurol.2014.2472 25420207\n20. Aboukarr A. Giudice M. Interaction between Monoamine Oxidase B Inhibitors and Selective Serotonin Reuptake Inhibitors Can. J. Hosp. Pharm. 2018 71 196 207 10.4212/cjhp.v71i3.2586 29955193\n21. Postuma R.B. Berg D. Stern M. Poewe W. Olanow C.W. Oertel W. Obeso J. Marek K. Litvan I. Lang A.E. MDS Clinical Diagnostic Criteria for Parkinson’s Disease Mov. Disord. 2015 30 1591 1599 10.1002/mds.26424 26474316\n22. Torbey E. Pachana N.A. Dissanayaka N.N.W. Depression rating scales in Parkinson’s disease: A critical review updating recent literature J. Affect. Disord. 2015 184 216 224 10.1016/j.jad.2015.05.059 26114228\n23. Tomlinson C.L. Stowe R. Patel S. Rick C. Gray R. Clarke C.R. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease Mov. Disord. 2010 25 2649 2653 10.1002/mds.23429 21069833\n24. Schade S. Mollenhauer B. Trenkwalder C. Levodopa Equivalent Dose Conversion Factors: An Updated Proposal Including Opicapone and Safinamide Mov. Disord. Clin. Pract. 2020 7 343 345 10.1002/mdc3.12921 32258239\n25. Stocchi F. Borgohain R. Onofrj M. Schapira A.H.V. Bhatt M. Lucini V. Giuliani R. Anand R. A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson’s disease patients Mov. Disord. 2012 27 106 112 10.1002/mds.23954 21913224\n26. Cattaneo C. Müller T. Bonizzoni E. Lazzeri G. Kottakis I. Keywood C. Long-Term Effects of Safinamide on Mood Fluctuations in Parkinson’s Disease J. Parkinsons. Dis. 2017 7 629 634 10.3233/JPD-171143 28777756\n27. Bianchi M.L.E. Riboldazzi G. Mauri M. Versino M. Efficacy of safinamide on non-motor symptoms in a cohort of patients affected by idiopathic Parkinson’s disease Neurol. Sci. 2019 40 275 279 10.1007/s10072-018-3628-3 30382437\n28. Alborghetti M. Nicoletti F. Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson’s Disease: From Bench to Bedside Curr. Neuropharmacol. 2019 17 861 873 10.2174/1570159X16666180830100754 30160213\n29. Cattaneo C. Jost W.H. Bonizzoni E. Long-Term Efficacy of Safinamide on Symptoms Severity and Quality of Life in Fluctuating Parkinson’s Disease Patients J. Parkinsons Dis. 2020 10 89 97 10.3233/JPD-191765 31594253\n30. Abbruzzese G. Kulisevsky J. Bergmans B. Gomez-Esteban J.C. Kägi G. Raw J. Stefani A. Warnecke T. Jost W.H. SYNAPSES Study Investigators Group A European Observational Study to Evaluate the Safety and the Effectiveness of Safinamide in Routine Clinical Practice: The SYNAPSES Trial J. Parkinsons Dis. 2020 10.3233/JPD-202224\n31. Ahmed M.A.A. A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson’s disease F1000Resarch 2019 8 2078 10.12688/f1000research.21372.1 32431802\n32. Gloria Martí-Andrés G. Jiménez-Bolaños R. Arbelo-González J.M. Pagonabarraga J. Carmen Duran-Herrera C. Valenti-Azcarate R. Luquin M.R. Safinamide in Clinical Practice: A Spanish Multicenter Cohort Study Brain. Sci. 2019 9 272 10.3390/brainsci9100272\n33. Baldo B.A. Rose M.A. The anesthetists, opioid analgesic drugs, and serotonin toxicity: A mechanistic and clinical review Br. J. Anaesth 2020 124 44e62 10.1016/j.bja.2019.08.010 31653394\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-3425",
"issue": "11(2)",
"journal": "Brain sciences",
"keywords": "Parkinson’s disease; antidepressants; depression; motor symptoms; safinamide; serotonin syndrome",
"medline_ta": "Brain Sci",
"mesh_terms": null,
"nlm_unique_id": "101598646",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33668408",
"pubdate": "2021-02-13",
"publication_types": "D016428:Journal Article",
"references": "20825266;21069833;30160213;8302306;9109902;21913224;29441484;26917951;26474316;20452823;18836343;27942720;31594253;32258239;24323641;31653394;32673884;26114228;22198405;32446176;31614574;19471044;25420207;30382437;32431802;25314256;22561875;28777756;25044402;29955193;17719828;33104040",
"title": "Impact of SAfinamide on Depressive Symptoms in Parkinson's Disease Patients (SADness-PD Study): A Multicenter Retrospective Study.",
"title_normalized": "impact of safinamide on depressive symptoms in parkinson s disease patients sadness pd study a multicenter retrospective study"
} | [
{
"companynumb": "ES-MYLANLABS-2021M1022526",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditional": "1",
... |
{
"abstract": "An 80-year-old man with metastatic melanoma had been receiving treatment with pembrolizumab from September 2015 until June 2017. Series FDG PET/CT scans from March 7, 2017, to June 14, 2018, showed the course of biopsy-proven pembrolizumab-induced sarcoidosis. Reported here is the first case of multiorgan sarcoidosis induced by pembrolizumab and its self-resolving course on FDG PET/CT.",
"affiliations": "From the Department of Nuclear Medicine, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX.",
"authors": "Lu|Yang|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D019788:Fluorodeoxyglucose F18; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000002408",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "44(2)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D008545:Melanoma; D000072078:Positron Emission Tomography Computed Tomography; D012507:Sarcoidosis",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "167-168",
"pmc": null,
"pmid": "30516667",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "FDG PET/CT Course of Pembrolizumab-Associated Multiorgan Sarcoidosis.",
"title_normalized": "fdg pet ct course of pembrolizumab associated multiorgan sarcoidosis"
} | [
{
"companynumb": "US-009507513-1901USA005593",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "To report a severe case of e-cigarette or vaping product use-associated lung injury with complex course requiring venovenous extracorporeal membrane oxygenation.\n\n\n\nCase report.\n\n\n\nPICU in an academic medical center.\n\n\n\nA 16-year-old girl presenting with gastrointestinal and respiratory symptoms was admitted to our PICU after having progressive respiratory failure and bilateral pulmonary ground-glass opacities on chest CT.\n\n\n\nVenovenous extracorporeal membrane oxygenation MEASUREMENTS AND MAIN RESULTS:: After extensive infectious workup was unrevealing, she reported a history of vaping e-cigarette containing either nicotine or delta-9-tetrahydrocannabinol oil prior to symptom onset. She was given a presumptive diagnosis of e-cigarette or vaping product use-associated lung injury. The PICU team in consultation with pulmonology and medical toxicology started high-dose IV methylprednisolone 1 mg/kg bid. Despite initial improvements, she continued to require positive pressure ventilation and developed pneumomediastinum with progression to tension pneumothoraces and a persistent air leak. Unable to maintain her oxygenation, she was placed on venovenous extracorporeal membrane oxygenation for a prolonged course and had a tracheostomy placement. The clinical course, severity, and range of interventions in affected patients around the country have varied widely. Respiratory symptoms have been the most severe, but the constellation of symptoms in e-cigarette or vaping product use-associated lung injury include constitutional symptoms (fevers, weight-loss) and gastrointestinal symptoms (nausea, vomiting, diarrhea). In many cases, steroid use led to rapid clinical improvements. However, other cases with severe illness, like our patient, necessitated high-dose IV steroids, intubation, and venovenous extracorporeal membrane oxygenation. The underlying etiology and pathophysiology of e-cigarette or vaping product use-associated lung injury remains unknown. The Centers for Disease Control and Prevention in conjunction with state/local health departments and the Food and Drug Administration is actively investigating the outbreak.\n\n\n\nClinicians need to be aware of the current outbreak of e-cigarette or vaping product use-associated lung injury and ask about vaping in patients presenting with gastrointestinal and respiratory symptoms. Treatment options are anecdotal and necessitate a multidisciplinary approach.",
"affiliations": "Division of Medical Toxicology, Department of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas, TX.;Division of Medical Toxicology, Department of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas, TX.;Division of Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.;Division of Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.;Department of Chemistry, University of North Texas, Denton, TX.;Department of Chemistry, University of North Texas, Denton, TX.;Division of Medical Toxicology, Department of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas, TX.",
"authors": "Aldy|Kim|K|;Cao|Dazhe James|DJ|;McGetrick|Molly|M|;Willcutts|David|D|;Verbeck|Guido|G|;De Silva|Imesha|I|;Hsu|Stephanie|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PCC.0000000000002264",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1529-7535",
"issue": "21(4)",
"journal": "Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies",
"keywords": null,
"medline_ta": "Pediatr Crit Care Med",
"mesh_terms": "D000293:Adolescent; D066300:Electronic Nicotine Delivery Systems; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D008168:Lung; D055370:Lung Injury; D000072137:Vaping",
"nlm_unique_id": "100954653",
"other_id": null,
"pages": "385-388",
"pmc": null,
"pmid": "32150124",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe E-Cigarette, or Vaping, Product Use Associated Lung Injury Requiring Venovenous Extracorporeal Membrane Oxygenation.",
"title_normalized": "severe e cigarette or vaping product use associated lung injury requiring venovenous extracorporeal membrane oxygenation"
} | [
{
"companynumb": "US-SGP-000006",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nTo estimate the prevalence of important side effects in patients with malignant disease who were receiving high doses of morphine as part of their palliative treatment.\n\n\nMETHODS\nData on patients were collected over 12 months.\n\n\nMETHODS\nTwo palliative care units in Western Australia.\n\n\nMETHODS\n19 Patients with malignant disease who were receiving morphine either subcutaneously or orally as the main analgesic. 10 Patients receiving a total daily dose of morphine of at least 500 mg orally or 250 mg parenterally were enrolled in the study. The other 9 patients were enrolled after an important problem thought to be related to the morphine had been identified. All of the patients were taking drugs to supplement the treatment.\n\n\nMETHODS\nThe dose of morphine or route of administration, or both, was changed in three patients.\n\n\nMETHODS\nDetermination of the prevalence of side effects in the patients. Assessment of the relation of any side effects with the supplemental drugs taken by the patients.\n\n\nRESULTS\nPlasma morphine and electrolyte concentrations were measured and a full history taken for each patient. Thirteen of the 19 patients had an important side effect; 12 of them had myoclonus and one had hyperalgesia of the skin. Plasma morphine concentrations were similar in patients with and without myoclonus, ranging from 158 to 3465 nmol/l and 39 to 2821 nmol/l respectively. Eight of the patients with side effects were taking an antipsychotic drug concurrently compared with none of those without side effects. A greater proportion of patients with side effects were taking the antinauseant drug thiethylperazine (6/13 v 2/6) and at least one non-steroidal anti-inflammatory drug (10/13 v 2/6), whereas a smaller proportion were taking a glucocorticosteroid (3/13 v 4/6). The estimated prevalence of important side effects in the total population of patients receiving palliative treatment in the two units was 2.7-3.6%.\n\n\nCONCLUSIONS\nMyoclonus as a side effect of treatment with morphine is more likely to occur in patients taking antidepressant or antipsychotic drugs as antiemetics or as adjuvant agents or non-steroidal anti-inflammatory drugs for additional analgesia. If a patient develops myoclonus the best approach may be to change the supplemental treatment.",
"affiliations": "Department of Pharmacology, University of Western Australia, Nedlands.",
