article dict | reports listlengths 1 3.97k |
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{
"abstract": "OBJECTIVE\nLumbar transforaminal epidural steroid injection is commonly used for treating lumbar radicular pain. We report a case of segmental spinal myoclonus that developed during lumbar transforaminal epidural injection with local anesthetic and steroid.\n\n\nMETHODS\nA 58-year-old woman with failed back surgery syndrome presented with low back and right L3 and L4 radicular pain. As she had responded well previously to diagnostic selective nerve root injection with local anesthetic at the right L3 and L4 levels, lumbar transforaminal epidural steroid injection at the same levels was scheduled. During injection of ropivacaine and triamcinolone at the right L3-4 intervertebral foramen, she complained of back pain and immediately developed involuntary contraction of her right hip. The procedure was terminated. No new neurological deficit was detected when she was examined 15 minutes after the procedure. There were no abnormalities from blood tests and magnetic resonance imaging of the lower thoracic and lumbar spine. A neurologist subsequently made the clinical diagnosis of segmental spinal myoclonus. The myoclonus improved over 1 month and eventually resolved completely.\n\n\nCONCLUSIONS\nSegmental spinal myoclonus is a rare complication after lumbar transforaminal epidural steroid and local anesthetic injection. Pain physicians should be aware of this potential complication.",
"affiliations": "From the Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, The University of Hong Kong, Hong Kong.",
"authors": "Wong|Stanley Sau Ching|SSC|;Qiu|Qiu|Q|;Cheung|Chi Wai|CW|",
"chemical_list": "D000779:Anesthetics, Local; D005938:Glucocorticoids; D014221:Triamcinolone; D000077212:Ropivacaine",
"country": "England",
"delete": false,
"doi": "10.1097/AAP.0000000000000742",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "43(5)",
"journal": "Regional anesthesia and pain medicine",
"keywords": null,
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000779:Anesthetics, Local; D055111:Failed Back Surgery Syndrome; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007268:Injections, Epidural; D008159:Lumbar Vertebrae; D008875:Middle Aged; D009207:Myoclonus; D000077212:Ropivacaine; D014221:Triamcinolone",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "554-556",
"pmc": null,
"pmid": "29462057",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Segmental Spinal Myoclonus Complicating Lumbar Transforaminal Epidural Steroid Injection.",
"title_normalized": "segmental spinal myoclonus complicating lumbar transforaminal epidural steroid injection"
} | [
{
"companynumb": "HK-TEVA-2018-HK-938450",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "Here, we describe the case of a male patient with Epstein-Barr virus post-transplantation lymphoproliferative disorder (EBV-PTLD), which developed 18 months after a haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and the administration of post-transplant cyclophosphamide (PTCy). Of note, no anti-thymoglobulin was used in the entire clinical course. Prior to the onset of EBV-PTLD, the patient had pulmonary chronic graft-versus-host disease and was treated with prednisolone and tacrolimus. After stopping immunosuppressive therapy, he was diagnosed with EBV-positive infectious mononucleosis PTLD, and EBV-associated hemophagocytic syndrome; therefore, dexamethasone and rituximab monotherapies were administered. After four courses of rituximab, EBV-DNA was no longer detected in the peripheral blood, and the patient's laboratory data improved. Overall, this study highlights the need to predict the risk factors associated with the development of EBV-PTLD in transplanted patients after haplo-HSCT with PTCy.",
"affiliations": "Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan. terao.toshiki@kameda.jp.;Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan.;Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan.;Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan.;Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan.;Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan.;Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan.;Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, 929 Higashi-chou, Kamogawa, Chiba, 296-8602, Japan.",
"authors": "Terao|Toshiki|T|http://orcid.org/0000-0002-6728-3346;Tsushima|Takafumi|T|;Fukumoto|Ami|A|;Kuzume|Ayumi|A|;Miura|Daisuke|D|;Narita|Kentaro|K|;Takeuchi|Masami|M|;Matsue|Kosei|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-021-03111-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "114(1)",
"journal": "International journal of hematology",
"keywords": "Chronic graft-versus-host disease; Epstein-Barr virus; Haploidentical stem-cell transplantation; Post-transplant cyclophosphamide; Post-transplantation lymphoproliferative disorder",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D003520:Cyclophosphamide; D020031:Epstein-Barr Virus Infections; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D008232:Lymphoproliferative Disorders; D008297:Male",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "136-140",
"pmc": null,
"pmid": "33675520",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "EBV-PTLD in a patient after haploidentical stem-cell transplantation with post-transplant cyclophosphamide.",
"title_normalized": "ebv ptld in a patient after haploidentical stem cell transplantation with post transplant cyclophosphamide"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1019105",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "The purpose of our case report is to generate awareness among the providers about the rising abuse of loperamide, which is a readily available nonprescription medication for its opiate-like actions and the risk of severe cardiac complications as a consequence of the same. It is currently becoming a significant concern among the healthcare fraternity due to its increasing abuse owing to its opioid agonistic activity. Our patient was a 32-year-old female who presented to the ED with ventricular dysrhythmias and persistent, prolonged QT interval secondary to excessively high doses of over-the-counter (OTC) loperamide abuse. More and more cases of loperamide abuse and its cardiotoxic potential are being reported in the literature, highlighting the increasing incidence of this problem.",
"affiliations": "Family and Community Medicine, Southern Illinois University School of Medicine, Springfield, USA.;Family and Community Medicine, Southern Illinois University School of Medicine, Springfield, USA.;Family and Community Medicine, Southern Illinois University School of Medicine, Springfield, USA.;Family and Preventive Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.;Internal Medicine, Topiwala National Medical College, Mumbai, IND.",
"authors": "Sapra|Amit|A|;Bhandari|Priyanka|P|;Gupta|Supriya|S|;Kraleti|Shashank|S|;Bahuva|Ronak|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.6314",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.6314Family/General PracticeEmergency MedicineCardiologyA Rising Concern of Loperamide Abuse: A Case Report on Resulting Cardiac Complications Muacevic Alexander Adler John R Sapra Amit 1Bhandari Priyanka 1Gupta Supriya 1Kraleti Shashank 2Bahuva Ronak 3\n1 \nFamily and Community Medicine, Southern Illinois University School of Medicine, Springfield, USA \n2 \nFamily and Preventive Medicine, University of Arkansas for Medical Sciences, Little Rock, USA \n3 \nInternal Medicine, Topiwala National Medical College, Mumbai, IND \nAmit Sapra drasapra@yahoo.co.in6 12 2019 12 2019 11 12 e631426 11 2019 6 12 2019 Copyright © 2019, Sapra et al.2019Sapra et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/25394-a-rising-concern-of-loperamide-abuse-a-case-report-on-resulting-cardiac-complicationsThe purpose of our case report is to generate awareness among the providers about the rising abuse of loperamide, which is a readily available nonprescription medication for its opiate-like actions and the risk of severe cardiac complications as a consequence of the same. It is currently becoming a significant concern among the healthcare fraternity due to its increasing abuse owing to its opioid agonistic activity. Our patient was a 32-year-old female who presented to the ED with ventricular dysrhythmias and persistent, prolonged QT interval secondary to excessively high doses of over-the-counter (OTC) loperamide abuse. More and more cases of loperamide abuse and its cardiotoxic potential are being reported in the literature, highlighting the increasing incidence of this problem.\n\nloperamideprolonged qt intervalabusecardiotoxicityThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nLoperamide is an easily accessible over-the-counter (OTC) available anti-diarrheal medication, usually considered safe on a daily dose of 2-16 mg/day. Loperamide is a peripherally acting mu-opioid receptor agonist exerting its effects mainly on the myenteric plexus of the gastrointestinal longitudinal muscle layer and thus decreasing the propulsive activity of the intestine. At the recommended doses, it lacks any central nervous system (CNS) effects of euphoria and analgesia [1]. At high doses around 50 mg/day, however, it starts penetrating CNS and starts manifesting these central effects as well as cardiotoxic effects [2-6]. The recent few years have seen an upsurge in the loperamide abuse among the pain medication seeking population, coinciding with the increasing restrictions that started being placed on the prescription opioids. The abusers typically have been ingesting high doses of the medication in order to achieve or prolong their opioid agonistic action as well to alleviate the opiate withdrawal issues. It has been called the “poor man’s methadone” and is being increasingly used for the opiate withdrawal symptoms [2].\n\nInterestingly enough, the increase in loperamide-related discussions in the fall of 2010 coincides with the introduction of reformulated, tamper-resistant oxycodone tablets [7]. The poison centers received more than twice the number of calls for intentional loperamide exposure between 2010 and 2015, and approximately 50% of abuse cases were reported after January 2014 [8]. Studies assessed the 2010-2015 US National Poison Data System loperamide exposures and identified a 91% increase of cases overtime with interestingly loperamide being the sole agent in 50% of the cases [9]. There is ample evidence of web-based discussions about loperamide’s use to self-treat withdrawal symptoms along with the rise of opioid dependence [10]. Studies have reported misusers describing their experiences, like “lope highs” after large consumptions of the medicine as ”better than any oxycodone” [8]. Unfortunately, high doses of loperamide have profound cardiotoxic effects, including serious dysrhythmias [1-2, 11].\n\nCase presentation\nA 32-year-old female with a past medical history of chronic back pain, fibromyalgia, chronic pain syndrome, and past opioid usage presented to our ED with atypical chest pain, palpitations, and shortness of breath. She also gave a history of near-syncopal episodes in the past. The day before she presented to the ED, the patient had a syncopal episode and \"turning purple\" at home, prompting her daughter to call the emergency medical services (EMS), but the patient canceled the EMS after she awakened from this episode (likely due to Torsade’s de Pointes). On arrival to the ED, she had an episode of polymorphic ventricular tachycardia, which was sustained, and the patient spontaneously self-converted to sinus rhythm with frequent premature ventricular contractions and ventricular bigeminy (Figure 1). She had a persistently prolonged QT interval, and nonspecific ST changes were noted. She was put on telemetry, where 19 beats of Torsade’s were noted. The patient denied any known personal or family history of heart disease or any congenital QT syndrome. She is an everyday cigarette smoker and denied any alcohol or any other illicit drug use. Toxicology studies were unremarkable.\n\nFigure 1 Electrocardiogram of the pateint in the ED showing polymorphic ventricular tachycardia (blue arrows) and ventricular bigeminy (red arrow).\nLabs were normal except for hypokalemia, which was replaced. Her serial cardiac enzymes were normal imaging of the chest, abdomen, and pelvis was unremarkable. The patient received amiodarone and magnesium in the ED and was put on continuous telemetry. Despite this intervention the patient continued to show ventricular bigeminy and short runs of polymorphic ventricular tachycardia (Figure 2). The patient was upgraded to the intensive care unit (ICU), for closer monitoring and evaluation. The electrophysiology and cardiology services were consulted. The patient underwent an echocardiogram, which showed a normal ejection fraction, normal right and left ventricular functions, and no valvular abnormalities. The patient later endorsed that she was on oxycodone, fentanyl patch, and hydrocodone for her chronic pain issues. Her primary care had weaned her off the medications, and she was not getting any more opioid prescriptions. She also confided that she had been consuming 200 tablets of 2 mg over-the-counter (OTC) loperamide every week to \"extend her opioid analgesic prescription for her chronic pain issues\" and that she had taken one high dose of 200 tablets of 2 mg all at once before today's ED visit. Due to the long half-life of loperamide, the patient was advised to continue admission to the ICU till the QT interval stabilizes. Further plan was made to send her home on life vest with outpatient follow-up for implantable cardiac defibrillator (ICD) therapy. She did not seem interested in any of the above-stated therapies and adamantly refused any outpatient or inpatient opiate rehabilitation. While all these discussions were taking place, the patient left the hospital against medical advice (AMA).\n\nFigure 2 Electrocardiogram of the pateint in the ED continuing to show frequent premature ventricular contractions (red arrows) ventricular tachycardia and prolnged QT interval (blue arrows).\nThe patient again presented to our ED with chest pain, shortness of breath, nausea, and vomiting on the following day. She was still bradycardic in the '50s along with persistent, prolonged QT interval and ventricular bigeminy (Figure 3). Electrophysiology and cardiology services were again consulted, and the patient also underwent coronary angiography, which did not show any significant blockage or evidence of structural heart disease. It was again reiterated to her about the importance of considering life vest versus ICD versus medical management. She was also advised to refrain from loperamide use entirely and to quit cigarette smoking. Despite all the advice and education from several physicians and hospital staff, the patient again left the hospital AMA and was unfortunately lost to follow up.\n\nFigure 3 Electrocardiogram of the patient the next day when she again presented to the ED, still continuing to show the frequent premature ventricular complexes (red arrows) and bigeminal pattern along with the prolonged QT interval (blue arrows) which had only marginally improved. \nDiscussion\nLoperamide is a mu-opioid receptor agonist usually used to treat diarrhea and often available as an over-the-counter medication. Unfortunately, there seems to have been a steady rise in recreational abuse for its opioid-like effects in recent years [12]. The cardiac complications have ranged from often presenting as QRS widening, QTC prolongation, ventricular tachycardia, Torsade’s de Pointes, or a Brugada-like syndrome [4, 11, 13-14]. The Illinois Poison Center (IPC) took care of 137 cases of loperamide exposures from 2014 to 2016, out of which 18 overdosed for the purpose of abuse, withdrawal prevention, or withdrawal treatment. Most loperamide abuse cases were reported to have a significantly prolonged QT interval [15]. Although the cause of the QT prolongation is not yet completely understood, the calcium channel blockage effect seen in animal models has been proposed as one of the mechanisms, among others [16]. There is a distinct structural similarity between loperamide, methadone, and the potent human ether-a-go-go (hERG) receptor blocker terbinafine, as all three of these molecules have multiple phenyl rings [17]. It is also being proposed that the QT-prolonging effect of loperamide could be due to the hERG blockade effect similar to terbinafine [16-17]. \n\nLoperamide has been safely used for many years without any significant problems, and the recent upsurge in its adverse effects seems to stem from the ingestion of this medication in toxic amounts. This upsurge seems to have been unfortunately propagated through the websites, web forums, and web discussions with anonymous posts. In the 2013 study on the user generated content (UGC) for the extra-medical usage of loperamide among illicit drug, Daniulaityte et al. found that almost 70% users discussed loperamide as a remedy to self-treat opioid withdrawal symptoms and 25% discussed its high doses to produce the euphoric effects [18]. Case reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS) in 2016 provided evidence that toxic doses of loperamide were associated with Torsade's de Pointes and other serious cardiac events [19]. The majority of these cases occurred in the setting of drug abuse to prevent opioid withdrawal or to produce euphoric effects. Optimal management of loperamide-associated toxicity is still unclear and treatment is aimed at giving anti-arrhythmic, magnesium or sodium bicarbonate in some cases.\n\nConclusions\nThe Food and Drug Administration (FDA) continues to undertake stringent measures after the 2014-2016 increase in deaths due to cardiac causes secondary to loperamide abuse. In June 2016, FDA issued Black Box warning about serious heart problems, including Torsade's cardiac arrest and sudden cardiac death with high doses of loperamide use. In April 2017, FDA ordered additional alert along with the Black Box warning. In January 2018, FDA started working with manufacturers to use blister packs or other single-dose packaging and to limit the number of doses per package of loperamide that could be sold OTC. More recently, in September 2019, the FDA approved the new packaging for the brand name OTC loperamide in an attempt to prevent abuse and misuse. The maximum allowed daily dose of OTC loperamide for adult usage is 8 mg/day. The new carton is to contain no more than 48 mg of loperamide and requires unit dose blister packaging.\n\nWith our case, we attempt to increase the awareness of this innocuous drug's misuse needs to spread among providers, especially primary care providers emergency physicians as well as cardiologist, who may encounter this problem more often than they previously realized. It is equally imperative to educate the patients about the potential risks of overuse. At the same time, public health awareness about this growing menace needs to be created, and more stringent laws need to be passed to prevent further life-threatening cardiac complications of loperamide's abuse.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Loperamide cardiotoxicity: \"A Brief Review\" Ann Noninvasive Electrocardiol Akel T Bekheit S 0 23 2017 \n2 Ventricular fibrillation due to overdose of loperamide, the “poor man’s methadone” J Community Hosp Intern Med Perspect Salama A Levin Y Jha P Alweis R 222 226 7 2017 29046747 \n3 Loperamide, the \"Poor Man’s Methadone\": Brief Review J Psychoactive Drugs Stanciu CN Gnanasegaram SA 18 21 49 2017 https://www.ncbi.nlm.nih.gov/pubmed/27918873 27918873 \n4 Not your regular high: cardiac dysrhythmias caused by loperamide .Clin Toxicol (Phila) Wightman RS Hoffman RS Howland MA Rice B Biary R. Lugassy D 454 458 54 2017 \n5 The long QT teaser: loperamide abuse Am J Med Enakpene EO Riaz IB Shirazi FM Raz Y Indik JH 1083 1086 128 2015 26052029 \n6 Cardiac conduction disturbance after loperamide abuse Clin Toxicol (Phila) Marraffa JM Holland MG Sullivan RW Morgan BW Oakes JA Wiegand TJ Hodgman MJ 952 957 52 2014 25345436 \n7 Effect of abuse-deterrent formulation of oxycontin N Engl J Med Cicero TJ Ellis MS Surratt HL 187 189 367 2012 22784140 \n8 Is there such a thing as a ’lope’ dope? Analysis of loperamide-related European Medicines Agency (EMA) pharmacovigilance database reports PLoS One Schifano F Chiappini S 0 13 2018 https://www.ncbi.nlm.nih.gov/pubmed/30286103 \n9 Epidemiologic trends in loperamide abuse and misuse Ann Emerg Med Vakkalanka JP Charlton NP Holstege CP 73 78 69 2017 27823872 \n10 Trends in prescription drug abuse and dependence, co-occurrence with other substance use disorders, and treatment utilization: results from two national surveys Addict Behav McCabe SE Cranford JA West BT 1297 1305 33 2008 18632211 \n11 Loperamide abuse and cardiotoxicity J Community Hosp Intern Med Perspect Smith NA Sehring M Chambers J 275 7 2017 29046761 \n12 Loperamide trends in abuse and misuse over 13 years: 2002-2015 Pharmacotherapy Lasoff DR Koh CH Corbett B Minns AB Cantrell FL 249 253 37 2017 27995643 \n13 Loperamide induced life threatening ventricular arrhythmia Case Rep Cardiol Upadhyay A Bodar V Malekzadegan M Singh S Frumkin W Mangla A Doshi K 5040176 2016 2016 27547470 \n14 Notes from the field: cardiac dysrhythmias after loperamide abuse -- New York, 2008-2016 Morbidity Mortality Weekly Rep Eggleston W Marraffa JM Stork CM 1276 1277 65 2016 \n15 Loperamide: an old drug with rising concern Official Newsjournal of the Illinois Council of Health-System Pharmacists Weber AJ Lim ES Burda A DesLauriers C 2017 https://www.ichpnet.org/publications_resources/keeposted/articles/2017/Vol_43-05/43-05-ed_affairs.pdf \n16 Loperamide: blockade of calcium channels as a mechanism for antidiarrheal effects J Pharmacol Exp Ther Reynolds IJ Gould RJ Snyder SH 628 632 231 1984 https://www.ncbi.nlm.nih.gov/pubmed/6502516 6502516 \n17 Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches Bioorg Med Chem Lett Pearlstein RA Vaz RJ Kang J 1829 1835 13 2003 12729675 \n18 \"I just wanted to tell you that loperamide WILL WORK\": a web-based study of extra-medical use of loperamide Drug Alcohol Depend Daniulaityte R Carlson R Falck R 241 244 130 2012 23201175 \n19 Adverse event detection using the FDA post-marketing drug safety surveillance system: cardiotoxicity associated with loperamide abuse and misuse J Am Pharm Assoc (2003) Swank KA Wu E Kortepeter C McAninch J Levin RL 0 57 2017\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(12)",
"journal": "Cureus",
"keywords": "abuse; cardiotoxicity; loperamide; prolonged qt interval",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e6314",
"pmc": null,
"pmid": "31938606",
"pubdate": "2019-12-06",
"publication_types": "D002363:Case Reports",
"references": "27918873;22784140;30286103;29046761;26052029;27855148;27022002;27823872;6502516;12729675;27547470;29046747;27995643;18632211;25345436;29125226;28073687;23201175",
"title": "A Rising Concern of Loperamide Abuse: A Case Report on Resulting Cardiac Complications.",
"title_normalized": "a rising concern of loperamide abuse a case report on resulting cardiac complications"
} | [
{
"companynumb": "US-JNJFOC-20201205508",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOPERAMIDE HYDROCHLORIDE"
},
"drugadditional": "3... |
{
"abstract": "BACKGROUND\nLactobacillus sp. is a low virulence bacterium, which rarely causes infection in immunocompetent individuals and usually is considered a contaminant. Normally this organism is susceptible to β-lactam antibiotics, yet resistant strains have been reported.\nHere, we report a case of a 60-year-old renal transplant recipient who developed an intra-abdominal abscess which grew a carbapenem-resistant Lactobacillus casei. This is significant since it is the first report of a clinical isolate of Lactobacillus sp. that demonstrated both microbiological and clinical resistance to carbapenem use. Moreover, the probiotic supplement that the patient had taken also grew a similar organism raising the concern of probiotic associated infection in immunocompromised individual.",
"affiliations": "Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 2.112, Houston, TX, 77030, USA. Jakapat.Vanichanan@uth.tmc.edu.;Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.;Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.;Division of Renal Disease and Hypertension, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.;Division of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 2.112, Houston, TX, 77030, USA.",
"authors": "Vanichanan|Jakapat|J|;Chávez|Violeta|V|;Wanger|Audrey|A|;De Golovine|Aleksandra M|AM|;Vigil|Karen J|KJ|",
"chemical_list": "D015780:Carbapenems",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-016-0903-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "44(6)",
"journal": "Infection",
"keywords": "Carbapenem; Drug resistant; Intra-abdominal infection; Lactobacillus; Probiotic; Renal transplant",
"medline_ta": "Infection",
"mesh_terms": "D015780:Carbapenems; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D059413:Intraabdominal Infections; D007778:Lactobacillus; D008297:Male; D008875:Middle Aged; D019936:Probiotics; D066027:Transplant Recipients; D018440:beta-Lactam Resistance",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "793-796",
"pmc": null,
"pmid": "27142043",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8909843;23426446;15636620;18279948;20664519;7944727;2331851;20844225;11728051;11897608;14679449;21040283;15599646;8161628;16447101;23710593;24115946;17369278;17846036;9402355",
"title": "Carbapenem-resistant Lactobacillus intra-abdominal infection in a renal transplant recipient with a history of probiotic consumption.",
"title_normalized": "carbapenem resistant lactobacillus intra abdominal infection in a renal transplant recipient with a history of probiotic consumption"
} | [
{
"companynumb": "US-ZYDUS-013679",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACTOBACILLUS CASEI"
},
"drugadditional": "3",
... |
{
"abstract": "To evaluate the use of ondansetron in a tertiary care pediatric health system, assess the incidence of ventricular tachyarrhythmia within 24 hours of ondansetron, and identify the characteristics of children experiencing a ventricular tachyarrhythmia after ondansetron, to identify potential risk factors.\n\n\n\nThis retrospective chart review identified children ≤18 years of age who received ondansetron within 24 hours prior to a ventricular tachyarrhythmia. Those identified were evaluated for other diagnoses, concomitant medication use, electrolyte abnormalities, or underlying conduction abnormalities that may have contributed to the arrhythmia.\n\n\n\nA total of 199 773 doses of ondansetron were administered to 37 794 patients over 58 009 visits. Average dose was 0.13 mg/kg/dose (range 0.005-0.86 mg/kg/dose). Seven patients received ondansetron within 24 hours prior to a ventricular arrhythmia. All 7 patients had underlying congenital cardiac conduction abnormalities (n = 3) or other major cardiac diagnoses (n = 4). In clinical review, torsades de pointes was found in only 1 of the 7 patients.\n\n\n\nThis retrospective study found the risk of ventricular arrhythmia within 24 hours after ondansetron administration was 3 in 100 000 patients treated annually (0.003%). Children with major cardiac conditions could be considered for electrocardiogram screening and continuous cardiac monitoring while receiving ondansetron. Our findings do not support recommendations for electrocardiogram screening or continuous monitoring of other pediatric populations receiving ondansetron.",
"affiliations": "Department of Pharmacy, Children's Hospital of Wisconsin, Milwaukee, WI.;Wisconsin Poison Center, Children's Hospital of Wisconsin, Milwaukee, WI; Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI. Electronic address: dgummin@chw.org.;Department of Pharmacy, Children's Hospital of Wisconsin, Milwaukee, WI.;Department of Pediatrics, Section of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI.;Department of Pediatrics, Section of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI.;Department of Pediatrics, Northwestern University, Chicago, IL; Lurie Children's Hospital of Chicago, Chicago, IL.",
"authors": "Moeller|Jaclyn R|JR|;Gummin|David D|DD|;Nelson|Tom J|TJ|;Drendel|Amy L|AL|;Shah|Breanne K|BK|;Berger|Stuart|S|",
"chemical_list": "D017294:Ondansetron",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2016.08.058",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "179()",
"journal": "The Journal of pediatrics",
"keywords": "Torsades de Pointes; long QT syndrome; ondansetron; pediatric; ventricular arrhythmia",
"medline_ta": "J Pediatr",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D017294:Ondansetron; D012189:Retrospective Studies; D018570:Risk Assessment; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "118-123.e1",
"pmc": null,
"pmid": "27665040",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk of Ventricular Arrhythmias and Association with Ondansetron.",
"title_normalized": "risk of ventricular arrhythmias and association with ondansetron"
} | [
{
"companynumb": "PHHY2016US132400",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ONDANSETRON HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Diagnosis of hypersensitivity (HS) reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in children is complex. The real prevalence of NSAID HS remains unknown because a drug provocation test (DPT) is not always performed with the culprit NSAID.\n\n\n\nTo describe and compare the diagnostic workup among different European centers and to find out the real proportion of NSAID HS by performing a DPT with the culprit drug.\n\n\n\nWe retrospectively collected data from children (0-10 years) and adolescents (10-18 years) with a history of NSAID reactions and who underwent a complete allergy workup including DPTs with the culprit in 6 different pediatric centers: Belgrade, Florence, Geneva, Madrid, Porto, and Rome.\n\n\n\nA total of 693 children with a history of NSAID reactions were enrolled, and a total of 526 DPTs were performed with the culprit NSAID. The diagnosis of NSAID HS was confirmed in 19.6% (103 of 526) of children by performing a DPT with the culprit drug. The major differences in the allergy workup among the 6 centers concerned the duration of the DPT and the practical use of skin tests for diagnosing NSAID HS. In addition, the use of acetyl salicylic acid to differentiate single reactor or cross-intolerance patients is not common, except in Spain.\n\n\n\nThe value of this study is that although different approaches are used around Europe to diagnose NSAID HS, we found that the percentage of confirmed NSAID HS is less than 20%. This highlights the importance of the DPT in confirming or excluding NSAID HS in the pediatric population.",
"affiliations": "Allergy Unit, Department of Pediatrics, Anna Meyer Children's University Hospital, Florence, Italy.;University Children's Hospital, Medical Faculty University of Belgrade, Belgrade, Serbia.;Allergy Unit, Infanta Leonor University Hospital, Madrid, Spain.;Allergy and Clinical Immunology Service, Centro Hospitalar e Universitário do Porto, Porto, Portugal.;Allergy Unit, Presidio Columbus, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Allergy Unit, Department of Pediatrics, Anna Meyer Children's University Hospital, Florence, Italy.;Pediatric Allergy Unit, Geneva University Hospitals, Geneva, Switzerland.;University Children's Hospital, Medical Faculty University of Belgrade, Belgrade, Serbia.;Allergy Department, Pediatric Hospital Bambino Gesù, Rome, Vatican City.;Pediatric Allergy Unit, Geneva University Hospitals, Geneva, Switzerland. Electronic address: Jeanchristoph.caubet@gmail.com.",
"authors": "Mori|Francesca|F|;Atanaskovic-Markovic|Marina|M|;Blanca-Lopez|Natalia|N|;Gomes|Eva|E|;Gaeta|Francesco|F|;Sarti|Lucrezia|L|;Bergmann|Marcel M|MM|;Tmusic|Vladimir|V|;Valluzzi|Rocco L|RL|;Caubet|Jean-Christoph|JC|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2019.10.049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "8(3)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Acetyl salicylic acid; Adolescents; Allergy workup; Aspirin; Children; Drug provocation tests; Hypersensitivity; Ibuprofen; Nonsteroidal anti-inflammatory drugs; Paracetamol",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D005060:Europe; D006801:Humans; D004364:Pharmaceutical Preparations; D012189:Retrospective Studies; D013030:Spain",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "1022-1031.e1",
"pmc": null,
"pmid": "31785410",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A Multicenter Retrospective Study on Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Children: A Report from the European Network on Drug Allergy (ENDA) Group.",
"title_normalized": "a multicenter retrospective study on hypersensitivity reactions to nonsteroidal anti inflammatory drugs nsaids in children a report from the european network on drug allergy enda group"
} | [
{
"companynumb": "IT-JNJFOC-20190424919",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLURBIPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Diphyllobothrium latum (D. latum) infection in humans is uncommon in the United States. Although there has been a drastic decline in the report of D. latum infection in this region, physicians should be aware of an uncommon presentation and its clinical relevance. We report a case of 55-year-old female of Ecuadorian/Peruvian origin who presented with an unknown cause of chronic right lower quadrant abdominal pain for 2 months without other particular symptoms. Initial workup revealed evidence of iron deficiency anemia, and stool occult blood test was positive. She was scheduled for a colonoscopy to assess the source of occult gastrointestinal bleeding. During her bowel preparation, she passed a 25 cm long white tapeworm-like material confirmed microscopically. Despite passing a worm she continued to have abdominal pain. During the colonoscopy, another worm was found lodged in the appendiceal orifice. The colonoscopic images revealed a segmented tapeworm showing contractile motility, approximately 12 cm in length and 6 mm wide in the appendiceal orifice. The scope was unsuccessful in removing the worm. The parasitological and microbiological examination of the passed worm was positive for D. latum. D. latum a fish tapeworm that infects humans after the ingestion of raw or undercooked fish. The patient had a history of often eating lightly marinated raw fish (\"ceviche\") in Peru several months before presentation. It is uncommon for D. latum infection to present with iron deficiency anemia. As the worm absorbs approximately 80% of dietary vitamin B12, prolonged D. latum infection usually causes vitamin B12 deficiency and megaloblastic anemia, which is reported to affect about 40% of cases. Abdominal pain related to mechanical obstruction is reported, but this case is unique in that the worm preferentially attached to the appendiceal orifice causing subacute focal appendiceal pain. She was treated with a single dose of oral praziquantel. After the treatment, she developed minor cramping for the next 2 days which resolved by day 3, and recalled passing half-inch sized pieces of white tissue and subsequently improved. Although D. latum infection is an uncommon cause of chronic abdominal pain with iron deficiency anemia, it is crucial to consider because of the potentially treatable outcome.",