"authors": "Potter|J M|JM|;Reid|D B|DB|;Shaw|R J|RJ|;Hackett|P|P|;Hickman|P E|PE|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000932:Antiemetics; D014150:Antipsychotic Agents; D009020:Morphine",
"country": "England",
"delete": false,
"doi": "10.1136/bmj.299.6692.150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8138",
"issue": "299(6692)",
"journal": "BMJ (Clinical research ed.)",
"keywords": null,
"medline_ta": "BMJ",
"mesh_terms": "D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000932:Antiemetics; D014150:Antipsychotic Agents; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine; D009207:Myoclonus; D009369:Neoplasms; D010166:Palliative Care",
"nlm_unique_id": "8900488",
"other_id": null,
"pages": "150-3",
"pmc": null,
"pmid": "2475196",
"pubdate": "1989-07-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "6418061;6315187;2997413;2417096;2888950;3428802;2895346;3400849;3966753;5406114;13957;581884;110577;119252;6110767;6276842;6756878;6187275",
"title": "Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs.",
"title_normalized": "myoclonus associated with treatment with high doses of morphine the role of supplemental drugs"
} | [
{
"companynumb": "AU-PFIZER INC-2010034488",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INDOMETHACIN"
},
"drugadditional": "3",
... |
{
"abstract": "Antiepileptic drug treatment can induce psychosis in some patients. However, there are no agreed definitions or diagnostic criteria for antiepileptic drug-induced psychotic disorder in the classification systems of either epileptology or psychiatry. In this study we investigated the clinical spectrum of antiepileptic drug-induced psychotic disorder in patients with epilepsy. The medical records of all patients with epilepsy who were diagnosed by a neuropsychiatrist as having a psychotic disorder at the Royal Melbourne Hospital from January 1993 to June 2015 were reviewed. Data were extracted regarding epilepsy and its treatment, psychotic symptoms profile and outcome. The diagnosis of epilepsy was established in accordance to the classification system of the International League Against Epilepsy while that of psychotic disorder was made according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposal on neuropsychiatric disorders in epilepsy. Patients with antiepileptic drug-induced psychotic disorder were compared to those with psychotic disorders unrelated to antiepileptic drugs assessed over the same period (non-antiepileptic drug induced psychotic disorder group). Univariate comparisons were performed and variables with a value of P < 0.1 were selected for the multivariate logistic regression analysis. The records of 2630 in-patients and outpatients with epilepsy were screened, from which 98 (3.7%) with psychotic disorders were identified. Among these, 14 (14.3%) were diagnosed to have antiepileptic drug-induced psychotic disorder. Excluding one patient who developed psychosis after valproate withdrawal, 76.9% in the antiepileptic drug induced psychotic disorder group were female and the percentage of temporal lobe involvement was higher in the antiepileptic drug induced psychotic disorder group (69.2% versus 38.1%, P < 0.05). Current use of levetiracetam was higher in antiepileptic drug-induced psychotic disorder group (84.6% versus 20.2%, P < 0.01) while use of carbamazepine was higher in the comparator group (15.4% versus 44.0%, P < 0.05). Multivariate logistic regression confirmed four factors associated with antiepileptic drug-induced psychotic disorder: female gender, temporal lobe involvement and use of levetiracetam, and a negative association with carbamazepine. Disorganized behaviours and thinking were more common in the antiepileptic drug-induced psychotic disorder group (100% versus 72.6% and 76.9% versus 38.1%, respectively; P < 0.05). The percentage of continuous treatment with antipsychotic drugs was lower in the antiepileptic drug-induced psychotic disorder group (15.4% versus 66.7%, P < 0.01). No patients experienced a chronic course in antiepileptic drug-induced psychotic disorder group whereas 40.5% did in non-antiepileptic drug induced psychotic disorder (P < 0.05). Our findings indicated that one in seven patients with epilepsy who developed psychosis had antiepileptic drug-induced psychotic disorder. In these patients, female gender, temporal lobe involvement and current use of levetiracetam were significantly associated with antiepileptic drug induced psychotic disorder compared to other types of psychosis, while carbamazepine had a negative association. Disorganized behaviours and thinking were predominant in antiepileptic drug-induced psychotic disorder. Patients with antiepileptic drug-induced psychotic disorder differed from non-antiepileptic drug-induced psychotic disorders in having better outcome.",
"affiliations": "1 Departments of Medicine and Neurology, The Melbourne Brain Centre, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia 2 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;3 Melbourne Neuropsychiatry Centre, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia.;1 Departments of Medicine and Neurology, The Melbourne Brain Centre, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia.;3 Melbourne Neuropsychiatry Centre, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia.;3 Melbourne Neuropsychiatry Centre, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia.;1 Departments of Medicine and Neurology, The Melbourne Brain Centre, The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia patrick.kwan@unimelb.edu.au.",
"authors": "Chen|Ziyi|Z|;Lusicic|Ana|A|;O'Brien|Terence J|TJ|;Velakoulis|Dennis|D|;Adams|Sophia J|SJ|;Kwan|Patrick|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/brain/aww196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-8950",
"issue": "139(Pt 10)",
"journal": "Brain : a journal of neurology",
"keywords": "AED-induced psychotic disorder; antiepileptic drug; epilepsy; psychosis",
"medline_ta": "Brain",
"mesh_terms": null,
"nlm_unique_id": "0372537",
"other_id": null,
"pages": "2668-2678",
"pmc": null,
"pmid": "27503872",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Psychotic disorders induced by antiepileptic drugs in people with epilepsy.",
"title_normalized": "psychotic disorders induced by antiepileptic drugs in people with epilepsy"
} | [
{
"companynumb": "AU-ALVOGEN-2016-ALVOGEN-086194",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",... |
{
"abstract": "Hypoglycemia associated with sulfamethoxazole therapy in patients with chronic renal insufficiency has previously been documented. We report the case of an elderly patient with relatively normal renal function who developed severe hypoglycemia associated with trimethoprim-sulfamethoxazole therapy.",
"affiliations": "College of Community Health Sciences, University of Alabama, Tuscaloosa.",
"authors": "McKnight|J T|JT|;Gaskins|S E|SE|;Pieroni|R E|RE|;Machen|G M|GM|",
"chemical_list": "D000892:Anti-Infective Agents, Urinary; D004338:Drug Combinations; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim; D013420:Sulfamethoxazole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-8652",
"issue": "1(2)",
"journal": "The Journal of the American Board of Family Practice",
"keywords": null,
"medline_ta": "J Am Board Fam Pract",
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"abstract": "A 55-year-old woman was admitted to our hospital complaining of constipation and abdominal distention. She had a history of right breast surgery for cancer at the age of 48 years. An abdominalCT scan revealed tumors at the antrum of the stomach and the ascending colon, and the tumor at the ascending colon caused obstruction of the colon. She was diagnosed with breast cancer recurrence and was administered combination chemotherapy consisting of gemcitabine and paclitaxel. Ileus improved after this treatment, and she was discharged from the hospital and was able to receive outpatient chemotherapy. After 8 months, she experienced symptoms of ileus again, and conservative treatment was considered impossible. Therefore, she underwent distal gastrectomy and right hemicolectomy. Histological and immunohistological analyses confirmed that the tumors were breast cancer metastases. Chemotherapy with gemcitabine and paclitaxel helped our patient to return to daily life and improved her prognosis.",
"affiliations": "Dept. of Surgery, Mito Kyodo General Hospital.",
"authors": "Watanabe|Motonobu|M|;Ishibashi|Osamu|O|;Maeda|Masamitsu|M|;Kondo|Tadashi|T|;Watanabe|Muneaki|M|;Dai|Yuichi|Y|;Ohkohchi|Nobuhiro|N|",
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"title": "A Case of Gastrointestinal Metastases of Breast Cancer Effectively Treated with Gemcitabine and Paclitaxel Combination Chemotherapy.",
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"abstract": "Introduction. Simultaneous bilateral fractures of the femoral neck are considered very rare injuries. Few cases were reported in the literature. Most cases were reported in elderly patients with underlying bone pathology. Case Report. We report a case of a 31-year-old male patient who presented to the emergency department with bilateral hip pain and inability to bear weight after a sudden loss of consciousness and fall while running on a treadmill. The patient had a recent history of anabolic steroids, growth hormone, and other supplements used for bodybuilding. Radiological studies confirmed bilateral neck of femur fracture. Laboratory investigations revealed pan-pituitary axis insufficiency and mild vitamin D deficiency, and his EEG suggested a seizure attack. The patient was treated with three 6.5 mm cannulated cancellous screws on one side and a sliding hip screw on the other side and was followed with strict physical therapy and rehabilitation plan. 6 months from the injury, a radiographic bilateral union achieved with the patient back to his normal daily activity and noncontact sports.\nWe report this rare case of bilateral neck of femur fracture in a young adult after a generalized seizure attack with underlying metabolic disturbances. Ruling out other biological underlying etiologies, early diagnosis and early fracture anatomic reduction and fixation are crucial to decrease potential complications such as avascular necrosis and fracture nonunion.",
"affiliations": "Orthopedic Surgery Department, Hamad General Hospital, Doha, Qatar.;Orthopedic Surgery Department, Hamad General Hospital, Doha, Qatar.;Orthopedic Surgery Department, Hamad General Hospital, Doha, Qatar.;Orthopedic Surgery Department, Hamad General Hospital, Doha, Qatar.;Orthopedic Surgery Department, Hamad General Hospital, Doha, Qatar.;Orthopedic Surgery Department, Hamad General Hospital, Doha, Qatar.",
"authors": "Alkaramani|Eslam|E|;Salameh|Motasem|M|https://orcid.org/0000-0002-1369-8837;Adam|Mohammed|M|;George|Bivin|B|;Alser|Yaser|Y|;Ahmed|Ghalib|G|https://orcid.org/0000-0003-4326-7250",