"affiliations": "Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA.;Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA.;Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA.",
"authors": "Sharma|Konika|K|;Wijarnpreecha|Karn|K|;Merrell|Nancy|N|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.14740/gr989w",
"fulltext": "\n==== Front\nGastroenterology ResGastroenterology ResElmer PressGastroenterology Research1918-28051918-2813Elmer Press 10.14740/gr989wCase ReportDiphyllobothrium latum Mimicking Subacute Appendicitis Diphyllobothrium latumSharma Konika acWijarnpreecha Karn aMerrell Nancy aba Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USAb Division of Digestive Disease, Bassett Medical Center, Cooperstown, NY, USAc Corresponding Author: Konika Sharma, Department of Internal Medicine, Bassett Medical Center, One Atwell Road, Cooperstown, NY 13326, USA. Email: drkonika@gmail.com6 2018 31 5 2018 11 3 235 237 3 2 2018 23 4 2018 Copyright 2018, Sharma et al.2018This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Diphyllobothrium latum (D. latum) infection in humans is uncommon in the United States. Although there has been a drastic decline in the report of D. latum infection in this region, physicians should be aware of an uncommon presentation and its clinical relevance. We report a case of 55-year-old female of Ecuadorian/Peruvian origin who presented with an unknown cause of chronic right lower quadrant abdominal pain for 2 months without other particular symptoms. Initial workup revealed evidence of iron deficiency anemia, and stool occult blood test was positive. She was scheduled for a colonoscopy to assess the source of occult gastrointestinal bleeding. During her bowel preparation, she passed a 25 cm long white tapeworm-like material confirmed microscopically. Despite passing a worm she continued to have abdominal pain. During the colonoscopy, another worm was found lodged in the appendiceal orifice. The colonoscopic images revealed a segmented tapeworm showing contractile motility, approximately 12 cm in length and 6 mm wide in the appendiceal orifice. The scope was unsuccessful in removing the worm. The parasitological and microbiological examination of the passed worm was positive for D. latum. D. latum a fish tapeworm that infects humans after the ingestion of raw or undercooked fish. The patient had a history of often eating lightly marinated raw fish (“ceviche”) in Peru several months before presentation. It is uncommon for D. latum infection to present with iron deficiency anemia. As the worm absorbs approximately 80% of dietary vitamin B12, prolonged D. latum infection usually causes vitamin B12 deficiency and megaloblastic anemia, which is reported to affect about 40% of cases. Abdominal pain related to mechanical obstruction is reported, but this case is unique in that the worm preferentially attached to the appendiceal orifice causing subacute focal appendiceal pain. She was treated with a single dose of oral praziquantel. After the treatment, she developed minor cramping for the next 2 days which resolved by day 3, and recalled passing half-inch sized pieces of white tissue and subsequently improved. Although D. latum infection is an uncommon cause of chronic abdominal pain with iron deficiency anemia, it is crucial to consider because of the potentially treatable outcome.\n\nDiphyllobothrium latumDiphyllobothriosisIron deficiency anemia\n==== Body\nIntroduction\nDiphyllobothrium latum (D. latum) is one of the longest intestinal tapeworms that infects humans [1]. The recent epidemiologic study reported that approximately 20 million people are infected worldwide and tend to have endemicity in areas where consumption of raw fish is popular (Scandinavia, Northern Europe, Russia, Japan) [2]. The Centers for Disease Control and Prevention estimated that up to 200 cases occurred during 1977 to 1981, but the prevalence has declined over the last 100 years [3]. The first case of D. latum infection in the United States was reported in a child born in Minnesota [4]. Humans are infected by ingesting larvae in raw or poorly cooked freshwater fish acting as a second intermediate host harboring the infective forms. Despite the large size, many D. latum infections are reported to be asymptomatic [5]. Twenty-five percent can present with diarrhea, abdominal pain, recurrent abdominal pain, fatigue, headache, constipation or pernicious anemia [6, 7]. We present an interesting case diagnosed with D. latum infection with an unusual presentation of chronic right lower abdominal pain mimicking subacute appendicitis.\n\nCase Report\nA 55-year-old female of Ecuadorian/Peruvian origin presented with an unknown cause of chronic right lower quadrant abdominal pain for 2 months. She denied diarrhea, nausea, vomiting, fever, or other particular symptoms. She had no significant medical or family history. Except for mild pallor and tenderness in right-lower quadrant area of the abdomen, no pertinent findings were found from physical examination. Laboratory evaluation revealed mild anemia from iron deficiency (low serum iron 41 µg/dL, low iron saturation 11%, total iron binding capacity 382 µg/dL, and decreased mean corpuscular volume 62.9 fL). Vitamin B12 and folate values were in the normal range. A gynecological cause of anemia was excluded. A fecal occult blood test was positive. The patient was scheduled for a colonoscopy to assess the source of occult gastrointestinal bleeding. During her bowel preparation, she passed a 25 cm long white tapeworm-like material. Despite passing the worm she continued to have focal right lower abdominal pain. Colonoscopy documented another worm approximately 12 cm in length, 6 mm wide was found lodged in the appendiceal orifice as shown in Figures 1 and 2. Attempts at gentle snare extraction were unsuccessful. Parasitological and microbiological examination confirmed that the first passed worm was positive for D. latum. The patient had a history of eating raw fish in Peru called “ceviche” (pieces of raw fish freshly marinated in lemon and salt) several months before presentation. She was treated with a single dose of 600 mg oral praziquantel. After the treatment, she developed minor cramping for the next 2 days which resolved by day 3, and recalled passing half-inch sized pieces of white tissue and subsequently improved. No eggs were seen in the stool samples checked in 3 months later. She has no residual abdominal pain.\n\nFigure 1 A segmented tapeworm showing contractile motility in the appendiceal orifice.\n\nFigure 2 A segmented tapeworm.\n\nDiscussion\nThe colonoscopic images revealed a segmented tapeworm showing contractile motility, approximately 12 cm long, 6 mm wide, attached inside the appendix. Mature D. latum can reach a maximum length of up to 25 m [1] consisting of a large number of segments called proglottids which are rectangular in shape, 3 - 5 mm long and 9 - 12 mm wide. D. latum infection can be caused by the ingestion of raw and undercooked fish. Humans are the main definitive host for D. latum. Most infected cases are asymptomatic, and about 40% may have vitamin B12 deficiency, but only 2% progress to anemia [8]. Prolonged D. latum infection usually causes vitamin B12 deficiency and megaloblastic anemia by parasite-mediated dissociation of the vitamin B12-intrinsic factor complex in the gut lumen making B12 unavailable to the host [9]. This can cause neurological damage to the host including central nervous system degenerative and peripheral neuropathy. Adult tapeworms are easily treated with praziquantel. A single dose of 25 mg/kg is highly effective against D. latum infection in humans [10]. The best prophylaxis is to avoid the consumption of raw or undercooked fish. It is uncommon of D. latum infection in humans, to present with chronic abdominal pain with iron deficiency anemia, especially in a non-endemic area as in this case. Physicians should be aware of this uncommon presentation, and meticulous history-taking, including recent travel and raw fish ingestion, are important clues leading to early diagnosis and treatment. In addition, since it may be found accidentally during colonoscopy, endoscopists should recognize the parasite and its treatment.\n\nWe present a case of an uncommon presentation of D. latum infection in humans with a chronic unknown cause of abdominal pain and anemia. Even though it rarely occurs, awareness of D. latum manifestation which leads to early diagnosis and treatment should be accentuated to the physician. Treatment does not seem to represent a serious problem, unlike a low awareness of the infection risk when eating raw or undercooked fish. Better education for populations, particularly in the regions under potential risk of infection, is necessary [11].\n\nFunding\nNone.\n\nConflict of Interest\nWe do not have any financial or non-financial potential conflict of interest.\n\nAuthor Contributions\nSharma K: acquisition of data, drafting the articles, final approval; Wijarnpreecha K: acquisition of data, drafting the articles, interpretation of the data, final approval; Merrell N: conception and critical revision, final approval.\n==== Refs\nReferences\n1 Scholz T Garcia HH Kuchta R Wicht B Update on the human broad tapeworm (genus diphyllobothrium), including clinical relevance Clin Microbiol Rev 2009 22 1 146 160 Table of Contents 10.1128/CMR.00033-08 19136438 \n2 Chai JY Darwin Murrell K Lymbery AJ Fish-borne parasitic zoonoses: status and issues Int J Parasitol 2005 35 11-12 1233 1254 10.1016/j.ijpara.2005.07.013 16143336 \n3 Dick TA Nelson PA Choudhury A Diphyllobothriasis: update on human cases, foci, patterns and sources of human infections and future considerations Southeast Asian J Trop Med Public Health 2001 32 Suppl 2 59 76 12041607 \n4 Nickerson WS The broad tapeworm in Minnesota, with the report of a case of infection acquired in the state JAMA 1906 46 711 713 10.1001/jama.1906.62510370017001e \n5 Nakamura-Uchiyama F Hiromatsu K Ishiwata K Sakamoto Y Nawa Y The current status of parasitic diseases in Japan Intern Med 2003 42 3 222 236 10.2169/internalmedicine.42.222 12705786 \n6 Lee SH Park H Yu ST Diphyllobothrium latum infection in a child with recurrent abdominal pain Korean J Pediatr 2015 58 11 451 453 10.3345/kjp.2015.58.11.451 26692882 \n7 Von Bonsdorff B Pernicious anemia caused by Diphyllobothrium latum, in the light of recent investigations Blood 1948 3 1 91 102 18920893 \n8 Schantz PM Tapeworms (cestodiasis) Gastroenterol Clin North Am 1996 25 3 637 653 10.1016/S0889-8553(05)70267-3 8863044 \n9 Vuylsteke P Bertrand C Verhoef GE Vandenberghe P Case of megaloblastic anemia caused by intestinal taeniasis Ann Hematol 2004 83 7 487 488 10.1007/s00277-003-0839-2 14730392 \n10 Groll E Praziquantel for cestode infections in man Acta Trop 1980 37 3 293 296 6106371 \n11 Tavares LE Luque JL do Bomfim TC Human diphyllobothriasis: reports from Rio de Janeiro, Brazil Revista brasileira de parasitologia veterinaria = Brazilian Journal of Veterinary Parasitology: Orgao Oficial do Colegio Brasileiro de Parasitologia Veterinaria 2005 14 2 85 87\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1918-2805",
"issue": "11(3)",
"journal": "Gastroenterology research",
"keywords": "Diphyllobothriosis; Diphyllobothrium latum; Iron deficiency anemia",
"medline_ta": "Gastroenterology Res",
"mesh_terms": null,
"nlm_unique_id": "101519422",
"other_id": null,
"pages": "235-237",
"pmc": null,
"pmid": "29915635",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": "19136438;6106371;8863044;12041607;14730392;16153350;18920893;12705786;16143336;26692882",
"title": "Diphyllobothrium latum Mimicking Subacute Appendicitis.",
"title_normalized": "diphyllobothrium latum mimicking subacute appendicitis"
} | [
{
"companynumb": "US-BAYER-2018-047890",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRAZIQUANTEL"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPatients with small-cell lung cancer (SCLC) have a dismal prognosis with limited overall survival (OS) despite a high response rate to chemotherapy. Recently, immune checkpoint inhibitors, combined with chemotherapy, as the first-line treatment for extensive-stage (ES)-SCLC have shown improvement in clinical outcomes.\n\n\nMETHODS\nReal-world data from 68 Korean ES-SCLC patients, treated with atezolizumab, etoposide, and carboplatin at Yonsei Cancer Center between June 2019 and November 2020, were retrospectively analyzed to determine safety and efficacy using Cox regression analysis.\n\n\nRESULTS\nThe median follow-up was 11.6 months. The median progression-free survival was 4.6 months (95% confidence interval [CI] 4.0-5.2), and the median OS was 12.0 months (95% CI 7.4-16.6). Baseline bone metastasis, immune-related adverse events (IRAEs), and elevated LDH were related to OS (hazard ratio 2.18, 0.33, and 4.64; P = 0.05, 0.02, and 0.003, respectively). Among the 42 patients with disease progression, liver metastasis progression and baseline bone metastasis were associated with inferior OS, but without statistical significance (hazard ratio 2.47 and 1.97; P = 0.25 and 0.26, respectively). Overall, 61 (89.7%) patients experienced treatment-related adverse events (TRAEs), with hematologic toxicities as the most common grade 3-4 TRAEs. Twenty-two (32.4%) patients experienced IRAEs, with skin rash as the most common, and five (7.4%) patients had grade-3 IRAEs (pneumonitis, hyperglycemia, and aspartate aminotransferase elevation).\n\n\nCONCLUSIONS\nAtezolizumab, combined with etoposide and carboplatin, showed efficacy and safety in our real-world data. Further studies are needed to predict the response to immunotherapy in SCLC.",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Pathology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea. Minhee_hong@yuhs.ac.",
"authors": "Lee|Seoyoung|S|;Shim|Hyo Sup|HS|;Ahn|Beung-Chul|BC|;Lim|Sun Min|SM|;Kim|Hye Ryun|HR|;Cho|Byoung Chul|BC|;Hong|Min Hee|MH|http://orcid.org/0000-0003-3490-2195",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-021-03052-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-7004",
"issue": null,
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Asian; IMpower133 Study; Immunotherapy; Korea; Real-world data",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": null,
"nlm_unique_id": "8605732",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34568975",
"pubdate": "2021-09-27",
"publication_types": "D016428:Journal Article",
"references": "30207593;30741509;29535913;25115410;30316010;33285097;7474472;19097774;29658856;30280635;31679945;30345906;30779529;32402160;33657295;30855195;32760014;25071979;23205072;31752994;30506406;30442524;29290265;28975219;30848091;27062698;25582496;27269741;30926931;33482121;33398162",
"title": "Efficacy and safety of atezolizumab, in combination with etoposide and carboplatin regimen, in the first-line treatment of extensive-stage small-cell lung cancer: a single-center experience.",
"title_normalized": "efficacy and safety of atezolizumab in combination with etoposide and carboplatin regimen in the first line treatment of extensive stage small cell lung cancer a single center experience"
} | [
{
"companynumb": "KR-PFIZER INC-202101349984",
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"occurcountry": "KR",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
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"drugadditional": "4",
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{
"abstract": "Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect.\n\n\n\nPatients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity.\n\n\n\nAmong the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy.\n\n\n\nThis is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.",
"affiliations": "Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.;Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.;Service d'anatomie pathologique, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.;Service d'anatomie pathologique, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.;Institute of Surgical Pathology, University Zurich, Zurich, Switzerland.;Institute of Surgical Pathology, University Zurich, Zurich, Switzerland.;Centre de Technologies Moléculaires Appliquées, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.;Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.;Centre de Technologies Moléculaires Appliquées, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.;Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.;Institut Universitaire de Pathologie-IUP, Lausanne, Switzerland.;Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium. marc.vandeneynde@uclouvain.be.",
"authors": "Sacré|Anne|A|;Lanthier|Nicolas|N|;Dano|Hélène|H|;Aydin|Selda|S|;Leggenhager|Daniela|D|;Weber|Achim|A|;Dekairelle|Anne-France|AF|;De Cuyper|Astrid|A|;Gala|Jean-Luc|JL|;Humblet|Yves|Y|;Sempoux|Christine|C|;Van den Eynde|Marc|M|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011725:Pyridines; C000715591:UGT1A9 protein, human; C559147:regorafenib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.13217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "36(11)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "hepatotoxicity; liver histology; metastatic colorectal cancer; regorafenib",
"medline_ta": "Liver Int",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001530:Belgium; D056486:Chemical and Drug Induced Liver Injury; D015179:Colorectal Neoplasms; D051544:Cytochrome P-450 CYP3A; D005260:Female; D014453:Glucuronosyltransferase; D006801:Humans; D008099:Liver; D008297:Male; D009362:Neoplasm Metastasis; D010671:Phenylurea Compounds; D011401:Promoter Regions, Genetic; D011725:Pyridines; D012189:Retrospective Studies; D000090264:UDP-Glucuronosyltransferase 1A9",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "1590-1594",
"pmc": null,
"pmid": "27500989",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Regorafenib induced severe toxic hepatitis: characterization and discussion.",
"title_normalized": "regorafenib induced severe toxic hepatitis characterization and discussion"
} | [
{
"companynumb": "BE-BAUSCH-BL-2016-025142",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe life-threatening, drug-induced, systemic hypersensitivity reaction. We report two patients who developed DIHS during treatment for acute myeloid leukemia. Awareness of DIHS is necessary when systemic eruptions and high fever occur in leukemic patients, especially with rapid hematopoietic recovery after chemotherapies.",
"affiliations": null,
"authors": "Suzuki|Hiroshi I|HI|;Asai|Takashi|T|;Tamaki|Zenshiro|Z|;Hangaishi|Akira|A|;Chiba|Shigeru|S|;Kurokawa|Mineo|M|",
"chemical_list": "D000890:Anti-Infective Agents; D000914:Antibodies, Viral; D003561:Cytarabine; D000493:Allopurinol; D015255:Idarubicin",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.12029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "93(3)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000368:Aged; D000493:Allopurinol; D000890:Anti-Infective Agents; D000914:Antibodies, Viral; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D003561:Cytarabine; D003875:Drug Eruptions; D005077:Exanthema Subitum; D005260:Female; D005334:Fever; D006410:Hematopoiesis; D015654:Herpesvirus 6, Human; D015614:Histiocytosis; D006801:Humans; D015255:Idarubicin; D016867:Immunocompromised Host; D015470:Leukemia, Myeloid, Acute; D015479:Leukemia, Myelomonocytic, Acute; D017254:Leukemic Infiltration; D008875:Middle Aged; D012867:Skin; D014775:Virus Activation",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "469-70",
"pmc": null,
"pmid": "18310542",
"pubdate": "2008-03",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Drug-induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia.",
"title_normalized": "drug induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia"
} | [
{
"companynumb": "JP-PFIZER INC-2008070415",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Androgenetic alopecia is an androgen-induced pattern of progressive hair loss, which occurs in genetically predisposed people. This study aimed to determine long-term safety, tolerability and efficacy of dutasteride 0.5 mg, an inhibitor of 5-α-reductase, in Japanese male patients with androgenetic alopecia. This was a multicenter, open-label, prospective outpatient study (clinicaltrials.gov NCT01831791, GSK identifier ARI114264) in which patients took dutasteride 0.5 mg p.o. once daily for 52 weeks. Primary end-points included adverse event assessment, incidence of drug-related adverse event and premature discontinuations. Secondary end-points included hair growth, hair restoration and global improvement in hair. A total of 120 patients were enrolled, of whom 110 completed 52 weeks of treatment. Nasopharyngitis, erectile dysfunction and decreased libido were the most frequently reported adverse events and most adverse events were mild. Drug-related adverse events were reported with an incidence of 17%, none of which led to study withdrawal. Hair growth (mean target area hair count at week 52), hair restoration (mean target area hair width at week 52) and global appearance of hair (mean of the median score at week 52) improved from baseline during the study. As a potential future treatment option for male androgenetic alopecia, dutasteride 0.5 mg exhibited long-term safety, tolerability and efficacy within this study population.",
"affiliations": "Yaesu Sakura-dori Clinic, Tokyo, Japan.;ToCROM Clinic, Tokyo, Japan.;PS Clinic, Fukuoka, Japan.;GlaxoSmithKline Research & Development, Research Triangle Park, North Carolina, USA.;GlaxoSmithKline Research & Development, Tokyo, Japan.;Department of Dermatology, Tokyo Medical University, Tokyo, Japan.;Department of Dermatology, Tokyo Women's Medical University, Tokyo, Japan.;GlaxoSmithKline Research & Development, Research Triangle Park, North Carolina, USA.",
"authors": "Tsunemi|Yuichiro|Y|;Irisawa|Ryokichi|R|;Yoshiie|Hiromu|H|;Brotherton|Betsy|B|;Ito|Hisahiro|H|;Tsuboi|Ryoji|R|;Kawashima|Makoto|M|;Manyak|Michael|M|;|||",
"chemical_list": "D058891:5-alpha Reductase Inhibitors; D000068538:Dutasteride",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.13310",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "43(9)",
"journal": "The Journal of dermatology",
"keywords": "5-alpha-reductase inhibitor; dihydrotestosterone; dutasteride; male androgenetic alopecia; safety",
"medline_ta": "J Dermatol",
"mesh_terms": "D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000328:Adult; D000505:Alopecia; D000068538:Dutasteride; D006197:Hair; D006801:Humans; D015994:Incidence; D007564:Japan; D000069451:Long Term Adverse Effects; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "1051-8",
"pmc": null,
"pmid": "26893187",
"pubdate": "2016-09",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Long-term safety and efficacy of dutasteride in the treatment of male patients with androgenetic alopecia.",
"title_normalized": "long term safety and efficacy of dutasteride in the treatment of male patients with androgenetic alopecia"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2016SP014055",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DUTASTERIDE"
},
"drugadditional... |
{
"abstract": "Anemia is a common finding in the perioperative setting with significant untoward consequences including worsening of outcomes and diminished quality of life as well as increased risk of allogeneic blood transfusions. Here, we present 3 cases that illustrate how anemia can be perioperatively managed in patients undergoing cardiac, orthopedic, and oncology surgeries. Timely detection of anemia prior to high-blood loss surgeries can allow clinicians to manage it and optimize hemoglobin level, making patients better prepared for the surgery. Treatment of anemia should be guided by the etiology and may include erythropoietic agents, folic acid, B12, and iron preparations. Other blood management strategies geared toward reducing surgical blood loss such as autologous transfusion techniques and agents to optimize hemostasis are used during surgery and in the immediate postoperative period. Patients should be closely monitored following surgery for signs of ongoing bleeding in need of control. Finally, screening for and management of anemia should continue in the postoperative and postdischarge period, as persistence and recurrence of anemia can further undermine patient's outcomes.",
"affiliations": "Department of Anesthesiology and Critical Care Medicine, and.;Department of Anesthesiology and Critical Care Medicine, and.;Department of Pathology and.",
"authors": "Shander|Aryeh|A|;Kaufman|Margit|M|;Goodnough|Lawrence T|LT|",
"chemical_list": "D004921:Erythropoietin; D007501:Iron",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019003945",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "136(7)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000740:Anemia; D016063:Blood Loss, Surgical; D001804:Blood Transfusion, Autologous; D017707:Erythrocyte Transfusion; D004921:Erythropoietin; D006801:Humans; D007501:Iron; D019990:Perioperative Care; D011183:Postoperative Complications",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "814-822",
"pmc": null,
"pmid": "32556314",
"pubdate": "2020-08-13",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "How I treat anemia in the perisurgical setting.",
"title_normalized": "how i treat anemia in the perisurgical setting"
} | [
{
"companynumb": "US-AMGEN-USASP2020206765",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "Multiple myeloma (MM) is a common hematological malignancy with poorly understood recurrence and relapse mechanisms. Notably, bortezomib resistance leading to relapse makes MM treatment significantly challenging. To clarify the drug resistance mechanism, we employed a quantitative proteomics approach to identify differentially expressed protein candidates implicated in bortezomib-resistant recurrent and relapsed MM (RRMM). Bone marrow aspirates from five patients newly diagnosed with MM (NDMM) were compared with those from five patients diagnosed with bortezomib-resistant RRMM using tandem mass tag-mass spectrometry (TMT-MS). Subcellular localization and functional classification of the differentially expressed proteins were determined by gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and hierarchical clustering analyses. The top candidates identified were validated with parallel reaction monitoring (PRM) analysis using tissue samples from 11 NDMM and 8 RRMM patients, followed by comparison with the NCBI Gene Expression Omnibus (GEO) dataset of 10 MM patients and 10 healthy controls (accession no.: GSE80608). Thirty-four differentially expressed proteins in RRMM, including proteinase inhibitor 9 (SERPINB9), were identified by TMT-MS. Subsequent functional enrichment analyses of the identified protein candidates indicated their involvement in regulating cellular metabolism, apoptosis, programmed cell death, lymphocyte-mediated immunity, and defense response pathways in RRMM. The top protein candidate SERPINB9 was confirmed by PRM analysis and western blotting as well as by comparison with an NCBI GEO dataset. We elucidated the proteome landscape of bortezomib-resistant RRMM and identified SERPINB9 as a promising novel therapeutic target. Our results provide a resource for future studies on the mechanism of RRMM.",
"affiliations": "Hematology Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.;Hematology Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.;Hematology Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.;Hematology Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.;Hematology Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.;Immunology Department, Harbin Medical University, Harbin, Heilongjiang, P.R. China.;Laboratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang, P.R. China.;Hematology Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.",
"authors": "Chen|Yao|Y|;Quan|Lina|L|0000-0001-8995-7156;Jia|Chuiming|C|;Guo|Yiwei|Y|;Wang|Xinya|X|;Zhang|Yu|Y|;Jin|Yan|Y|;Liu|Aichun|A|",
"chemical_list": "D020543:Proteome; C102316:SERPINB9 protein, human; D015843:Serpins; D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": "10.1021/acs.jproteome.1c00007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1535-3893",
"issue": "20(5)",
"journal": "Journal of proteome research",
"keywords": "SERPINB9; multiple myeloma; parallel reaction monitoring; proteomics; recurrence and relapse",
"medline_ta": "J Proteome Res",
"mesh_terms": "D000069286:Bortezomib; D006801:Humans; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D020543:Proteome; D040901:Proteomics; D015843:Serpins",
"nlm_unique_id": "101128775",
"other_id": null,
"pages": "2673-2686",
"pmc": null,
"pmid": "33650432",
"pubdate": "2021-05-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Proteomics-Based Approach Reveals the Involvement of SERPINB9 in Recurrent and Relapsed Multiple Myeloma.",
"title_normalized": "proteomics based approach reveals the involvement of serpinb9 in recurrent and relapsed multiple myeloma"
} | [
{
"companynumb": "CN-TAKEDA-2022TUS038516",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe current study was undertaken to determine the relationship between postmortem (PM) peripheral blood (PB) and liver fentanyl concentrations and the role of measuring liver fentanyl concentrations in cause of death investigations in medical examiner cases in which fentanyl was identified.\n\n\nMETHODS\nFB and liver tissue were routinely collected at autopsy from 4 Minnesota medical examiners' offices in 2010-2011. Samples were analyzed by gas chromatography-mass spectrometry (GC-MS).\n\n\nRESULTS\nPB fentanyl ranged from <2-15μg/L in non-drug related deaths (n=5), <2-22μg/L from mixed drug toxicity (n=26) and 3.7-56μg/L from fentanyl toxicity (n=33). Liver fentanyl ranged from 11 to 104μg/kg, 6 to 235μg/kg, and 18 to 365μg/kg, respectively. PB and liver fentanyl showed a modest correlation (r=0.67). PM interval to the liver/blood ratio showed a decreasing ratio over increasing PM interval in cases from fentanyl and mixed drug toxicity. Liver fentanyl concentrations best define therapeutic use at <23μg/kg and fatal toxicity at >56μg/kg, without substantial overlap as found in blood fentanyl concentrations.\n\n\nCONCLUSIONS\nDiscriminatory liver fentanyl concentrations suggestive of therapeutic or toxic drug levels may better assist cause of death determination in cases of suspected fentanyl toxicity than postmortem PB concentrations. Peripheral blood fentanyl concentrations appear to undergo postmortem redistribution, associated with an increasing PM interval.",
"affiliations": "University of Minnesota, Minneapolis, MN, USA.",
"authors": "Palamalai|Vikram|V|;Olson|Kalen N|KN|;Kloss|Julie|J|;Middleton|Owen|O|;Mills|Kelly|K|;Strobl|A Quinn|AQ|;Thomas|Lindsey C|LC|;Apple|Fred S|FS|",
"chemical_list": "D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9120",
"issue": "46(7-8)",
"journal": "Clinical biochemistry",
"keywords": null,
"medline_ta": "Clin Biochem",
"mesh_terms": "D005283:Fentanyl; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008099:Liver; D011180:Postmortem Changes; D013997:Time Factors",
"nlm_unique_id": "0133660",
"other_id": null,
"pages": "598-602",
"pmc": null,
"pmid": "23485343",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Superiority of postmortem liver fentanyl concentrations over peripheral blood influenced by postmortem interval for determination of fentanyl toxicity.",
"title_normalized": "superiority of postmortem liver fentanyl concentrations over peripheral blood influenced by postmortem interval for determination of fentanyl toxicity"
} | [
{
"companynumb": "US-JNJFOC-20130500564",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nBased on common pharmacodynamic mechanisms, recent efforts to develop second generation alternatives for organophosphate (OP) prophylaxis have expanded to include cholinesterase (ChE) inhibiting compounds traditionally approved for use in the treatment of Alzheimer's disease (AD). The primary purpose of this study was to determine the extent to which low-dose huperzine A, galantamine, or donepezil selectively inhibited acetylcholinesterase (AChE) versus butyrylcholinesterase (BChE) activity in healthy adults and whether such inhibition impacted neurobehavioral performance.\n\n\nMETHODS\nIn addition to hourly red blood cell cholinesterase sampling, neurobehavioral function was assessed before and after a single oral dose of huperzine A (100 or 200 μg), galantamine (4 or 8 mg), donepezil (2.5 or 5mg), or placebo (n=12 subjects per drug/dose).\n\n\nRESULTS\nCompared to placebo, both dosages of huperzine A and galantamine inhibited circulating AChE but not BChE. With the exception of huperzine A (200 μg), which maintained declarative recall performance across sessions, compounds did not improve neurobehavioral performance. Some aspects of neurobehavioral performance correlated with AChE activity, although associations may have reflected time of day effects.\n\n\nCONCLUSIONS\nAlthough huperzine A and galantamine significantly inhibited AChE (and likely increased central acetylcholine levels), neither compound improved neurobehavioral performance. The latter was likely due to ceiling effects in this young, healthy test population. Under conditions of reduced cholinergic activity (e.g., Alzheimer's disease), AChE inhibition (and corresponding maintenance of cholinergic tone) could potentially maintain/augment some aspects of neurobehavioral function.",
"affiliations": "Walter Reed Army Institute of Research, United States. Electronic address: kmorasch@gmail.com.;Fort Belvoir Community Hospital, United States.;Walter Reed Army Institute of Research, United States.;United States Army Medical Research and Materiel Command, United States.",
"authors": "Morasch|Katherine C|KC|;Aaron|Christopher L|CL|;Moon|James E|JE|;Gordon|Richard K|RK|",
"chemical_list": "D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D012717:Sesquiterpenes; C050426:huperzine A; D005702:Galantamine; D000077265:Donepezil; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-9384",
"issue": "138()",
"journal": "Physiology & behavior",
"keywords": "Acetylcholinesterase inhibition; Donepezil; Galantamine; Huperzine A; Neurobehavioral performance; Organophosphate prophylaxis",
"medline_ta": "Physiol Behav",
"mesh_terms": "D000110:Acetylcholinesterase; D000293:Adolescent; D000328:Adult; D000470:Alkaloids; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases; D000077265:Donepezil; D005260:Female; D005702:Galantamine; D006801:Humans; D007189:Indans; D008297:Male; D008568:Memory; D010880:Piperidines; D011930:Reaction Time; D012717:Sesquiterpenes; D055815:Young Adult",
"nlm_unique_id": "0151504",
"other_id": null,
"pages": "165-72",
"pmc": null,
"pmid": "25455867",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Physiological and neurobehavioral effects of cholinesterase inhibition in healthy adults.",
"title_normalized": "physiological and neurobehavioral effects of cholinesterase inhibition in healthy adults"
} | [
{
"companynumb": "US-JNJFOC-20141202695",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GALANTAMINE HYDROBROMIDE"
},
"drugadditional": nu... |
{
"abstract": "BACKGROUND\nAzelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported.\n\n\nMETHODS\nIn the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient's physician that the patient's serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient's serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment.\n\n\nCONCLUSIONS\nAzelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.",
"affiliations": "Department of Pharmacy, Chutoen General Medical Center, 1-1 Shobugaike, Kakegawa, Shizuoka, 436-8555, Japan. prunus.mume.2.9.2@gmail.com.;Department of Pharmacy, Chutoen General Medical Center, 1-1 Shobugaike, Kakegawa, Shizuoka, 436-8555, Japan.;Laboratory of Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.;Department of Pharmacy, Chutoen General Medical Center, 1-1 Shobugaike, Kakegawa, Shizuoka, 436-8555, Japan.",
"authors": "Ide|Naohito|N|http://orcid.org/0000-0002-0292-3672;Mochizuki|Ayaka|A|;Kagawa|Yoshiyuki|Y|;Ito|Masaharu|M|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s40780-021-00230-x",
"fulltext": "\n==== Front\nJ Pharm Health Care Sci\nJ Pharm Health Care Sci\nJournal of Pharmaceutical Health Care and Sciences\n2055-0294\nBioMed Central London\n\n34847962\n230\n10.1186/s40780-021-00230-x\nCase Report\nA case of complete atrioventricular block with extremely high blood concentration of azelnidipine\nhttp://orcid.org/0000-0002-0292-3672\nIde Naohito prunus.mume.2.9.2@gmail.com\n\n12\nMochizuki Ayaka 1\nKagawa Yoshiyuki 2\nIto Masaharu 1\n1 Department of Pharmacy, Chutoen General Medical Center, 1-1 Shobugaike, Kakegawa, Shizuoka, 436-8555 Japan\n2 grid.469280.1 0000 0000 9209 9298 Laboratory of Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526 Japan\n1 12 2021\n1 12 2021\n2021\n7 4828 8 2021\n5 11 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\nAzelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported.\n\nCase presentation\n\nIn the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment.\n\nConclusions\n\nAzelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.\n\nKeywords\n\nAzelnidipine\nAdverse events\nCalcium channel blocker\nComplete atrioventricular block\nDrug interaction\nSimvastatin\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nAll calcium channel blockers (CCBs) commonly block the L-type calcium ion channel. The main therapeutic effects of CCBs include vasodilation of coronary and peripheral arteries, negative inotropic effects, and a decrease in heart rate and atrioventricular conduction [1, 2]. There are 3 categories of CCBs: dihydropyridines, benzothiazepines, and phenylalkylamines. Benzothiazepine CCBs (e.g., diltiazem) and phenylalkylamine CCBs (e.g., verapamil) are more selective for the myocardium than for vascular smooth muscle. Therefore, these CCBs are characterized by a weak antihypertensive effect and a strong negative inotropic effect, which may cause bradycardia and atrioventricular block. Dihydropyridine CCBs have strong vasodilator actions and are often used to treat hypertension. However, rapid vasodilation can cause adverse effect such as hot flushes, headache, and reflex tachycardia. Azelnidipine, classified as a dihydropyridine CCB, has a higher lipophilicity compared to other CCBs, resulting in higher affinity with vascular tissue and prolonged distribution in the tissue [3–5]. Therefore, its antihypertensive effects are mild, duration of its activities long, and a single dose daily can control blood pressure for 24 h [4, 6, 7]. In addition, azelnidipine has few adverse effects such as hot flushes and headaches. Whilst benzothiazepine and phenylalkylamine CCBs may result in bradycardia and atrioventricular block, dihydropyridine CCBs rarely cause such adverse effects, as shown in vivo [1, 2]. Rather, dihydropyridine CCBs generally trigger reflex tachycardia. Unlike other dihydropyridine CCBs, azelnidipine does not increase heart rate, but rather decreases it [4, 5, 7–9]. To the best of the authors’ knowledge, there have been no previous case reports of complete atrioventricular block (CAVB) with azelnidipine treatment. The present case report is one of an elderly patient who had been taking azelnidipine for a long time and had suspected CAVB, which she thought may be an adverse event associated with azelnidipine treatment.\n\nCase presentation\n\nThe patient was a 92-year-old woman who regularly saw her private physician and was being treated for hypertension, hyperlipidemia and chronic gastritis with azelnidipine 16 mg/day, simvastatin 5 mg/day, famotidine 20 mg/day, irsogladine maleate 4 mg/day and mosapride citrate hydrate 15 mg/day. Her medications had not been changed in over a decade, and she had never been diagnosed with CAVB. She complained of dyspnea and palpitation, and was consequently examined by her private physician (Day 1). She was prescribed furosemide 20 mg/day, spironolactone 25 mg/day and cibenzoline 100 mg/day. Three days later (Day 4), the patient was diagnosed with CAVB by electrocardiogram (ECG), and referred to our medical center by her private physician. When she arrived at our medical center, her blood pressure was 159/66 mmHg, and her heart rate was 44 beats/min. The patient’s ECG upon arrival at our center is shown in Fig. 1 and laboratory data is shown in Table 1. The patient was immediately hospitalized and underwent surgery for implantation of a temporary pacemaker, and intravenous furosemide treatment commenced. Oral administration of furosemide, spironolactone and cibenzoline was discontinued, however all other oral medications, including azelnidipine, continued. Three days after admission (Day 7), the patient returned to a normal sinus rhythm and the symptoms of dyspnea resolved. The temporary pacemaker was removed and intravenous furosemide discontinued. After removal of the temporary pacemaker, ECG examination did not show CAVB and the patient was discharged 9 days after her initial admission (Day 13). Three weeks after discharge from the hospital, she was again diagnosed by her private physician with CAVB and was again referred to our hospital (Day 34). As the patient had recurrent episodes of CAVB, it was arranged that she was registered for surgical implant of a permanent pacemaker. Her medications were investigated once again, and it was surmised that CAVB may have occurred as an adverse event associated with azelnidipine treatment. Both azelnidipine and simvastatin are metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). These drugs are capable of competitively blocking the metabolism of the other. The authors proposed to the physician that azelnidipine and simvastatin be discontinued and the patient’s serum azelnidipine levels be measured, before surgery for the permanent pacemaker be conducted. The drugs were accordingly discontinued and surgical implant of a permanent pacemaker canceled. One week after discontinuation of the drugs (Day 41), a 24 h ambulatory ECG confirmed an episode of CAVB in the early morning, however no subjective symptoms such as dyspnea were observed. One month later a 24 h ambulatory ECG showed no episode of CAVB (Day 71). It was later observed that serum azelnidipine levels after 6 h of medication was 63.4 ng/mL. Over the course of the next 5 months, 24 h ambulatory ECGs were performed once a month, with no evidence of CAVB. The patient’s clinical course is summarized in Table 2. Fig. 1 Electrocardiogram of patient on first arrival at the medical center\n\nTable 1 Laboratory data upon hospitalization\n\nLaboratory parameter\tValue\t\t\nWhite blood cell\t12,100\tcount/μL\t\nRed blood cell\t351 × 104\tcount/μL\t\nHemoglobin\t11.0\tg/dL\t\nPlatelet\t24.6 × 104\tcount/μL\t\nTotal protein\t7.1\tg/dL\t\nTotal albumin\t3.7\tg/dL\t\nTotal bilirubin\t0.8\tmg/dL\t\nTotal cholesterol\t172\tmg/dL\t\nCholinesterase\t305\tIU/L\t\nCreatine Phosphokinase\t94\tIU/L\t\nAspartate aminotransferase\t29\tIU/L\t\nAlanine aminotransferase\t30\tIU/L\t\nLactate dehydrogenase\t254\tIU/L\t\nBlood urea nitrogen\t48.9\tmg/dL\t\nSerum creatinine Serum creatinine\t1.38\tmg/dL\t\neGFR\t27.5\tmL/min/1.73 m2\t\nSodium\t142\tmEq/L\t\nPotassium\t4.8\tmEq/L\t\nChlorine\t109\tmEq/L\t\neGFR Estimated glomerular filtration rate\n\nTable 2 Clinical course of a 92-year-old female patient diagnosed with complete atrioventricular block\n\nTime\tEvent\t\nFor more than 10 years before admission\tUse of azelnidipine 16 mg/day and simvastatin 5 mg/day\t\nDay 1\tPatient complained of dyspnea and palpitations.\t\nPatient was prescribed furosemide, spironolactone and cibenzoline.\t\nDay 4\tPatient was diagnosed with complete atrioventricular block (CAVB) and hospitalized.\t\nOral administration of furosemide, spironolactone and cibenzoline was discontinued.\t\nIntravenous administration of furosemide was started.\t\nTemporary pacemaker was implanted.\t\nDay 7\tPatient returned to a normal sinus rhythm, and the symptoms of dyspnea resolved.\t\nIntravenous administration of furosemide was discontinued.\t\nTemporary pacemaker was removed.\t\nDay 13\tPatient was discharged.\t\nDay 34\tPatient was again diagnosed with CAVB.\t\nOral administration of azelnidipine and simvastatin was discontinued.\t\nDay 41\tElectrocardiogram (ECG) confirmed an episode of CAVB.\t\nNo subjective symptoms were observed.\t\nDay 71\tECG showed no episode of CAVB.\t\nOver the course of the next 5 months\tECG was performed once a month, with no evidence of CAVB.\t\n\nThe Naranjo adverse drug reaction probability scale was used to determine the probability that CAVB was an adverse reaction associated with azelnidipine treatment [10]. The Naranjo scale generated a score of 5 (Table 3), suggesting a probable causal relationship between CAVB and azelnidipine treatment. A MEDLINE search was also conducted for articles published between 2003 and June 2021 with search terms such as “azelnidpine AND bradycardia” or “azelnidipine AND atrioventricular block”. However, the literature search did not result in any case studies reporting an association between azelnidipine and bradycardia or atrioventricular block. Table 3 Naranjo Adverse Drug Reaction Probability Scale score of the patient\n\nQuestions\tAnswer\tScore\t\nAre there previous conclusive reports on this reaction?\tNo\t0\t\nDid the adverse event occur after the suspected drug was administered?\tYes\t+ 2\t\nDid the adverse ereaction improve when the drug was discontinued or a specific antagonist was administered?\tYes\t+ 1\t\nDid the adverse reaction reappear when the drug was readministered?\tDo not know\t0\t\nAre there alternative causes (other than the drug) that could have on their own caused the reaction?\tDo not know\t0\t\nDid the reaction reappear when a placebo was given?\tDo not know\t0\t\nWas the drug detected in the blood (or other fluids) in concentrations know to be toxic?\tYes\t+ 1\t\nWas the reaction more severe when the dose was increased or less severe when the dose was decreased?\tDo not know\t0\t\nDid the patient have a similar reaction to the same or similar drugs in any previous exposure?\tDo not know\t0\t\nWas the adverse event confirmed by any objective evidence?\tYes\t+ 1\t\nTotal score\t\t5\t\n\nDiscussion and conclusions\n\nDihydropyridine CCBs intrinsically reduce sinus node function and have a bradycardic effect, similar to benzothiazepine and phenylalkylamine CCBs. However, in vivo studies have shown that the sympathetic nervous system is stimulated by the antihypertensive reflex, which not only masks the intrinsic bradycardia effect, but also causes tachycardia when the reflex is strong [9]. An increase in heart rate has been shown to be an independent risk factor for cardiovascular events [11], indicating the importance of not elevating heart rate. Generally, at clinical doses, dihydropyridine CCBs do not prolong atrioventricular conduction or refractoriness or cause sinus node suppression [1]. However, azelnidipine, a dihydropyridine CCB, has been reported to cause a significant decrease in heart rate in dogs and spontaneously hypertensive rats (SHRs) [5, 9]. In clinical trials in humans, it has also been reported that long-term administration of azelnidipine tends to decrease heart rate [4, 6, 7]. These properties are thought to be attributed to the very small effect azelnidipine has on the sympathetic nervous system [4]. Therefore, azelnidipine differs from other dihydropyridine CCBs, in that it does not cause reflex tachycardia in vivo, but rather a decrease in heart rate. Kuramoto et al. reported a decrease in pulse rate of 2 beat/min after 6 weeks administration of azelnidipine at 16 mg/day [7], and Kario et al. reported a 3.5 beat/min decrease in pulse rate after 12 weeks of azelnidipine treatment [6]. No adverse events of bradycardia or atrioventricular block were reported. Katayama et al. reported that in a study of 210 hypertensive diabetic patients treated with azelnidipine 8 to 16 mg/day and temocapril hydrochloride 2 to 4 mg/day, respectively, there was only one case of possible atrioventricular block (AVB) that occurred as an adverse event due to treatment [12]. The authors noted however that the AVB case may have been an incidental adverse event.\n\nKuramoto et al. reported that Cmax and Tmax were 48.3 ± 19.0 ng/mL and 4.14 ± 1.46 h, respectively, in patients with essential hypertension treated daily with 16 mg azelnidipine for an extensive length of time [7]. In the present case report, the patient presented with a serum concentration of azelnidipine of 63.4 ng/mL 6 h after being administered 16 mg azelnidipine. The serum level of azelnidipine in the present case was well above the peak, even though the serum levels were measured well after Tmax. Therefore, we assume that if the serum levels of azelnidipine had been measured at Tmax, they would have been even higher than 63.4 ng/mL.\n\nOur patient’s medications were managed by her family, so it was considered unlikely that she had overdosed on them. It is possible that the high serum levels in this case study are a result of a decrease in hepatic metabolic function due to age and is one of the causes of the drug’s interactions with CYP3A4. The metabolism of azelnidipine may have been competitively inhibited by combination treatment with simvastatin, which, similar to azelnidipine, is metabolized by CYP3A4. As most dihydropyridine CCBs are metabolized by CYP3A4, inhibition of CYP3A4 metabolization of CCBs may result in unchanged or high serum concentrations of dihydropyridine CCBs and subsequent adverse events [1, 2]. Common drugs with CYP3A4 inhibitory effects include itraconazole, cimetidine, and simvastatin [13]. Using human liver microsomes, Kazui et al. reported the Ki values of CYP3A4-inhibiting drugs against azelnidipine [14]. It was reported that metabolism of azelnidipine was inhibited by the CYP3A4-inhibiting drugs with the following Ki values: itraconazole, 0.065 μM; cimetidine, 0.8 mM, and simvastatin, 9.3 μM. As itraconazole strongly inhibits CYP3A4, concomitant use of it with azelnidipine is contraindicated [15]. The combination of simvastatin and azelnidipine treatment may also increase the serum levels of each drug and increase the risk of adverse effects associated with this combination treatment, as noted in the patient information booklet included in the combination treatment package [15]. The Cmax after oral administration of 5 mg simvastatin is 0.012 μM [16], which is well below the previously described Ki value of simvastatin (9.3 μM) [14]. Therefore, when simvastatin and azelnidipine are used concomitantly at normal doses, it is very unlikely that simvastatin will inhibit the metabolism of azelnidipine and consequently increase the blood concentration of the drug. However, as in the present case, there is a rare possibility that the concomitant use of these drugs may increase the blood concentration of azelnidipine, so caution should be exercised.\n\nThe patient in this case study had been taking azelnidipine and simvastatin for more than 10 years without any occurrence of CAVB. The authors conclude that the most likely cause for the sudden adverse event of CAVB is an age-related decrease in drug metabolism in the liver, however the reason for this remains unclear. In this patient, serum levels of azelnidipine at the time of CAVB occurrence were higher than normal, and indeed higher than reported peak levels. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine treatment. These results show that a score of 5 on the Naranjo scale is “probable”, indicating that CAVB is a possible adverse effect of azelnidipine treatment.\n\nThe findings of the present case study suggest that elderly patients receiving azelnidipine at 16 mg/day with concomitant CYP3A4 inhibitors may have elevated blood levels of azelnidipine, that may result in CAVB. Therefore, in the elderly, it is considered necessary to avoid concomitant use of CYP3A4 inhibitors.\n\nAbbreviations\n\nAVB Atrioventricular block\n\nCAVB Complete atrioventricular block\n\nCCB Calcium channel blocker\n\nCYP3A4 Cytochrome P450 enzyme 3A4\n\nECG Electrocardiogram\n\nSHR Spontaneously hypertensive rat\n\nThis manuscript has been checked by a native English-speaking medical editor from Yamada Translation Bureau, Inc.\n\nAuthors’ contributions\n\nNI and AM monitored the patients and carried out acquisition of the patient data. NI conceived the pharmacokinetic study and drafted the manuscript. YK and MI helped to draft the manuscript. All authors have read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nData used in this case report will not be shared owing to the risk of identifying an individual.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study was approved by the Ethics Committee of Chutoen General Medical Center.\n\nConsent for publication\n\nInformed consent was obtained from the patient.\n\nCompeting interests\n\nThe authors declare that they have no competing interest.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Abernethy DR Schwart JB Calcium-antagonist drugs N Engl J Med 1999 341 19 1447 1457 10.1056/NEJM199911043411907 10547409\n2. McKeever RG Hamilton RJ Calcium Channel Blockers: StatPearls [Internet] 2020 Florida Treasure Island: StatPearls Publishing\n3. Wellington K Scott LJ Azelnidipine Drugs. 2003 63 23 2613 2621 10.2165/00003495-200363230-00004 14636080\n4. Sada T Saito H Pharmacological profiles and clinical effects of azelnidipine, a long-acting calcium channel blocker Nihon Yakurigaku Zasshi 2003 122 6 539 547 10.1254/fpj.122.539 14639008\n5. Sada T Mizuno M Miyama C Ohata K Oizumi K Yamamura N Pharmacological properties of Azelnidipine, a long-acting Calcium Channel blocker with high-affinity for vascular tissues (part 2) Jpn Pharmacol Ther 2002 30 711 720\n6. Kario K Sato Y Shirayama M Takahashi M Shiosakai K Hiramatsu K Komiya M Shimada K Inhibitory effects of azelnidipine tablets on morning hypertension Drugs R D 2013 13 1 63 73 10.1007/s40268-013-0006-8 23512719\n7. Kuramoto K Ichikawa S Hirai A Kanada S Nakachi T Ogihara T Azelnidipine and amlodipine: a comparison of their pharmacokinetics and effects on ambulatory blood pressure Hypertens Res 2003 26 3 201 208 10.1291/hypres.26.201 12675275\n8. Kumagaya H Onami T Iigaya K Takimoto C Hayashi K Saruta T Mechanism of a reduction in heart rate by azelnidipine as investigated in terms of the peripheral and central nervous systems Prog Med 2004 24 2659 2664\n9. Fujisawa M Yorikane R Chiba S Koike H Chronotropic effect of azelnidipine, a slow- and long-acting dihydropyridine-type calcium channel blocker, in anesthetized dogs: a comparison with amlodipine J Cardiovasc Pharmacol 2009 53 4 325 332 10.1097/FJC.0b013e31819f1be1 19295444\n10. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 10.1038/clpt.1981.154 7249508\n11. Palatini P Julius S Heart rate and the cardiovascular risk J Hypertens 1997 15 1 3 17 10.1097/00004872-199715010-00001 9050965\n12. Katayama S Kawamori R Iwamoto Y Saito I Kuramoto K In half of hypertensive diabetics, co-administration of a calcium channel blocker and an angiotensin-converting enzyme inhibitor achieved a target blood pressure of <130/80 mmHg: the azelnidipine and temocapril in hypertensive patients with type 2 diabetes (ATTEST) study Hypertens Res 2008 31 8 1499 1508 10.1291/hypres.31.1499 18971523\n13. Ament PW Bertolino JG Liszewski JL Clinically significant drug interactions Am Fam Physican 2000 61 1745 1754\n14. Kazui M Ikeda T Yamazoe Y Drug interaction of ca-channel blockers Prog Med 2004 24 2653 2658\n15. Calblock (azelnidipine) [package insert]. Tokyo, Japan: Daiichi Sankyo Company, Ltd.; 2003.\n16. Lipovas (simvastatin) [interview form]. Tokyo, Japan: Organon; 2021.\n\n",
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"issue": "7(1)",
"journal": "Journal of pharmaceutical health care and sciences",
"keywords": "Adverse events; Azelnidipine; Calcium channel blocker; Complete atrioventricular block; Drug interaction; Simvastatin",
"medline_ta": "J Pharm Health Care Sci",
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"pmid": "34847962",
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"title": "A case of complete atrioventricular block with extremely high blood concentration of azelnidipine.",
"title_normalized": "a case of complete atrioventricular block with extremely high blood concentration of azelnidipine"
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"abstract": "BACKGROUND\nSystemic capillary leak syndrome is a highly rare disorder of unknown cause. The disease is characterized by episodes of transient vascular collapse, which leads to hypotensive shock and anasarca. Previous treatment of this potentially devastating condition has been largely ineffective. We evaluated intravenous immunoglobulin prophylactic therapy in a cohort of 29 patients with systemic capillary leak syndrome in a longitudinal follow-up study.\n\n\nMETHODS\nAll patients received treatments at the discretion of their primary providers and retrospectively via questionnaire-recorded symptoms beginning with their first documented episode of systemic capillary leak syndrome to May 31, 2014.\n\n\nRESULTS\nA total of 22 of 29 patients responded to the questionnaire, and 18 of the 22 respondents received monthly prophylaxis with intravenous immunoglobulin during the study period for a median interval of 32 months. The median annual attack frequency was 2.6 per patient before intravenous immunoglobulin therapy and 0 per patient after initiation of intravenous immunoglobulin prophylaxis (P = .0001). A total of 15 of 18 subjects with a history of 1 or more acute systemic capillary leak syndrome episodes experienced no further symptoms while taking intravenous immunoglobulin therapy.\n\n\nCONCLUSIONS\nIntravenous immunoglobulin prophylaxis is associated with a dramatic reduction in the occurrence of systemic capillary leak syndrome attacks in most patients, with minimal side effects. A prospective, randomized trial may be necessary to fully assess the benefits of intravenous immunoglobulin for systemic capillary leak syndrome and to determine the optimal dosage and duration of therapy.",
"affiliations": "Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md.;Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md.;Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md.;Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md.;Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Md. Electronic address: kdruey@niaid.nih.gov.",
"authors": "Xie|Zhihui|Z|;Chan|Eunice C|EC|;Long|Lauren M|LM|;Nelson|Celeste|C|;Druey|Kirk M|KM|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9343",
"issue": "128(1)",
"journal": "The American journal of medicine",
"keywords": "Intravenous immunoglobulin; Systemic capillary leak syndrome; Vascular leak",
"medline_ta": "Am J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D019559:Capillary Leak Syndrome; D005500:Follow-Up Studies; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "0267200",
"other_id": null,
"pages": "91-5",
"pmc": null,
"pmid": "25193271",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "21135305;22385628;24787070;20634497;10375339;24490827;13693909;20569743;21464348;20643990;21893630;24134172",
"title": "High-dose intravenous immunoglobulin therapy for systemic capillary leak syndrome (Clarkson disease).",
"title_normalized": "high dose intravenous immunoglobulin therapy for systemic capillary leak syndrome clarkson disease"
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"abstract": "OBJECTIVE\nWe aimed to evaluate whether hormonal therapy immediately after postsurgical recurrence of ovarian endometrioma controls disease progression and can be an alternative therapeutic option to avoid multiple repeat surgeries.\n\n\nMETHODS\nWe enrolled 146 patients treated for endometrioma at the University Hospital of Kyoto Prefectural University of Medicine between 2009 and 2015. After laparoscopic cystectomy using the stripping technique, opening of cul-de-sac obliterations and complete resection of the deep infiltrating endometriosis lesions, the patients either received no treatment (n = 83), oral contraceptives (OC; n = 32) or dienogest (DNG; n = 27), depending on their medical history. Four patients were excluded because they changed their regimens during the follow-up period. All patients were followed up every 3 months. Patients who developed recurrence of endometrioma immediately received DNG, OC or gonadotropin-releasing hormone agonist.\n\n\nRESULTS\nOverall, 16 patients developed a recurrence of the endometrioma (12 in the nontreatment group, three in the OC group and one in the DNG group). The 11 patients with recurrence were treated with DNG immediately after the diagnosis of recurrent endometrioma. Among them, seven patients continued treatment with DNG (2 mg) for 24 months. After 24 months of treatment with DNG, complete resolution of recurrent endometrioma was achieved in four (57.1%) of seven patients. There was no improvement in the three patients who received OC and one patient who underwent secondary surgery.\n\n\nCONCLUSIONS\nDNG therapy early after recurrence of postsurgical endometrioma appears to be viable for reducing the risk of repeated surgery.",
"affiliations": "Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.;Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.",
"authors": "Koshiba|Akemi|A|;Mori|Taisuke|T|;Okimura|Hiroyuki|H|;Akiyama|Kanoko|K|;Kataoka|Hisashi|H|;Takaoka|Osamu|O|;Ito|Fumitake|F|;Matsushima|Hiroshi|H|;Kusuki|Izumi|I|;Kitawaki|Jo|J|",
"chemical_list": "D006727:Hormone Antagonists; C023635:dienogest; D009277:Nandrolone",
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"doi": "10.1111/jog.13725",
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"issn_linking": "1341-8076",
"issue": "44(10)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "dienogest; endometrioma; endometriosis; recurrence; secondary surgery",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D004715:Endometriosis; D005260:Female; D006727:Hormone Antagonists; D006801:Humans; D009277:Nandrolone; D012008:Recurrence; D012086:Reoperation; D055815:Young Adult",
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"title": "Dienogest therapy during the early stages of recurrence of endometrioma might be an alternative therapeutic option to avoid repeat surgeries.",
"title_normalized": "dienogest therapy during the early stages of recurrence of endometrioma might be an alternative therapeutic option to avoid repeat surgeries"
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"abstract": "BACKGROUND\nTreatment of breast cancer during pregnancy (BCP) remains a challenge to physicians. Surgery and chemotherapy during pregnancy are widely used for the treatment of BCP. Herein, we reported 3 Chinese patients with BCP who underwent chemotherapy during pregnancy and were followed up for adverse effects.\nThree female patients (case 1, case 2, and case 3) of 37-, 32-, and 28-year-old with breast masses were enrolled. Case 1 had been pregnant for over 4 months, case 2 over 7 months, and case 3 for 7 months. Ultrasound findings revealed a mass in the left breast in cases 1 and 2 (30 mm × 26 mm × 23 mm and 34 mm × 16 mm × 40 mm), and case 3 had 2 masses in the outer upper quadrant of right breast (27 mm × 27 mm × 26 mm, 18 mm × 17 mm × 17 mm) and 2 fixed enlarged lymph nodes in the right axillary fossa, respectively.\nAll breast masses were diagnosed by core needle biopsy, and the result was infiltrating ductal carcinoma.\n\n\nMETHODS\nChemotherapy regimen administered during pregnancy was EwP (epirubicin 80 mg/m, d1 + paclitaxel 80 mg/m, d1, 8, 15, and cycled every 21 days). During pregnancy, case 1 received 5 cycles, case 2 received 1 cycle, and case 3 received 2 cycles.\n\n\nRESULTS\nCase 2 patient experienced grade III bone marrow suppression once. Electrocardiogram (ECG) result of case 3 showed occasional occurrence of ventricular premature beats, with no complaint of discomfort. All 3 patients experienced uterine contractions, which caused preterm labor in case 2. Adverse events were nausea, hair loss, acid reflux, and constipation. Neonatal jaundice occurred in the premature infant (case 2), which was resolved by phototherapy. No relapse or metastasis was observed in the 3 cases and the infants are growing normally.\n\n\nCONCLUSIONS\nBoth patients and infants well tolerated the combination chemotherapy of epirubicin and paclitaxel during pregnancy. There were few drug toxicities and adverse effects.",
"affiliations": "Department of Breast Surgery, The International Peace Maternity and Child Health Hospital of China Welfare Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