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"fulltext": "\n==== Front\nCase Rep OrthopCase Rep OrthopCRIORCase Reports in Orthopedics2090-67492090-6757Hindawi 10.1155/2020/8972542Case ReportSimultaneous Bilateral Neck of Femur Fracture in a Young Adult with Underlying Metabolic Disturbances Alkaramani Eslam https://orcid.org/0000-0002-1369-8837Salameh Motasem Adam Mohammed George Bivin Alser Yaser https://orcid.org/0000-0003-4326-7250Ahmed Ghalib gahmed@hamad.qaOrthopedic Surgery Department, Hamad General Hospital, Doha, QatarAcademic Editor: Johannes Mayr\n\n2020 29 1 2020 2020 897254213 11 2019 5 1 2020 25 1 2020 Copyright © 2020 Eslam Alkaramani et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction. Simultaneous bilateral fractures of the femoral neck are considered very rare injuries. Few cases were reported in the literature. Most cases were reported in elderly patients with underlying bone pathology. Case Report. We report a case of a 31-year-old male patient who presented to the emergency department with bilateral hip pain and inability to bear weight after a sudden loss of consciousness and fall while running on a treadmill. The patient had a recent history of anabolic steroids, growth hormone, and other supplements used for bodybuilding. Radiological studies confirmed bilateral neck of femur fracture. Laboratory investigations revealed pan-pituitary axis insufficiency and mild vitamin D deficiency, and his EEG suggested a seizure attack. The patient was treated with three 6.5 mm cannulated cancellous screws on one side and a sliding hip screw on the other side and was followed with strict physical therapy and rehabilitation plan. 6 months from the injury, a radiographic bilateral union achieved with the patient back to his normal daily activity and noncontact sports. \n\nConclusion\n We report this rare case of bilateral neck of femur fracture in a young adult after a generalized seizure attack with underlying metabolic disturbances. Ruling out other biological underlying etiologies, early diagnosis and early fracture anatomic reduction and fixation are crucial to decrease potential complications such as avascular necrosis and fracture nonunion.\n\nQatar National Library\n==== Body\n1. Introduction\nFemoral neck fractures in adults younger than 50 represent 2-3% of all neck of femur fractures [1]. Most of these fractures in this age group are caused by high-energy trauma [1, 2]. Simultaneous atraumatic bilateral femoral neck fractures in young adults are considered very rare injuries. Few cases were reported in literature in this age group [3–9]. These fractures are associated with complications such as avascular necrosis and nonunion [10, 11]. Anatomical reduction and early fixation and rehabilitation are crucial to avoid such devastating complications. We report this rare case of bilateral neck of femur fracture in a young adult after a grand mal seizure combined with metabolic disturbances.\n\n2. Case Report\nA 31-year-old male—previously healthy—was brought to the emergency department by ambulance after he lost his consciousness and fell down during running on a treadmill with no witnesses to the event. He was complaining of bilateral hip pain and inability to bear weight. The patient denied any incontinence but reported tongue biting. The patient had a history of drug abuse for body building purposes for the past 3 years. He reported taking anabolic steroids, growth hormone, thyroxine, and creatinine with no professional supervision and no compliance for dose limits.\n\nUpon physical examination, the patient was confused, with tender bilateral hips and externally rotated lower limbs, with no neurovascular compromise. Laboratory investigations revealed pan-pituitary axis insufficiency and mild vitamin D deficiency (Table 1). Radiological investigations showed bilateral neck of femur fractures. Both of which were graded as type IV according to Garden's classification (Figure 1). A computed tomography (CT) scan of the pelvis confirmed the diagnosis with more comminution seen in the left side (Figure 2). A CT scan of the head was done and was unremarkable. Endocrinologists were consulted, and the advice was to keep the patient on corticosteroids and wean him off after the surgical intervention.\n\nThe patient was stabilized and cleared for surgical intervention. He was operated on the same day of admission. A fracture table was used to facilitate closed reduction. After sound reduction fixation was achieved by 6.5 mm cannulated cancellous screws on one side and a sliding hip screw with an antirotation screw on the other side. The senior author's decision to fix the left side with a sliding hip screw was explained by more comminution and higher risk of construct failure compared to the right side. Immediate postoperative images showed acceptable reduction and fixation (Figure 3). Later during the admission, the neurology team was consulted and an Electroencephalogram (EEG) showed Frontal Intermittent Rhythmic Delta Activity (FIRDA), and Magnetic Resonance Image (MRI) of the brain was unremarkable. The patient was diagnosed as a case of Generalized Tonic Clonic Seizure (GTCS) and was started on levetiracetam.\n\nThe patient was discharged on a wheel chair at the beginning and gradually converted to partial- and then full-weight bearing within four months. He had a total of six months of regular follow-up postoperatively with strict physical therapy and rehabilitation plan. In the last follow-up 18 months postinjury, a plain radiograph showed complete fracture union on both sides with no signs of avascular necrosis (Figure 4). His gait was normal, and he could return back to his normal daily activity and noncontact sports.\n\nA follow-up EEG and video monitoring after stopping the hormones and supplements for 6 months were unremarkable, the final diagnosis was a single episode of GCTS due to an overdose of anabolic hormones, and the epilepsy medication was stopped by the neurologist.\n\n3. Discussion\nWe presented this rare case of a 31-year-old healthy male patient with simultaneous atraumatic bilateral neck of femur fractures, and this type of injury in this age group was reported in the literature in few case reports and was the result of high-energy trauma, seizure activity [3, 4, 7], electrical shock [9], or altered bone metabolism [5, 6, 8].\n\nOur case was diagnosed with GTCS with abnormal EEG with no detectable brain lesions on imaging studies, and FIRDA was linked with metabolic disturbances [12, 13] in neurophysiological studies. This would explain this abnormal activity in our patient's EEG who had pan-hypopituitarism due to hormonal abuse for his weight loss and bodybuilding regimen.\n\nThe strong muscle contractions during seizure attacks can cause fractures and dislocations with a rate of 1% [14]. Bilateral neck of femur fractures compromised 6% of the fractures that occur after generalized seizures [15]. Nevertheless, sustaining bilateral neck of femur fracture after a single convulsion should raise the suspicion of underlying bone disease. Our case had a mild deficiency in vitamin D which is endemic in our region, and the other significant finding was the inhibition of his hypothalamic-pituitary access. We believe that the patient's vitamin D deficiency and the concurrent use of steroids altered his bone metabolism and rendered his bone weaker.\n\nCagirmaz et al. [7] reported a similar case of a 24-year-old male that was treated with bilateral closed reduction and percutaneous screw fixation; postoperatively, the patient was diagnosed with osteopenia with −1.9 T score in the lumbar spine. Shah et al. [4] reported a simultaneous bilateral neck of femur fracture after a hypoglycemic seizure attack in a 30-year-old male, with both sides fixed closed with percutaneous screws.\n\nIn conclusion, we present this case of a young adult with atraumatic bilateral neck of femur fracture after a tonic clonic seizure with underlying metabolic bone disease. Ruling out underlying biological etiology, early diagnosis and early fracture anatomic reduction and fixation are crucial in the management of bilateral neck of femur fractures.\n\nAcknowledgments\nThe publication of this article was funded by Qatar National Library.\n\nConflicts of Interest\nThe authors declare that they have no conflict of interest.\n\nFigure 1 Anteroposterior pelvis radiograph showing the bilateral Garden 4 neck of femur fractures.\n\nFigure 2 Axial and coronal pelvis CT scan cuts showing bilateral neck of femur fracture.\n\nFigure 3 Immediate postoperative pelvis and hip radiographs.\n\nFigure 4 18-month follow-up images showing radiographic union of both sides with no signs of avascular necrosis.\n\nTable 1 Patient's lab results on the day of admission.\n\nLab\tResult\tNormal hospital range\t\nVitamin D\t19 ng/ml\t10–30 ng/ml—mild-to-moderate deficiency\t\nPTH—plasma\t149 pg/ml\t15–65 pg/ml\t\nCalcium corrected\t2.05 mmol/l\t2.10–2.55 mmol/l\t\nACTH\t<2 pg/ml\t5–60 pg/ml\t\nCortisol\t<22 nmol/l\t138–580 nmol/l\t\nSHBG\t9.0 nmol/l\t10.0–55.0 nmol/l\t\nFSH\t0.20 IU/ml\t1.00–19.00 IU/ml\t\nLH\t<0.5 IU/l\t1.0–9.0 IU/l\t\nTestosterone\t1.06 nmol/l\t10.40–35.00 nmol/l\t\nTSH\t0.35 mIU/l\t0.45–4.50 mIU/l\t\nFT3\t2.32 pmol/l\t2.89–4.88 pmol/l\t\nFT4\t9.7 pmol/l\t9.0–20.0 pmol/l\t\nPTH = parathyroid hormone; ACTH = adrenocorticotropic hormone; SHBG = sex hormone-binding globulin; FSH = follicular-stimulating hormone; LH = luteinizing hormone; TSH = thyroid-stimulating hormone; FT3 = free triiodothyronine; FT4 = free thyroxine.\n==== Refs\n1 Robinson C. M. Court-Brown C. M. McQueen M. M. Christie J. Hip fractures in adults younger than 50 years of age: epidemiology and results Clinical Orthopaedics and Related Research 1995 312 238 246 \n2 Askin S. R. Bryan R. S. Femoral neck fractures in young adults Clinical Orthopaedics and Related Research 1976 114 259 264 \n3 Haronian E. Silver J. W. Mesa J. Simultaneous bilateral femoral neck fracture and greater tuberosity shoulder fracture resulting from seizure Orthopedics 2002 25 7 757 758 12138963 \n4 Shah H. M. Grover A. Gadi D. Bilateral neck femur fracture following a generalized seizure - a rare case report Archives of Bone and Joint Surgery 2014 2 4 255 257 25692154 \n5 Yoon B.-H. Kwon M.-S. Atraumatic bilateral fracture of the femoral neck in young male patient with suspected osteomalacia Journal of Bone Metabolism 2017 24 3 197 200 10.11005/jbm.2017.24.3.197 28955696 \n6 Selek O. Memisoglu K. Selek A. Bilateral femoral neck fatigue fracture due to osteomalacia secondary to celiac disease: report of three cases Archives of Iranian Medicine 2015 18 8 542 544 26265523 \n7 Cagirmaz T. Yapici C. Orak M. M. Guler O. Bilateral femoral neck fractures after an epileptic attack: a case report International Journal of Surgery Case Reports 2015 6 107 110 10.1016/j.ijscr.2014.12.003 2-s2.0-84919614894 25528038 \n8 Arisumi S. Mawatari T. Ikemura S. Matsui G. Iguchi T. Mitsuyasu H. Spontaneous bilateral femoral neck fractures in a young male adult: a case report and literature review BMC Musculoskeletal Disorders 2019 20 1 p. 449 10.1186/s12891-019-2857-9 2-s2.0-85073436591 31615567 \n9 Nekkanti S. C V. Js S. T. R R. Raj S. An unusual case of simultaneous bilateral neck of femur fracture following electrocution injury-a case report and review of literature Journal of Orthopaedic Case Reports 2016 6 3 70 72 10.13107/jocr.2250-0685.514 28116275 \n10 Stockton D. J. O’Hara L. M. O’Hara N. N. Lefaivre K. A. O’Brien P. J. Slobogean G. P. High rate of reoperation and conversion to total hip arthroplasty after internal fixation of young femoral neck fractures: a population-based study of 796 patients Acta Orthopaedica 2019 90 1 21 25 10.1080/17453674.2018.1558380 2-s2.0-85061059813 30712497 \n11 Slobogean G. P. Sprague S. A. Scott T. Bhandari M. Complications following young femoral neck fractures Injury 2015 46 3 484 491 10.1016/j.injury.2014.10.010 2-s2.0-84924366471 25480307 \n12 Faigle R. Sutter R. Kaplan P. W. Electroencephalography of encephalopathy in patients with endocrine and metabolic disorders Journal of Clinical Neurophysiology 2013 30 5 505 516 10.1097/WNP.0b013e3182a73db9 2-s2.0-84885467263 24084183 \n13 Accolla E. A. Kaplan P. W. Maeder-Ingvar M. Jukopila S. Rossetti A. O. Clinical correlates of frontal intermittent rhythmic delta activity (FIRDA) Clinical Neurophysiology 2011 122 1 27 31 10.1016/j.clinph.2010.06.005 2-s2.0-78650173723 20673647 \n14 Finelli P. F. Cardi J. K. Seizure as a cause of fracture Neurology 1989 39 6 858 860 10.1212/wnl.39.6.858 2725885 \n15 Grzonka P. Rybitschka A. De Marchis G. M. Marsch S. Sutter R. Bone fractures from generalized convulsive seizures and status epilepticus—a systematic review Epilepsia 2019 60 5 996 1004 10.1111/epi.14738 2-s2.0-85065028725 31021422\n\n",
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"title": "Simultaneous Bilateral Neck of Femur Fracture in a Young Adult with Underlying Metabolic Disturbances.",
"title_normalized": "simultaneous bilateral neck of femur fracture in a young adult with underlying metabolic disturbances"