"authors": "Ye|Xin|X|;He|Qi|Q|;Zhou|Xiaoyun|X|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29145270MD-D-17-0026710.1097/MD.0000000000008582085825600Research ArticleClinical Case ReportStudy on the adverse effects following chemotherapy for breast cancer diagnosis during pregnancy The first case report in ChinaYe Xin MSHe Qi BSZhou Xiaoyun BS∗Ling. Shizhang Department of Breast Surgery, The International Peace Maternity and Child Health Hospital of China Welfare Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.∗ Correspondence: Xiaoyun Zhou, Department of Breast Surgery, The International Peace Maternity and Child Health Hospital of China Welfare Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China (e-mail: xyun_zhou@hotmail.com).11 2017 17 11 2017 96 46 e858212 1 2017 13 10 2017 18 10 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nTreatment of breast cancer during pregnancy (BCP) remains a challenge to physicians. Surgery and chemotherapy during pregnancy are widely used for the treatment of BCP. Herein, we reported 3 Chinese patients with BCP who underwent chemotherapy during pregnancy and were followed up for adverse effects.\n\nPatient concerns:\nThree female patients (case 1, case 2, and case 3) of 37-, 32-, and 28-year-old with breast masses were enrolled. Case 1 had been pregnant for over 4 months, case 2 over 7 months, and case 3 for 7 months. Ultrasound findings revealed a mass in the left breast in cases 1 and 2 (30 mm × 26 mm × 23 mm and 34 mm × 16 mm × 40 mm), and case 3 had 2 masses in the outer upper quadrant of right breast (27 mm × 27 mm × 26 mm, 18 mm × 17 mm × 17 mm) and 2 fixed enlarged lymph nodes in the right axillary fossa, respectively.\n\nDiagnoses:\nAll breast masses were diagnosed by core needle biopsy, and the result was infiltrating ductal carcinoma.\n\nInterventions:\nChemotherapy regimen administered during pregnancy was EwP (epirubicin 80 mg/m2, d1 + paclitaxel 80 mg/m2, d1, 8, 15, and cycled every 21 days). During pregnancy, case 1 received 5 cycles, case 2 received 1 cycle, and case 3 received 2 cycles.\n\nOutcomes:\nCase 2 patient experienced grade III bone marrow suppression once. Electrocardiogram (ECG) result of case 3 showed occasional occurrence of ventricular premature beats, with no complaint of discomfort. All 3 patients experienced uterine contractions, which caused preterm labor in case 2. Adverse events were nausea, hair loss, acid reflux, and constipation. Neonatal jaundice occurred in the premature infant (case 2), which was resolved by phototherapy. No relapse or metastasis was observed in the 3 cases and the infants are growing normally.\n\nLessons:\nBoth patients and infants well tolerated the combination chemotherapy of epirubicin and paclitaxel during pregnancy. There were few drug toxicities and adverse effects.\n\nKeywords\nbreast cancerchemotherapychildrenpregnancyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nBreast cancer diagnosed during pregnancy (breast cancer during pregnancy [BCP]) is reported to be delayed by 1–3 months, owing to the physiological changes that occur in the breast during pregnancy. These changes have a proliferative effect on glandular and ductal tissues.[1] However, postponing the treatment in order to continue the pregnancy may result in the progression of cancer. At present, multiple clinical trials and breast cancer practice guidelines, including European Society for Medical Oncology (ESMO) clinical practice guidelines and the National Comprehensive Cancer Network, suggest that exposure to chemotherapy is feasible and safe during pregnancy, only 2nd and 3rd trimesters.[2–6] Chemotherapy is used widely during pregnancy, but there are no reports in China till date. This novel study in China was designed to explore the drug toxicity, adverse effects, and tolerance following chemotherapy in Chinese BCP patients. Ethical approval was given by the medical ethics committee of the International Peace Maternity and Child Health Hospital of China Welfare Institute, and all the participants provided written informed consent.\n\n2 Case report\n2.1 Case 1\nA 37-year-old female patient who had been pregnant for over 4 months was admitted to our hospital on August 5, 2014 with a complaint of “left breast mass for 2 months”. Ultrasound findings revealed a mass in the left breast (30 mm × 26 mm × 23 mm) and no enlargement of bilateral axillary lymph nodes. Pathological findings of core needle biopsy (CNB) indicated grade II infiltrating ductal carcinoma (IDC), while immunohistochemical (IHC) findings showed estrogen receptor (ER)(−), progesterone receptor (PR)(−), human epidermal growth factor receptor 2 (HER2)(−), and Ki67 (10%+) and the results were presented in Table 1. The patient received therapeutic regimen, including 5 cycles of neoadjuvant chemotherapy during pregnancy, delivery, 1 cycle of neoadjuvant chemotherapy after delivery, and then modified radical mastectomy. Chemotherapy regimen used was EwP (epirubicin 80 mg/m2, d1 + paclitaxel 80 mg/m2, d1, 8, 15, cycled every 21 days). The specific therapeutic process used in the study was presented in Table 2.\n\nTable 1 Clinical features, clinicopathologic characteristics, and adverse effects of 3 patients.\n\nTable 2 Therapeutic process of 3 patients.\n\n2.2 Case 2\nA 32-year-old female patient who had been pregnant for over 7 months was admitted to our hospital on January 6, 2015 with a complaint of “left breast mass for 1 week.” Ultrasound findings demonstrated a mass in the left breast (34 mm × 16 mm × 40 mm) and no enlargement of bilateral axillary lymph nodes. Diagnosis by CNB indicated grade II IDC, while IHC findings showed ER(30%+), PR(40%+), HER2(1+), and Ki67(40%+) (Table 1). The patient received therapeutic regimen, including 1 cycle of neoadjuvant chemotherapy during pregnancy, delivery, 3 cycles of neoadjuvant chemotherapy after delivery, then modified radical mastectomy and 4 cycles of adjuvant chemotherapy and endocrine therapy. Similar to case 1, the neoadjuvant chemotherapy used during pregnancy was EwP (Table 2).\n\nAfter delivery, neoadjuvant chemotherapy was adjusted to TAC (docetaxel 75 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2, d1, cycled every 21 days).\n\nPostoperative pathologic diagnosis showed a grade III IDC and axillary lymph nodal metastases. The IHC findings indicated ER(80%++), PR(80%+++), HER2(2+), and Ki67(60%+). HER2(−) and HER2(1+) indicated by IHC findings define as HER2-negative. HER2(3+) indicated by IHC findings define as HER2-positive. HER2(2+) indicated by IHC findings is equivocal result. The fluorescence in situ hybridization (FISH) assay could identify whether HER2 is positive or negative. However, the FISH assay was not performed due to patient's economic difficulty, so that we could not decide whether trastuzumab should be given to this patient for adjuvant treatment. Trastuzumab is a targeted drug for the treatment of HER2-positive patients.\n\n2.3 Case 3\nA 28-year-old female patient who had been pregnant for 7 months was admitted to our hospital on October 12, 2015 with a complaint of “right breast masses for 4 months”. Ultrasound findings showed 2 masses in the outer upper quadrant of right breast (27 mm × 27 mm × 26 mm, 18 mm × 17 mm × 17 mm) and 2 fixed enlargement lymph nodes in the right axillary fossa. CNB indicated an IDC, while IHC findings showed ER(−), PR(−), HER2(−), and Ki67 (90%+). Results from the aspiration biopsy demonstrated the right axillary lymph nodes, and pathological examination indicated adenocarcinoma. Abdominal ultrasound showed no liver metastasis. Cancer was staged as cT2N2M0 (Table 1). The patient received therapeutic regimen, including 2 cycles of neoadjuvant chemotherapy during pregnancy, delivery, 2 cycles of neoadjuvant chemotherapy after delivery, then modified radical mastectomy and 12 cycles of adjuvant chemotherapy and radiotherapy. The neoadjuvant chemotherapy used during pregnancy and after delivery were the same as those for case 1 EwP (Table 2). After operation, the adjuvant chemotherapy was adjusted to wPCb (carboplatin AUC = 2, d1 + paclitaxel 80 mg/m2, d1, weekly).\n\nTo implement chemotherapy as early as possible after delivery, a cesarean section was performed at a gestational age of 37 weeks and 4 days in order to shorten the waiting time interval for delivery.\n\nThe postoperative pathological diagnosis showed a grade III IDC and no axillary lymph nodal metastases. The IHC results indicated ER(−), PR(−), HER2(−), and Ki67 (95%+).\n\nNo family history of breast cancer was reported in all the 3 cases. All of them were healthy, and ECOG scores were zero.\n\nCase 2 patient experienced grade III bone marrow suppression once, white blood cell count was 1.9 × 109/L and neutrophil count was 0.64 × 109/L (Fig. 1). The granulocyte-colony stimulating factor (G-CSF) was administered to raise the white blood cell counts and neutrophil counts. No bone marrow suppression was observed in cases 1 and 3. No hematological toxicity, hepatic toxicity, and nephrotoxicity were observed in all the 3 cases.\n\nFigure 1 Variations of white blood cell and neutrophil counts in the 3 patients during pregnancy. Neo-chemo = neoadjuvant chemotherapy.\n\nThe 1st ECG (electrocardiogram) result of case 3 showed occasional occurrence of ventricular premature beats, while the patient reported no complaint of discomfort. Therefore, no specific treatment was administered and no abnormality was observed in the ECG findings during the next 13 cycles of chemotherapy.\n\nUterine contraction appeared in all 3 patients. Uterine contraction was transient and ceased spontaneously in case 1, while caused preterm delivery in case 2. Case 3 patient experienced regular uterine contractions, which were stopped by using magnesium sulfate (7.5 g intravenously guttae, 1 day).\n\nNo patient experienced pregnancy-induced hypertension or eclampsia.\n\nAdverse events included were nausea, hair loss, acid reflux, and constipation.\n\nTill now, no recurrence or metastasis was observed in the 3 patients. The follow-up periods were 23-months for cases 1 and 2, and 13-months for case 3, respectively.\n\nNeonatal jaundice occurred in the premature infant of case 2(n = 1) who was recovered with phototherapy for 4 days and neonatal jaundice did not relapse after 1 month of follow-up. No malformation was observed in the 3 infants, and their heights and weights were all within the normal ranges to their corresponding gestational ages. All infants grew normally during the follow-up periods (Table 3). The time periods of sitting, standing, walking, and speaking of all the 3 infants were similar to that of normal infants. The infants had echocardiogram and ECG at the age of 2 years. Results showed that all outcomes were normal and LVEFs were 67% (case 1) and 63% (case 2), respectively. The infant of case 3 is under 2 years old till now.\n\nTable 3 Impact of chemotherapy on the fetus.\n\n3 Discussion\nCurrently, the well-recognized reasons for the poor prognosis of BCP include delay in diagnosis and postponement of treatment to assure birth of a healthy infant.[7] It is important to explore the suitable and effective treatment during pregnancy to achieve the win–win outcome for both patients as well as infants.\n\nChemotherapy during pregnancy is feasible and safe. First trimester is the main embryonic period and chemotherapy causes major congenital anomalies including neural-tube defects, amelia, atrial septal defect, ventricular septal defect, etc.[8] Second and early 3rd trimesters are the periods of central nervous system development and minor organ formation including ears, eyes, teeth, and external genitalia.[8] Distinct from the 1st trimester, the teratogenicity rate of chemotherapy during 2nd trimester and early 3rd trimester was similar to that of the normal pregnancy rate (3%).[9,10] Based on the current literature, no neurological damage such as cognitive impairment or hearing loss was observed during the long-term follow-up period.[11,12] Cardonick et al[11] investigated the central nervous system toxicity of chemotherapy-exposed children in utero and found that there was no statistical difference between the in utero chemotherapy-exposed children and nonexposed controls in the aspects of cognitive ability, cognitive scores, school performance, or behavioral competence. Therefore, we approved the feasibility and safety of chemotherapy during pregnancy. Also the 1st course of chemotherapy was given to all patients during 2nd and 3rd trimesters.\n\nAnthracycline-based chemotherapeutic regimen followed by with or without taxanes was examined to be an optimal choice of treatment recommended by the ESMO clinical practice guidelines.[2] Amant et al[12] investigated the outcomes of infants when exposed in utero to chemotherapy, most of them are anthracycline-based, and found that their ECG and echocardiography were within the normal ranges. In our study, no complaints and clinical manifestations of heart discomfort were reported in children up to now. Moreover, the echocardiogram examination and ECG were normal. In 2010, studies showed that taxanes seldom crossed the placental barrier of pregnant baboons.[13,14] So, ESMO guidelines approved the safety of taxanes and recommended the use of taxanes during pregnancy if needed.[2] Cyclophosphamide passes through the placental barrier and enters into the breast milk; however, it is used during the 2nd and 3rd trimesters to reduce the teratogenicity rate from 18% during the 1st trimester to 1%.[15] Based on the above studies, we had selected much safer chemotherapeutic drugs, including epirubicin (a kind of anthracyclines drugs) and paclitaxel (a kind of taxanes drugs), to conduct individualized treatment for the 3 patients in order to achieve the treatment effect and have healthy infants. Spontaneous delivery could occur any time after 34 weeks of gestation. Hence, ESMO guidelines suggested that chemotherapy should not be administered beyond 33 weeks of gestation and recommended that weekly paclitaxel regimen is preferred, to reduce the toxicity and adverse effects and avoid delivery during the nadir period.[2] Moreover, physiological increase in the number of white blood cells is observed in the pregnant women during the gestational period.[16] As a result, the bone marrow suppression was observed just once as a result of all 8 cycles. Considering the stage cT2N2M0 and no bone marrow suppression, case 3 was administered beyond 33rd week of gestation and underwent iatrogenic cesarean section in order to shorten the interval to receive follow-up treatment.\n\nAdverse effects of chemotherapy during pregnancy are challenging to all patients, infants, and physicians. Cardonick et al[17] reported the gestational use of taxanes and found uterine contractions in 2 patients; while the side effects of neonates include premature birth, neutropenia, and hyperbilirubinemia. Our study results demonstrated uterine contraction in all the 3 patients during chemotherapy. Decision of drug inhibition or immediate delivery was made by the obstetricians according to the degree of contraction and the condition of fetus. Case 2 had preterm delivery, while the other 2 had transient uterine contraction, which was ceased spontaneously or by magnesium sulfate. The causes of preterm delivery are preterm premature rupture of membranes, lower genital tract and urinary tract infections, other pregnancy complications, uterine malformations, etc. Above all, though it is hard to say that chemotherapy is the direct cause of preterm delivery, we should pay attention to the uterine contractions during treatment. Our patients had acid reflux occasionally. However, since cimetidine and proton pump inhibitor are prohibited during pregnancy, oral administration of soda water was recommended by us for relieving the symptom.\n\n4 Conclusion\nThe 3 cases discussed above have demonstrated feasibility and tolerance with the use of chemotherapy during the 2nd and 3rd trimesters. Our findings showed good efficacy with combined chemotherapeutic regimen of epirubicin and paclitaxel in the patients. Also, the findings demonstrated excellent fetomaternal tolerance with limited application of adjuvant drugs. Although our experience and conclusion were based on only 3 cases, this is the first Chinese report that covered the use of chemotherapy during pregnancy for BCP patients. More studies with larger sample size are required for further validation.\n\nAcknowledgements\nThe authors thank to the 3 patients for accepting the therapeutic regimen after discussion and communication.\n\nAbbreviations: BCP = breast cancer during pregnancy, CNB = core needle biopsy, ECG = electrocardiogram, ER = estrogen receptor, ESMO = European Society for Medical Oncology, HER2 = human epidermal growth factor receptor 2, IDC = infiltrating ductal carcinoma, IHC = immunohistochemical, PR = progesterone receptor.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Rovera F Frattini F Coglitore A \nBreast cancer in pregnancy . Breast J \n2010 ;16 (Suppl 1) :S22 –5 .21050304 \n[2] Peccatori FA Azim HA JrOrecchia R \nCancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol \n2013 ;24 (Suppl 6) :vi160 –70 .23813932 \n[3] Gradishar WJ Anderson BO Blair SL \nBreast cancer version 3.2014 . J Natl Compr Canc Netw \n2014 ;12 :542 –90 .24717572 \n[4] Rovera F Chiappa C Coglitore A \nManagement of breast cancer during pregnancy . Int J Surg \n2013 ;11 (Suppl 1) :S64 –8 .24380557 \n[5] Zagouri F Psaltopoulou T Dimitrakakis C \nChallenges in managing breast cancer during pregnancy . J Thorac Dis \n2013 ;5 (Suppl 1) :S62 –7 .23819029 \n[6] Framarino-Dei-Malatesta M Piccioni MG Brunelli R \nBreast cancer during pregnancy: a retrospective study on obstetrical problems and survival . Eur J Obstet Gynecol Reprod Biol \n2014 ;173 :48 –52 .24332095 \n[7] Amant F von Minckwitz G Han SN \nPrognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study . J Clin Oncol \n2013 ;31 :2532 –9 .23610117 \n[8] Cardonick E \nTreatment of maternal cancer and fetal development . Lancet Oncol \n2012 ;13 :218 –20 .22326923 \n[9] Cardonick E Dougherty R Grana G \nBreast cancer during pregnancy: maternal and fetal outcomes . Cancer J \n2010 ;16 :76 –82 .20164696 \n[10] Cardonick E Usmani A Ghaffar S \nPerinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy: results of an international registry . Am J Clin Oncol \n2010 ;33 :221 –8 .19745695 \n[11] Cardonick EH Gringlas MB Hunter K \nDevelopment of children born to mothers with cancer during pregnancy: comparing in utero chemotherapy-exposed children with nonexposed controls . Am J Obstet Gynecol \n2015 ;212 :830 –1 .25637847 \n[12] Amant F Van Calsteren K Halaska MJ \nLong-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study . Lancet Oncol \n2012 ;13 :256 –64 .22326925 \n[13] Calsteren KV Verbesselt R Devlieger R \nTransplacental transfer of paclitaxel, docetaxel, carboplatin, and trastuzumab in a baboon model . Int J Gynecol Cancer \n2010 ;20 :1456 –64 .21307819 \n[14] Van Calsteren K Verbesselt R Ottevanger N \nPharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study . Acta Obstet Gynecol Scand \n2010 ;89 :1338 –45 .20846067 \n[15] Howdeshell KL Shelby MD Walker VR \nNTP Monograph: Developmental Effects and Pregnancy Outcomes Associated With Cancer Chemotherapy Use During Pregnancy . NTP Monogr \n2013 ;i–214 .\n[16] You-ji F Keng Q Ding M \nObstetrics and Gynecology . 2005 ;China : People's Medical Publishing House , 40-41 .\n[17] Cardonick E Bhat A Gilmandyar D \nMaternal and fetal outcomes of taxane chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature . Ann Oncol \n2012 ;23 :3016 –23 .22875836\n\n",
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"issue": "96(46)",
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"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D002681:China; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic",
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"references": "23610117;22326925;19745695;20164696;20846067;24380557;24332095;24736875;22875836;22326923;25637847;23819029;23813932;21050304;21307819;24717572",
"title": "Study on the adverse effects following chemotherapy for breast cancer diagnosis during pregnancy: The first case report in China.",
"title_normalized": "study on the adverse effects following chemotherapy for breast cancer diagnosis during pregnancy the first case report in china"
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"abstract": "BACKGROUND\nIntravenous thrombolysis (IVT) has now become a standard treatment in eligible patients with acute ischemic stroke (AIS) who present within 4.5 h of symptom onset.\n\n\nOBJECTIVE\nTo determine the usefulness of IVT and the subset of patients who will benefit from IVT in AIS within 4.5 h.\n\n\nMETHODS\nPatients with AIS within 4.5 h of symptom onset who underwent IVT were studied prospectively. The study period was from October 2011 to October 2015.\n\n\nRESULTS\nA total of 97 patients were thrombolysed intravenously. The mean onset to needle time in all patients was 177.2 ± 62 min (range: 60-360). At 3 months follow-up, favorable outcome was seen in 65 patients (67.1%) and poor outcome including death in the remaining 32 patients (32.9%). Factors predicting favorable outcome was age <65 years (P = 0.02), the National Institute of Health Stroke Scale (NIHSS) <15 (P < 0.001), small vessel occlusion (P = 0.006), cardioembolism (P = 0.006), and random blood sugar (RBS) <250 mg/dl (P < 0.001). Factors predicting poor outcome was diabetes mellitus (P = 0.01), dyslipidemia (P = 0.01), NIHSS at admission >15 (P = 0.03), RBS >250 mg/dl (P = 0.01), Dense cerebral artery sign, age, glucose level on admission, onset-to-treatment time, NIHSS on admission score >5 (P = 0.03), and occlusion of large artery (P = 0.02).\n\n\nCONCLUSIONS\nMilder baseline stroke severity, blood glucose <250 mg/dL, younger patients (<65 years), cardioembolic stroke, and small vessel occlusion benefit from recombinant tissue plasminogen activator.",
"affiliations": "Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.;Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.;Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.;Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.;Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.;Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.;Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.;Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India.",
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"doi": "10.4103/0976-3147.193558",
"fulltext": "\n==== Front\nJ Neurosci Rural PractJ Neurosci Rural PractJNRPJournal of Neurosciences in Rural Practice0976-31470976-3155Medknow Publications & Media Pvt Ltd India JNRP-8-3810.4103/0976-3147.193558Original ArticleIntravenous Thrombolysis for Acute Ischemic Stroke: Review of 97 Patients Mehta Anish Mahale Rohan Buddaraju Kiran Majeed Anas Sharma Suryanarayana Javali Mahendra Acharya Purushottam Srinivasa Rangasetty Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru, Karnataka, IndiaAddress for correspondence: Dr. Rangasetty Srinivasa, Department of Neurology, MS Ramaiah Medical College and Hospital, Bengaluru - 560 054, Karnataka, India. E-mail: anishmehta1302@gmail.comJan-Mar 2017 8 1 38 43 Copyright: © Journal of Neurosciences in Rural Practice2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nIntravenous thrombolysis (IVT) has now become a standard treatment in eligible patients with acute ischemic stroke (AIS) who present within 4.5 h of symptom onset.\n\nObjective:\nTo determine the usefulness of IVT and the subset of patients who will benefit from IVT in AIS within 4.5 h.\n\nMaterials and Methods:\nPatients with AIS within 4.5 h of symptom onset who underwent IVT were studied prospectively. The study period was from October 2011 to October 2015.\n\nResults:\nA total of 97 patients were thrombolysed intravenously. The mean onset to needle time in all patients was 177.2 ± 62 min (range: 60–360). At 3 months follow-up, favorable outcome was seen in 65 patients (67.1%) and poor outcome including death in the remaining 32 patients (32.9%). Factors predicting favorable outcome was age <65 years (P = 0.02), the National Institute of Health Stroke Scale (NIHSS) <15 (P < 0.001), small vessel occlusion (P = 0.006), cardioembolism (P = 0.006), and random blood sugar (RBS) <250 mg/dl (P < 0.001). Factors predicting poor outcome was diabetes mellitus (P = 0.01), dyslipidemia (P = 0.01), NIHSS at admission >15 (P = 0.03), RBS >250 mg/dl (P = 0.01), Dense cerebral artery sign, age, glucose level on admission, onset-to-treatment time, NIHSS on admission score >5 (P = 0.03), and occlusion of large artery (P = 0.02).\n\nConclusion:\nMilder baseline stroke severity, blood glucose <250 mg/dL, younger patients (<65 years), cardioembolic stroke, and small vessel occlusion benefit from recombinant tissue plasminogen activator.\n\nKEYWORDS\nAcute ischemic strokediabetesintravenous thrombolysisoutcomerecombinant tissue plasminogen activator\n==== Body\nINTRODUCTION\nThe administration of intravenous recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke (AIS) within 3 h of symptom onset has been known to improve the outcome as per The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study.[1] There was 30% relative risk reduction of death or disability at the 90-day follow-up with rt-PA treatment.[1] The window period was extended to 4.5 h following the results of the European Cooperative Acute Stroke Study III.[2] However, with the advent of intra-arterial thrombolysis/endovascular mechanical thrombectomy and demonstration of their superiority in the recent studies with respect to recanalization of occluded vessels and outcome, intravenous thrombolysis (IVT) has lost its sheen among the interventional neurologists worldwide.[34] However, IVT still has a role to play in the management of AIS in the resource-poor settings of the developing countries. The present study was aimed at determining the usefulness of IVT and the subset of patients who will benefit in AIS within 4.5 h.\n\nMATERIALS AND Methods\nThis was a prospective, single center, and observational study. The study was approved by the Institutional Scientific Committee and ethics review board. Patients with AIS within 4.5 h of symptom onset who underwent IVT were studied prospectively. The study period was from October 2011 to October 2015. In total, 97 patients with AIS presenting within 4.5 h, who had received IVT with rt-PA were analyzed. Patients presenting within 4.5 h of symptoms suggestive of stroke were evaluated by a neurologist. Patients underwent nonenhanced computed tomography (CT) scans of the brain which were evaluated by a neurologist or a radiologist or both. Informed consent was obtained from all eligible patients. Inclusion and exclusion criteria were according to guidelines proposed by the American Heart Association/American Stroke Association.[5] All patients were treated with IV rt-PA (alteplase, Boehringer-Ingelheim, Ingelheim, Germany). A dose of 0.9 mg/kg with 10% as a bolus and the rest as an infusion over 1 h was given to the eligible patients. They were admitted in intensive care unit for monitoring for the first 24 h. Follow-up CT scan of brain was done at 24 h postthrombolysis in all patients.\n\nData\nDemographic data and clinical characteristics\nData on the demographic characteristics, presenting symptoms, risk factors such as hypertension, diabetes mellitus (DM), dyslipidemia, ischemic heart disease, atrial fibrillation, rheumatic heart disease, alcohol, and nicotine abuse, etc., time of symptom onset (defined by the time they were “last seen to be well”), time from symptom onset to rt-PA administration (onset to needle time), door to needle time (time from presentation to the hospital to initiation of thrombolysis), dose of rt-PA, Dense cerebral artery sign, age, glucose level on admission, onset-to-treatment time, NIHSS on admission (DRAGON) score,[6] National Institute of Health Stroke Scale (NIHSS) score at admission, at day 1, day 7, and day 90 were recorded.[7] Various subtypes of ischemic stroke as per the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria were determined.[8] Patients were followed up at day 90 for clinical assessment and to record the outcome. The hospital mortality and its causes were recorded. Symptomatic intracerebral hemorrhage (ICH) was defined as per NINDS rt-PA stroke study criteria, which is hemorrhage associated with worsening of ≥1 point on the NIHSS score.[1]\n\nInvestigations\nFollowing laboratory data were collected: Hemoglobin level, total leukocyte count, platelet count, packed cell volume, prothrombin time and international normalized ratio, activated plasma thromboplastin time, blood urea nitrogen, serum creatinine, serum electrolytes, random blood sugar (RBS), glycated hemoglobin, fasting lipid profile, serum homocysteine, D-dimer, serological testing for human immunodeficiency virus, hepatitis-B virus, and syphilis. The following imaging characteristics were noted: The presence of signs of AIS at baseline CT scan, vascular territory involved (anterior cerebral, middle cerebral, vertebrobasilar artery, and watershed areas), angiographic findings (normal, occlusion of internal carotid, middle cerebral (M1 and M2), anterior cerebral, and vertebrobasilar artery) and presence of asymptomatic and symptomatic ICH.\n\nOutcome\nThe functional outcome of each patient was assessed using modified Rankin scale (mRS) and Barthel Index (BI). The mRS score was recorded at day 7 and day 90 and BI at day 90. BI evaluates 10 domains of activities of daily living which include feeding, grooming, bowel, and bladder, bed-to-chair transfer, dressing, mobility, bathing, toilet, and climbing stairs.[9] Favorable outcome was considered as an mRS score of ≤2 and BI score of ≥95.\n\nStatistical analysis\nThe frequency with percentage was calculated for categorical variables and mean ± standard deviation with range was calculated for continuous variables. Student's unpaired t-test was used for the comparison of continuous variables and the Chi-square test for the proportions. The predictors of outcome were determined by univariate analysis that included the following variables: Demographic (gender, age), risk factors such as hypertension, DM, dyslipidemia, ischemic heart disease, atrial fibrillation, rheumatic heart disease, alcohol and nicotine use, systolic and diastolic blood pressure, NIHSS score at admission, onset to needle time, dose of rt-PA, RBS, glycated hemoglobin, serum homocysteine level, DRAGON score, abnormalities on angiography, asymptomatic and symptomatic hemorrhage, subtypes according to TOAST classification. Variables with a significant P value (≤0.05) in univariate analysis were considered for multivariate analysis (logistic-regression analysis). Statistical analyses were performed using SPSS 17 software, IBM. inc, Texas, USA.\n\nRESULTS\nA total of 97 patients were thrombolysed intravenously with rt-PA during the study period. Baseline characteristics of the patients are shown in Table 1. AIS in the anterior circulation was seen in 85 (87.6%) and in posterior circulation in 12 (12.4%) patients. The mean onset to needle time in all patients was 177.2 ± 62 min (range: 60–360). A total of 57 patients (59%) were thrombolysed within 180 min; 36 (37%) in between 180 and 270 min, and 4 (4%) above 270 min of symptom onset. The mean door to needle time in all patients was 45.8 ± 7.0 min (range: 30–55) with median of 45 min. All the patients were thrombolysed within the recommended 60 min or less of their arrival to hospital. The dose of rt-PA used was 50 mg in 65 of the 97 patients. 20 patients received 60 mg, and 12 patients received 70 mg.\n\nTable 1 Baseline characteristics of 97 patients’ thrombolysed with recombinant tissue plasminogen activator\n\nOutcome according to stroke subtype\nThe outcome of patients following IVT with respect to stroke subtype is shown in Table 2. Cardioembolic stroke and small vessel occlusion subtype had favorable outcome.\n\nTable 2 Outcome according to the stroke subtype\n\nOutcome at 3 months\nAt 3 months follow-up, favorable outcome in the form of functional independence (mRS score ≤2) was seen in 65 patients (67.1%) and poor outcome including death (mRS score ≥3) in the remaining 32 patients (32.9%). One patient died within 1 week due to refractory cardiogenic pulmonary edema and another patient within 2 weeks due to sepsis.\n\nRadiological findings\nAngiographic abnormalities were noted in 46 (47.4%) patients. Internal carotid artery occlusion was noted in 27 (58.7%) patients, middle cerebral artery occlusion in 13 (28.3%) patients; and vertebrobasilar artery occlusion in 6 (13%) patients. Repeat angiography was done in 4 patients postthrombolysis within 48 h. There was total recanalization in 2 patients [Figures 1 and 2].\n\nFigure 1 Brain magnetic resonance imaging diffusion-weighted imaging shows bright signal in the right middle cerebral artery territory (a) (red arrow); apparent diffusion coefficient shows corresponding dark signal (b) (red arrow); magnetic resonance angiography at admission shows nonvisualization of M2 (c) (red arrow); magnetic resonance angiography at 48 h postthrombolysis shows recanalization (d) (red arrow)\n\nFigure 2 Brain magnetic resonance imaging diffusion-weighted imaging shows bright signal in the left middle cerebral artery territory (a) (red arrow); apparent diffusion coefficient shows corresponding dark signal (b) (red arrow); magnetic resonance angiography at admission shows nonvisualization of M2 (c) (red arrow); magnetic resonance angiography at 48 h postthrombolysis shows recanalization (d) (red arrow)\n\nPredictive factors of outcome\nFactors predicting favorable outcome were age <65 years (P = 0.02), NIHSS <15 (P < 0.001), small vessel occlusion (P = 0.006), cardioembolism (P = 0.006), and RBS <250 mg/dl (P < 0.001). Factors predicting poor outcome were DM (P < 0.001), dyslipidemia (P = 0.02), higher NIHSS score at admission (P < 0.001), NIHSS >15 (P < 0.001), higher RBS at admission (P < 0.001), RBS more than 250 mg/dl (P < 0.001), higher diastolic blood pressure (P = 0.04), higher DRAGON score (P < 0.001), DRAGON score >5 (P < 0.001), higher glycated hemoglobin level (P < 0.001), elevated serum homocysteine level (P = 0.004), large artery occlusion (P < 0.001), asymptomatic hemorrhage (P < 0.001), and symptomatic hemorrhage (P = 0.02). The predictive factors of outcome following IVT have been summarized in Table 3. On multivariate analysis, following factors were significant predicting poor outcome: DM (P = 0.01), dyslipidemia (P = 0.01), NIHSS at admission >15 (P = 0.03), RBS >250 mg/dl (P = 0.01), DRAGON score >5 (P = 0.03), and occlusion of large artery (P = 0.02).\n\nTable 3 Predictive factors of outcome after intravenous thrombolysis\n\nDISCUSSION\nOcclusion of cerebral artery cause critical reduction in cerebral perfusion pressure within minutes that results in central infarct core with irreversibly damaged cerebral tissue and surrounding hypoperfused ischemic penumbra with still viable cerebral tissue. The role of thrombolytics is to salvage the ischemic penumbra by restoring the blood supply. The present study was aimed at analyzing the data of 97 patients who underwent IVT which was collected over a 4-year period. We found a favorable outcome at 3-month follow-up in 67% patients. Favorable outcome was seen in 39% patients in the NINDS trial.[1] According to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), 54% patients had a good outcome, and study by Litwin et al., 61% patients had favorable outcomes.[1011] The rate of symptomatic hemorrhage in our study was % as compared to 6.4% in the NINDS study and 3.3% in the Standard Treatment with Alteplase to Reverse Stroke study.[12]\n\nWe found that patients with age <65 years had favorable outcome following IVT. However, age more than 65 years did not predict poor outcome either. A meta-analysis of individual patient data from 6756 patients in nine randomized trials comparing alteplase with placebo or open control showed that the proportional benefits were similar for patients aged older than 80 years compared with younger patients.[13] In the study by Caso et al., age was not the independent risk factor for adverse outcome.[14] However, study by Mouradian et al., reported that older patients with more severe baseline stroke had lesser benefit with IVT as compared to younger patients.[15]\n\nThe previous reports have shown that women with AIS on conservative treatment have worse functional outcomes as compared with men.[16] A systematic review on the outcome of intravenous rt-PA according to gender by Meseguer et al. showed no evidence of gender differences in outcomes after IV rt-PA therapy.[17] We also found no gender differences in the outcome following IVT.\n\nWe found that the patients with cardioembolic stroke and small vessel occlusion had favorable outcome. However, patients with large artery occlusion had poor outcome following IVT. Favorable outcome of cardioembolic stroke post IVT may be related to fresh blood clots that get easily dissolved by thrombolytic agents rather than old blood clots. A study by Molina et al., reported that the rate of complete recanalization at 6 h was higher (P = 0.006) in patients with cardioaortic embolic (CE) stroke compared to those with other stroke subtypes.[18] Another study by Prefasi et al., (2014) reported that CE infarctions might benefit more from IV rt-PA than other etiology.[19] A study by the Helsinki Stroke Thrombolysis Registry Group found that patients with small-vessel disease strokes were likely to have a good outcome.[20] A study by Pan et al. found that patients with small-vessel disease strokes had a good outcome.[21] Favorable outcome in small-vessel disease may be attributed to younger age and milder stroke severity.[22] The occurrence of atheroma and embolism apart from lipohyalinosis alone and perfusion defects on magnetic resonance imaging perfusion scan has been attributed to the beneficiality of thrombolysis in lacunar infarcts.[2324] There is chance of worsening in patients with lacunar infarcts even though they have milder stroke severity. Early neurological deterioration has been reported to occur in 20–30% patients with lacunar infarcts.[25] A study by Caso et al. reported that patients with carotid artery occlusion had poor outcome.[14]\n\nThe onset to treatment time (OTT) is critical to the success of IVT treatment. Earlier the institution of rt-PA better is the outcome as evidenced by several large trials. About two-thirds of patients in our study received rt-PA within 180 min of onset of symptoms. This can explain the higher rate of favorable outcome (67%) in our study. The NIHSS score on admission has been shown to be directly related to patients’ outcomes. We found that patients with NIHSS score <15 had a favorable outcome. A study by Demchuk et al. found that milder baseline stroke severity was an independent predictor of favorable outcome following IVT.[26] A study by Pan et al. found that patients with lower NIHSS score at admission had a good outcome.[21]\n\nDyslipidemia has also been reported to affect the outcome of patients after receiving IV rt-PA. This is due to the formation of nondissolvable lipid-rich thrombus, which could in turn cause larger infarction and hemorrhagic transformation.[27] We found that patients with dyslipidemia had a poor outcome. A study by Bruno et al. showed that with increasing admission blood glucose and admission mean blood pressure, the odds for favorable outcome progressively decreased.[28] In our study, patients who had poor outcome had significantly higher diastolic blood pressure. We found significantly elevated serum homocysteine level in patients who had poor outcome. A study by Zhong et al. found that high plasma homocysteine level was associated with increased risk of major disability in women but not in men.[29] Hyperglycemia at the onset of acute stroke may adversely affect the outcome. We found that patients who are diabetic and RBS of more than 250 mg/dl had a poor outcome. DM is also associated with reduced fibrinolysis capacity and increased the concentration of serum plasminogen activator inhibitor-1.[30] Patients with DM had less chance of improvement, lower rate of functional independency, and a higher rate of mortality as per SITS-MOST.[10]\n\nThe DRAGON score predicts functional outcome in the hyperacute phase of IVT treatment of ischemic stroke patients.[6] The score consists of 6 parameters with a maximum score of 10 that includes: dense cerebral artery sign or early infarct signs on admission CT head scan, age, glucose level on admission, OTT, NIHSS on admission. In our study, patients with DRAGON score of more than 5 had poor outcome.\n\nThe limitations of the study are that the sample size was small and was a single-center experience. We did not do repeat angiography in a large number of patients post thrombolysis in whom there were angiographic abnormalities.\n\nCONCLUSION\nIntravenous rt-PA has been found to be useful in treatment in AIS within 4.5 h of symptom onset. However, all patients with AIS do not benefit from IV rt-PA. There is need to identify subgroups of patients who will benefit from rt-PA, especially in resource-poor settings. Milder baseline stroke severity, blood glucose <250 mg/dL, younger patients (<65 years), cardioembolic stroke, and small vessel occlusion benefit from rt-PA. The presence of hyperglycemia (RBS >250 mg/dl), dyslipidemia, severe baseline stroke severity, higher DRAGON score, and large artery occlusion have poor outcome with IV rt-PA.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group N Engl J Med 1995 333 1581 7 7477192 \n2 Hacke W Kaste M Bluhmki E Brozman M Dávalos A Guidetti D Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke N Engl J Med 2008 359 1317 29 18815396 \n3 Saver JL Jahan R Levy EI Jovin TG Baxter B Nogueira R SOLITAIRE™ with the intention for thrombectomy (SWIFT) trial: Design of a randomized, controlled, multicenter study comparing the SOLITAIRE™ Flow Restoration device and the MERCI Retriever in acute ischaemic stroke Int J Stroke 2014 9 658 68 23130938 \n4 Berkhemer OA Fransen PS Beumer D van den Berg LA Lingsma HF Yoo AJ A randomized trial of intraarterial treatment for acute ischemic stroke N Engl J Med 2015 372 11 20 25517348 \n5 Del Zoppo GJ Saver JL Jauch EC Adams HP Jr American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: A science advisory from the American Heart Association/American Stroke Association Stroke 2009 40 2945 8 19478221 \n6 Strbian D Meretoja A Ahlhelm FJ Pitkäniemi J Lyrer P Kaste M Predicting outcome of IV thrombolysis-treated ischemic stroke patients: The DRAGON score Neurology 2012 78 427 32 22311929 \n7 Goldstein LB Bertels C Davis JN Interrater reliability of the NIH stroke scale Arch Neurol 1989 46 660 2 2730378 \n8 Adams HP Jr Bendixen BH Kappelle LJ Biller J Love BB Gordon DL Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST Trial of Org 10172 in Acute Stroke Treatment Stroke 1993 24 35 41 7678184 \n9 Mahoney FI Barthel DW Functional evaluation: The Barthel index Md State Med J 1965 14 61 5 \n10 Wahlgren N Ahmed N Dávalos A Ford GA Grond M Hacke W Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST): An observational study Lancet 2007 369 275 82 17258667 \n11 Litwin T Kobayashi A Skowronska M Czlonkowska A Thrombolysis in acute ischaemic stroke within 3 hours of symptom onset: A report of the first 100 cases Neurol Neurochir Pol 2008 42 1 5 18365956 \n12 Albers GW Bates VE Clark WM Bell R Verro P Hamilton SA Intravenous tissue-type plasminogen activator for treatment of acute stroke: The standard treatment with alteplase to reverse stroke (STARS) study JAMA 2000 283 1145 50 10703776 \n13 Emberson J Lees KR Lyden P Blackwell L Albers G Bluhmki E Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: A meta-analysis of individual patient data from randomised trials Lancet 2014 384 1929 35 25106063 \n14 Caso V Paciaroni M Venti M Palmerini F Silvestrelli G Milia P Determinants of outcome in patients eligible for thrombolysis for ischemic stroke Vasc Health Risk Manag 2007 3 749 54 18078026 \n15 Mouradian MS Senthilselvan A Jickling G McCombe JA Emery DJ Dean N Intravenous rt-PA for acute stroke: Comparing its effectiveness in younger and older patients J Neurol Neurosurg Psychiatry 2005 76 1234 7 16107357 \n16 Niewada M Kobayashi A Sandercock PA Kaminski B Czlonkowska A International Stroke Trial Collaborative Group Influence of gender on baseline features and clinical outcomes among 17,370 patients with confirmed ischaemic stroke in the international stroke trial Neuroepidemiology 2005 24 123 8 15637449 \n17 Meseguer E Mazighi M Labreuche J Arnaiz C Cabrejo L Slaoui T Outcomes of intravenous recombinant tissue plasminogen activator therapy according to gender: A clinical registry study and systematic review Stroke 2009 40 2104 10 19372440 \n18 Molina CA Montaner J Arenillas JF Ribo M Rubiera M Alvarez-Sabín J Differential pattern of tissue plasminogen activator-induced proximal middle cerebral artery recanalization among stroke subtypes Stroke 2004 35 486 90 14707233 \n19 Prefasi D Fuentes B Martínez-Sánchez P Rodríguez-Sanz A Ruiz-Ares G Sanz-Cuesta B Intravenous thrombolysis in stroke patients under 55 years of age: Is there a different effect according to etiology and severity? J Thromb Thrombolysis 2014 37 557 64 23943341 \n20 Mustanoja S Meretoja A Putaala J Viitanen V Curtze S Atula S Outcome by stroke etiology in patients receiving thrombolytic treatment: Descriptive subtype analysis Stroke 2011 42 102 6 21106955 \n21 Pan YT Lee JD Lin YH Huang YC Weng HH Lee M Comparisons of outcomes in stroke subtypes after intravenous thrombolysis Springerplus 2016 5 47 26835227 \n22 Fluri F Hatz F Rutgers MP Georgiadis D Sekoranja L Schwegler G Intravenous thrombolysis in patients with stroke attributable to small artery occlusion Eur J Neurol 2010 17 1054 60 20136649 \n23 Jeong HG Kim BJ Yang MH Han MK Bae HJ Neuroimaging markers for early neurologic deterioration in single small subcortical infarction Stroke 2015 46 687 91 25677600 \n24 Poppe AY Coutts SB Kosior J Hill MD O’Reilly CM Demchuk AM Normal magnetic resonance perfusion-weighted imaging in lacunar infarcts predicts a low risk of early deterioration Cerebrovasc Dis 2009 28 151 6 19546542 \n25 Hwang YH Seo JG Lee HW Park SP Suh CK Early neurological deterioration following intravenous recombinant tissue plasminogen activator therapy in patients with acute lacunar stroke Cerebrovasc Dis 2008 26 355 9 18728362 \n26 Demchuk AM Tanne D Hill MD Kasner SE Hanson S Grond M Predictors of good outcome after intravenous tPA for acute ischemic stroke Neurology 2001 57 474 80 11502916 \n27 Urbach H Hartmann A Pohl C Omran H Wilhelm K Flacke S Local intra-arterial thrombolysis in the carotid territory: Does recanalization depend on the thromboembolus type? Neuroradiology 2002 44 695 9 12185548 \n28 Bruno A Levine SR Frankel MR Brott TG Lin Y Tilley BC Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial Neurology 2002 59 669 74 12221155 \n29 Zhong C Xu T Xu T Peng Y Wang A Wang J Plasma Homocysteine and prognosis of acute ischemic stroke: A gender-specific analysis from CATIS randomized clinical trial Mol Neurobiol 2016 doi:10.1007/s12035-016-9799-0 Epub ahead of print \n30 Trost S Pratley R Sobel B Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes Curr Diab Rep 2006 6 47 54 16522281\n\n",
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"issue": "8(1)",
"journal": "Journal of neurosciences in rural practice",
"keywords": "Acute ischemic stroke; diabetes; intravenous thrombolysis; outcome; recombinant tissue plasminogen activator",
"medline_ta": "J Neurosci Rural Pract",
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"pages": "38-43",
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"title": "Intravenous Thrombolysis for Acute Ischemic Stroke: Review of 97 Patients.",
"title_normalized": "intravenous thrombolysis for acute ischemic stroke review of 97 patients"
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"abstract": "OBJECTIVE\nTo report rhabdomyolysis (RML) causing third-degree atrioventricular block secondary to a possible interaction between atorvastatin, esomeprazole, and clarithromycin.\n\n\nMETHODS\nA 51-year-old white woman presented to the emergency department with severe weakness, near syncope, shortness of breath, and chest pain. On admission, her electrocardiogram demonstrated bradycardia (40 beats/min) and third-degree heart block. A creatine kinase (CK) level was >7000 U/L. Her medication history was significant for long-term use of atorvastatin (>1 y), a 6-week history of esomeprazole use, and three 500-mg doses of clarithromycin just prior to admission. Her symptoms of weakness, shortness of breath, and chest pain coincided with starting the esomeprazole. During her hospitalization, the woman required pacemaker placement and her CK continued to rise to >40,000 U/L. Screening for other causes of RML, such as thyrotoxicosis, infection, and immune or hepatic diseases, was negative. She gradually improved over a 26-day hospitalization.\n\n\nCONCLUSIONS\nThis is a case of RML resulting in third-degree atrioventricular blockade. An objective causality assessment of the adverse reaction via the Naranjo probability scale revealed a probable association with atorvastatin and a possible association with esomeprazole and clarithromycin. The pharmacokinetic profiles of these agents suggest that a possible contribution to this reaction was P-glycoprotein (PGP) inhibition by esomeprazole altering atorvastatin's normally significant first-pass clearance.\n\n\nCONCLUSIONS\nPGP drug interactions with atorvastatin and other hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) may be associated with unreported risks for RML. Further investigation into PGP impact on HMG-CoA appears warranted.",
"affiliations": "Pharmacy Department, Lutheran Hospital, Fort Wayne, IN 46804-4160, USA.",
"authors": "Sipe|Brooke E|BE|;Jones|Ronald J|RJ|;Bokhart|Gordon H|GH|",
"chemical_list": "D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D017291:Clarithromycin; D064098:Esomeprazole",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1C396",
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"issn_linking": "1060-0280",
"issue": "37(6)",
"journal": "The Annals of pharmacotherapy",
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"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000069059:Atorvastatin; D017291:Clarithromycin; D004347:Drug Interactions; D064098:Esomeprazole; D005260:Female; D006327:Heart Block; D006538:Heptanoic Acids; D006801:Humans; D008875:Middle Aged; D011758:Pyrroles; D012206:Rhabdomyolysis",
"nlm_unique_id": "9203131",
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"pages": "808-11",
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"pubdate": "2003-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction.",
"title_normalized": "rhabdomyolysis causing av blockade due to possible atorvastatin esomeprazole and clarithromycin interaction"
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"activesubstancename": "ESOMEPRAZOLE"
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"abstract": "In this case report, we describe a 70-year-old male patient who sustained Kounis syndrome induced by cisatracurium administration immediately following induction of general anesthesia. Acute coronary syndrome combined with anaphylactic shock, termed Kounis syndrome, should be investigated in percutaneous coronary intervention to solve this complex and life-threatening condition. A team effort by cardiologist and anesthesiologist is essential for successful resuscitation. In general, the incidence of an anaphylactic reaction to cisatracurium is low, but a high serum IgE level in combination with a positive skin prick test in our patient was strongly suggestive of cisatracurium-induced Kounis syndrome. In addition, a cross-reaction between cisatracurium and rocuronium is reported.",
"affiliations": "Department of Anesthesiology, Chang Gung Memorial Hospital-Kaohsiung Medical Center and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.",
"authors": "Yang|Ya-Ling|YL|;Huang|Hui-Wen|HW|;Yip|Hon-Kan|HK|;Jawan|Bruno|B|;Tseng|Chia-Chih|CC|;Lu|Hsiao-Feng|HF|",
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"abstract": "Ectopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non-sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure.\n\n\nCONCLUSIONS\nCushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.Cushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.Etomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone.",
"affiliations": "Department of Medicine , Lehigh Valley Health Network , Allentown, Pennsylvania, 18103 , USA.;Division of Endocrinology, Department of Medicine , Lehigh Valley Health Network , Allentown, Pennsylvania, 18103 , USA.;Division of Endocrinology, Department of Medicine , Lehigh Valley Health Network , Allentown, Pennsylvania, 18103 , USA.",
"authors": "Bucciarelli|Maura|M|;Lee|Ya-Yu|YY|;Magaji|Vasudev|V|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepedmEDM Case ReportsEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol EDM15005110.1530/EDM-15-0051Insight into Disease Pathogenesis or Mechanism of TherapyCushing's storm secondary to a rare case of ectopic ACTH secreting metastatic breast cancer ACTH secreting metastatic breast cancerBucciarelli Maura 2Lee Ya-Yu 1Magaji Vasudev 11 Division of Endocrinology, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USA2 Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USACorrespondence should be addressed to V Magaji Email: vasudevgmagaji@gmail.com2 9 2015 2015 2015 15005110 8 2015 2 9 2015 © 2015 The authors2015This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nEctopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non-sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure.\n\nLearning points\n\nCushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.\n\nCushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.\n\nEtomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone.\n==== Body\nBackground\nEctopic adrenocorticotrophic hormone (ACTH) production causing Cushing's syndrome is most often associated with small cell carcinoma of the lung, but less common aetiologies include non-small cell lung carcinoma, carcinoids, pancreatic tumours, medullary thyroid carcinoma and pheochromocytoma (1). Breast cancer is a very rare cause of ectopic ACTH syndrome (2)\n(3). Psychiatric manifestations from ectopic ACTH syndrome are seen in about half the cases (1). Our patient is a rare case of posterior reversible encephalopathy syndrome (PRES) with ectopic ACTH-associated Cushing's syndrome from breast cancer. Etomidate infusion, which inhibits 11-β-hydroxylase, at non-sedating doses in a monitored setting and oral metyrapone subsequently was successful for the reduction of hypercortisolism. Spironolactone was used to block the mineralocorticoid action of excessive cortisol and deoxycortisol resulting from etomidate inhibition of cortisol synthesis. This was a novel and unique strategy to successfully control the blood pressure and reduce cortisol levels needed for PRES management resulting in the patient's psychosis resolution.\n\nCase presentation\nA 31-year-old female with triple negative, high grade invasive right breast ductal carcinoma treated with chemotherapy, bilateral mastectomy and radiation presented with acute psychosis. She had T2N1M0 infiltrating ductal breast carcinoma treated neoadjuvantly with four cycles of doxorubicin and cyclophosphamide followed by four cycles of paclitaxel followed by bilateral mastectomies and radiation therapy. On presentation she had not slept for 4 days and was hyperenergetic, easily distracted, impulsive with racing thoughts and pressured speech and paranoid that her husband was trying to hurt her. On exam she had a round, ruddy, hirsuite face with acne and her blood pressure was 156/108.\n\nInvestigation\nLaboratory studies showed potassium 1.7 mEq/l (normal range 3.7–5.2 mEq/l), random cortisol >70 mcg/dl (normal range 6–23 mcg/dl) and 1 and 8 mg overnight dexamethasone tests showed cortisol >100 mcg/dl (normal range <1.8 mcg/dl). She had elevations in AST to 103 IU/l (normal range 10–34 IU/l), ALT 237 IU/l (normal range 8–37 IU/l), ACTH 1173 pg/ml (normal range 9–52 pg/ml), total testosterone 170 ng/dl (normal range 15–70 ng/dl in women), DHEA-S 499 mcg/dl (normal range 45–270 mcg/dl), 17 OH progesterone 1780 ng/dl (normal range <200 ng/dl) and 24-h urine cortisol (UFC) 14766 mcg/day (normal range 10–100 mcg/24 h). A computed tomography (CT) of the abdomen showed extensive hepatic metastatic disease and bilateral adrenal hyperplasia. Renin, aldosterone, plasma metanephrines, chromagranin A, corticotropin-releasing hormone and gastrin levels were normal. Imaging was negative for thyroid nodule, thymic neoplasm and bronchial carcinoid. Core liver biopsy revealed metastatic breast adenocarcinoma that was negative for neuroendocrine markers CD56, synaptophysin, neuron specific enolase, chromogranin and ACTH. A CT of the head showed white matter disease consistent with PRES (Fig. 1).\n\nFigure 1 CT head with contrast showing diffuse areas of abnormal low attenuation mostly involving the subcortical white matter of the medial frontal and parietal lobes as well as the subcortical and deep white matter of the occipital and posterior temporal lobes consistent with PRES.\n\nTreatment\nShe was hypertensive and psychotic despite using mifepristone with multiple antihypertensives including lisinopril, aldactone and metoprolol, targeting a systolic blood pressure of 110–130. Transaminitis did not allow mifepristone dose increase above 600 mg/day and utilization of ketoconazole. Etomidate infusion at 0.1 mg/kg per min in intensive care unit (ICU) controlled her hypertension and cortisol levels to 20–30 mcg/dl. UFC decreased to 820 mcg/day. She was transitioned to metyrapone 1250 mg per mouth (p.o.) every 6 h and spironolactone 100 mg p.o. every 6 h. Repeat CT scans showed resolution of white matter disease following blood pressure control (Fig. 2).\n\nFigure 2 Resolution of PRES change noted on CT scan.\n\nOutcome and follow-up\nPost-hospitalization, monthly random cortisol ranged between 7.5 and 15.5 mcg/dl for 8 months. Since the patient's re-biopsy was 10% ER positive, the patient was started on tamoxifen and completed nine cycles of gemcitabine/carboplatin. Her lower cortisol levels allowed de-escalation of the metyrapone dose to 500 mg p.o. every 6 h and provided useful biochemical evidence of chemotherapeutic success of her breast cancer management. There was improvement in her liver metastases on repeat CT scans. Her metastatic bone lesions were treated with denosumab. She died after 9 months from the time of her initial presentation with ectopic ACTH Cushing's syndrome despite chemotherapy after developing new progressive metastatic lung, bone and liver lesions associated with worsening liver functions, Cushing's recurrence and rapid respiratory failure.\n\nDiscussion\nParaneoplastic syndromes could have varied presentation including, for example, endocrine hypercalcemia, syndrome of inappropriate anti diuretic hormone (SIADH), peripheral neuropathy, Eaton-Lambert syndrome and dermatomyositis-polymyositis. Mild hypercortisolism in malignancy characterized by loss of circadian rhythm is associated with poor prognosis and can be mediated through interleukin-6 and interleukin-10 independent of ACTH levels (2). Cushing's syndrome resulting usually from ectopic ACTH secretion and rarely from ectopic CRH has been described in literature (3). Cushing's syndrome presentation is associated with a huge underlying tumour burden, inadequate chemotherapy response and increased susceptibility to infections from immunosuppression and has very diverse clinical manifestations characterized by symptoms of proximal muscle weakness, acne, altered mental status, hyperpigmentation, hirsuitism, hypertension along with biochemical alteration of hyperglycemia, hypokalemia, alkalosis, high testosterone and DHEA-S levels (4).\n\nThe patient's work up was negative for more likely causes including neuroendocrine tumour, medullary thyroid cancer, pituitary and adrenal tumours, thymic masses and pheochromocytoma. Among the very few cases of breast cancer causing ectopic Cushing's syndrome-described ACTH staining, mRNA demonstration by real-time PCR and in situ hybridization technique have been used (3)\n(5). In breast cancer, neuroendocrine differentiated carcinoma with ectopic ACTH secretion and breast carcinoma with neuroendocrine differentiation has been described (6). The lack of ACTH staining of the tumour in our case could be explained by the possibility that the subpopulation of ACTH-producing cells may have not be biopsied (7). However, the biochemical response of cortisol reduction following initiation of chemotherapy for breast cancer supports the diagnosis of breast cancer associated ectopic ACTH secretion in our patient.\n\nEqually important to the assessment of ectopic Cushing's aetiology was the patient's psychosis that needed emergent management. The acute psychosis evaluation with imaging revealed changes consistent with PRES characterized by hypertensive encephalopathy. PRES is associated with radiologic findings of symmetrical, bilateral grey and white matter abnormalities in the posterior cerebrum typically involving the temporal, parietal and occipital regions. The symptoms include headaches, decreased alertness, confusion, speech or vision abnormalities, seizures and vomiting. PRES has been associated with hypertensive encephalopathy, eclampsia, immunosuppressive therapy, systemic lupus erythromatosis, Henoch-Schonlein purpura, transplant patients and HIV (8)\n(9)\n(10).\n\nPRES associated with Cushing's syndrome has been previously reported in children. Two were related to high dose methylprednisolone and one was from micronodular adrenocortical disease that was treated with hydrochlorothiazide and propranolol (11)\n(12)\n(13). To our knowledge, this is the first case of adult PRES associated with hypertension from ectopic ACTH causing Cushing's syndrome. Timely diagnosis and prompt intervention for PRES with blood pressure reduction is needed to avoid permanent brain damage. Hypercortisolism-induced hypertension is related to cortisol effects on vasculature, as well as mineralocorticoid, excess (14). Despite having overall weak mineralocorticoid action, cortisol is usually inactivated by the kidneys through the 11-β-hydroxysteroid dehydrogenase by converting cortisol to inactive cortisone, which protects renal mineralocorticoid receptors from minimizing its hypertensive effects (15). However, with hypercortisolism, the renal deactivation system is overwhelmed causing hypertension. Psychosis most likely resulted from hypercortisolism and uncontrolled hypertension leading to PRES. Our dilemma was that mifepristone, which blocks cortisol action, could not be escalated due to liver dysfunction, and antihypertensives including lisinopril, aldactone and metoprolol were not controlling the blood pressure (Fig. 3).\n\nFigure 3 Dilemma in managing the patient's psychosis and PRES.\n\nA strategy of cortisol reduction and mitigation of hypertension caused by excess cortisol production was needed (16)\n(17)\n(18). Initiation of i.v. etomidate in the intensive care unit followed by a transition to oral metyrapone to block 11-β-hydroxylation of deoxycortisol to produce cortisol and simultaneous oral spironolactone use to antagonize the mineralocorticoid action of deoxycortisol and cortisol successfully controlled her hypertension and prevented recurrence of her psychosis (Fig. 4). To the best of our knowledge, this is also the first case of a successful treatment of PRES associated with Cushing's using etomidate followed by metyrapone transition with oral spironolactone (Table 1).\n\nFigure 4 Strategy to manage patient's psychosis and PRES.\n\nTable 1 Outlining the hormones in time in correlation with chemotherapy\n\n\nDay\n\t\nChemotherapy cycle initiation day\n\t\nCortisol (mcg/dl)\t\n24-h urine free cortisol (mcg/day)\t\nMetyrapone dose oral every 6 h\n\t\nEtomidate\n\t\nACTH (pg/ml)\t\n0\t\t145.6\t14 766\t\t\t\t\n10\t\t114.5\t\t\tStarted\t1173\t\n11\t\t39.2\t820\t\t\t\t\n15\tI\t32.4\t\t750 mg\t\t\t\n17\t\t24.5\t\t1250 mg\tStopped\t\t\n21\t\t22.2\t\t1250 mg\t\t243\t\n22\t\t56\t688\t750 mg\t\t\t\n37\t\t14.7\t\t1000 mg\t\t\t\n39\tII\t\t\t1000 mg\t\t\t\n57\t\t15.7\t\t1000 mg\t\t105\t\n60\tIII\t\t\t1000 mg\t\t\t\n78\t\t16.6\t\t1000 mg\t\t157\t\n81\tIV\t\t\t1000 mg\t\t\t\n101\tV\t9.7\t\t250 mg\t\t32\t\n122\tVI\t12.9\t\t250 mg\t\t15\t\n172\tVII\t\t\t250 mg\t\t\t\n179\t\t10\t\t250 mg\t\t17\t\n193\tVIII\t\t\t250 mg\t\t\t\n211\t\t7.6\t\t250 mg\t\t58\t\n213\t\t\t16.94\t250 mg\t\t\t\n224\tIX\t\t\t250 mg\t\t\t\nThough our patient subsequently died, our intervention of treating her psychosis facilitated re-initiation of chemotherapy and extended her life for nine more months. We would like to acknowledge the team efforts by the ICU nurses and physicians, pharmacy, haematologist-oncologists, neurologists, psychiatrists, hospital medicine team and social workers at Lehigh valley Hospital Muhlenberg.\n\nPatient consent\nThe consent form has not been obtained because the patient is deceased.\n\nAuthor contribution statement\nAll co-authors listed contributed substantially to the preparation of this manuscript.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n==== Refs\nReferences\n1 \n\nIlias \nI \n, \nTorpy \nDJ \n, \nPacak \nK \n, \nMullen \nN \n, \nWesley \nRA \n & \nNieman \nLK \n. 2005 \nCushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health . 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Endocrinology and Metabolism Clinics of North America \n23 \n585 –606 .7805656 \n5 \n\nWigg \nSJ \n, \nEhrlich \nAR \n & \nFuller \nPJ \n. 1999 \nCushing's syndrome secondary to ectopic ACTH secretion from metastatic breast carcinoma . Clinical Endocrinology \n50 \n675 –678 . 10.1046/j.1365-2265.1999.00726.x \n10468935 \n6 \n\nUchida \nN \n, \nIshiguro \nK \n, \nSuda \nT \n, \nHorie \nY \n & \nNishimura \nM \n. 2010 \nACTH-producing breast cancer: a patient report . Yonago Acta Medica \n53 \n71 –75 .24031121 \n7 \n\nKenchaiah \nM \n & \nHyer \nS \n. 2012 \nCushing's Syndrome due to Ectopic ACTH from bronchial carcinoid: a case report and review . Case Reports in Endocrinology \n2012 \nArticle ID 215038, 4 pages \n10.1155/2012/215038 \n\n8 \n\nArzanian \nMT \n, \nShamsian \nBS \n, \nKarimzadeh \nP \n, \nKajiyazdi \nM \n, \nMalek \nF \n & \nHammoud \nM \n. 2014 \nPosterior reversible encephalopathy syndrome in pediatric hematologic-oncologic disease: literature review and case presentation . Iranian Journal of Child Neurology \n8 \n1 –10 .24949044 \n9 \n\nHinchey \nJ \n, \nChaves \nC \n, \nAppignani \nB \n, \nBreen \nJ \n, \nPao \nL \n, \nWang \nA \n, \nPessin \nMS \n, \nLamy \nC \n, \nMas \nJL \n & \nCaplan \nLR \n. 1996 \nA reversible posterior leukoencephalopathy syndrome . New England Journal of Medicine \n334 \n494 –500 . 10.1056/NEJM199602223340803 \n8559202 \n10 \n\nCasey \nSO \n, \nSampaio \nRC \n, \nMichel \nE \n & \nTruwit \nCL \n. 2000 \nPosterior reversible encephalopathy syndrome: utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions . AJNR. American Journal of Neuroradiology \n21 \n1199 –1206 .10954269 \n11 \n\nLodish \nM \n, \nPatronas \nNJ \n & \nStratakis \nCA \n. 2010 \nReversible posterior encephalopathy syndrome associated with micronodular adrenocortical disease and Cushing syndrome . European Journal of Pediatrics \n169 \n125 –126 . 10.1007/s00431-009-0990-4 \n19415327 \n12 \n\nİncecik \nF \n, \nHergüner \nMÖ \n, \nYıldızdaş \nD \n, \nYılmaz \nM \n, \nMert \nG \n, \nHoroz \nÖO \n & \nAltunbaşak \nŞ \n. 2013 \nPosterior reversible encephalopathy syndrome due to pulse methylprednisolone therapy in a child . Turkish Journal of Pediatrics \n55 \n455 –457 .24292045 \n13 \n\nKumar \nS \n & \nRajam \nL \n. 2011 \nPosterior reversible encephalopathy syndrome (PRES/RPLS) during pulse steroid therapy in macrophage activation syndrome . Indian Journal of Pediatrics \n78 \n1002 –1004 . 10.1007/s12098-011-0368-2 \n21318395 \n14 \n\nVaughan \nCJ \n & \nDelanty \nN \n. 2000 \nHypertensive emergencies . Lancet \n356 \n411 –417 . 10.1016/S0140-6736(00)02539-3 \n10972386 \n15 \n\nWalker \nBR \n, \nStewart \nPM \n, \nShackleton \nCH \n, \nPadfield \nPL \n & \nEdwards \nCR \n. 1993 \nDeficient inactivation of cortisol by 11-β-hydroxysteroid dehydrogenase in essential hypertension . Clinical Endocrinology \n39 \n221 –227 . 10.1111/j.1365-2265.1993.tb01778.x \n8370136 \n16 \n\nDrake \nWM \n, \nPerry \nLA \n, \nHinds \nCJ \n, \nLowe \nDG \n, \nReznek \nRH \n & \nBesser \nGM \n. 1998 \nEmergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis . Journal of Clinical Endocrinology and Metabolism \n83 \n3542 –3544 .9768661 \n17 \n\nPreda \nVA \n, \nSen \nJ \n, \nKaravitaki \nN \n & \nGrossman \nAB \n. 2012 \nEtomidate in the management of hypercortisolaemia in Cushing's syndrome: a review . European Journal of Endocrinology \n167 \n137 –143 . 10.1530/EJE-12-0746 \n22577107 \n18 \n\nFeelders \nRA \n, \nHofland \nLJ \n & \nde Herder \nWW \n\nMedical treatment of Cushing's syndrome: adrenal-blocking drugs and ketaconazole . Neuroendocrinology \n92 \nSuppl 1 \n2010 \n111 –115 . 10.1159/000314292 \n20829630\n\n",
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"abstract": "Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug hypersensitivity reaction characterized by rash, fever and multi-organ failure. Limbic encephalitis (LE) is a rare disorder characterized by cognitive dysfunction with memory disturbance, seizures and psychiatric symptoms. We herein present an unusual case of DRESS syndrome due to lamotrigine with reactivation of Epstein-Barr virus, which developed autoimmune LE and syndrome of inappropriate antidiuretic hormone secretion. Discontinuation of lamotrigine, administration of methylprednisolone and intravenous immunoglobulin led to improvement. The LE in this case might have been caused by an autoimmune inflammatory mechanism associated with DRESS syndrome.",
"affiliations": "Department of Internal Medicine, Hacettepe University Faculty of Medicine, Turkey.",
"authors": "Ozisik|Lale|L|;Tanriover|Mine Durusu|MD|;Saka|Esen|E|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(10)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001327:Autoimmune Diseases; D004342:Drug Hypersensitivity; D004802:Eosinophilia; D005076:Exanthema; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007177:Inappropriate ADH Syndrome; D000077213:Lamotrigine; D020363:Limbic Encephalitis; D013577:Syndrome; D014227:Triazines",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1393-6",
"pmc": null,
"pmid": "27181555",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autoimmune Limbic Encephalitis and Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated with Lamotrigine-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Syndrome.",
"title_normalized": "autoimmune limbic encephalitis and syndrome of inappropriate antidiuretic hormone secretion associated with lamotrigine induced drug rash with eosinophilia and systemic symptoms dress syndrome"
} | [
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"companynumb": "TR-IMPAX LABORATORIES, INC-2016-IPXL-00649",
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"activesubstancename": "DIVALPROEX SODIUM"
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"abstract": "Malignant renal subcapsular effusions commonly arise from primary or metastatic renal neoplasms. The current case report presents a rare case of malignancy with a massive renal subcapsular effusion accompanied by a malignant pleural effusion of an unknown primary site, which underwent progression to carcinomatous meningitis during chemotherapy. The type of adenocarcinoma present was determined by effusion cytology. Intravenous chemotherapy (docetaxel plus oxaliplatin and gemcitabine plus cisplatin) were administered; however, the disease still progressed. Time to progression was 9 months during treatment of gefitinib. Comprehensive therapies, including intracavity chemotherapy, immunotherapy and gefitinib, were shown to be effective and prolonged the patient's survival time.",
"affiliations": "The Comprehensive Cancer Center, Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 2l0008, P.R. China.",
"authors": "Zhu|Li-Jing|LJ|;Liu|Bao-Rui|BR|;Qian|Xiao-Ping|XP|;Kong|Wei-Wei|WW|;Hu|Wen-Jing|WJ|;DU|Juan|J|;Zhu|Hai-Qing|HQ|",
"chemical_list": null,
"country": "Greece",