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"abstract": "Combining conventional chemotherapy with targeted therapy has been proposed to improve the pathologic complete response (pCR) rate in patients with inflammatory breast cancer (IBC). Epidermal growth factor receptor (EGFR) expression is an independent predictor of low overall survival in patients with IBC.\n\n\n\nTo evaluate the safety and efficacy of the anti-EGFR antibody panitumumab plus neoadjuvant chemotherapy in patients with primary human epidermal growth factor receptor 2 (HER2)-negative IBC.\n\n\n\nWomen with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy. Median follow-up time was 19.3 months. Tumor tissues collected before and after the first dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pCR.\n\n\n\nPatients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks.\n\n\n\nThe primary end point was pCR rate; the secondary end point was safety. The exploratory objective was to identify biomarkers predictive of pCR.\n\n\n\nForty-seven patients were accrued; 7 were ineligible. The 40 enrolled women had a median age of 57 (range, 23-68) years; 29 (72%) were postmenopausal. Three patients did not complete therapy because of toxic effects (n = 2) or distant metastasis (n = 1). Nineteen patients had triple-negative and 21 had hormone receptor-positive IBC. The pCR and pCR rates were overall, 11 of 40 (28%; 95% CI, 15%-44%); triple-negative IBC, 8 of 19 (42%; 95% CI, 20%-66%); and hormone receptor-positive/HER2-negative IBC, 3 of 21 (14%; 95% CI, 3%-36%). During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events. There were no treatment-related deaths. The most frequent nonhematologic adverse event was skin rash. Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression.\n\n\n\nThis combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC. A randomized phase 2 study is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers.\n\n\n\nClinicalTrials.gov Identifier: NCT01036087.",
"affiliations": "Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.;Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston.;Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston.;Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston.;Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston.;Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston.;Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.",
"authors": "Matsuda|Naoko|N|;Wang|Xiaoping|X|;Lim|Bora|B|;Krishnamurthy|Savitri|S|;Alvarez|Ricardo H|RH|;Willey|Jie S|JS|;Parker|Charla A|CA|;Song|Juhee|J|;Shen|Yu|Y|;Hu|Jianhua|J|;Wu|Wenhui|W|;Li|Nan|N|;Babiera|Gildy V|GV|;Murray|James L|JL|;Arun|Banu K|BK|;Brewster|Abenaa M|AM|;Reuben|James M|JM|;Stauder|Michael C|MC|;Barnett|Chad M|CM|;Woodward|Wendy A|WA|;Le-Petross|H T Carisa|HTC|;Lucci|Anthony|A|;DeSnyder|Sarah M|SM|;Tripathy|Debu|D|;Valero|Vicente|V|;Ueno|Naoto T|NT|",
"chemical_list": "D000077544:Panitumumab; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2018.1436",
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"issn_linking": "2374-2437",
"issue": "4(9)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000505:Alopecia; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005221:Fatigue; D005260:Female; D006801:Humans; D007970:Leukopenia; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000077544:Panitumumab; D018719:Receptor, ErbB-2; D055815:Young Adult",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "1207-1213",
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"pmid": "29879283",
"pubdate": "2018-09-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "17973572;25429827;24794243;19910308;27072223;12748244;14570950;23618408;19901111;28978083;28368261;26840566;19483462;19150933;25728945;24950183;28271910;26869049;26136341;25928118;23073759;19237579;19097774;24351399;27340049;24827135;22508812;25092775;17351259;19825949",
"title": "Safety and Efficacy of Panitumumab Plus Neoadjuvant Chemotherapy in Patients With Primary HER2-Negative Inflammatory Breast Cancer.",
"title_normalized": "safety and efficacy of panitumumab plus neoadjuvant chemotherapy in patients with primary her2 negative inflammatory breast cancer"
} | [
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"abstract": "To evaluate the risk of preterm birth in low-risk women with cervical length (CL) ≤25 mm on transvaginal ultrasound (TVUS) managed with vaginal progesterone (VagP) therapy versus cerclage.\n\n\n\nThis is a retrospective cohort of women with no prior history of preterm birth or cervical insufficiency and CL ≤ 25 mm on TVUS, managed with either VagP therapy alone or cerclage (with or without VagP). The primary outcome was rate of preterm delivery < 37 weeks gestational age (GA). Secondary outcomes included delivery at ≤ 32 or ≤ 28 weeks GA, premature preterm rupture of membranes, pregnancy latency, GA at delivery, and composite neonatal outcome.\n\n\n\nWomen undergoing cerclage placement (n = 31) were older and had an earlier GA at the time of diagnosis of short cervix compared with women receiving VagP (n = 62). Delivery at < 37 weeks occurred in 21/62 (33.9%) in the VagP group and 14/31 (45.2%) in the cerclage group (adjusted odds ratio: 1.72, 95% confidence interval: 0.52, 5.66). There were no differences in secondary outcomes.\n\n\n\nCerclage compared with VagP therapy did not decrease risk of preterm birth in women with CL ≤ 25 mm. Further research is needed to determine optimal management in such women given a residual 40% risk of preterm birth despite optimal therapy.",
"affiliations": "Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina.",
"authors": "Wood|Amber M|AM|;Dotters-Katz|Sarah K|SK|;Hughes|Brenna L|BL|",
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"country": "United States",
"delete": false,
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"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D000282:Administration, Intravaginal; D000328:Adult; D023802:Cerclage, Cervical; D002584:Cervix Uteri; D003131:Combined Modality Therapy; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011256:Pregnancy Outcome; D047928:Premature Birth; D011374:Progesterone; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012306:Risk; D002581:Uterine Cervical Incompetence; D055815:Young Adult",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "111-117",
"pmc": null,
"pmid": "30112757",
"pubdate": "2019-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Cervical Cerclage versus Vaginal Progesterone for Management of Short Cervix in Low-Risk Women.",
"title_normalized": "cervical cerclage versus vaginal progesterone for management of short cervix in low risk women"
} | [
{
"companynumb": "US-ALLERGAN-1841523US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
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"activesubstancename": "PROGESTERONE"
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"abstract": "The authors present clinical case of orthotopic liver transplantation for cirhosis due to chronic viral hepatitis C in a subject with severe hemophilia A. Preoperatively performed pharmacokinetic study with recombinant F VIII confirmed satisfactory in vivo recovery of 2.1 %. A bolus application of 52 units F VIII/kg body weight with target F VIII activity over 100.0 % was administred shortly before the transplantation started. Totally, 30 000 units of recombinant F VIII, 3 thrombocyte concentrates, 2 erythrocyte concentrates, 5 units of virally inactivated plasma, 1 unit of fresh frozen plasma and 3 500 antithrombin units were used. There were no perioperative or postoperative bleeding complications, F VIII substitution was stopped on postoperative day 3. The patient was discharged on twentieth postoperative day.",
"affiliations": null,
"authors": "Polák|Pavel|P|;Smejkal|Petr|P|;Romanová|Gabriela|G|;Zavřelová|Jiřina|J|;Hrdličková|Radomíra|R|;Blahutová|Šárka|Š|;Husová|Libuše|L|;Zvarová|Marta|M|;Penka|Miroslav|M|",
"chemical_list": "D005169:Factor VIII",
"country": "Czech Republic",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-773X",
"issue": "66(5)",
"journal": "Vnitrni lekarstvi",
"keywords": "chronic viral hepatitis C; hemophilia A; liver transplantation",
"medline_ta": "Vnitr Lek",
"mesh_terms": "D005169:Factor VIII; D006467:Hemophilia A; D006801:Humans; D016031:Liver Transplantation",
"nlm_unique_id": "0413602",
"other_id": null,
"pages": "85-89",
"pmc": null,
"pmid": "32942877",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Liver transplantation as potential curative method in severe hemophilia A: case report and literature review.",
"title_normalized": "liver transplantation as potential curative method in severe hemophilia a case report and literature review"
} | [
{
"companynumb": "CZ-BAYER-2020-259014",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
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"activesubstance": {
"activesubstancename": "CARVEDILOL"
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"abstract": "Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy.\n\n\n\nTo determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC.\n\n\n\nThis phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019.\n\n\n\nPembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment.\n\n\n\nSafety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates.\n\n\n\nAmong the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months.\n\n\n\nThese findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study.\n\n\n\nClinicalTrials.gov Identifier: NCT02621398.",
"affiliations": "Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.;Department of Radiation Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Therapeutic Radiology, Smilow Cancer Center, Yale School of Medicine, Yale University, New Haven, Connecticut.;Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.;Department of Radiation Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Section of Medical Oncology, Department of Medicine, Smilow Cancer Center, Yale School of Medicine, Yale University, New Haven, Connecticut.;Division of Hematology Oncology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia.;Division of Hematology Oncology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia.;Department of Radiation Oncology, New York Proton Center, New York, New York.;Department of Radiation Oncology, Winship Cancer Institute, Emory School of Medicine, Emory University Atlanta, Georgia.;Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University.;Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University.",
"authors": "Jabbour|Salma K|SK|;Berman|Abigail T|AT|;Decker|Roy H|RH|;Lin|Yong|Y|;Feigenberg|Steven J|SJ|;Gettinger|Scott N|SN|;Aggarwal|Charu|C|;Langer|Corey J|CJ|;Simone|Charles B|CB|;Bradley|Jeffrey D|JD|;Aisner|Joseph|J|;Malhotra|Jyoti|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016190:Carboplatin; C582435:pembrolizumab; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2019.6731",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2437",
"issue": "6(6)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel; D061026:Programmed Cell Death 1 Receptor; D016896:Treatment Outcome",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "848-855",
"pmc": null,
"pmid": "32077891",
"pubdate": "2020-06-01",
"publication_types": "D017426:Clinical Trial, Phase I; D018848:Controlled Clinical Trial; D016428:Journal Article",
"references": "28811975;28529893;21903745;25506582;27788043;23787994;30955977;25601342;31294749;19097774;23462419;28478231;30280635;25422491;30620668;24382348;24353914;30280658;20351327;29658856;28551359;28529894;26433823;31200833",
"title": "Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.",
"title_normalized": "phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non small cell lung cancer a nonrandomized controlled trial"
} | [
{
"companynumb": "US-PFIZER INC-2019211393",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
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"drugadditional": "3",
... |
{