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"doi": "10.3892/ol.2013.1451",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2013.1451ol-06-03-0709ArticlesA multiple cavity malignancy involving the renal capsule, pleura and meninges: A case report and review of the literature ZHU LI-JING 1LIU BAO-RUI 1QIAN XIAO-PING 1KONG WEI-WEI 1HU WEN-JING 1DU JUAN 1ZHU HAI-QING 21 The Comprehensive Cancer Center, Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 2l0008, P.R. China2 Department of Pathology, Nanjing Brain Hospital, Nanjing, Jiangsu 2l0029, P.R. ChinaCorrespondence to: Professor Xiao-Ping Qian, The Comprehensive Cancer Center, Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, Jiangsu 2l0008, P.R. China, E-mail: qianxiaoping211@hotmail.com9 2013 09 7 2013 09 7 2013 6 3 709 712 03 3 2013 24 6 2013 Copyright © 2013, Spandidos Publications2013This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.Malignant renal subcapsular effusions commonly arise from primary or metastatic renal neoplasms. The current case report presents a rare case of malignancy with a massive renal subcapsular effusion accompanied by a malignant pleural effusion of an unknown primary site, which underwent progression to carcinomatous meningitis during chemotherapy. The type of adenocarcinoma present was determined by effusion cytology. Intravenous chemotherapy (docetaxel plus oxaliplatin and gemcitabine plus cisplatin) were administered; however, the disease still progressed. Time to progression was 9 months during treatment of gefitinib. Comprehensive therapies, including intracavity chemotherapy, immunotherapy and gefitinib, were shown to be effective and prolonged the patient’s survival time.\n\nneoplasmsunknown primary sitepleural effusionrenaladenocarcinoma\n==== Body\nIntroduction\nCancer of unknown primary site (CUP) is a category of malignancy with undetectable primary site upon diagnosis. It is characterized by diverse clinical manifestations and poor prognosis (1). The histological types include adenocarcinoma, squamous cell carcinoma, neuroendocrine tumors and carcinoma not otherwise specified. Adenocarcinoma of unknown primary site accounts for 60–70% of all cases of CUP and is commonly identified in the liver, lung, bone and lymph nodes (1,2). Metastatic adenocarcinoma of unknown primary site, first presenting with malignant renal subcapsular effusions, is extremely rare and has not been analyzed in previous studies. The current case report presents a patient with adenocarcinoma of unknown primary site that initially presented with renal subcapsular and pleural effusion followed by carcinomatous meningitis. The treatment of this specific type of carcinoma is subsequently discussed. Written informed consent was obtained from the patient.\n\nCase report\nPatient presentation and diagnosis\nA 45-year-old female was admitted to The Comprehensive Cancer Center, Drum Tower Hospital (Nanjing, China) on April 9, 2006 with flank pain, cough and dyspnea. One month prior to admission, the patient had suffered from left flank pain. Abdominal ultrasonography at the patient’s local hospital revealed a subcapsular effusion, a small cyst in the left kidney and a calculus of 0.8 cm in diameter in the upper right ureter. The patient was treated for lithiasis for ~1 month with no amelioration and subsequently developed a cough and dyspnea. A computed tomography (CT) scan revealed right pleural and subcapsular effusions in the left kidney (Fig. 1A). A thorough examination of the individual was performed, including an intravenous urogram, mammography, gynecological ultrasonography, whole gastrointestinal barium contrast imaging and colonoscopy, however, no abnormalities were identified.\n\nUpon admission, a physical examination revealed high blood pressure (160/100 mmHg), lowered respiratory sounds in the right lung and a mass in the left loin. Blood tests showed an elevated level of serum creatinine (196 μmol/l) and serum tumor markers, cancer antigen (CA)125 (168 U/ml; reference range, <35 U/ml), carcinoembryonic antigen (CEA; 15.3 ng/ml; reference range, <5.0 ng/ml) and CA153 (68 U/ml; reference range, <25 U/ml) and a urine test was negative. The cytopathological examination of the pleural effusion was positive for poorly-differentiated adenocarcinoma cells. To identify the primary tumor site, the patient received a systemic positron emission tomography (PET)/CT scan, which identified a small nodule measuring 7×12×9 mm in the upper lobule of the right lung and right pleural (Fig. 1B and C) and subcapsular effusions of the kidneys (Fig. 1D), with normal 18F-fluorodeoxyglucose (FDG) uptake. Due to its size and site, a fine-needle biopsy of the lung nodule was not performed and therefore, the patient was diagnosed with a carcinoma of unknown primary site.\n\nTreatment and clinical course\nChemotherapy was initiated and agents with high renal toxicity were excluded to avoid the deterioration of the patient’s kidney function. Intravenous docetaxel (40 mg/m2 on days 1 and 8, every 3 weeks) plus oxaliplatin (75 mg/m2 on days 1 and 8, every 3 weeks) and intrapleural interleukin-2 (1×109 U on days 3 and 10, every 3 weeks) was administered. The pleural effusion subsided after being drained three times and intrapleural interleukin-2 administration. Following the initial course of chemotherapy, the cough and dyspnea ameliorated and serum levels of creatinine and tumor markers decreased. Following three cycles of chemotherapy, the CT scan showed no change in the pulmonary nodule (Fig. 2B and D) or subcapsular effusion (Fig. 2A and C). Next, renal subcapsular drainage was performed and ~330 and 960 ml stale hematoid fluid was aspirated from the left and right sides, respectively. The levels of CA125, CA199 and CA153 tumor markers were significantly elevated in the drained fluid and adenocarcinoma cells were evident upon analysis of the drainage cytology (Fig. 1E). Following sequential treatments of interleukin-2 and bleomycin administered intrasubcapsularly, the amount of drained fluid decreased (Fig. 2C and E) and turned yellow and clear. The abdominal symptoms were ameliorated and the patient’s blood pressure and serum creatinine level returned to normal; however, no clear changes to the lung nodule were observed (Fig. 2F). Subsequently, the patient received an additional three cycles of systemic chemotherapy with gemcitabine (1,000 mg/m2 on days 1 and 8, every 3 weeks) plus cisplatin (25 mg/m2 daily for 3 days ).\n\nThe patient’s condition was stable prior to an intense headache that developed three weeks after the final administration of gemcitabine plus cisplatin. The individual exhibited no vomiting or blurred vision, the blood pressure remained normal and the brain and spinal MRI scans were negative. A lumber puncture was performed and the cerebrospinal fluid was positive for a large number of adenocarcinoma cells (Fig. 1F). Immunostaining was positive for epithelial membrane antigen and pan-cytokeratin, but negative for vimentin, glial fibrillary acidic protein, cluster of differentiation (CD)3, CD20, CD30 and CD68. Meningeal metastasis and carcinomatous meningitis were diagnosed and the patient received 10 mg intrathecal methotrexate weekly, but refused cranial and spinal cord radiation therapy. Following a total of 40 mg intrathecal methotrexate chemotherapy, the patient’s headache was ameliorated and the cerebrospinal fluid was negative for tumor cells. The individual was administered with 250 mg gefitinib daily for the following nine months, during which the disease status was stable. However, following this, the patient developed paroxysmal syncope and epileptic seizures. No abnormalities were identified in the cranial MRI. Following an additional four months of treatment, the patient succumbed to carcinoma of unknown primary site on March 20, 2008, ~23.5 months after the initial diagnosis. An autopsy was not performed according to the wishes of the patient’s family.\n\nDiscussion\nCUP comprises 2–5% of all diagnosed tumors (1,2). It represents a heterogeneous group of metastatic tumors that share unique clinical features, including early dissemination, a clinical absence of a primary tumor, unpredictable metastatic patterns and aggressiveness, and patients tend to have an unfavorable prognosis. Adenocarcinoma of unknown primary site commonly presents in the liver, lungs, lymph nodes and bones and is rarely identified with malignant pleural or peritoneal effusions (3). A malignant renal subcapsular effusion of unknown primary site is extremely rare and has not been analyzed in previous studies. The current case report presents an unusual manifestation of CUP with massive malignant renal subcapsular and pleural effusions and subsequent carcinomatous meningitis. No solid metastasis was identified during a thorough examination.\n\nRenal subcapsular effusions may be hydroceles or hematoceles, and various mechanisms, including venous, lymphatic and urine regurgitation, may contribute to a subcapsular hydrocele of the kidney. However, a hematocele is likely to be caused by trauma, a renal tumor, vascular disease, infection, nephritis, blood dyscrasias, calculus or hydronephrosis (4). With an incidence rate of 57.7%, spontaneous subcapsular or perirenal hematomas are commonly associated with primary renal neoplasms, of which 33.4% are malignant with renal cell carcinoma predominance and 24.3% are benign with angiomyolipoma predominance (5). In addition, tumors occasionally arise from metastasis of extrarenal primary tumors to the kidney (6). In the present case report, the subcapsular effusion was hematoid and positive for adenocarcinoma cells. The renal parenchyma was negative for any discernible lesions with the exception of a cyst in the left kidney, which did not resemble a common entity of a metastasis of adenocarcinoma cells and did not change throughout the duration of the treatment process. In addition, the urine test was negative for tumor cells or hematuria. As the effusion was bilateral, subcapsular metastasis from the extrarenal site was hypothesized.\n\nNo consensus has been made with regard to the standard therapy for CUP and particularly for multiple malignant cavity effusions. Empiric chemotherapy with 5-fluorouracil, doxorubicin or cisplatin-based regimens have previously produced relatively low response rates and few complete responses (7). Broad spectrum antineoplastic agents, including taxanes, topoisomerase I inhibitors, gemcitabine and vinorelbine, have been investigated in epithelial CUP, and platinum and taxane combination therapy is now widely used in clinical practice. However, a previous meta-analysis showed that no types of chemotherapy have been confirmed to prolong survival in patients with CUP (8). Paclitaxel/docetaxel-containing combination regimens have been used in specific phase II trials and the preliminary results have shown response rates between 23 and 38.7% (9–11). Briasoulis et al reported encouraging results from phase II data on carboplatin and paclitaxel combination therapy for patients with CUP (12). The overall response rate by an intention-to-treat analysis was 38.7% and the median overall survival time was 13 months with a median follow-up of 28 months. A recent randomized study compared empiric therapy with paclitaxel/carboplatin/etoposide against gemcitabine/irinotecan, each followed by single-agent gefitinib, and subsequently identified a comparable efficacy. However, gemcitabine/irinotecan therapy revealed a more favorable toxicity profile (13). In the current case report, the docitaxel/oxiplatin and gemcitabine/cisplatin regimens were administered to the patient successively, but the efficacy was limited since the tumor rapidly metastasized to the meninges and caused carcinomatous meningitis.\n\nAs a maintenance therapy, gefitinib was effective and the patient’s condition was stabilized for nine months despite metastasis of the tumor to the meninges and subsequent carcinomatous meningitis, for which the median survival time is 2–3 months. Patients untreated or unresponsive to treatment exhibit a median survival of 4–6 weeks (14,15). Overexpression of epidermal growth factor receptor (EGFR) has been observed frequently in a large subset of CUP and gefitinib is effective in a broad spectrum of tumor types (16–19). Although no previous randomized studies have analyzed the effect of gefitinib in CUP, a previous prospective study reported that the combination of vascular endothelial growth factor receptor inhibitor (bevacizumab) and EGFR inhibitor (erlotinib) in CUP has a better median survival than previously reported with second-line chemotherapy and is similar to the results of a number of first-line therapies (20). Gefitinib maintenance therapy was also included in a recent prospective randomized trial (13). The role of gefitinib in adenocarcinoma with CUP is promising and must be analyzed in future studies.\n\nIn conclusion, the current case report presents the case of a patient with a malignant effusion in multiple cavities and demonstrates the intracavity administration of chemotherapeutic agents. Interleukin-2 appeared to be effective for controlling the effusion, however, systemic chemotherapy with docetaxel plus oxaliplatin, followed with gemcitabine plus cisplatin, appeared non-effective and the patient exhibited disease progression with involvement of the central nervous system, indicating the refractory entity and poor prognosis of this type of carcinoma. The overall survival time of the patient was ~24 months, which was considerably higher than the normal median survival of individuals with CUP. Gefitinib was identified to be promising for maintenance therapy and was shown to prolong the patient’s survival.\n\nAcknowledgements\nThe authors would like to thank Tom Morse (Office of the President, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China) for his assistance in correcting the original manuscript.\n\nFigure 1 Radiological and cytopathological manifestations of metastatic adenocarcinoma of an unknown primary site. (A) Abdominal contrast-enhanced computed tomography (CT) scan (March 7, 2006) showing a cyst, renal subcapsular effusion and mild hydrocele in the left kidney. (B) Mediastinal window of the CT scan one month later (April 10, 2006) showing a solid nodule in the upper right lung. Positron emission tomography (PET)/CT (April 10, 2006) showing (C) bilateral subcapsular and (D) right pleural effusions. The site of increased 18F-fluorodeoxyglucose (FDG) uptake indicates the puncture point between the ribs. Cytology of the (E) subcapsular effusion, as determined by hematoxylin and eosin staining, and cytology of the (F) cerebrospinal fluid, as determined by Wright’s stain, showing large numbers of adenocarcinomatous cells.\n\nFigure 2 (A and B) CT scans prior to treatment (April 10, 2006) showing bilateral renal subcapsular effusion, a cyst in the kidney, a right pleural effusion and a nodule in the upper lobule of the right lung. (C and D) Following three cycles of intravenous chemotherapy and intra-pleural immunotherapy (June 23, 2006) the pleural effusion subsided but the nodule in the right lung and the subcapsular effusions did not change. (E and F) Following an additional three cycles of intravenous and subcapsular chemotherapy and immunotherapy (September, 7 2006), the subcapsular effusion significantly decreased and no apparent changes to the lung nodule were observed.\n==== Refs\nReferences\n1 Pavlidis N Briasoulis E Hainsworth J Greco FA Diagnostic and therapeutic management of cancer of an unknown primary Eur J Cancer 39 1990 2005 2003 12957453 \n2 Hainsworth JD Greco FA Treatment of patients with cancer of an unknown primary site N Engl J Med 329 257 263 1993 8316270 \n3 Morris GJ Greco FA Hainsworth JD Cancer of unknown primary site Semin Oncol 37 71 79 2010 20494696 \n4 Kendall AR Senay BA Coll ME Spontaneous subcapsular renal hematoma: diagnosis and management J Urol 139 246 250 1988 3339720 \n5 McDougal WS Kursh ED Persky L Spontaneous rupture of the kidney with perirenal hematoma J Urol 114 181 184 1975 1159905 \n6 Demos TC Schiffer MS Reynes CJ Metastatic leiomyosarcoma of the kidney with spontaneous perirenal hemorrhage Diagn Imaging Clin Med 53 87 90 1984 6561121 \n7 Hainsworth JD Greco A Neoplasms of unknown primary site Holland-Frei Cancer Medicine Bast RC Jr Kufe DW Pollock RE 5th edition BC Decker Hamilton, ON, Canada 2114 2124 2000 \n8 Golfinopoulos V Pentheroudakis G Salanti G Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: multiple-treatments meta-analysis Cancer Treat Rev 35 570 573 2009 19539430 \n9 Greco FA Erland JB Morrissey LH Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin Ann Oncol 11 211 215 2000 10761758 \n10 Greco FA Burris HA III Litchy S Gemcitabine, carboplatin and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study J Clin Oncol 15 1651 1656 2002 11896116 \n11 El-Rayes BF Shields AF Zalupski M A phase II study of carboplatin and paclitaxel in adenocarcinoma of unknown primary Am J Clin Oncol 28 152 156 2005 15803009 \n12 Briasoulis E Kalofonos H Bafaloukos D Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study J Clin Oncol 18 3101 3107 2000 10963638 \n13 Hainsworth JD Spigel DR Clark BL Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial Cancer J 16 70 75 2010 20164695 \n14 Grant R Naylor B Greenberg HS Junck L Clinical outcome in aggressively treated meningeal carcinomatosis Arch Neurol 51 457 461 1994 8179494 \n15 Jayson GC Howell A Carcinomatous meningitis in solid tumours Ann Oncol 7 773 786 1996 8922190 \n16 Pavlidis N Briassoulis E Bai M Overexpression of C-myc, Ras and C-erbB-2 oncoproteins in carcinoma of unknown primary origin Anticancer Res 15 2563 2567 1995 8669824 \n17 Fukuoka M Yano S Giaccone G Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected] J Clin Oncol 21 2237 2246 2003 12748244 \n18 Massard C Voigt JJ Laplanche A Carcinoma of an unknown primary: are EGF receptor, Her-2/neu and c-Kit tyrosine kinases potential targets for therapy? Br J Cancer 97 857 861 2007 17876336 \n19 Kris MG Natale RB Herbst RS Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial JAMA 290 2149 2158 2003 14570950 \n20 Hainsworth JD Spigel DR Farley C Minnie Pearl Cancer Research Network Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network J Clin Oncol 25 1747 1752 2007 17470864\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1792-1074",
"issue": "6(3)",
"journal": "Oncology letters",
"keywords": "adenocarcinoma; neoplasms; pleural effusion; renal; unknown primary site",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "709-712",
"pmc": null,
"pmid": "24137395",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": "8669824;1159905;17876336;8316270;8922190;19539430;20494696;10963638;17470864;3339720;6561121;10761758;14570950;11896116;12748244;8179494;12957453;20164695;15803009",
"title": "A multiple cavity malignancy involving the renal capsule, pleura and meninges: A case report and review of the literature.",
"title_normalized": "a multiple cavity malignancy involving the renal capsule pleura and meninges a case report and review of the literature"
} | [
{
"companynumb": "CN-CIPLA LTD.-2018CN10255",
"fulfillexpeditecriteria": "1",
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"patient": {
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"activesubstancename": "GEFITINIB"
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{
"abstract": "A 76-year-old woman with rheumatoid arthritis, osteoporosis and multiple comorbidities presented with septic left elbow prosthesis. Treatment included combination antibiotic therapy and removal of the prosthesis. Weeks later she was started on teriparatide. Her elbow symptoms resolved. In our experience, this is the first case in the literature reporting teriparatide efficacy in the treatment of septic arthritis.",
"affiliations": "Department of Rheumatology, University College London Hospitals NHS Trust, 3rd Floor Central, 250 Euston Road, London, NW1 2PG, UK.",
"authors": "Mouyis|Maria|M|;Fitz-Clarence|Halina|H|;Manson|Jessica|J|;Ciurtin|Coziana|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019379:Teriparatide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-015-2909-y",
"fulltext": null,
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"issn_linking": "0770-3198",
"issue": "34(4)",
"journal": "Clinical rheumatology",
"keywords": null,
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001172:Arthritis, Rheumatoid; D004551:Elbow Joint; D058569:Elbow Prosthesis; D005260:Female; D006801:Humans; D010024:Osteoporosis; D011475:Prosthesis Failure; D018805:Sepsis; D019379:Teriparatide; D016896:Treatment Outcome",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "799-800",
"pmc": null,
"pmid": "25739846",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21459959;21902160;23354115;25187868",
"title": "Teriparatide: an unexpected adjunct for the treatment of a long-standing infected elbow prosthesis prevented arm amputation.",
"title_normalized": "teriparatide an unexpected adjunct for the treatment of a long standing infected elbow prosthesis prevented arm amputation"
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"companynumb": "GB-BAYER-2015-375509",
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"abstract": "Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment modality for primary myelofibrosis (MF) and related myeloproliferative neoplasms. Older age at diagnosis and age-related comorbidities make most patients ineligible for allo-HCT, given concerns for nonrelapse mortality (NRM). Here we report the outcomes of 37 consecutive recipients of allo-HCT for MF performed at a single center between 2009 and 2018 with a standardized institutional protocol. Most patients received ruxolitinib before HCT (n = 32), and those with splenomegaly >22 cm received pretransplantation splenic irradiation. The median age at HCT was 60 years (range, 40 to 74 years), and 68% of the cohort carried a JAK2 driver mutation. All patients received fludarabine/busulfan-based conditioning; 22 patients (59%) received a reduced-intensity conditioning regimen. All patients received peripheral blood grafts, from a matched sibling donor in 16 patients (43%), an unrelated donor in 20 patients, and a haploidentical-related donor in 1 patient. Sixty-one percent had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, 40% had a Karnofsky Performance Status score <90, and 24% had a high-risk DIPSS Plus score. With a median follow-up of 40.2 months (range, 16.9 to 115 months), the 3-year overall survival and relapse-free survival were 81.1% (95% confidence interval [CI], 64.4% to 90.5%) and 78.4% (95% CI, 61.4% to 88.5%), respectively. Only 2 patients relapsed/progressed after transplant. NRM at 2 years was 16.2% (95% CI, 6.5% to 29.9%). All patients engrafted. Sixteen patients were treated with ruxolitinib post-transplantation for graft-versus-host disease, graft rejection/relapse, or persistent MF. These results suggest that pretransplantation ruxolitinib, fludarabine/busulfan-based conditioning, and splenic management are keys to improved transplantation outcomes in patients undergoing allo-HCT for MF.",
"affiliations": "Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: schhabra@mcw.edu.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.;Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.",
"authors": "Chhabra|Saurabh|S|;Narra|Ravi K|RK|;Wu|Ruizhe|R|;Szabo|Aniko|A|;George|Gemlyn|G|;Michaelis|Laura C|LC|;D'Souza|Anita|A|;Dhakal|Binod|B|;Drobyski|William R|WR|;Fenske|Timothy S|TS|;Jerkins|James H|JH|;Pasquini|Marcelo C|MC|;Rizzo|R Douglas|RD|;Saber|Wael|W|;Shah|Nirav N|NN|;Shaw|Bronwen E|BE|;Hamadani|Mehdi|M|;Hari|Parameswaran N|PN|",
"chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2020.01.010",
"fulltext": null,
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"issn_linking": "1083-8791",
"issue": "26(5)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Allogeneic hematopoietic cell transplantation; JAK inhibition; Myelofibrosis; Ruxolitinib",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000368:Aged; D002066:Busulfan; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009570:Nitriles; D055728:Primary Myelofibrosis; D011720:Pyrazoles; D011743:Pyrimidines; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "893-901",
"pmc": null,
"pmid": "31982543",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fludarabine/Busulfan Conditioning-Based Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis: Role of Ruxolitinib in Improving Survival Outcomes.",
"title_normalized": "fludarabine busulfan conditioning based allogeneic hematopoietic cell transplantation for myelofibrosis role of ruxolitinib in improving survival outcomes"
} | [
{
"companynumb": "NVSC2020US082703",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
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"abstract": "We report the case of a first trimester toxoplasmosis infection in a renal transplant recipient. Real-time polymerase chain reaction in amniotic fluid at 18 weeks was negative for Toxoplasma gondii but at 26 weeks major fetal hydrocephalus was discovered leading to medical termination of pregnancy. Pathological examination confirmed lesions consistent with congenital toxoplasmosis. The herein case report, as well as data from the French reference centre for congenital Toxoplamosis (1835 cases in the past eight years), suggests that the strategy of management of pregnancy's first trimester Toxoplasmosis infection in patients treated by immunosuppressive therapy needs to be reconsidered.",
"affiliations": "Service de gynécologie-obstétrique et médecine de la reproduction, hôpital Antoine-Béclère, Assistance-Publique Hôpitaux de Paris, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France; Université Paris Sud, Le Kremlin-Bicêtre, France. Electronic address: monika.hermann@aphp.fr.;Service de parasitologie mycologie, hôpital Cochin, hôpitaux universitaires Paris centre, Assistance-Publique Hôpitaux de Paris, Paris, France; Faculté de médecine, université Paris Descartes, Paris, France; National Reference Center for Toxoplasmosis, France; ToxoSurv network, France.;National Reference Center for Toxoplasmosis, France; ToxoSurv network, France; Laboratoire parasitologie-mycologie, hôpital Maison-Blanche, CHU Reims, France; EA 3800, université Reims-Champagne-Ardenne, Reims, France.;National Reference Center for Toxoplasmosis, France; ToxoSurv network, France; Laboratoire de parasitologie-mycologie, CHU Angers, France.;Faculté de médecine, université Paris Descartes, Paris, France; Service de néphrologie, hôpital Européen Georges-Pompidou, Assistance-Publique Hôpitaux de Paris, Paris, France.;Service de gynécologie-obstétrique et médecine de la reproduction, hôpital Antoine-Béclère, Assistance-Publique Hôpitaux de Paris, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France; Université Paris Sud, Le Kremlin-Bicêtre, France.",
"authors": "Hermann|M|M|;Yéra|H|H|;Villena|I|I|;Cimon|B|B|;Thervet|E|E|;Benachi|A|A|",
"chemical_list": "D016054:DNA, Protozoan",
"country": "France",
"delete": false,
"doi": "10.1016/j.jogoh.2017.08.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2468-7847",
"issue": "46(8)",
"journal": "Journal of gynecology obstetrics and human reproduction",
"keywords": "Congenital toxoplasmosis; PCR; Renal transplant",
"medline_ta": "J Gynecol Obstet Hum Reprod",
"mesh_terms": "D000328:Adult; D000653:Amniotic Fluid; D016054:DNA, Protozoan; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011296:Prenatal Diagnosis; D060888:Real-Time Polymerase Chain Reaction; D014125:Toxoplasmosis, Congenital; D066027:Transplant Recipients",
"nlm_unique_id": "101701588",
"other_id": null,
"pages": "661-663",
"pmc": null,
"pmid": "28851620",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diagnosis of congenital toxoplasmosis in a renal transplant recipient mother.",
"title_normalized": "diagnosis of congenital toxoplasmosis in a renal transplant recipient mother"
} | [
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"companynumb": "FR-ASTELLAS-2017US043953",
"fulfillexpeditecriteria": "1",
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"patient": {
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... |
{
"abstract": "BACKGROUND\nImmunotherapy is now a standard of care in oncology. There is a need to improve our knowledge about immune-related adverse events, especially infectious diseases.\n\n\nMETHODS\nWe describe the case of a 49-year old male who received anti-PD1 therapy, to treat metastatic melanoma with pulmonary metastasis. After 3 cycles of nivolumab, computed tomography scanning showed a decrease of the pulmonary metastasis in the upper left lobe, but revealed new pulmonary lesions such as tree-in-bud and a lung cavity in the same lobe. This was diagnosed as pulmonary tuberculosis with no antibiotic resistance identified. The patient continued the immunotherapy and was initiated onto a standard anti-tuberculosis therapy. In the absence of an initial positive IFN-γ release assay (Quantiferon) test, but as there might have been a history of primary infection during childhood, a reactivation of tuberculosis was considered to be likely.\n\n\nCONCLUSIONS\nThis is the ninth case of tuberculosis infection under immunotherapy and it underlines the need to consider infection risks in patients undergoing immunotherapy. An INF-γ release assay screening test should be considered an essential part of the pre-treatment work-up.",
"affiliations": "Service de pneumologie, université Paul-Sabatier, hôpital Larrey, CHU de Toulouse, Toulouse, France. Electronic address: viatge.t@chu-toulouse.fr.;Service de pneumologie, université Paul-Sabatier, hôpital Larrey, CHU de Toulouse, Toulouse, France.;Service de pneumologie, CH de Montauban, Montauban, France.;Service de radiologie, CH de Montauban, Montauban, France.;Service de pneumologie, CH de Montauban, Montauban, France.",
"authors": "Viatgé|T|T|;Mazières|J|J|;Zahi|S|S|;Fajadet|P|P|;Pétureau|F|F|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab",
"country": "France",
"delete": false,
"doi": "10.1016/j.rmr.2020.06.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8425",
"issue": "37(7)",
"journal": "Revue des maladies respiratoires",
"keywords": "Immune checkpoint inhibitors; Immunotherapy; Immunothérapie; Inhibiteurs de point de contrôle; Lung; Melanoma; Mélanome; Neoplasm metastasis; Néoplasie métastatique; Poumons; Tuberculose; Tuberculosis",
"medline_ta": "Rev Mal Respir",
"mesh_terms": "D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D055985:Latent Tuberculosis; D008175:Lung Neoplasms; D008297:Male; D008545:Melanoma; D050296:Microbial Viability; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "8408032",
"other_id": null,
"pages": "595-601",
"pmc": null,
"pmid": "32636051",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anti-PD1 immunotherapy followed by tuberculosis infection or reactivation.",
"title_normalized": "anti pd1 immunotherapy followed by tuberculosis infection or reactivation"
} | [
{
"companynumb": "FR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-078731",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
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"drugaddi... |
{
"abstract": "Delirious mania (the coexistence of delirium and mania) is described in the literature but not recognised in standard nosologies. We report a woman in her late 30s, with no psychiatric history, who presented with concurrent symptoms of mania and delirium. She was diagnosed with COVID-19 pneumonia (positive reverse transcription-PCR test). There was no history of substance misuse or concurrent medical illness. CT head scan was normal as were blood investigations, other than elevated inflammatory markers. She received standard treatment for COVID-19 pneumonia and lorazepam and quetiapine to treat her neuropsychiatric symptoms. She made a full recovery after 9 days. She was apyrexial with normal oxygen saturation throughout her illness. The case shows that severe neuropsychiatric symptoms can complicate otherwise mild COVID-19 pneumonia with neuroinflammation being a possible mechanism. A diagnosis of delirious mania appears to better capture the complexity of the presentation than a diagnosis of mania or delirium alone.",
"affiliations": "Psychiatry, Hamad Medical Corporation, Doha, Qatar Phaddad@hamad.qa.;Consultation Liaison Psychiatry, Hamad Medical Corporation, Doha, Qatar.;Psychiatry, Hamad Medical Corporation, Doha, Qatar.;Psychiatry, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Haddad|Peter M|PM|;Alabdulla|Majid|M|;Latoo|Javed|J|;Iqbal|Yousaf|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(11)",
"journal": "BMJ case reports",
"keywords": "COVID-19; bipolar I disorder; delirium; psychiatry (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001714:Bipolar Disorder; D000086382:COVID-19; D003693:Delirium; D005260:Female; D006801:Humans; D000087122:Mania; D000086402:SARS-CoV-2",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34725060",
"pubdate": "2021-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3137394;33836148;34294651;32458193;4684288;18191210;32733668;32907692;32437679;32946031;33843248;30839323;28458141;33328211;32512352;25981208;32696264;14709766;23198239;22295008;32823051;32838241;27856235;11256658;33184265;26979387;33674185;22716018;34196908;33936680",
"title": "Delirious mania in a patient with COVID-19 pneumonia.",
"title_normalized": "delirious mania in a patient with covid 19 pneumonia"
} | [
{
"companynumb": "QA-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-324386",
"fulfillexpeditecriteria": "1",
"occurcountry": "QA",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
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{
"abstract": "IgG4-related disease represents a heterogeneous group of disease characterized by infiltration of various tissues by IgG4 plasmocytes. In case of liver infiltration, this condition classically mimics primary sclerosing cholangitis or multifocal cholangiocarcinoma due to inflammation that preferentially affects the intra- and extrahepatic bile duct. Diagnostic criteria have recently been reviewed in order to better define the disease and help physicians make the diagnosis. Herein, we present the case of a patient who died after liver surgery for suspected cholangiocarcinoma that finally turned out to be IgG4-associated liver disease, a condition being out of current consensual criteria. The patient presented with progressive cholestasis identified by MR cholangiography as an isolated hilar mass responsible for dilatation of the left and right intrahepatic bile duct suspicious for a Klatskin tumor. The IgG4 blood level was normal as was biliary cytology. The patient underwent right portal embolization followed by right extended hepatectomy. Pathologic examination found no tumor but intense fibrosclerotic infiltration with a marked inflammatory infiltrate characterized by IgG4-positive plasmocytes. Despite immunosuppressive treatment, cholestasis was never controlled and successive biopsies of the remaining liver showed progressive cholestasis, liver infiltrate and no bile duct regeneration. The patient finally presented an upper gastrointestinal hemorrhage leading to death 4 months after hepatectomy and appropriate immunosuppressive therapy.",
"affiliations": "Geneva University Hospitals, Geneva, Switzerland.;Geneva University Hospitals, Geneva, Switzerland.;Geneva University Hospitals, Geneva, Switzerland.;Geneva University Hospitals, Geneva, Switzerland.",
"authors": "Bochatay|Laurent|L|;Majno|Pietro|P|;Giostra|Emiliano|E|;Frossard|Jean Louis|JL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000448989",
"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000448989crg-0010-0512Case ReportIsolated Liver Hilar Infiltration by IgG4 Inflammation Mimicking Cholangiocarcinoma Bochatay Laurent *Majno Pietro Giostra Emiliano Frossard Jean Louis Geneva University Hospitals, Geneva, Switzerland*Dr. Laurent Bochatay, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, CH-1205 Geneva (Switzerland), E-Mail laurent.bochatay@hcuge.chSep-Dec 2016 6 10 2016 6 10 2016 10 3 512 517 7 7 2016 9 8 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.IgG4-related disease represents a heterogeneous group of disease characterized by infiltration of various tissues by IgG4 plasmocytes. In case of liver infiltration, this condition classically mimics primary sclerosing cholangitis or multifocal cholangiocarcinoma due to inflammation that preferentially affects the intra- and extrahepatic bile duct. Diagnostic criteria have recently been reviewed in order to better define the disease and help physicians make the diagnosis. Herein, we present the case of a patient who died after liver surgery for suspected cholangiocarcinoma that finally turned out to be IgG4-associated liver disease, a condition being out of current consensual criteria. The patient presented with progressive cholestasis identified by MR cholangiography as an isolated hilar mass responsible for dilatation of the left and right intrahepatic bile duct suspicious for a Klatskin tumor. The IgG4 blood level was normal as was biliary cytology. The patient underwent right portal embolization followed by right extended hepatectomy. Pathologic examination found no tumor but intense fibrosclerotic infiltration with a marked inflammatory infiltrate characterized by IgG4-positive plasmocytes. Despite immunosuppressive treatment, cholestasis was never controlled and successive biopsies of the remaining liver showed progressive cholestasis, liver infiltrate and no bile duct regeneration. The patient finally presented an upper gastrointestinal hemorrhage leading to death 4 months after hepatectomy and appropriate immunosuppressive therapy.\n\nKey Words\nIgG4 liver diseaseCholangiocarcinomaHilar filling defect\n==== Body\nIntroduction\nIgG4-mediated disease is a multisystemic condition and is characterized by the infiltration of various tissues by IgG4-positive plasmocytes. The salivary glands, retroperitoneum, retroocular tissue, pancreas and hepatobiliary system can all be affected [1, 2]. Type 1 autoimmune pancreatitis is the most studied disease but is still rare [3]. The hepatobiliary system is involved in 60–80% of the patients with type 1 autoimmune pancreatitis [4, 5, 6], most of the time mimicking primary sclerosing cholangitis in cholangiographic studies. Different classification systems have been proposed so far, but an international pathological consensus has been finally reached in 2012 [7], defining minimal conditions to diagnose IgG4-related disease (table 1). Furthermore, a classification of cholangiography features in IgG4-related sclerosing cholangitis has been proposed to help classify four patterns affecting the biliary tract [6]. Diagnosis and imaging criteria are aimed at helping clinicians to distinguish between IgG4 hepatobiliary disease and alternative diagnosis such as primary sclerosing cholangitis, pancreatic cancer, chronic pancreatitis, gallbladder and bile duct cancer.\n\nWe here present the case of a patient who died after liver surgery for suspected cholangiocarcinoma that finally revealed as IgG4 liver disease being out of consensual criteria.\n\nCase Presentation\nA 66-year-old male was admitted to our hospital because of persistent diarrhea, discolored stools, dark urine and weight loss. The liver tests showed significant cholestasis [alkaline phosphatase 4 times the upper normal limits (UNL), gamma-glutamyltransferase 20 times UNL and total bilirubin 1.2 times UNL], while MRI showed a thickening of the biliary convergence and the initial part of the left bile duct without surrounding infiltration. The intrahepatic biliary tree was slightly dilated. 3D reconstruction showed a hilar filling defect of the biliary tree (fig 1). The lesion was highly suspicious for a Klatskin tumor, and the patient underwent percutaneous drainage with sampling, while an internal-external drain was left in place. Carbohydrate antigen 19-9 was 16 kU/l (normal <37) and carcinoembryonic antigen was 2.2 μg/l (normal <4.6). Total immunoglobulin was IgG 13 mg/l, IgA 2.83 g/l and IgM 1.14 g/l), while the subclass IgG4 was 1.3 g/l. The ratio IgG4/IgG was 9%. Biliary cytology was negative. Because of the strong suspicion of Klatskin tumor, the patient had a right portal embolization extended to segment IV in order to anticipate an extended right hepatectomy including segment IV, later allowing a right hepatectomy extended to segments I and IV with hilar lymphadenectomy.\n\nPathologic examination identified intense fibrosclerotic infiltration of the left and right biliary tract with marked inflammatory infiltrate characterized by IgG4 plasmocytes and an important amount of polymorphonuclear eosinophils. Circumferential ‘peel of onion’-like fibrosis was also observed. There were no signs of malignancy. Plasmocytes were stained positive for IgG4. The surrounding liver parenchyma was normal.\n\nThe diagnosis of IgG4-related hepatobiliary disease was finally made, and prednisone was started. The postoperative course was complicated by a progressive increase of cholestasis parameters within the next 4 weeks (fig 2). Liver biopsy identified major biliary duct dystrophia with IgG4 infiltration, explaining the progressive cholestasis. Treatment was reinforced with a combination of azathioprine and prednisone, allowing a slight improvement of the liver tests and patient discharge.\n\nOne week later, the patient was readmitted with worsening jaundice. A CT scan excluded bile duct stenosis, while liver biopsy still showed a severe bile duct dystrophia. However, IgG4 plasmocytes had disappeared, and significant bilirubinostasis accumulating within the bile duct, portal space as well as inside the hepatocytes was observed. There were no ductular proliferative reactions.\n\nThe patient presented duodenal ulcer bleeding (Forrest Ia), leading to hemorrhagic shock and finally death 4 months after the right hepatectomy (fig 2). The patient's autopsy demonstrated several liver damages that could explain the abnormal liver tests and function (prothrombin time 62%, factor V 65%). Liver autopsy showed liver atrophy and inadequate liver regeneration. The biliary dystrophies were identical with those already demonstrated by previous liver biopsies. Massive upper gastrointestinal hemorrhage was responsible for the immediate death of the patient.\n\nDiscussion\nIgG4-related biliary disease induces most frequently stenosis and dilation of isolated or multiple branches of the biliary tree, mimicking primary sclerosing cholangitis or cholangiocarcinoma. International guidelines recommend against fine-needle punction or aspiration for the diagnosis of cholangiocarcinoma as long as it is considered surgically curable because of the risk of seeding cancer cells along the needle tract [7]. Serum dosage of immunoglobulin subtype, looking for IgG4 and brush cytology can help excluding IgG4-related disease before proceeding to surgery and is part of the diagnostic criteria [8, 9]. The current case illustrates the fact that IgG4-related disease remains difficult to diagnose before surgery. As soon as the liver explant was analyzed by the pathologist, showing no tumor cells but massive plasmocytes IgG4-positive associated with bile ducts injuries, the diagnosis became evident.\n\nAlthough prednisone was soon introduced, the patient's condition worsened, justifying combined azathioprine and prednisone treatment. Successive liver biopsies showed massive destruction of the small bile duct, explaining the progressive worsening of the cholestasis. Prednisone was probably at least partly effective as IgG4-positive plasmocytes infiltrated in the hepatic tissue disappeared between the day of surgery and the 2 successive liver biopsies. However, severe biliary dystrophy with the lack of regeneration of the small bile ducts observed in the second biopsy might explain the absence of improvement of the patient's liver tests. Finally, a fatal hemorrhage occurred.\n\nMisdiagnosed type 1 pancreatitis leads to surgery for suspected pancreatic adenocarcinoma in many cases, as described in the literature [1]. Hopefully, this situation is much less common for IgG4-mediated biliary tract involvement. Case reports and few series of IgG4-related sclerosing cholangitis of patients undergoing surgery are described in the literature [10, 11, 12], but our case was different to some extent. First, sclerosing cholangitis was not suspected because of an intact intrahepatic and extrahepatic bile duct apart from the hilar stenosis. Indeed, the absence of multiple biliary stenosis, a normal serum IgG and IgG4 levels and a normal IgG4/IgG ratio made the putative diagnosis of hilar cholangiocarcinoma most likely. Portal embolization, hepatic radical surgery and delay in prednisone treatment may have led to disease progression. The lack of hepatic reserve following large hepatic resection may have altered bile duct regeneration and promoted hepatic failure (prothrombin time 62%, factor V 65%). Finally, prednisone, physical stress following repeated hospitalizations as well as major surgery led to duodenal ulcers and fatal hemorrhage.\n\nConclusion\nThe diagnosis of IgG4-related biliary disease remains difficult because a blood test to rule out such diagnosis does not exist. The recourse to more invasive diagnostic tools such as percutaneous or endoscopic drainage allowing bile duct sampling is therefore often required. When surgically curable cholangiocarcinoma is the most likely diagnosis, tissue sampling is not a diagnostic option. IgG4-related bile duct isolated stenosis is rare, but this specific diagnosis should be kept in mind because consequences can be fatal, as illustrated in this case.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nAll authors declare that they have no conflicts of interest relevant to this paper.\n\nFig. 1 MRI 3D reconstruction of the biliary tree showing central hilar filling defect. The arrow indicates magnification of the hilar region. The circle underlines a tissue-like structure responsible for the filling defect of the biliary convergence.\n\nFig. 2 Clinical course illustrated by cholestasis chemistry. Modifications in cholestasis chemistry were observed in major clinical events, indicated by arrows, from the time of hospitalization until the occurrence of death. APL = Alkaline phosphatase; GGT = gamma-glutamyltransferase.\n\nTable 1 2012 international pathological consensus defining minimal conditions to diagnose IgG4-related disease\n\nMajor histopathological features associated with IgG4-related disease\t\n1.\tDense lymphoplasmacytic infitrate\t\n2.\tFibrosis, arranged at least focally in a storiform pattern\t\n3.\tObliterative phlebitis\t\n\t\nOther histolpathological features associated with IgG4-related disease\t\n1.\tPhlebitis without obliteration of the lumen\t\n2.\tIncreased number of eosinophils\t\n\t\nMinimal criteria for IgG4-related disease in/at a new organ/site\t\n1.\tCharacteristic histopathological finding with an elevated IgG4t plasma cells and IgG4-to-IgG ratio\t\n2.\tHigh serum IgG4 concentrations\t\n3.\tEffective response to glucocorticoid therapy\t\n4.\tReports of other organ involvement that is consistent with IgG4-related disease\n==== Refs\nReferences\n1 Kazuich O Masahito Y Toshiyuki M Kazushige U Recent advances in the concept and pathogenesis of IgG4-related disease in the hepato-bilio-pancreatic system Gut Liver 2014 8 462 470 25228969 \n2 Lang D Zwerina J Pieringer H IgG4-related disease: current challenges and future prospects Ther Clin Risk Manag 2016 12 189 199 26929632 \n3 Inoue D Yoshida K Yoneda N IgG4-related disease: dataset of 235 consecutive patients Medicine (Baltimore) 2015 94 e680 25881845 \n4 Okazaki K Uchida K Koyabu M Miyoshi H Takaoka M Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease J Gastroenterol 2011 46 277 288 21452084 \n5 Okazaki K Uchida K Matsushita M Takaoka M How to diagnose autoimmune pancreatitis by the revised Japanese clinical criteria J Gastroenterol 2007 42 suppl 18 32 38 17520221 \n6 Okazaki K Kawa S Kamisawa T Amendment of the Japanese consensus guidelines for autoimmune pancreatitis, 2013 I Concept and diagnosis of autoimmune pancreatitis. J Gastroenterol 2014 49 567 588 24639057 \n7 Khan SA Davidson BR Goldin RD Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update Gut 2012 61 1657 1669 22895392 \n8 Ohara H Okazaki K Tsubouchi H Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012 J Hepatobiliary Pancreat Sci 2012 19 536 542 22717980 \n9 Deshande V Zen Y Chan JK Consensus statement on the pathology of IgG4-related disease Mod Pathol 2012 25 1181 1192 22596100 \n10 Maeda M Shimada K A case of IgG4-related sclerosing cholangitis mimicking an intrahepatic cholangiocellular carcinoma Jpn J Clin Oncol 2012 42 153 22291208 \n11 Erdogan D Kloek JJ ten Kate FJ Rauws EA Busch OR Gouma DJ Immunoglobulin G4-related sclerosing cholangitis in patients resected for presumed maliganant bile duct strictures Br J Surg 2008 95 727 734 18418862 \n12 Miki A Sakuma Y Ohzawa H Sanada Y Sasanuma H Lefor AT Sata N Yasuda Y Immunoglobulin G4-related sclerosing cholangitis mimicking hilar cholangiocarcinoma diagnosed with following bile duct resection: report of a case Int Surg 2015 100 480 485 25785331\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "10(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Cholangiocarcinoma; Hilar filling defect; IgG4 liver disease",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "512-517",
"pmc": null,
"pmid": "27843427",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "25785331;18418862;22717980;25228969;22596100;25881845;22291208;24639057;26929632;22895392;17520221;21452084",
"title": "Isolated Liver Hilar Infiltration by IgG4 Inflammation Mimicking Cholangiocarcinoma.",
"title_normalized": "isolated liver hilar infiltration by igg4 inflammation mimicking cholangiocarcinoma"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-137887",
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"activesubstancename": "AZATHIOPRINE"
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"abstract": "Patients treated for lung cancer may develop lung toxicity induced by chemotherapy (DILD), radiation or combined radiation recall pneumonitis. In the literature, some cases of immune-mediated pneumonitis have been reported associated with immunotherapy. The clinical and radiologic features of interstitial lung toxicity are unspecific, dyspnoea and dry cough are the most common symptoms while the most frequent radiological pattern is the cryptogenic organizing pneumonia (COP). Why only some individuals treated with these drugs develop interstitial lung toxicity is unclear.In the last few years some studies have reported the utility of KL 6 for the evaluation of DILD. The treatment is based on high doses of systemic steroids or immune suppressor. In this study we report severe interstitial lung damage in patients treated with different anti-blastic, immune and radiation therapies. Treated with surgery, chemotherapy, immuno and radiotherapy for lung cancer, they unfortunately died of severe DILD.",
"affiliations": "University Hospital Careggi, Department of Clinical and Experimental Biomedical Sciences. bargagli2@gmail.com.",
"authors": "Bargagli|Elena|E|;Bonti|Viola|V|;Bindi|Alessandra|A|;Scotti|Vieri|V|;Pistolesi|Massimo|M|;Voltolini|Luca|L|;Ferrari|Katia|K|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2018.917",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1122-0643",
"issue": "88(2)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
"keywords": "Drugs, Interstitial Lung Toxicity,Chemotherapy, Ooncological Immunotherapy",
"medline_ta": "Monaldi Arch Chest Dis",
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"pages": "917",
"pmc": null,
"pmid": "29927195",
"pubdate": "2018-06-21",
"publication_types": "D016428:Journal Article",
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"title": "Fibrotic lung toxicity induced by cytotoxic drugs, radiation and immunotherapy in patients treated for lung cancer.",
"title_normalized": "fibrotic lung toxicity induced by cytotoxic drugs radiation and immunotherapy in patients treated for lung cancer"
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"abstract": "A patient with human immunodeficiency virus-1 infection presented with sub-acute liver failure, temporally related to commencement of an antiretroviral therapy regimen containing dolutegravir (Triumeq). The patient was not a carrier of HLA-B5701, and abacavir hypersensitivity was unlikely. We believe this is the first report of severe dolutegravir-related hepatotoxicity resulting in sub-acute liver failure and transplantation and highlights a potential need for closer monitoring after drug initiation.",
"affiliations": "1 Institute of Liver Studies, King's College Hospital, London, UK.;2 Department of Genitourinary Medicine and HIV, 156767 Croydon University Hospital , Croydon, UK.;1 Institute of Liver Studies, King's College Hospital, London, UK.;3 Department of Sexual Health and HIV, The Caldecot Centre, King's College Hospital, London, UK.;1 Institute of Liver Studies, King's College Hospital, London, UK.;2 Department of Genitourinary Medicine and HIV, 156767 Croydon University Hospital , Croydon, UK.;4 Institute of Liver Studies, Liver Histopathology Laboratory, King?s College Hospital, London, UK.;1 Institute of Liver Studies, King's College Hospital, London, UK.",
"authors": "Wang|Bo|B|0000-0003-1052-5145;Abbott|Laura|L|;Childs|Kate|K|;Taylor|Chris|C|;Agarwal|Kosh|K|;Cormack|Ian|I|;Miquel|Rosa|R|;Suddle|Abid|A|",
"chemical_list": "D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; C562325:dolutegravir",
"country": "England",
"delete": false,
"doi": "10.1177/0956462417734099",
"fulltext": null,
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"issn_linking": "0956-4624",
"issue": "29(4)",
"journal": "International journal of STD & AIDS",
"keywords": "Antiretroviral therapy; dolutegravir; human immunodeficiency virus; liver; toxicity",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D005260:Female; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008099:Liver; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D016896:Treatment Outcome",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "414-417",
"pmc": null,
"pmid": "29059031",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Dolutegravir-induced liver injury leading to sub-acute liver failure requiring transplantation: a case report and review of literature.",
"title_normalized": "dolutegravir induced liver injury leading to sub acute liver failure requiring transplantation a case report and review of literature"
} | [
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"activesubstancename": "ACETAMINOPHEN"
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"abstract": "Since their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93-1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3-4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.",
"affiliations": "Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.;Department of Oncology and Onco-hematology, Università degli Studi di Milano, Milan, Italy.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Hematology Unit, Milan, Italy.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Hematology Unit, Milan, Italy.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Hematology Unit, Milan, Italy.;Department of Oncology and Onco-hematology, Università degli Studi di Milano, Milan, Italy.",
"authors": "Capecchi|Marco|M|;Serpenti|Fabio|F|;Giannotta|Juri|J|;Pettine|Loredana|L|;Reda|Gianluigi|G|;Martinelli|Ida|I|;Artoni|Andrea|A|;Barcellini|Wilma|W|;Fattizzo|Bruno|B|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.680411",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.680411\nOncology\nOriginal Research\nOff-Label Use of Thrombopoietin Receptor Agonists: Case Series and Review of the Literature\nCapecchi Marco 1 2 * †\n\nSerpenti Fabio 2 3 †\n\nGiannotta Juri 3 4\nPettine Loredana 4\nReda Gianluigi 4\n\nMartinelli Ida 2\nArtoni Andrea 2\nBarcellini Wilma 4\n\nFattizzo Bruno 3 4\n\n1Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy\n2Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy\n3Department of Oncology and Onco-hematology, Università degli Studi di Milano, Milan, Italy\n4Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Hematology Unit, Milan, Italy\nEdited by: Luca Laurenti, Agostino Gemelli University Polyclinic, Italy\n\nReviewed by: Howard Allen Liebman, University of Southern California, United States; Mohamed Mahmoud Moussa, Ain Shams University, Egypt\n\n*Correspondence: Marco Capecchi, marco.capecchi@unimi.it\nThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work\n\n28 9 2021\n2021\n11 68041118 3 2021\n06 9 2021\nCopyright © 2021 Capecchi, Serpenti, Giannotta, Pettine, Reda, Martinelli, Artoni, Barcellini and Fattizzo\n2021\nCapecchi, Serpenti, Giannotta, Pettine, Reda, Martinelli, Artoni, Barcellini and Fattizzo\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nSince their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93–1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3–4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.\n\nthrombopoietin receptor agonist\neltrombopag\nromiplostim\nmyelodysplastic syndromes\ntransplant\nlymphoproliferative syndromes\nMinistero della Salute 10.13039/501100003196\n==== Body\npmcIntroduction\n\nSince thrombopoietin receptor agonists (TPO-RAs) eltrombopag and romiplostim were licensed in the United States for treatment of immune thrombocytopenia (ITP) in 2008, their use has progressively increased, and they are currently available in more than 100 countries (1). Both TPO-RAs bind to the thrombopoietin (TPO) receptor, causing conformational change, activating the JAK2/STAT5 pathway, and resulting in higher megakaryocyte progenitor proliferation and increased platelet production. Indications for their use are similar in the United States and Europe. Eltrombopag (Revolade®, Promacta®) is approved for second-line therapy of ITP patients older than 1 year of age with a disease lasting at least 6 months (2), for second-line therapy of severe aplastic anemia after failure of immune suppressive therapy (3), and for the treatment of thrombocytopenia in adults with chronic hepatitis C treated with interferon-based regimens (4). Romiplostim (Nplate®) is only approved as second-line treatment for chronic ITP patients (i.e., after 12 months from diagnosis). Two other TPO-RAs have been recently approved, namely avatrombopag (Doptelet®) and lusutrombopag (Mulpleo®), specifically licensed for the treatment of patients with thrombocytopenia secondary to chronic liver disease undergoing invasive procedures (5, 6).\n\nAs for safety, the initial concerns on the risk of myelofibrosis induction have not been confirmed. Only a small number of patients develop moderate to severe reticulin and/or collagen fibrosis, which is usually reversible after drug discontinuation (7). A higher rate of venous thromboembolism has been reported, with a two- to threefold increased risk as compared with non-TPO-RA treated ITP patients (8, 9). Cataract and transiminitis are eltrombopag-associated adverse effects, whereas the development of neutralizing antibodies and pain after injection are associated to romiplostim (1).\n\nEmerging evidence is being produced about TPO-RA efficacy and safety profile in different settings other than the registered ones. Overall, it appears relevant to understand which are the main clinical needs and the most promising fields in which to broaden TPO-RA use, given their convenient and safe profile. We hereby report our real-life single-center experience of TPO-RA use in unlabeled conditions and provide inherent literature review.\n\nMethods\n\nWe conducted an observational retrospective study to report the response rates and safety profile of TPO-RA used off-label. All consecutive patients aged >18 years and receiving out-of-label TPO-RA at our center between January 2010 and June 2020 were included. Patients were divided into three main groups according to the underlying cause of thrombocytopenia: post-transplant thrombocytopenia, myelodysplastic syndrome (MDS), and thrombocytopenia associated to lymphoproliferative diseases. All patients were assessed at baseline by whole blood counts with differential, peripheral blood smear, liver and kidney function tests, hemolytic markers (LDH, bilirubin, haptoglobin, reticulocytes), antiplatelet antibodies, and antiphospholipid antibodies and underwent a bone marrow evaluation with cytogenetic studies (karyotype for all patients and FISH for MDS patients), according to clinical practice. In MDS patients, a myeloid gene panel evaluating 69 genes implied in myeloid neoplasms had been performed at diagnosis in two patients; the test was unavailable for the others. Data on underlying disease, previous lines of therapy, drug dosing, discontinuation, bleeding/thrombotic events, and other adverse events were recorded. Clinical status and platelet response were recorded at 1, 3, 6, and 12 months after beginning of the drug. In patients with thrombocytopenia other than the ITP candidate to treatment with TPO-RA, a bone marrow evaluation at baseline is always performed. MDS patients receive further bone marrow assessments every 6 months and whenever clinically indicated. Patient monitoring and education for thrombotic complications and liver function tests evaluation were performed according to current clinical practice for ITP patients treated with TPO-RA. Response criteria were defined as partial response (PR) (platelet count >30,000) and complete response (CR) (platelet count >100,000). Adverse events were defined according to the CTCAE version 5.0.\n\nResults\n\nFrom January 2010 to June 2020, a total of 81 patients have been treated with a TPO-RA (eltrombopag or romiplostim) at our referral center. A total of 67 patients received the TPO-RA for in-label conditions—ITP (54 patients) or aplastic anemia (13 patients)—while 14 patients received a TPO-RA for unlabeled conditions (Figure 1 and Table 1). Among the latter group, four patients had a transplant-associated thrombocytopenia, eight suffered from MDS, and two had thrombocytopenia associated to a lymphoproliferative neoplasm. The median patient age was 62.5 years (range 36–86). All patients were treated with eltrombopag except for one who received romiplostim. The median duration of therapy was 285 days (range 93–1,513 days) with 4 patients (29%) discontinuing the drug. Figure 2 shows median platelet trends over time among the different groups (Figure 2A) and platelet counts over time for each MDS patient (Figure 2B). Regarding responses to TPO-RA treatment, we only observed an increase in platelet counts, while no changes were recorded in erythrocytes and leukocytes in all the three clinical settings. No patient received blood transfusions or myeloid growth factors.\n\nFigure 1 Flowchart of thrombopoietin receptor agonist (TPO-RA) treated patients at our center in the last 10 years. Aplastic anemia (AA) refers to aplastic anemia patients treated in second line after failure of immunosuppressive therapy as for current drug indications; we had no off-label AA patient treated in first line. MDS, myelodysplastic syndrome; LPD, lymphoproliferative disease; ITP, autoimmune thrombocytopenia.\n\nTable 1 Patient outcome stratified by group.\n\nPATIENT ID\tGROUP\tNUMBER OF PREVIOUS THERAPY LINES\tTPO-RA\tMAXIMAL DOSE\tDURATION OF THERAPY\tRESPONSE\tTIME TO RESPONSE\tADVERSE EVENT\t\nT-01\tTA-T\t1\tELTROMBOPAG\t150 mg die\t181 d\tPR\t87\t0\t\nT-02\tTA-T\t1\tELTROMBOPAG\t75 mg die\t1513 d\tPR\t60\tG1 liver\t\nT-03\tTA-T\t2\tROMIPLOSTIM\t6 mcg/kg/w\t439 d\tCR\t119\t0\t\nT-04\tTA-T\t2\tELTROMBOPAG\t50 mg die\t93 d\tCR\t17\t0\t\nM-01\tMDS\t1\tELTROMBOPAG\t75 mg die\t702 d\tPR\t49\t0\t\nM-02\tMDS\t2\tELTROMBOPAG\t75 mg die\t1486 d\tPR\t57\t0\t\nM-03\tMDS\t3\tELTROMBOPAG\t75 mg die\t93 d\tNR\t-\tPD to AML\t\nM-04\tMDS\t3\tELTROMBOPAG\t50 mg die\t354 d\tCR\t14\t0\t\nM-05\tMDS\t1\tELTROMBOPAG\t50 mg die\t216 d\tPR\t40\t0\t\nM-06\tMDS\t2\tELTROMBOPAG\t150 mg die\t317 d\tNR\t-\t0\t\nM-07\tMDS\t4\tELTROMBOPAG\t150 mg die\t252 d\tPR\t25\t0\t\nM-08\tMDS\t1\tELTROMBOPAG\t50 mg die\t516 d\tPR\t44\t0\t\nL-01\tLPD\t4\tELTROMBOPAG\t25 mg die\t111 d\tPR\t20\t0\t\nL-02\tLPD\t2\tELTROMBOPAG\t50 mg die\t158 d\tPR\t139\t0\t\nEach row defines a patient. T-AT, transplant-associated thrombocytopenia; MDS, myelodysplastic syndrome; LPD, lymphoproliferative disease; TPO-RA, thrombopoietin receptor agonist; CR, complete response; PR, partial response; NR, non-response; G1, grade 1; PD to AML, progression to acute myeloid leukemia.\n\nFigure 2 (A) Median platelet count at baseline, 3, 6, and 12 months per group of patients. At 6 and 12 months, no data are reported for the lymphoproliferative patients because the median follow-up was inferior to 6 months in this group. LPD, lymphoproliferative disease; MDS, myelodysplastic syndrome; M, months. (B) Platelet counts over time for each MDS patient.\n\nTransplant Group\n\nOne patient received an autologous hematopoietic stem cell transplant (HSCT) due to an AL amyloidosis that was complicated by graft failure, leading to persistent thrombocytopenia in the post-transplant period. No more autologous stem cells were available to perform a second transplant procedure, and the patient was not suitable for an allogenic stem cell transplant given the comorbidities. After failure of danazol therapy, she was treated with eltrombopag at the same dose licensed for aplastic anemia (150 mg daily) reaching platelet transfusion independency at 3 months from TPO-RA start.\n\nThe other three patients of this group received a solid organ transplant (two liver and one kidney). The median time from transplantation to the onset of thrombocytopenia was 7 days for liver-transplanted patients. The kidney-transplanted patient had instead a late-onset thrombocytopenia (4 years and 2 months after transplantation) associated with graft rejection. Thrombocytopenia in these patients was interpreted as immune-mediated, but all failed steroid therapy. Two of them also received high-dose intravenous immunoglobulins, with only a transient PR in the kidney-transplanted patient. The median time from thrombocytopenia onset to TPO-RA therapy start was only 13 days (10–149 days), as the general clinical conditions of the patients required fast intervention to raise platelet counts. Two patients started eltrombopag 50 mg daily, and one of them had to increase the dose to 75 mg daily due to suboptimal response. The other patient was treated with romiplostim 1 mcg/kg per week, gradually increased to 6 mcg/kg per week to obtain a response. All patients responded, and median platelet counts increased from 8,000/mcl (range 2,000–30,000/mcl) pre-TPO therapy to 62,000/mcl (range 51,000–260,000/mcl), 91,000/mcl (range 43,000–139,000/mcl), and 74,000/mcl (range 64,000–84,000/mcl) at 3, 6, and 12 months, respectively (Figure 2).\n\nThe overall response rate (ORR) was 100% (1 CR and 3 PR). After 3 years of therapy, one patient who underwent liver transplantation stopped eltrombopag due to grade 1 hepatic toxicity together with a stable PR, which persisted even after TPO-RA discontinuation, until more than 6 months of follow-up (189 days). The median duration of therapy was 310 days (range 93–1,513), and overall survival (OS) was 100% with all patients being alive and in good general conditions at last follow-up visit.\n\nMyelodysplastic Syndrome Group\n\nEight patients received eltrombopag because of thrombocytopenic MDS. Six patients had low international prognostic scoring system (IPSS)/revised-IPSS, and the other two had intermediate-1 IPSS/revised-IPSS. Only one patient had abnormal cytogenetics with chromosome 8 trisomy. Mutational analysis with NGS was performed in two patients, one bearing a DNMT3A mutation with a variant allele frequency (VAF) of 3.6% and the other showing no detectable mutations. Five patients had a hypocellular bone marrow, three of them showing also reduced megakaryocytes. The other three patients showed an increased number of megakaryocytes, one of them with marked dysplastic features. Antiplatelet antibodies were found in five cases. The median number of therapy lines before TPO-RA was 2 (range 1–4). These included steroids (all patients, 5 PR), Cyclosporin A (3 patients, 2 PR), intravenous immunoglobulin (IVIG, 3 patients, 1 PR and 1 CR), danazol (3 patients, 2 PR), and rituximab (1 patient, transient PR). The median time elapsed from onset of thrombocytopenia to eltrombopag therapy was 1,582 days (range 30–5,878 days), and the median platelet count was 20,000/mcl (range 13,000–230,000/mcl) before therapy. Eltrombopag was started at 50 mg daily and raised according to clinical judgment, with a median steady dose of 75 mg (50–150 mg). The median platelet count was 53,000/mcl (range 5,000–150,000/mcl), 38,000/mcl (range 8,000–104,000/mcl), and 59,000/mcl (25,000–203,000/mcl) at 3, 6, and 12 months, respectively. ORR was 75% (5 PR and 1 CR). Three patients discontinued TPO-RA, two because of failure after 3 (93 days) and 10 months (317 days) of therapy, respectively. Interestingly, these patients were the only ones with intermediate-1 risk score according to IPSS/r-IPSS risk stratification, and both had an increased number of dysplastic megakaryocytes in their bone marrow biopsies. The other patient discontinued the drug due to persisting CR for more than 11 months (340 days). This patient experienced transient drops in platelet counts while tapering TPO-RA but was able to stop the drug keeping a sustained CR for 9 months (279 days). Thereafter, a relapse occurred again, successfully rescued with TPO-RA. No adverse events were observed in this group of patients. The median duration of therapy was 336 days (range 93–1,486 days) and the OS was 88%. The patient who died had a 15-year history of thrombocytopenic MDS heavily pretreated with steroids, IVIG, danazol, cyclosporine, and finally eltrombopag with no response. Three months after TPO-RA start, the patient evolved to AML, received induction chemotherapy and bone marrow transplantation, and thereafter died because of an infection complication. The long history of refractory disease and the short course of eltrombopag therapy before disease progression make it difficult to evaluate a possible cause–effect relationship between TPO-RA treatment and leukemic progression.