"abstract": "Although anticoagulation therapy could reduce the risk of strokes in patients with atrial fibrillation (AF), large-scale investigations in the direct oral anticoagulant (DOAC) and AF catheter ablation (CA) era are lacking.\nThis study was designed as a prospective, multicenter, observational study and a total of 2113 patients from 22 institutions were enrolled in the Hyogo area.\nThe mean age and CHADS2 score were 70.1 ± 10.8 years old and 1.5 ± 1.1, respectively. The follow-up period was 355 ± 43 days. CA was performed in 614 (29%) and DOACs were prescribed in 1118 (53%) patients. Ischemic strokes/systemic embolisms (SEs) and major bleeding occurred in 13 (0.6%) and 17 (0.8%) patients, respectively. New onset dementia, hospitalizations for cardiac events, and all-cause death occurred in eight (0.4%), 60 (2.8%), and 29 (1.4%) patients, respectively. A multivariate analysis demonstrated that persistent AF and the body weight (BW) were associated with ischemic strokes/SEs and major bleeding, respectively (persistent AF: hazard ratio, 9.57; 95%CI, 1.2-74.0; P = .03; BW: hazard ratio, 0.94; 95%CI, 0.90-0.99; P = .02). AFCA history was associated with the cardiac events (hazard ratio, 0.44; 95%CI, 0.20-0.99; P = .04). Age was associated with new onset dementia (hazard ratio, 1.1; 95%CI, 1.0-1.2; P = .03).\nIn the DOAC and CA era, the incidence of ischemic strokes/SEs, major bleeding and cardiac events could be dramatically reduced in patients with AF. However, some unsolved issues of AF management still remain especially in elderly patients with persistent AF and a low BW.",
"affiliations": "Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe Japan.;Kita-harima Medical Center Sanda Japan.;Takeuchi Clinic Kobe Japan.;Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe Japan.;Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe Japan.;Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe Japan.;Kobe City Medical Center General Hospital Kobe Japan.;Kakogawa Central City Hospital Kakogawa Japan.;Odake Internal Medicine Cardiology Kobe Japan.;Okada Clinic Kobe Japan.;Himeji Cardiovascular Center Himeji Japan.;Kawahara Internal Medicine Kobe Japan.;Ooyama kinen Hospital Kobe Japan.;Kobe Century Memorial Hospital Kobe Japan.;Ichikawa Internal Medicine Cardiology Kakogawa Japan.;Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe Japan.",
"authors": "Hyogo|Kiyohiro|K|;Yoshida|Akihiro|A|;Takeuchi|Motoshi|M|;Kiuchi|Kunihiko|K|;Fukuzawa|Koji|K|;Takami|Mitsuru|M|;Kobori|Atsushi|A|;Okajima|Katsunori|K|;Odake|Michio|M|;Okada|Toshio|T|;Shimane|Akira|A|;Kawahara|Yasuhiro|Y|;Sekiya|Junichi|J|;Sano|Hiroshi|H|;Ichikawa|Yasunori|Y|;Hirata|Ken-Ichi|KI|;|||",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1002/joa3.12226",
"fulltext": "\n==== Front\nJ ArrhythmJ Arrhythm10.1002/(ISSN)1883-2148JOA3Journal of Arrhythmia1880-42761883-2148John Wiley and Sons Inc. Hoboken 10.1002/joa3.12226JOA312226Original ArticleOriginal ArticleOne‐year clinical outcomes of anticoagulation therapy among Japanese patients with atrial fibrillation: The Hyogo AF Network (HAF‐NET) Registry HYOGO et al.Hyogo Kiyohiro MD\n1\nYoshida Akihiro MD\n2\nTakeuchi Motoshi MD\n3\nKiuchi Kunihiko MD\n1\nkunihikokiuchi@yahoo.co.jp Fukuzawa Koji MD\n1\nTakami Mitsuru MD\n1\nKobori Atsushi MD\n4\nOkajima Katsunori MD\n5\nOdake Michio MD\n6\nOkada Toshio MD\n7\nShimane Akira MD\n8\nKawahara Yasuhiro MD\n9\nSekiya Junichi MD\n10\nSano Hiroshi MD\n11\nIchikawa Yasunori MD\n12\nHirata Ken‐ichi MD\n1\nthe HAF‐NET Registry Investigators \n1 \nSection of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine\nKobe University Graduate School of Medicine\nKobe\nJapan\n\n2 \nKita‐harima Medical Center\nSanda\nJapan\n\n3 \nTakeuchi Clinic\nKobe\nJapan\n\n4 \nKobe City Medical Center General Hospital\nKobe\nJapan\n\n5 \nKakogawa Central City Hospital\nKakogawa\nJapan\n\n6 \nOdake Internal Medicine Cardiology\nKobe\nJapan\n\n7 \nOkada Clinic\nKobe\nJapan\n\n8 \nHimeji Cardiovascular Center\nHimeji\nJapan\n\n9 \nKawahara Internal Medicine\nKobe\nJapan\n\n10 \nOoyama kinen Hospital\nKobe\nJapan\n\n11 \nKobe Century Memorial Hospital\nKobe\nJapan\n\n12 \nIchikawa Internal Medicine Cardiology\nKakogawa\nJapan\n* Correspondence\n\nKunihiko Kiuchi, Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Hospital, 7‐5‐2 Kusunoki‐cho, Chuo‐ku, Kobe city, Japan.\n\nEmail: kunihikokiuchi@yahoo.co.jp\n16 8 2019 10 2019 35 5 10.1002/joa3.v35.5697 708 30 5 2019 27 6 2019 31 7 2019 © 2019 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.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\nBackground\nAlthough anticoagulation therapy could reduce the risk of strokes in patients with atrial fibrillation (AF), large‐scale investigations in the direct oral anticoagulant (DOAC) and AF catheter ablation (CA) era are lacking.\n\nMethods\nThis study was designed as a prospective, multicenter, observational study and a total of 2113 patients from 22 institutions were enrolled in the Hyogo area.\n\nResults\nThe mean age and CHADS2 score were 70.1 ± 10.8 years old and 1.5 ± 1.1, respectively. The follow‐up period was 355 ± 43 days. CA was performed in 614 (29%) and DOACs were prescribed in 1118 (53%) patients. Ischemic strokes/systemic embolisms (SEs) and major bleeding occurred in 13 (0.6%) and 17 (0.8%) patients, respectively. New onset dementia, hospitalizations for cardiac events, and all‐cause death occurred in eight (0.4%), 60 (2.8%), and 29 (1.4%) patients, respectively. A multivariate analysis demonstrated that persistent AF and the body weight (BW) were associated with ischemic strokes/SEs and major bleeding, respectively (persistent AF: hazard ratio, 9.57; 95%CI, 1.2‐74.0; P = .03; BW: hazard ratio, 0.94; 95%CI, 0.90‐0.99; P = .02). AFCA history was associated with the cardiac events (hazard ratio, 0.44; 95%CI, 0.20‐0.99; P = .04). Age was associated with new onset dementia (hazard ratio, 1.1; 95%CI, 1.0‐1.2; P = .03).\n\nConclusions\nIn the DOAC and CA era, the incidence of ischemic strokes/SEs, major bleeding and cardiac events could be dramatically reduced in patients with AF. However, some unsolved issues of AF management still remain especially in elderly patients with persistent AF and a low BW.\n\natrial fibrillationcatheter ablationdementiadirect oral anticoagulantswarfarin source-schema-version-number2.0component-idjoa312226cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:10.10.2019\n\n\nHyogo \nK \n, \nYoshida \nA \n, \nTakeuchi \nM \n, et al; On behalf of the HAF‐NET Registry Investigators \n. One‐year clinical outcomes of anticoagulation therapy among Japanese patients with atrial fibrillation: The Hyogo AF Network (HAF‐NET) Registry . J Arrhythmia . 2019 ;35 :697 –708 . 10.1002/joa3.12226\n==== Body\nAbbreviations\nAFatrial fibrillation\n\nCAcatheter ablation\n\nDOACdirect oral anticoagulants\n\n1 INTRODUCTION\nThe number of patients with atrial fibrillation (AF) is increasing at a rapid rate and is expected to reach beyond one million patients in Japan as the population ages.1 AF has a major risk of thromboembolisms and heart failure. Several studies reported that AF is also related to new onset dementia.2 The annual incidence of cerebral thromboembolisms in AF patients is almost 2%‐4% in Japan and increases with the CHADS2 score/CHA2DS2‐VASc score number.3, 4 Direct oral anticoagulants (DOACs) have been widely used to prevent cerebral infarctions in patients with AF. The advantages of DOACs over warfarin in reducing cerebral infarctions and bleeding complications have been demonstrated in several randomized clinical trials (RCT).5, 6, 7, 8 However, the long‐term outcomes of DOAC use remain unclear in the catheter ablation (CA) era.\n\nAF catheter ablation (AFCA) is widely performed, and some investigations have reported that it is more effective for preventing AF recurrences than medical therapy.9, 10 CA in patients with heart failure has been reported to be associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than medical therapy, while the impact is less in patients without heart failure.11, 12 Evidence that the mortality improves in patients who undergo CA is still limited. Therefore, it is important to reveal how to select the best treatment of AF based on each patient's background.\n\nAF patients without strokes have been followed by cardiologists in Japan. However, once cerebral vascular events occur, those patients are followed by brain surgeons or neurologists. Therefore, it is difficult for primary care doctors to share the events. To share those events, we established the HAF‐NET (HYOGO ATRIAL FIBRILLATION NETWORK) registry, which pooled the data from primary care doctors, brain surgeons, and neurologists. The primary end point was the composite of symptomatic cerebral infarctions including transient ischemic attacks (TIAs), systemic embolisms (SEs), and fatal bleeding complications requiring hospitalization including an intracranial hemorrhage. Secondary end points included a composite of a composite of new onset dementia, cardiac events requiring hospitalization, and all‐cause death. Our goal of this study was to examine the incidence of both primary and secondary endpoints and to identify the predictors for the composite primary end point, secondary end point, and each event including stroke/SE, major bleeding, new onset dementia, hospitalization for cardiac event and all‐cause mortality and to clarify the reality of AF management in Japan by using the data form the HAF‐NET Registry.\n\n2 METHODS\n2.1 Study cohort\nThe HAF‐NET Registry is multicenter, prospective, observational study of Japanese patients with AF. The patients were enrolled from April 2015 to August 2016. Inclusion criteria were those aged 20 or older in whom AF was diagnosed by a 12‐lead or Holter electrocardiogram. There were no exclusion criteria. A total of 22 institutions, all of which were located in Hyogo Prefecture, participated in this registry. They consisted of eight cardiovascular centers, two affiliated or community hospitals, and 12 primary care clinics. All patients were followed through a review of the inpatient and outpatient medical records, and additional information was obtained through contact with the patients, relatives, and/or referring physicians by mail or telephone. The data were checked by clinical research coordinators. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, CONSORT 2010 guidelines and was approved by the ethical committees of Kobe University (Committee of 2014.10.02., Approval No.1643). This study will be registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN‐CTR) (UMIN000036784), and the posted information will be updated as needed to reflect the protocol amendments and study progress.\n\n2.2 Registration card and data collection\nAll patients had a certification of attendance, which contained information including the anticoagulation therapy regimen and contact information of the primary care doctor (Figure 1). Even though clinical adverse events occurred while being seen by secondary care doctors, they could inform the primary care doctor of the events by using this card. The primary care doctor was able to log into the website and register information about any adverse clinical events. The clinical patient data were registered on the online database system by the doctor in charge at each institution. The data were automatically checked for any missing or contradictory entries and values out of the normal range. Additional editing checks were performed by the clinical research coordinators at the general office of the registry.\n\nFigure 1 Registration card. The left panel shows the front side of the registration card where the actual anticoagulation therapy could be checked. The following text was described in the registration card: “Please inform your primary care doctor of the following events: Ischemic stroke, SE, Hemorrhagic stroke, new onset dementia, hospitalization for major bleeding, hospitalization for cardiac event, all‐cause mortality” was written by Japanese. The right panel shows the opposite side of the registration card where the patient name and birthday, primary care doctor's name and telephone number were written. The following text was described in the registration card: “Please always carry this card to inform your doctors of anticoagulation therapy. When you see a doctor, please show this card your doctors, dentists and pharmacists. According to the doctor's suggestion, please do not change the dosage of anticoagulants by self‐determination. Please inform your primary care doctor when the anticoagulation therapy reluctantly stopped.”\n\nThe baseline clinical background data were as follows: patient clinical characteristics including the date of birth, age, gender, body weight, serum creatinine level, date when AF was diagnosed, history of treatment including CA, cardiac surgery, percutaneous coronary intervention, or coronary arterial bypass grafting, type of AF, comorbidities, and risk factors including heart failure, hypertension, diabetes mellitus, strokes/TIAs, vascular disease, valvular disease, ischemic heart disease, cardiomyopathy, dementia, whether patients smoked or consumed alcohol at the time of enrollment, a reduced left ventricular function (%FS < 25% or EF < 35%), current medications including anticoagulant drugs (DOACs or warfarin) and antiplatelet drugs, and subjective symptoms including palpitations, dyspnea and dizziness. Paroxysmal AF was defined as AF that terminated spontaneously within 7 days, while persistent AF was defined as AF that lasted for > 7 days but could be terminated with medication or electrical cardioversion. Long‐lasting persistent AF was defined as AF that lasted > 1 year.\n\nThe risk of a stroke was evaluated by the CHADS2 score and CHA2DS2‐VASc score.13 The risk of bleeding was evaluated by the HAS‐BLED score.14 A PT‐INR of 1.6‐2.6 was the optimal therapeutic range for patients aged 70 or older and a PT‐INR of 2.0‐3.0 was appropriate for patients aged 69 or younger.\n\n2.3 Primary and secondary endpoints\nThe primary endpoints of this registry were symptomatic cerebral infarctions including TIAs, SEs, and fatal bleeding complications requiring hospitalization including an intracranial hemorrhage. A TIA was defined as a sudden onset of focal neurologic symptoms and/or a sign lasting less than 24 hours, brought on by a transient decrease in the blood flow, which rendered the brain ischemic in the area producing the symptom. Fatal bleeding complications were defined as a reduction in the hemoglobin level by ≥2 g/dL, a transfusion of ≥ 2 units of blood, or symptomatic bleeding in a critical area or organ, following the International Society on Thrombosis and Hemostasis definition. The secondary end points were a composite of new onset dementia, cardiac events requiring hospitalization, and all‐cause death. The diagnosis of dementia was based on the Mini‐Mental State Examination and/or Hasegawa dementia rating scale.\n\n2.4 Statistical analysis\nContinuous data were presented as the mean ± SD for normally distributed variables. Medians and quartiles were given for nonnormally distributed variables. If these data followed a normal distribution, they were tested with an unpaired t‐test or Welch test. If not, they were tested with a Mann‐Whitney test. Categorical variables were analyzed with the Fisher's exact test. Cox proportional hazards regression models were used to estimate the hazard ratios and 95% confidence intervals for each event. Previously reported variables including age, gender, BW, AF type, AFCA history, valvular disease, ischemic heart disease, cardiomyopathy, EF less than 35%, heart failure, hypertension, age > 75 years, diabetes mellitus, stroke/TIA, vascular disease, antiplatelet drug, DOAC use, and HAS‐BLED were also selected as cofounders. The multivariable Cox proportional hazards regression model included variables with a P < .05 using an unadjusted Cox proportional hazard regression analysis. To compare the clinical events between the warfarin and DOAC users, 667 age, BW, and CHADS2 score‐matched DOAC and warfarin users were tested. The cumulative incidence of a stroke or SE was determined by the Kaplan‐Meier method. The survival analysis between warfarin and DOACs was performed using a log‐rank test. A value of P < .05 was considered statistically significant. All statistical analyses were performed using SPSS, Release 25 software (SPSS).\n\n3 RESULTS\nA total of 2113 patients were enrolled from 38 institutions in Hyogo prefecture between April 2015 and August 2016. Of those, 1343 (64%) were enrolled from cardiovascular centers, 66 (3%) from affiliated or community hospitals, and 704 (33%) from private clinics. Two thousand and seventy (98%) of the 2113 patients were followed for 1 year after the enrollment and the mean follow‐up period was 355 ± 43 days.\n\n3.1 Baseline characteristics of the registered patients\nThe baseline characteristics of the registered patients are summarized in Table 1. Almost 70% of the patients were male. The mean age was 70.1 years and 36% of them were aged 75 or over. Half of the patients had paroxysmal AF. Almost half of the patients were symptomatic and the most common subjective symptom was palpitations. The mean CHADS2 and CHA2DS2‐VASc scores were 1.5 ± 1.1 and 2.6 ± 1.6, respectively. Figure 2 shows the patients distribution according to the CHADS2 score and CHA2DS2‐VASc score. A CHADS2 score = 1 and CHA2DS2‐VASc score = 3 were the most common subpopulations. Table 2 shows the comorbidities of the patients. Hypertension was by far the most prevalent underlying disease, and 21.3% of the patients suffered from heart failure, of which 5.2% had an ejection fraction of <35%. Ischemic heart disease and valvular disease were present in 7.2% and 13.1%, respectively. Of those, mitral regurgitation was remarkably frequent. Of note, dementia was present in 2.7% of the patients. Almost 30% of the patients had a history of CA.\n\nTable 1 Baseline characteristics of the patients\n\n \t\nOverall\n\n(n = 2113)\n\t\nWarfarin\n\n(n = 725)\n\t\nDOAC\n\n(n = 1118)\n\t\nP value\t\nMale (%)\t1459 (69%)\t493 (68%)\t778 (70%)\t.471\t\nWeight (kg)\t63.9 ± 12.7\t62.5 ± 12.6\t65.0 ± 12.7\t<.001\t\nAge (years old)\t70.1 ± 10.8\t73.1 ± 9.9\t68.9 ± 10.5\t<.001\t\n20‐29\t8 (0.4%)\t0 (0%)\t5 (0.4%)\t \t\n30‐39\t17 (0.8%)\t2 (0.3%)\t9 (0.8%)\t \t\n40‐49\t72 (3.4%)\t14 (2%)\t39 (3%)\t \t\n50‐59\t225 (11%)\t52 (7%)\t129 (12%)\t \t\n60‐69\t616 (29%)\t165 (23%)\t364 (33%)\t \t\n70‐79\t782 (37%)\t289 (40%)\t419 (37%)\t \t\n80‐89\t366 (17%)\t191 (26%)\t143 (13%)\t \t\n90‐99\t27 (1.3%)\t12 (2%)\t10 (1%)\t \t\n≥75\t761 (36%)\t266 (37%)\t379 (34%)\t<.001\t\nRange\t20‐95\t37‐94\t20‐94\t \t\nSerum creatinine (mg/dL)\t0.97 ± 0.65\t1.07 ± 0.75\t0.88 ± 0.36\t<.001\t\nType of AF\t \t \t \t<.001\t\nParoxysmal AF\t1,066 (50%)\t273 (38%)\t595 (53%)\t \t\nPersistent AF\t546 (26%)\t180 (25%)\t319 (29%)\t \t\nLong lasting persistent AF\t501 (24%)\t272 (37%)\t204 (18%)\t \t\nSymptomatic\t1,136 (54%)\t351 (48%)\t624 (56%)\t.002\t\nPalpitation\t916 (43%)\t255 (35%)\t522 (47%)\t<.001\t\nShortness of breath\t341 (16%)\t163 (22%)\t160 (14%)\t<.001\t\nGeneral fatigue\t102 (5%)\t50 (7%)\t47 (4%)\t.014\t\nDizziness\t40 (2%)\t14 (2%)\t18 (2%)\t.590\t\nNote\nValues are presented as the mean ± SD or n (%).\n\nAbbreviations: AF, atrial fibrillation; DOAC, direct oral anticoagulant.\n\nJohn Wiley & Sons, LtdFigure 2 The distribution of the CHADS2 and CHA2DS2‐VASc scores. Panel A shows the CAHDS2 score distribution and panel B the CHA2DS2‐VASc score distribution\n\nTable 2 Comorbidities\n\n \t\nOverall\n\n(n = 2113)\n\t\nWarfarin\n\n(n = 725)\n\t\nDOAC\n\n(n = 1118)\n\t\nP value\t\nStroke/TIA\t196 (9.3%)\t82 (11%)\t106 (10%)\t.208\t\nHeart failure\t463 (22%)\t244 (34%)\t193 (17%)\t<.001\t\nEF < 35%\t110 (5.2%)\t73 (10%)\t34 (3%)\t<.001\t\nValvular disease\t284 (13%)\t180 (25%)\t86 (8%)\t<.001\t\nAortic regurgitation\t77 (3.6%)\t44 (6%)\t25 (2%)\t<.001\t\nMitral regurgitation\t173 (8.2%)\t106 (15%)\t57 (5%)\t<.001\t\nTricuspid regurgitation\t63 (3.0%)\t47 (6%)\t12 (1%)\t<.001\t\nAortic stenosis\t40 (1.9%)\t27 (4%)\t7 (0.6%)\t<.001\t\nMitral stenosis\t28 (1.3%)\t26 (4%)\t2 (0.2%)\t<.001\t\nIschemic heart disease\t153 (7.2%)\t75 (10%)\t66 (6%)\t.001\t\nCardiomyopathy\t178 (8.4%)\t84 (12%)\t83 (7%)\t.003\t\nVascular disease\t130 (6.2%)\t53 (7%)\t66 (6%)\t.245\t\nDiabetes mellitus\t328 (16%)\t133 (18%)\t163 (15%)\t.032\t\nHypertension\t1,208 (57%)\t423 (58%)\t663 (59%)\t.698\t\nRenal disease\t242 (11%)\t137 (19%)\t77 (7%)\t<.001\t\nHemodialysis\t11 (0.5%)\t4 (0.6%)\t0 (0%)\t.024\t\nLiver disease\t31 (1.5%)\t6 (0.8%)\t22 (2%)\t.053\t\nDementia\t56 (2.7%)\t28 (4%)\t22 (2%)\t.009\t\nHistory of open‐heart surgery\t211 (10%)\t133 (18%)\t64 (6%)\t<.001\t\nHistory of CABG\t35 (1.7%)\t23 (3%)\t9 (0.8%)\t<.001\t\nHistory of PCI\t116 (5.5%)\t55 (8%)\t54 (5%)\t.015\t\nHistory of CA for AF\t614 (29%)\t163 (22%)\t277 (25%)\t.264\t\nPacemaker implantation\t114 (5.4%)\t66 (0.8%)\t40 (4%)\t<.001\t\nCHADS2 score\t1.5 ± 1.1\t1.8 ± 1.2\t1.4 ± 1.1\t<.001\t\nCHA2DS2‐VASc score\t2.6 ± 1.6\t3.0 ± 1.6\t2.5 ± 1.5\t<.001\t\nHAS‐BLED score\t1.3 ± 1.0\t1.6 ± 1.0\t1.2 ± 0.9\t<.001\t\nNote\nValues are presented as the n (%). Vascular disease indicates patients with a prior myocardial infarction, peripheral arterial disease, or aortic plaque. Renal disease indicates the patients with hemodialysis, transplantations, or abnormalities of the creatinine level of >2.26 mg/dL or >200 μmol/L. Liver disease indicates patients with cirrhosis or a bilirubin level > 2×normal with an AST/ALT/AP >3 × normal.\n\nAbbreviations: AF, atrial fibrillation; CABG, coronary arterial bypass grafting; EF, ejection fraction; TIA, transient ischemic attack; PCI, percutaneous coronary intervention.\n\nJohn Wiley & Sons, LtdCompared to the patients without a CA history, those with a history of CA had a younger age, mainly paroxysmal AF, fewer underlying diseases, lower CHADS2 and CHA2DS2‐VASc scores, and lower HAS‐BLED score (age: 65.7 ± 10.3 vs. 71.8 ± 10.6 years old, P < .001; heart failure: 15.3% vs. 24.6%, P < .001; CHADS2 score: 1.23 ± 1.12 vs. 1.59 ± 1.11, P < .001; CHA2DS2‐VASc score: 2.23 ± 1.68 vs. 2.73 ± 1.50, P < .001; HAS‐BLED score: 1.08 ± 0.97 vs. 1.40 ± 0.97, P < .001), while a stroke/TIA history was more frequently observed in those with an AFCA history (11.4% vs. 8.4%, P = .007). Of note, fewer anticoagulant drugs or antiplatelet drugs were used in the patients with an AFCA history (anticoagulant drug use: 71.5% vs. 93.6%, P < .001; antiplatelet drug use: 5.9% vs. 10.6%, P = .001).\n\n3.2 Medications in HAF‐NET patients\nFigure 3A showed the medications at enrollment. Anticoagulant drugs were used in 86% of the patients. DOACs were prescribed in almost half of the patients. Edoxaban was prescribed in a small number of the patients, because the enrollment of this study ended several months after edoxaban was released. Antiplatelet drugs were used for 9.2% of the patients. Figure 3B shows the distribution of each DOAC dose. Low‐dose users were common in both the dabigatran and edoxaban users, but not in the rivaroxaban and apixaban users. Of note, inadequate dose user was extremely low in DOAC group (10% in Rivaroxaban users, 10% in Apixaban users and 15 % in Edoxaban users).\n\nFigure 3 The proportion of anticoagulants and dosing. Panel A shows the proportion of anticoagulants and panel B the proportion of standard or low dosing of each DOAC. The numbers indicated the percentages\n\nCompared to the DOACs, warfarin was prescribed in elderly patients with a lower BW and higher creatinine level (age: 73.1 ± 9.9 vs. 68.9 ± 10.5 years old, P < .001; BW: 62.5 ± 12.6 vs. 65.0 ± 12.7, P < .001; serum creatinine level: 1.07 ± 0.75 vs. 0.88 ± 0.36, P < .001). The AF types including paroxysmal, persistent, and long‐lasting AF were equally distributed in the warfarin users, while paroxysmal AF was dominantly found in the DOAC users. The symptoms were less in the warfarin users (Table 1). Heart failure, an EF of <35%, valvular disease, ischemic heart disease, cardiomyopathy, diabetes mellitus, renal disease, hemodialysis, dementia, a history of open‐heart surgery, a CABG, and PCI were frequently observed in the warfarin users, which resulted in a higher CHADS2. CHA2DS2‐VASc and HAS‐BLED score as compared to the DOACs users (CHADS2 score: 1.8 ± 1.2 vs. 1.4 ± 1.1, P < .001; CHA2DS2‐VASc score: 3.0 ± 1.6 vs. 2.5 ± 1.5, P < .001, HAS‐BLED score: 1.6 ± 1.0 vs. 1.2 ± 0.9, P < .001; Table 2).\n\nNo anticoagulant therapy was performed in 270 (13%) patients who were significantly younger and their CHADS2 and CHA2DS2‐VASc scores were significantly lower (age: 66.2 ± 12.6 vs. 70.6 ± 10.4 years old, P < .001; CHADS2 score: 1.0 ± 0.9 vs. 1.6 ± 1.1, P < .001; CHA2DS2‐VASc score: 1.9 ± 1.5 vs. 2.7 ± 1.6, P < .001). Of note, a CA history was more frequently observed in patients without anticoagulant therapy than in those who did not undergo CA (174 [64%] of 270 vs. 440 [24%] of 1843 patients, P < .001).\n\n3.3 The incidence of primary and secondary endpoints and the clinical predictors\nA composite of the primary and secondary endpoints was found in 30 (1.4%) and 99 (4.4%) patients, respectively. Of those, ischemic strokes/SEs and major bleeding occurred in 13 (0.6%) and 17 (0.8%) patients, respectively. New onset dementia, hospitalization for cardiac events, and all‐cause death occurred in eight (0.4%), 60 (2.8%), and 29 (1.4%) patients, respectively. According to a multivariable Cox proportional hazard regression analysis, the most predictive model of a stroke/SE consisted of the AF type (persistent) and that of major bleeding consisted of the BW as well as the HAS‐BLED score (AF type: HR: 9.54, 95% CI: 1.23‐73.97, P = .03; BW: HR: 0.94, 95% CI: 0.90‐0.99, P = .03; HAS‐BLED score: HR: 1.82, 95% CI: 1.12‐2.96, P = .02; Table 3). The most predictive model of new onset dementia consisted of the age and diabetes mellitus (age: HR: 1.12, 95% CI: 1.01‐1.24, P = .03; diabetes mellitus: HR: 3.51, 95% CI: 1.17‐10.54, P = .03), that of hospitalization for cardiac events consisted of AFCA history as well as serum creatinine, heart failure (AFCA history: hazard ratio, 0.44; 95%CI, 0.20‐0.99; P = .04; serum creatinine: HR: 1.25, 95% CI: 1.02‐1.53, P = .03; heart failure: HR: 2.12, 95% CI: 1.12‐4.00, P = .02), and that of all‐cause mortality consisted of the age and EF less than 35% (age: HR: 1.21, 95% CI: 1.12‐1.32, P < .01; EF less than 35%: HR: 5.71, 95% CI: 1.68‐19.42, P < .01; Table 4).\n\nTable 3 Cox regression analysis of the primary endpoint and clinical characteristics\n\n \tStroke or SE\tMajor bleeding\tComposite primary endpoint\t\nAdjusted HR\t\nP value\tAdjusted HR\t\nP value\tAdjusted HR\t\nP value\t\nAge (years old)\t1.07 (1.00‐1.14)\t.06\t \t \t1.01 (0.94‐1.10)\t.72\t\nBW (kg)\t \t \t0.94 (0.90‐0.99)\t.03\t0.97 (0.93‐1.00)\t.08\t\nAF type (persistent)\t9.54 (1.23‐73.97)\t.03\t \t \t1.89 (0.75‐4.74)\t.18\t\nAF ablation history\t \t \t \t \t0.24 (0.05‐1.09)\t.06\t\nValvular disease\t \t \t1.65 (0.54‐4.99)\t.38\t2.06 (0.86‐4.95)\t.11\t\nIschemic heart disease\t \t \t3.23 (0.81‐12.94)\t.10\t2.46 (0.77‐7.90)\t.13\t\nCardiomyopathy\t \t \t \t \t1.25 (0.35‐4.52)\t.73\t\nEF < 35%\t \t \t1.79 (0.50‐6.50)\t.37\t2.03 (0.58‐7.15)\t.27\t\nHeart failure\t \t \t2.76 (0.81‐9.41)\t2.76\t1.78 (0.70‐4.40)\t.23\t\nAge > 75 years\t \t \t \t \t0.71 (0.21‐2.41)\t.59\t\nDiabetes mellitus\t3.51 (1.17‐10.54)\t.03\t \t \t3.05 (1.32‐7.03)\t<.01\t\nStroke/TIA\t \t \t \t \t2.26 (0.72‐7.10)\t.16\t\nVascular disease\t3.41 (0.92‐12.65)\t.07\t \t \t1.29 (0.35‐4.74)\t.70\t\nAntiplatelet drugs\t \t \t0.88 (0.21‐3.63)\t.85\t1.01 (0.30‐3.43)\t.99\t\nHAS‐BLED score\t \t \t1.82 (1.12‐2.96)\t.02\t \t \t\nAbbreviations: AF, atrial fibrillation; BW, body weight; EF, ejection fraction; SE, systemic embolism; TIA, transient ischemic attack.\n\nJohn Wiley & Sons, LtdTable 4 Cox regression analysis of the secondary endpoint and clinical characteristics\n\n \tNew onset dementia\tHospitalization for cardiac event\tAll‐cause mortality\tComposite secondary endpoint\t\nAdjusted HR\t\nP value\tAdjusted HR\t\nP value\tAdjusted HR\t\nP value\tAdjusted HR\t\nP value\t\nAge (years old)\t1.12 (1.01‐1.24)\t.03\t1.70 (0.94‐3.12)\t.08\t1.21 (1.12‐1.32)\t<.01\t1.04 (1.00‐1.08)\t.06\t\nBW (kg)\t \t \t \t \t0.99 (0.95‐1.03)\t.59\t1.00 (0.98‐1.02)\t.65\t\nAF type (persistent)\t \t \t \t \t0.59 (0.27‐1.33)\t.21\t1.11 (0.69‐1.80)\t.66\t\nSerum creatinine\t \t \t1.25 (1.02‐1.53)\t.03\t \t \t1.20 (1.00‐1.43)\t.05\t\nAF ablation history\t \t \t0.44 (0.20‐0.99)\t.04\t0.25 (0.03‐1.94)\t.18\t0.50 (0.25‐0.99)\t.04\t\nValvular disease\t1.70 (0.35‐8.30)\t.52\t2.27 (1.22‐4.22)\t<.01\t1.68 (0.70‐4.03)\t.24\t1.68 (1.01‐2.78)\t.05\t\nIschemic heart disease\t \t \t1.73 (0.71‐4.22)\t.23\t0.82 (0.22‐3.10)\t.77\t1.23 (0.57‐2.66)\t.59\t\nCardiomyopathy\t \t \t \t \t1.49 (0.14‐15.48)\t.74\t \t \t\nEF < 35%\t \t \t2.04 (0.27‐15.14)\t.90\t5.71 (1.68‐19.42)\t<.01\t2.65 (0.63‐11.20)\t.18\t\nHeart failure\t4.92 (0.86‐28.19)\t.07\t2.12 (1.12‐4.00)\t.02\t2.37 (0.94‐5.96)\t.07\t2.24 (1.35‐3.73)\t<.01\t\nAge > 75 years\t \t \t \t \t0.51 (0.12‐2.21)\t.37\t1.15 (0.58‐2.29)\t.70\t\nDiabetes mellitus\t3.51 (1.17‐10.54)\t.03\t \t \t1.34 (0.48‐3.71)\t.57\t0.88 (0.48‐1.62)\t.70\t\nStroke/TIA\t \t \t \t \t1.73 (0.55‐5.43)\t.34\t \t \t\nVascular disease\t3.41 (0.92‐12.65)\t.07\t1.98 (0.79‐4.97)\t.14\t3.18 (0.92‐10.94)\t.07\t2.31(1.13‐4.75)\t.02\t\nAntiplatelet drugs\t \t \t1.44 (0.56‐3.67)\t.45\t1.22 (0.38‐3.95)\t.74\t1.22 (0.59‐2.50)\t.59\t\nAbbreviations: AF; atrial fibrillation; BW; body weight; EF; ejection fraction; SE; systemic embolism; TIA; transient ischemic attack.\n\nJohn Wiley & Sons, LtdFocusing on the patients without anticoagulation therapy, a composite primary and secondary endpoints was found in two (0.7%) and 11 (4.1%) of 270 patients, respectively. Of those, ischemic strokes/SEs and major bleeding occurred in one (0.4%) and one (0.4%) patients, respectively. New onset of dementia, hospitalization for cardiac event and all‐cause death occurred in one (0.4%), six (2.2%), and five (1.9%) patients, respectively. Notably, 174 (64%) of 270 patients without anticoagulation therapy had CA history. Although hospitalization for cardiac event was found in four (2%) of 174 patients, no other events including stroke/SE, major bleeding, new onset of dementia and all‐cause death were found in the 174 patients with CA. Furthermore, 614 (29%) of 2113 patients had CA history regardless of anticoagulation therapy, primary and secondary endpoints were found in 4(0.7%) and 18(3%), respectively. Of those, stroke/SE, major bleeding, new onset of dementia, hospitalization for cardiac event, and all‐cause death were found in one (0.2%), three (0.5%), two (0.3%), 15 (2%) and one (0.2%) patients, respectively.\n\nTo assess the clinical impact of the DOACs, 667 age, BW, CHADS2 score‐matched DOAC and warfarin users were compared (DOAC vs. warfarin; age: 72.0 ± 9.3 vs. 72.2 ± 9.7, P = .67; BW: 62.2 ± 11.5 vs. 62.9 ± 12.7, P = .30; CHADS2 score: 1.7 ± 1.1 vs. 1.7 ± 1.1, P = .96). A composite of the primary and secondary endpoints was found in nine (1.3%) and 24 (3.6%) DOAC users, and in 15 (2.2%) and 36 (5.4%) of the 667 warfarin users, respectively. Of those, the incidence of the ischemic strokes/SEs was significant less in DOAC users (1 [0.1%] of 667 vs. 8 [1.2%] of 667, log‐rank P = 0.02; Figure 4). The incidence of the other endpoints including major bleeding, new onset dementia, hospitalization for cardiac events, and all‐cause death did not differ between the DOAC and warfarin users (major bleeding: 8 [1.2%] vs. 7 [1.0%] of 667 patients, P = .79; new onset of dementia: 1 [0.1%] vs. 3 [0.4%] of 667 patients, P = .32; hospitalization for cardiac event: 16 [2.4%] vs. 23 [3.4%] of 667 patients, P = .26; all‐cause death: 7 [1.0%] vs. 12 [1.8%] of 667 patients, P = .25).\n\nFigure 4 Kaplan‐Meier curve for the primary and secondary endpoints, ischemic strokes/SEs, major bleeding, new onset dementia, cardiac events, and all‐cause mortality between the warfarin and DOAC users. The clinical events were assessed among 667 age, BW, CHADS2 score, and CHA2DS2‐VASc score‐matched DOAC and warfarin users\n\n4 DISCUSSION\n4.1 Main findings of the study\nThe data from the HAF‐NET registry demonstrated a higher DOAC use and AFCA history as compared to the previous studies, which resulted in excellent outcomes after 1 year of follow‐up among Japanese patients with AF in the DOAC and AF ablation era. Persistent AF and a lower BW were strongly associated with stokes/SEs and major bleeding, respectively. AFCA history as well as age and heart failure were associated with the composite secondary endpoints including new onset dementia, hospitalization for cardiac events, and all‐cause mortality.\n\n4.2 Patient characteristics\nOne‐third (800 patients) of the patients in this registry were from Chuo‐Ku, which is located in the southern region of Kobe city. The population of Chuo‐Ku is approximately 135 000 people. Based on the epidemiological prevalence of AF in the Japanese population of 0.6%, the number of AF patients in Chuo‐Ku was estimated to be approximately 810. As the number in our registry was almost equal to the estimated AF patients in Chuo‐Ku, the AF patents in this registry were assumed to fully reflect a typical ward in Kobe city.\n\nIn Japan, real‐world data of the anticoagulation therapy in patients with AF have been published from two major AF registry such as FUSHIMI and SAKURA registry.15, 16 The enrollment of the FUSHIMI and SAKURA registries was performed from 2011 to 2014 and from 2013 to 2015, respectively. As compared to the patient characteristics of the patients enrolled by the FUSHIMI and SAKURA registries, younger patients with lower CHADS2 scores were enrolled in our registry. The mean age of the HAF‐NET, SAKURA, and FUSHIMI registries was 70, 72, and 74 years old, respectively. The mean BW was 64, 64, and 58 kg and persistent AF 49%, 63% and 54% in the enrolled patients, respectively. The prevalence of a stroke/TIA history was 9%, 11%, and 19 %, respectively. The mean CHADS2 scores were 1.5, 1.8, and 2.1, respectively.\n\nThe FUSHIMI registry recruited patients mainly from private clinics, while the HAF‐NET and SAKURA registries recruited those from cardiovascular centers, affiliated hospitals, community hospitals, and private clinics. Sixty‐four and 48 private clinics participated in the FUSHIMI and SAKURA registries, respectively, while there were only 15 in the HAF‐NET registry. The proportion of patients from private clinics completely differed. This might be the reason why the patient characteristics differed among the three registries.\n\n4.3 Medications in HAF‐NET patients\nWarfarin was prescribed in only around 30% of the patients in the HAF‐NET registry. As compared to the FUSHIMI and SAKURA registries, the proportion of warfarin users was significantly smaller in the HAF‐NET registry (32% vs. 54% vs. 48% in the HAF‐NET, SAKURA, and FUSHIMI registries). However, the proportion of DOAC users was significantly greater (53% vs. 46% vs. 2% in the HAF‐NET, SAKURA, and FUSHIMI registries). Several studies from the J‐RHYTHM and SHINKEN databases reported the increase in DOAC users, from 6.1% in 2012 to 20.4 % in 2014, and from none in 2007‐2009 to 25.5% in 2010‐2012.17, 18 The HAF‐NET registry demonstrated the actual anticoagulation therapy use in the DOAC era. The prevalence of a low‐dose usage of DOACs was significantly less in rivaroxaban/apixaban users than in dabigatran/edoxaban users. Of importance, the SAKURA registry identified inappropriately low dosing in 19.7 to 27.6% of the DOAC users. The proportion of an adjusted low dosing was estimated to be almost 20% in the rivaroxaban or apixaban users and almost 50% in the dabigatran or edoxaban users. Furthermore, postmarketing studies for each DOAC also estimated that the proportion of an adjusted low dosing was almost 30% in the rivaroxaban or apixaban users and almost 60% in the dabigatran or edoxaban users.19, 20, 21, 22 The proportion of this estimated adequately low‐dosing usage in the SAKURA registry was similar to our results. This indicated that the inadequate low dosing in the HAF‐NET registry was extremely less than that in the previous AF registries. Almost 8 years have passed since dabigatran was released as the first DOAC in 2011. Over the past decade, we have experienced the importance of adequate dosing of DOACs, which has increased major bleeding as well as strokes or TIAs. Therefore, adequate dosing might be challenged in the recent real world of AF anticoagulation therapy in Japan. Actually, our data clearly supported this challenge and demonstrated excellent outcomes.\n\n4.4 Primary and secondary endpoints and clinical predictors\nThe two major postmarket surveillance (PMS) studies (J‐Dabigatran surveillance, XAPASS) showed the incidence rates of major bleeding and thromboembolic events, suggesting that dabigatran and rivaroxaban were safe and effective in the Japanese clinical practice. The J‐Dabigatran surveillance demonstrated that major bleeding, strokes/SEs, and all‐cause death occurred in 1.1%, 1.2%, and 1.3%/year, respectively.19 The XAPASS study demonstrated that major bleeding, strokes/SEs, and all‐cause death occurred in 1.5%, 1.1%, and 2.1%/year, respectively.23 While the HAF‐NET registry demonstrated that major bleeding, strokes/SEs, and all‐cause death occurred in 0.6%, 0.8%, and 1.4%/year, which was likely better than that in the two major PMS studies. Although 13% of the patients without anticoagulation therapy and 30% of warfarin users were enrolled in the HAF‐NET registry, the CHADS2 score was lower and a CA history was found in almost 30% of the patients who mainly had a stroke history or no anticoagulation therapy. This might have reduced the AF burden, which resulted in an excellent outcome. Iguchi et al. demonstrated that patients with preexisting heart failure had higher unadjusted rates of strokes/SEs (HR, 1.40; 95% CI, 1.05‐1.85; P = .02 by a log‐rank test) as well as higher incidences of all‐cause death and a composite of all‐cause death or strokes/SEs.24 Although AFCA history could not be associated with strokes/SEs in the HAF‐NET registry, we could clearly demonstrate that the AFCA history could be associated with the lower cardiovascular hospitalization, which indicated that the possibility improving the higher strokes/SEs as well as higher incidences of all‐cause death and a composite of all‐cause death or strokes/SEs. Recently, Packer et al reported that the composite endpoints of mortality and cardiovascular hospitalization exhibited a significant 17% relative lower event rate for the CA group than medical therapy group. To improve the mortality as well as quality of life, CA might be aggressively considered especially in patients with heart failure or a stroke history.12\n\n\n4.5 Catheter ablation and anticoagulation therapy\nRecently, several studies have reported the impact of CA on the mortality and cardiovascular hospitalization in patients with AF. Especially in patients with heart failure, the impact has been greater. The CATSLE‐AF study clearly demonstrated that CA was associated with a significantly lower rate of the composite end point of death from any cause or hospitalization for worsening heart failure as compared to medical therapy. Although no statistical significance could be found, cerebrovascular accidents were dramatically reduced by CA as compared to medical therapy.11 Furthermore, the impact of CA has been greater in patients with an age of <65 years old, heart failure of <NYHA functional class II, and EF of ≧ 25%. The CABANA study also reported that the impact of CA was greater in patients with an age of <65 years old.12 Those two RCTs indicated the importance of early intervention to maintain sinus rhythm by CA in patients with AF. Patients with a CA history in the HAF‐NET registry had relatively low CHADS2 and CHA2DS2‐VASc scores and the incidence of clinical events was extremely low. This indicated that CA could be considered as an early intervention for AF management in the real world. Based on those clinical results, the Japanese guidelines have been updated and the latest one (2018 JCS/JHRS Guideline on Non‐Pharmacotherapy of Cardiac Arrhythmias) was published in May 2019. In the latest guidelines, CA was recommended as a class IIa indication for drug refractory, recurrent paroxysmal and persistent AF regardless of heart failure. This will facilitate the CA in patients with heart failure, which might strengthen the impact of CA on AF management in the next decade.\n\n4.6 Impact of DOACs on preventing clinical events\nPrevious RCTs have revealed better clinical outcomes especially for fatal bleeding under DOAC therapy than under warfarin therapy. However, fewer Japanese patients could be enrolled in those RCTs.5, 6, 7, 8 The SAKURA registry showed no significant differences in the rates of strokes or SEs, major bleeding, and all‐cause mortality for DOAC vs. warfarin users. Under propensity score matching, the incidence of strokes or SEs and all‐cause death remained equivalent, but the incidence of major bleeding was significantly lower among DOAC than warfarin users.25 In the HAF‐NET registry, the incidence of strokes or SEs was significantly lesser in the DOAC users, but not that for major bleeding. This discrepancy might be caused by the frequency of the CA history. Progression of AF was reported to be associated with an increased risk of clinical adverse events during the arrhythmia progression period from paroxysmal to persistent AF among Japanese patients with AF. The risk of adverse events was also transiently elevated during the progression period from paroxysmal to persistent AF and declined to a level equivalent to persistent AF after the progression.26 A CA history was found in almost 10% and 25% in the SAKURA an HAF‐NET registries, respectively. As compared to medical therapy, CA could strongly reduce the AF burden and no progression toward persistent AF was observed during a median follow‐up of 6 years especially in patients with paroxysmal AF.27 In such patients without AF recurrence after a successful CA, DOACs might be continued without a dose reduction, while the PT‐INR level might be controlled at a lower level to avoid the fatal bleeding. This suggested the importance of CA and DOACs for preventing strokes or SEs and the awareness of an adequate DOAC lower dosing after a successful CA.\n\n4.7 Dementia and AF\nA meta‐analysis reported that AF was independently associated with an increased risk of all forms of dementia.1 The incidence of dementia in the patients without AF was almost 3.0% during a follow‐up period of over 5 years. After a dementia diagnosis, the presence of AF was associated with a marked increased risk of mortality.2 Recently, individuals with AF have been reported to have an almost threefold increased risk of dementia during a 12 year follow‐up (HR 2.8; 95% CI 1.3‐5.7; P = .004). The population attributable risk for dementia resulting from AF was 13%. They concluded that patients with AF should be screened for cognitive symptoms.28 In the HAF‐NET registry, dementia diagnosed before enrollment was found in 56 (2.7%) of the patients and the incidence of new onset dementia was 8 (0.4%) patients. This annulus incidence of dementia was similar to that in patients without AF. This might be the impact from anticoagulation therapy with DOACs and a strong rhythm control therapy with CA. We hope that this impact would continue during the follow‐up of over 3 years because the average time to the development of dementia has been reported to be almost 3 years.\n\n4.8 Study limitations\nThis study had several limitations. First, this study was designed as a prospective observational study, therefore, only associations were shown, not causality. The possibility of unmeasured or residual confounding factors was not ruled out. Second, anticoagulant therapy was assessed at the time of the enrollment, but the changes in the medical therapy could not be assessed. Third, to assess the impact of the DOAC therapy, age, BW, and CHADS2 score‐matched DOAC, and warfarin users were compared because of the small number in each medical therapy group. Fourth, this study involved AF patients recruited from a small region of Japan, and therefore, the results might not be generalizable to the overall population.\n\n5 CONCLUSION\nThe HAF‐NET registry was characterized as (a) having a high incidence of DOAC prescriptions and a CA history and (b) including relatively younger patients with lower CHADS2 scores. In the DOAC and CA era, the incidence of ischemic strokes/SEs, major bleeding and hospitalization for the cardiac events could be strongly reduced in patients with AF. However, some unsolved issues of AF management still remain especially in elderly patients with persistent AF and a low BW.\n\nCONFLICT OF INTERESTS\nThe Section of Arrhythmia is supported by an endowment from Medtronic JAPAN and Abbott JAPAN. The authors have reported that they have no relationship relevant to the contents of this paper to disclose.\n\nSupporting information\n \n\nClick here for additional data file.\n\n ACKNOWLEDGEMENTS\nWe would like to thank John Martin for his linguistic assistance and Hiromasa Suzuki for his assistance with the clinical research coordination. The key personnel and institutions participating in the registry are as follows: Chief investigator: Yoshida A (Kita‐harima Medical Center) Vice‐chief investigator: Fukuzawa K (Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Hospital) Steering Committee: Yoshida A (Kita‐harima Medical Center), Takeuchi M (Kobe Medical Association), Fukuzawa K (Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Hospital) Statistical Analysis: Kiuchi K (Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Hospital) Participating institutions: Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Hospital (Hyogo K, Kiuchi K, Fukuzawa K, Takami M, Yamashita S, Matsumoto A, Ichibori H, Konishi H, Imada H, Kurose J, Nagamatsu Y, Suehiro H, Akita T, Takemoto M, Nakamura T, Sakai J); Department of Internal Medicine, Kobe University Hospital (Shinke T, Otake H, Hirata K); Kita‐harima Medical Center (Yoshida A, Awano K, Ohashi Y, Yamada S, Nakagawa M, Yamawaki K, Tagashira T, Hiraishi M, Nakabayashi A, Ishii T, Hamaguchi H, Oda T, Takada M, Nagata K, Takami K, Tsuda S); Takeuchi Clinic (Takeuchi M); Himeji Cardiovascular Center (Shimane A); Kakogawa Central City Hospital (Okajima K, Shimizu H, Onishi Y, Nakanishi T, Nakamura H, Kadotani M, Yasuda T, Miwa K, Kaetsu Y, Yatomi A, Matsuoka Y, Nakaoka H, Yamana S, Fujinami Y, Shimoura H, Shiraki R, Namura H); Aijinkai Healthcare Corporation Akashi (Sakamoto S); Kobe City Medical Center General Hospital (Kobori A, Furukawa Y, Sasaki Y); Kobe Century Memorial Hospital (Sano H, Suematsu M, Mataki H, Mizutani K, Masuda Y); Japanese Red Cross Kobe Hospital (Doi T); Ichikawa Internal Medicine Cardiology (Ichikawa Y); Odake Internal Medicine Cardiology (Odake M); Yano Internal medicine clinic (Yano T); Okukubo Clinic (Okukubo T); Kudo Internal medicine clinic (Kudo Y); Shima Internal medicine clinic (Shima T); Ooyama kinen Hospital (Sekiya J); Okada Clinic (Okada T); Tamada Internal medicine (Tamada K); Kawahara Internal Medicine (Kawahara Y); Tanaka Internal Medicine Cardiology (Tanaka C); Tabuchi Clinic (Tabuchi H).\n==== Refs\nREFERENCES\n1 \n\nSantangeli \nP \n, \nDi Biase \nL \n, \nBai \nR \n, \nMohanty \nS \n, \nPump \nA \n, \nCereceda Brantes \nM \n, et al. 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"fulltext_license": "CC BY",
"issn_linking": "1880-4276",
"issue": "35(5)",
"journal": "Journal of arrhythmia",
"keywords": "atrial fibrillation; catheter ablation; dementia; direct oral anticoagulants; warfarin",
"medline_ta": "J Arrhythm",
"mesh_terms": null,
"nlm_unique_id": "101263026",
"other_id": null,
"pages": "697-708",
"pmc": null,
"pmid": "31624507",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "30995869;27001190;30078823;19060419;30805052;20122875;28765759;23403369;22863685;31293700;20299623;26277496;23924888;30355097;21870978;24251359;29526914;30037427;27566295;30895641;30737182;21830957;29385358;30745002;19717844;24965079;26794283;30874766",
"title": "One-year clinical outcomes of anticoagulation therapy among Japanese patients with atrial fibrillation: The Hyogo AF Network (HAF-NET) Registry.",
"title_normalized": "one year clinical outcomes of anticoagulation therapy among japanese patients with atrial fibrillation the hyogo af network haf net registry"
} | [
{
"companynumb": "JP-DSJP-DSJ-2019-142731",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": null,
... |
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