\n\nLymphoproliferative Group\n\nTwo patients had a lymphoproliferative disorder, one chronic lymphocytic leukemia (CLL) and one indolent non-Hodgkin lymphoma (not histologically classified due to the patient’s frailty and comorbidities that contraindicated biopsy).\n\nThe CLL patient had a long history (about 10 years) of indolent untreated disease before the development of thrombocytopenia. He received steroids, rituximab, rituximab-bendamustine, and rituximab-idelalisib all without efficacy. Thereafter, eltrombopag 25 mg daily was started, and platelets rose to 60,000/mcl after 3 months of therapy. At last follow-up, he was still on TPO-RA treatment, in good general conditions, and without need for further CLL therapy.\n\nThe indolent non-Hodgkin lymphoma patient presented to the emergency department with grade 4 thrombocytopenia (platelet count 1,000/ml) associated with bleeding (grade 3 lower gastrointestinal tract hemorrhage). Steroids and IVIG were started without any improvement in terms of transfusion needs. After 2 weeks, she was put on eltrombopag 50 mg daily with a PR allowing hospital discharge. At 3 months from TPO-RA start, the platelet count was 70,000/mcl without any bleeding symptom and no adverse event reported.\n\nTPO-RA Off Label: Available Literature\n\nTable 2 shows the most important trials and reports of TPO-RA use in a number of unlabeled conditions, including myeloid neoplasms (mainly MDS, but also acute myeloid leukemia and chronic myelomonocytic leukemia), postchemotherapy setting of solid tumors, secondary ITP (associated to both lymphoproliferative syndromes and systemic lupus erythematosus, SLE), graft failure after hematopoietic stem cell transplant, thrombocytopenia after heart and lung transplantation, non-HCV-related chronic liver diseases, and inherited thrombocytopenia (10–52). The majority of these studies are small trials, mostly phase I/II, with less than 50 patients enrolled. The heterogeneity of the study designs and endpoints of the trials makes it difficult to compare their results. Anyway, the overall response rates, reported accordingly to the study primary objective, were high and satisfactory (more than 50%) in most cases. Some discrepancies can be appreciated in the results for the myeloid malignancies group, characterized by high heterogeneity in disease type and severity, ranging from low- to high-risk MDS patients and to acute myeloid leukemia; furthermore, medications associated to TPO-RA may also confound the picture. Of note, none of the published or ongoing studies have assessed the use of TPO-RA in the liver or renal post-transplant setting, and none is a real-life study.\n\nTable 2 Published and ongoing studies with TPO-RA used in unlabeled conditions.\n\nTRIAL\tAUTHOR\tSTUDY DESIGN\tDISEASE\tN° OF PTS\tDRUG\tRESULTS1\t\n\tRamadan et al. (10)\tphase I trial\tCMML\t7\tE\tORR 42%\t\n\tGudbrandsdottir et al. (11)\tretrospective\tmiscellaneous\t17\tE/R\tORR 40%\t\nNCT01481220\tSvensson et al. (12)\tphase I trial\thgh-risk MDS\t12\tE + A\tORR 75%\t\nNCT01286038\tDuong et al. (13)\tphase I trial\thigh-risk MDS/AML\t37\tE\tORR 24%\t\nNCT00903422\tPlatzbecker et al. (14)\tphase I/II RCT\thigh-risk MDS/AML\t98\tE\tORR 28%*\t\nNCT01440374\tMittelman et al. (15)\tphase II RCT\thigh-risk MDS/AML\t145\tE\tNA^\t\nNCT01893372\tSwaminathan et al. (16)\tphase II RCT\thgh-risk MDS\t28\tE +/- A\tORR 11%\t\nNCT02158936\tDickinson et al. (17)\tphase III RCT\thigh risk MDS\t356\tA +/- E\tORR 16%*\t\nNCT01890746\tFrey et al. (18)\tphase II RCT\tAML\t148\tE\tORR 70%*\t\nNCT00303472\tKantarjian HM et al. (19)\tphase I/II trial\tlow-risk MDS\t44\tR\tORR 46%\t\nNCT00303472\tSekeres et al. (20)\tphase I/II trial\tlow-risk MDS\t28\tR\tORR 61%\t\n2010-022890-33\tOliva et al. (21)\tphase I/II RCT\tlow-risk MDS\t90\tE\tORR 47%\t\nNCT00321711\tKantarjian et al. (22)\tphase II RCT\tlow-risk MDS\t40\tR + A\tNA^\t\nNCT00418665\tWang et al. (23)\tphase II RCT\tlow-risk MDS\t39\tR + L\tNA^\t\nNCT00321711\tGreenberg PL et al. (24)\tphase II RCT\thgh-risk MDS\t29\tR + D\tNA^\t\nNCT00614523\tKantarjian et al. (25)\tphase II RCT\tlow-risk MDS\t250\tR\tORR 38%\t\nNCT00472290\tFenaux et al. (26)\textension study\tlow-risk MDS\t60\tR\tORR 57%\t\nNCT04324060\tongoing\t\tlow-risk MDS\t\tE/R\t\t\nNCT01772420\tongoing\t\tlow-risk MDS\t\tE + L\t\t\nNCT02912208\tongoing\t\tlow-risk MDS\t\tE\t\t\n\tParameswaran R et al. (27)\tretrospective\tsolid tumor chemotherapy\t20\tR\tsuccess rate 70%\t\n\tGarcía Lagunar et al. (28)\tretrospective\tsolid tumor chemotherapy\t6\tE\tNA^\t\n\tAl-Samkari et al. (29)\tretrospective\tsolid tumor chemotherapy\t153\tR\tsuccess rate 79%\t\nNCT01147809\tWiner et al. (30)\tphase II RCT\tsolid tumor chemotherapy\t26\tE\tsuccess rate 86%\t\nNCT01147809\tWiner et al. (31)\tphase II RCT\tsolid tumor chemotherapy\t75\tE\tNA^\t\nNCT02052882\tSoff et al. (32)\tphase II RCT\tsolid tumor chemotherapy\t60\tR\tsuccess rate 93%\t\nNCT02227576\tLe Rhun et al. (33)\tphase II trial\tsolid tumor chemotherapy\t20\tR\tsuccess rate 60%\t\nNCT04485416\tongoing\tphase I trial\tsolid tumor chemotherapy\t\tE\t\t\nNCT02093325\tongoing\tphase III RCT\tsolid tumor chemotherapy\t\tE\t\t\n\tShobha V et al. (34)\tretrospective\tTP secondary to SLE\t12\tE\tORR 100%\t\n\tMaroun MC et al. (35)\tretrospective\tTP secondary to SLE\t3\tE\tORR 100%\t\n\tGonzález-López et al. (36)\tretrospective\tsecondary ITP\t87\tE\tORR 38%\t\nNCT01168921\tPaul S et al. (37)\tphase II trial\tTP secondary to CLL\t24\tE\tORR 82%\t\nNCT01610180\tVisco et al. (38)\tphase II trial\tTP secondary to LPD\t18\tE\tORR 78%\t\nNCT01610180\tongoing\tphase II trial\tTP secondary to CLL\t\tE\t\t\nNCT01168921\tongoing\tphase II trial\tTP secondary to CLL\t\tE\t\t\nNCT01610180\tongoing\tphase II trial\tTP secondary to LPD\t\tE\t\t\n\tFu et al. (39)\tretrospective\tpoor graft function after HSCT\t38\tE\tORR 63%\t\n\tMarotta et al. (40)\tretrospective\tpoor graft function after HSCT\t13\tE\tORR 53%\t\n\tTang et al. (41)\tretrospective\tpoor graft function after HSCT\t12\tE\tORR 83%\t\n\tTanaka et al. (42)\tretrospective\tpoor graft function after HSCT\t12\tE\tORR 60%\t\n\tSamarkandi et al. (43)\tretrospective\tpoor graft function after HSCT\t21\tE\tORR 75%\t\n\tHartranft et al. (44)\tretrospective\tpoor graft function after HSCT\t13\tR\tORR 53%\t\n\tYuan et al. (45)\tphase II trial\tpoor graft function after HSCT\t13\tE\tORR 62%\t\nNCT01980030\tPeffault de Latour et al. (46)\tphase I/II trial\tpoor graft function after HSCT\t24\tR\tORR 66%\t\nNCT03515447\tVourc’h et al. (47)\tbefore - after study\tTP in heart and lung transplant\t20\tR\tNA^\t\nNCT03437603\tongoing\tphase II trial\tpoor graft function after HSCT\t\tE\t\t\nNCT00861601\tKawaguchi et al. (48)\tphase I/II trial\tTP in iver disease - non HCV\t8\tE\tORR 48%\t\nNCT01133860\tPecci et al. (49)\tphase II trial\tinherited (MYH9)\t12\tE\tORR 91%\t\nNCT00909363\tGerrits et al. (50)\tphase II trial\tinherited (WAS)\t8\tE\tORR 62%\t\nNCT02422394\tOngoing\tphase II trial\tinherited\t\tE\t\t\nNCT04371939\tongoing\tphase II trial\tinherited (WAS)\t\tE\t\t\nNCT03638817\tongoing\tphase II trial\tinherited\t\tE\t\t\nStudies are grouped according to the indication for TPO-RA use. The number of trial as on ClinicalTrial.gov is reported when available. First author name is reported for published studies. RCT, randomized controlled trial; CMML chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; SLE, systemic lupus erythematosus; CLL, chronic lymphocytic leukemia; TP, thrombocytopenia; HSCT, hematopoietic stem cell transplantation; WAS, Wiskott–Aldrich syndrome; E, eltrombopag; R, romiplostim; A, azacytidine; L, lenalidomide; D, decitabine; ORR, overall response rate.\n\n1Response rates are reported according to the primary endpoint of each study and therefore different rates are not comparable between studies. For trials on solid cancer chemotherapy, the term success rate more than ORR is applied, as main objectives were thrombocytopenia prevention and ability not to delay chemotherapy cycles.\n\n*Experimental arm did not show better outcomes compared to placebo arm.\n\n^Not applicable, due to different aims and outcome measures; among outcome measures: higher PLT counts/nadir, lower PLT transfusion rates, lower clinically relevant thrombocytopenic event (CRTE).\n\nThe most explored field of investigation for these drugs remains myelodysplastic syndromes, especially in the low-risk setting, where thrombocytopenia is common and can impact the quality of life of patients with a good prognosis. Eight trials have already been completed (19–26) and three are ongoing, including a phase II/III trial, with a cumulative ORR of 45%. Despite some older reports pointing out an increased leukemogenesis risk (53), a recent phase II trial (15) did not confirm these data and showed a reduction in the need of platelet transfusion support and bleeding episodes also in patients with high-risk MDS or AML treated with eltrombopag. Similarly, a phase I/II study (26) found romiplostim to be safe in low-risk MDS patients with a good response rate in terms of platelet count. The biggest study available in MDS is a phase III randomized controlled trial (RCT) (17) conducted in high-risk MDS patients with eltrombopag coupled to azacytidine. This trial failed to show any benefit of eltrombopag and was terminated prematurely.\n\nRegarding chemotherapy-associated thrombocytopenia in solid tumors (27–33), TPO-RA reduced thrombocytopenic adverse events thus decreasing the delay between cycles and the need for chemotherapy dose reduction. A phase III RCT is currently ongoing on the use of eltrombopag for chemotherapy-induced thrombocytopenia in any solid tumor in Taiwan.\n\nITP secondary to SLE may not respond to disease-specific treatments (steroids, immunosuppressors, and biologics) and further impair patients’ quality of life. TPO-RA showed 100% response rates in a total of 15 SLE patients treated in two retrospective studies (34, 35).\n\nITP secondary to autoimmune and lymphoproliferative diseases (34–38) remains an understudied setting, with the majority of studies being retrospective and including a low number of patients, although with remarkable efficacy. Overall, 144 patients have been reported and the cumulative ORR was 57%. Indeed, thrombocytopenia refractory to first line steroids should be managed with lymphoma-specific treatment (e.g., chemo-immunotherapy in CLL) according to current guidelines.\n\nReports for the use of TPO-RA in inherited thrombocytopenia, such as MYH9-related disorders or Wiskott–Aldrich syndrome (49, 50), showed benefit on transfusion needs and hemostasis in a total of 80% of patients. There is also one report indicating benefit from TPO-RA in von Willebrand disease type 2B refractory to more conventional lines of therapy in emergency conditions (54).\n\nLastly, a promising field of interest, with an increasing number of reports in the last years, is the post- HSCT setting. TPO-RA could be of great benefit in prolonged cytopenia secondary to poor graft function that remains nowadays still difficult to manage and accounts for a significant proportion of nonrelapse mortality after transplant. Many recent retrospective series have reported encouraging results (39–46, 51, 52), with the biggest experience of the Spanish Group who reported an ORR of 72% in a cohort of 89 patients (51). Importantly, promising data exist in post-HSCT pediatric cohorts too (52).\n\nDiscussion\n\nIn this study, we report the safety and efficacy of TPO-RA use outside approved indications in real-life cohort from a single referral center. These clinical settings represent the real life encountered by hematologists handling thrombocytopenia. We found that TPO-RAs are effective and manageable even in off-label settings, despite possible detrimental cofactors linked to underlying conditions such as cancer and transplant. Indeed, all the transplanted patients and those with lymphoproliferative syndromes responded after about 3 months of TPO-RA therapy, and among myelodysplastic patients, six out of eight achieved at least a PR.\n\nOnly 1 transplanted patient out of 14 treated with eltrombopag experienced a grade 1 hepatic toxicity, with complete recovery after drug discontinuation. No other TPO-RA-related adverse events were observed during the study.\n\nOf note, one transplanted and one myelodysplastic patient maintained a stable response, partial and complete, respectively, after 189 and 279 days from TPO-RA discontinuation, showing that the achievement of a treatment-free remission is possible even in conditions other than ITP.\n\nThe favorable efficacy and safety profile emerging from our cohort is similar to that reported in the increasing number of studies addressing the use of TPO-RA in myeloid neoplasms (mainly MDS, but also acute myeloid leukemia and chronic myelomonocytic leukemia), in the postchemotherapy setting of solid tumors, in secondary ITP (associated to both lymphoproliferative syndromes or systemic lupus erythematosus), in graft failure after HSCT, in thrombocytopenia after heart and lung transplantation, in chronic liver diseases, and in inherited thrombocytopenia (Table 2). Thrombocytopenic low-risk MDS was the main clinical condition in which we used off-label eltrombopag. Compared to the biggest phase II trial of eltrombopag in low-risk MDS patients [EQol-MDS study (21)], we experienced a higher ORR (75% vs 47%) possibly due to the lower representation of intermediate-1 risk MDS in our cohort (25% vs 71%). Interestingly, the only two intermediate-1 risk patients were the ones who did not respond to eltrombopag.\n\nAn interesting point is that the employed doses of TPO-RA are extremely heterogeneous, reflecting the uncertainties in off-label conditions. Similarly, in this study, a wide range of doses of eltrombopag has been used, from 25 to 150 mg daily. However, both the lowest (25 mg) and the highest (150 mg) doses were associated with at least a PR, and the two CR occurred on eltrombopag at low dose (50 mg in both cases). This likely reflects the use of the off-label drug at the “minimal effective dose,” with the aim to limit toxicities, as currently suggested in ITP (55). On average, higher doses were requested in MDS-associated thrombocytopenia compared to transplant- and lymphoproliferative-associated thrombocytopenia, where the ITP dose (i.e., 50–75 mg daily) seems to be sufficient. This can be explained by the different pathogenesis of thrombocytopenia in these settings. In particular, post-transplant thrombocytopenia is the one that mostly resembles ITP, since the post-transplant period is characterized by a cytokine storm that may be responsible for the onset of cytopenia and may require several lines of immunosuppressive therapies other than steroids and IVIG (56). In contrast, thrombocytopenia associated with conditions that are characterized by a derangement of the myeloid stem cell, such as myelodysplasia, requires higher doses of TPO-RA to achieve a response. Indeed, TPO-RAs exert their stimulating/differentiating effect also on early hematopoietic stem cells (57); if the latter are dysplastic, the stimulus carried out by standard doses of TPO-RA may not be sufficient (58). As a matter of fact, doses as high as 300 mg daily have been used in RCT (15, 21). Clarifying the best TPO-RA schedule in MDS will be of great value, since 50% of these patients suffer from thrombocytopenia (59), which may be worsened by MDS therapy, and is mainly managed with transfusions and steroids.\n\nThe importance of bone marrow reserve is an issue also in lymphoproliferative diseases, where the use of TPO-RA induces an overall response of about 40–50% (58), which increases to 70–80% (the same of primary ITP), if considering only true immune-mediated thrombocytopenia.\n\nThrombotic events, although infrequent, have been reported in ITP patients treated with TPO-RA with an incidence rate ranging from 1.4 to 4.3 per 100 patient-years (1); if we consider the conditions other than ITP, the majority of studies reported an incidence of venous thromboembolism lower than 2% (range 0–1.6%), while higher rates (≥2%) were reported in MDS/AML and postchemotherapy ITP (conditions per se associated with increased thrombotic risk), possibly related to the higher doses of TPO-RA used. Consistently, despite the heterogeneity of available trials, a trend toward increased thrombosis frequency is noted with higher TPO-RA doses; and almost all studies using eltrombopag > 200 mg reported at least one thrombotic event. In our study, no patients developed a thrombotic event, neither venous nor arteriosus. Even if the small number of patients does not allow taking definitive conclusions, the long follow-up and the supramaximal doses of TPO-RA employed in some patients suggest that the risk of thrombosis is not significantly increased.\n\nFinally, some concerns about the potential clonal evolution induced by a sustained stem-cell stimulation under TPO-RA have been raised, particularly in aplastic anemia and MDS. However, in the prospective randomized EQoL-MDS study, leukemic evolution was comparable among the two arms (12% in eltrombopag versus 16% in the placebo arm), even if the long-term assessment is still ongoing (21). In our study, only one patient with a long history of heavily pretreated MDS presented a rapid evolution to acute leukemia (3 months after start of eltrombopag), making it difficult to evaluate a possible cause–effect relationship between TPO-RA treatment and leukemic progression. All the other patients were on long-term TPO-RA (range 216–1,486 days) without signs of evolution.\n\nConclusions\n\nOur real-life report of TPO-RA off-label use, even though on a small number of patients, highlights their efficacy and safety in difficult-to-manage thrombocytopenia forms, including post-transplant ITP and cases secondary to MDS and lymphoproliferative syndromes. Despite the awareness on thrombotic risk and on the possible clonal evolution should remain high, TPO-RA use in these conditions may have a significant impact on clinical management.\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 Comitato Etico Milano Area 2. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nMC and FS equally contributed to the manuscript. MC and BF designed the study. FS, JG, LP, and GR assessed the patients for eligibility, collected data, and critically revised the manuscript. MC, FS, BF, IM, AA, and WB contributed to developing the manuscript, and drafting and revising the text, tables, and figure. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by the Italian Ministry of Health—Bando Ricerca Corrente.\n\nConflict of Interest\n\nMC reports nonfinancial support from Roche, Novonordisk, and Sobi and honoraria from Daiichi Sankyo. AA reports nonfinancial support from Bayer and Roche and honoraria from Janssen outside of the submitted work. IM reports personal and nonfinancial support from Bayer and Roche outside of the submitted work. WB received consultation honoraria from Novartis, Apellis, Alexion, Agios, and Sanofi. BF received consultation honoraria from Amgen, Novartis, and Momenta.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\n1 Ghanima W Cooper N Rodeghiero F Godeau B Bussel JB . Thrombopoietin Receptor Agonists: Ten Years Later. Haematologica (2019) 104 (6 ):1112–23. doi: 10.3324/haematol.2018.212845\n2 Birocchi S Podda GM Manzoni M Casazza G Cattaneo M . 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Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia. J Clin Oncol (2019) 37 (31 ):2892–8. doi: 10.1200/JCO.18.01931\n33 Le Rhun E Devos P Houillier C Cartalat S Chinot O Di Stefano AL . Romiplostim for Temozolomide-Induced Thrombocytopenia in Glioblastoma: The PLATUM Trial. Neurology (2019) 93 (19 ):e1799–806. doi: 10.1212/WNL.0000000000008440\n34 Shobha V Sanil S Roongta R . Eltrombopag: Efficacy and Safety in Steroid Refractory Lupus-Associated Immune Thrombocytopenia. J Clin Rheumatol (2020) 26 (7 ):274–8. doi: 10.1097/RHU.0000000000001083\n35 Maroun MC Ososki R Andersen JC Dhar JP . Eltrombopag as Steroid Sparing Therapy for Immune Thrombocytopenic Purpura in Systemic Lupus Erythematosus. Lupus (2015) 24 (7 ):746–50. doi: 10.1177/0961203314559632\n36 González-López TJ Alvarez-Román MT Pascual C Sánchez-González B Fernández-Fuentes F Pérez-Rus G . Use of Eltrombopag for Secondary Immune Thrombocytopenia in Clinical Practice. Br J Haematol (2017) 178 (6 ):959–70. doi: 10.1111/bjh.14788\n37 Paul S Jain N Ferrajoli A O'Brien S Burger J Keating M . A Phase II Trial of Eltrombopag for Patients With Chronic Lymphocytic Leukaemia (CLL) and Thrombocytopenia. Br J Haematol (2019) 185 (3 ):606–8. doi: 10.1111/bjh.15581\n38 Visco C Rodeghiero F Romano A Valeri F Merli M Quaresimini G . Eltrombopag for Immune Thrombocytopenia Secondary to Chronic Lymphoproliferative Disorders: A Phase 2 Multicenter Study. Blood (2019) 134 (20 ):1708–11. doi: 10.1182/blood.2019001617\n39 Fu H Zhang X Han T Mo X Wang Y Chen H . Eltrombopag Is an Effective and Safe Therapy for Refractory Thrombocytopenia After Haploidentical Hematopoietic Stem Cell Transplantation. Bone Marrow Transpl (2019) 54 (8 ):1310–8. doi: 10.1038/s41409-019-0435-2\n40 Marotta S Marano L Ricci P Cacace F Frieri C Simeone L . Eltrombopag for Post-Transplant Cytopenias Due to Poor Graft Function. Bone Marrow Transpl (2019) 54 (8 ):1346–53. doi: 10.1038/s41409-019-0442-3\n41 Tang C Chen F Kong D Ma Q Dai H Yin J . Successful Treatment of Secondary Poor Graft Function Post Allogeneic Hematopoietic Stem Cell Transplantation With Eltrombopag. J Hematol Oncol (2018) 11 (1 ):103. doi: 10.1186/s13045-018-0649-6 30115080\n42 Tanaka T Inamoto Y Yamashita T Fuji S Okinaka K Kurosawa S . Eltrombopag for Treatment of Thrombocytopenia After Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transpl (2016) 22 (5 ):919–24. doi: 10.1016/j.bbmt.2016.01.018\n43 Samarkandi H Al Nahedh M Alfattani A Alsharif F Bakshi N Rasheed W . Evaluation of Eltrombopag in Thrombocytopenia Post Hematopoietic Cell Transplantation: Rertrospective Observational Trial. Hematol Oncol Stem Cell Ther (2020) S1658-3876 (20 ). doi: 10.1016/j.hemonc.2020.07.006\n44 Hartranft ME Clemmons AB DeRemer DL Kota V . Evaluation of Romiplostim for the Treatment of Secondary Failure of Platelet Recovery Among Allogeneic Hematopoietic Stem Cell Transplant Patients. J Oncol Pharm Pract (2017) 23 (1 ):10–7. doi: 10.1177/1078155215612240\n45 Yuan C Boyd AM Nelson J Patel RD Varela JC Goldstein SC . Eltrombopag for Treating Thrombocytopenia After Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transpl (2019) 25 (7 ):1320–4. doi: 10.1016/j.bbmt.2019.01.027\n46 Peffault de Latour R Chevret S Ruggeri AL Suarez F Souchet L Michonneau D . Romiplostim in Patients Undergoing Hematopoietic Stem Cell Transplantation: Results of a Phase 1/2 Multicenter Trial. Blood (2020) 135 (3 ):227–9. doi: 10.1182/blood.2019000358\n47 Vourc'h M Senage T Lepoivre T Volteau C Fortuit C Pattier S . Romiplostim as a Transfusion Saving Strategy in 20 Patients After Heart or Lung Transplantation: A Single Centre Before-After Pilot Study. Perfusion (2020) 35 (2 ):121–30. doi: 10.1177/0267659119864814\n48 Kawaguchi T Komori A Seike M Fujiyama S Watanabe H Tanaka M . Efficacy and Safety of Eltrombopag in Japanese Patients With Chronic Liver Disease and Thrombocytopenia: A Randomized, Open-Label, Phase II Study. J Gastroenterol (2012) 47 (12 ):1342–51. doi: 10.1007/s00535-012-0600-5\n49 Pecci A Gresele P Klersy C Savoia A Noris P Fierro T . Eltrombopag for the Treatment of the Inherited Thrombocytopenia Deriving From MYH9 Mutations. Blood (2010) 116 (26 ):5832–7. doi: 10.1182/blood-2010-08-304725\n50 Gerrits AJ Leven EA Frelinger AL 3rd Brigstocke SL Berny-Lang MA Mitchell WB . Effects of Eltrombopag on Platelet Count and Platelet Activation in Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia. Blood (2015) 126 (11 ):1367–78. doi: 10.1182/blood-2014-09-602573\n51 Bento L Bastida JM García-Cadenas I García-Torres E Rivera D Bosch-Vilaseca A . Thrombopoietin Receptor Agonists for Severe Thrombocytopenia After Allogeneic Stem Cell Transplantation: Experience of the Spanish Group of Hematopoietic Stem Cell Transplant. Biol Blood Marrow Transpl (2019) 25 (9 ):1825–31. doi: 10.1016/j.bbmt.2019.05.023\n52 Masetti R Vendemini F Quarello P Girardi K Prete A Fagioli F . Eltrombopag for Thrombocytopenia Following Allogeneic Hematopoietic Stem Cell Transplantation in Children. Pediatr Blood Cancer (2020) 67 (5 ):e28208. doi: 10.1002/pbc.28208 32065469\n53 Ogata K Tamura H . Thrombopoietin and Myelodysplastic Syndromes. Int J Hematol (2000) 72 (2 ):173–7.\n54 Espitia O Ternisien C Agard C Boisseau P Denis CV Fouassier M . Use of a Thrombopoietin Receptor Agonist in Von Willebrand Disease Type 2B (P.V1316M) With Severe Thrombocytopenia and Intracranial Hemorrhage. Platelets (2017) 28 (5 ):518–20. doi: 10.1080/09537104.2016.1246717\n55 Zaja F Carpenedo M Baratè C Borchiellini A Chiurazzi F Finazzi G . Tapering and Discontinuation of Thrombopoietin Receptor Agonists in Immune Thrombocytopenia: Real-World Recommendations. Blood Rev (2020) 41 :100647. doi: 10.1016/j.blre.2019.100647 31818701\n56 Pulanic D Lozier JN Pavletic SZ . Thrombocytopenia and Hemostatic Disorders in Chronic Graft Versus Host Disease. Bone Marrow Transpl (2009) 44 (7 ):393–403. doi: 10.1038/bmt.2009.196\n57 Imbach P Crowther M . Thrombopoietin-Receptor Agonists for Primary Immune Thrombocytopenia. N Engl J Med (2011) 365 (8 ):734–41. doi: 10.1056/NEJMct1014202\n58 Fattizzo B Levati G Cassin R Barcellini W . Eltrombopag in Immune Thrombocytopenia, Aplastic Anemia, and Myelodysplastic Syndrome: From Megakaryopoiesis to Immunomodulation. Drugs (2019) 79 (12 ):1305–19. doi: 10.1007/s40265-019-01159-0\n59 Alessandrino EP Amadori S Barosi G Cazzola M Grossi A Liberato LN . Evidence- and Consensus-Based Practice Guidelines for the Therapy of Primary Myelodysplastic Syndromes. A Statement From the Italian Society of Hematology. Haematologica (2002) 87 (12 ):1286–306.\n\n",
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"title": "Off-Label Use of Thrombopoietin Receptor Agonists: Case Series and Review of the Literature.",
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"abstract": "An 87-year-old woman with a long-standing history of hypertension, hypothyroidism and diabetes presented to us with scaly and pruritic vesicles of an erythematous base and crusted surface of 2-month duration. They first appeared on her abdomen and gradually spread to her lower back, thighs, before spreading to her upper and lower limbs. Her lesions were non-painful, aggravated by sun exposure only, and sparing mucous membranes. Nikolsky sign was positive with no discernible fluid-filled bullae. History was remarkable only for a doubling of her Lisinopril dosage 2 months prior to the appearance of her lesions, with no other potential environmental and/or drug triggers recognizable on history taking. In light of the appearance of her lesions after her Lisinopril dose escalation, in the absence of any other discernible triggers, an adverse drug reaction (ADR) was entertained, yielding a corresponding Naranjo ADR probability score of 7. Particularly, drug-induced pemphigus foliaceus was initially suspected given her clinical presentation and the morphology and distribution of her lesions. However, her skin biopsy altered our diagnosis to drug-induced bullous pemphigoid (BP) instead, making this the second case reported to date on Lisinopril-induced BP, and the first to report a dose-response variant of this adverse reaction.",
"affiliations": "Faculty of Medicine, American University of Beirut, Beirut, Lebanon.;Department of Family Medicine, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Family Medicine, American University of Beirut Medical Center, Beirut, Lebanon.",
"authors": "Ballout|Rami A|RA|0000-0002-7543-0895;Musharrafieh|Umayya|U|;Khattar|Joe|J|",
"chemical_list": "D000959:Antihypertensive Agents; D017706:Lisinopril",
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"keywords": "angiotensin II receptor; angiotensin-converting enzyme (ACE); autoimmune; blisters; drug-induced; pharmacovigilance",
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"mesh_terms": "D000369:Aged, 80 and over; D000959:Antihypertensive Agents; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D006973:Hypertension; D017706:Lisinopril; D010391:Pemphigoid, Bullous",
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"title": "Lisinopril-associated bullous pemphigoid in an elderly woman: a case report of a rare adverse drug reaction.",
"title_normalized": "lisinopril associated bullous pemphigoid in an elderly woman a case report of a rare adverse drug reaction"
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"abstract": "A 29-year-old female was referred to the urology clinic because of an incidentally found left renal mass discovered during workup for secondary erythrocytosis. Since 12 years of age, she has had headaches and poorly controlled hypertension refractory to trimodal antihypertensive therapy. Laboratory workup revealed markedly elevated aldosterone and renin levels. Computed tomography demonstrated a 3 cm left renal mass. The patient was admitted for intravenous blood pressure control. After partial nephrectomy, aldosterone and renin levels normalized. The patient was weaned off of blood pressure medications. Pathology was consistent with a juxtaglomerular cell tumor secreting renin (ie, reninoma).",
"affiliations": "Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA. Electronic address: Nima.Nassiri@med.usc.edu.;Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA.;Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA.;Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA.",
"authors": "Nassiri|Nima|N|;Maas|Marissa|M|;Fichtenbaum|Eric J|EJ|;Aron|Monish|M|",
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"mesh_terms": "D000328:Adult; D000450:Aldosterone; D000959:Antihypertensive Agents; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension; D007606:Juxtaglomerular Apparatus; D007680:Kidney Neoplasms; D009392:Nephrectomy; D012083:Renin; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"title": "A Young Female With Refractory Hypertension.",
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{
"abstract": "Angioimmunoblastic T cell lymphoma (AITL) is a rare but distinct type of T cell lymphoma with an aggressive course and high mortality. Most patients are diagnosed late in the disease and usually present with generalized lymphadenopathy. A minority have skin lesions at the time of diagnosis, more commonly in the form of nonspecific maculopapular rash with or without pruritus. We report a rare case of AITL presenting with chronic, recurrent angioedema and urticaria-like lesions and no palpable peripheral adenopathy. Primary Care physicians, dermatologists, and allergists must maintain a high index of suspicion for cutaneous manifestations of lymphoma, especially if the skin lesions are refractory to standard treatment. Timely diagnosis is essential to improve survival.",
"affiliations": "Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.;Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.;Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.;Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.",
"authors": "Kang|Mohleen|M|;Bhatia|Nitasha|N|0000-0003-0484-8159;Sauder|Adrienne|A|0000-0003-2254-4706;Feurdean|Mirela|M|",
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"doi": "10.1155/2016/8753235",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2016/8753235Case ReportAngioimmunoblastic T Cell Lymphoma Mimicking Chronic Urticaria Kang Mohleen \n1\n\n*\nhttp://orcid.org/0000-0003-0484-8159Bhatia Nitasha \n1\nhttp://orcid.org/0000-0003-2254-4706Sauder Adrienne \n2\nFeurdean Mirela \n1\n1Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA2Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA*Mohleen Kang: mohleenk@gmail.comAcademic Editor: Bettina Wedi\n\n2016 26 1 2016 2016 875323511 10 2015 17 12 2015 29 12 2015 Copyright © 2016 Mohleen Kang et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Angioimmunoblastic T cell lymphoma (AITL) is a rare but distinct type of T cell lymphoma with an aggressive course and high mortality. Most patients are diagnosed late in the disease and usually present with generalized lymphadenopathy. A minority have skin lesions at the time of diagnosis, more commonly in the form of nonspecific maculopapular rash with or without pruritus. We report a rare case of AITL presenting with chronic, recurrent angioedema and urticaria-like lesions and no palpable peripheral adenopathy. Primary Care physicians, dermatologists, and allergists must maintain a high index of suspicion for cutaneous manifestations of lymphoma, especially if the skin lesions are refractory to standard treatment. Timely diagnosis is essential to improve survival.\n==== Body\n1. Introduction\nPeripheral T cell lymphomas (PTCL) represent less than 15–20% of all non-Hodgkin's lymphomas in adults. Angioimmunoblastic T cell lymphoma (AITL) is a rare but distinct type of T cell lymphoma with an aggressive course and high mortality. It accounts for approximately 1% to 2% of non-Hodgkin's lymphoma and 15% to 20% of PTCL [1]. Most patients (89%) are diagnosed late in the disease and usually present with generalized lymphadenopathy (76%) [1]. A minority (21%) have skin lesions at the time of diagnosis, more commonly in the form of nonspecific exanthema mimicking a viral rash or a drug eruption [2]. While autoimmune paraneoplastic manifestations are common in AITL and can precede the diagnosis by many years, the association between angioedema, chronic urticaria, and T cell lymphoma is very rare [2, 3]. The index of suspicion for cutaneous manifestations of lymphoma must be high, especially if the skin lesions are refractory to standard treatment. Timely diagnosis is essential to improve survival.\n\n2. Presentation\nA 56-year-old Hispanic male with hypertension and two-year history of chronic idiopathic urticaria with recurrent episodes each lasting about a week presented to the emergency department (ED) with facial edema, rash, pruritus, and difficulty breathing. The patient stated that he woke up from sleep feeling his “throat was closing” and with hoarse voice. He reported an erythematous, pruritic rash over his back, chest, and abdomen that had been present for the past month. Prior to arriving at the emergency room, the patient used an epinephrine pen but noted no improvement in symptoms.\n\nThe patient was not on any antihypertensive medications and denied family history of angioedema or urticaria.\n\nHe had been diagnosed and suffering from “recurrent idiopathic angioedema and urticaria” for the past 2 years. The first episode involved right ankle edema, which progressed over the course of three weeks to the entire right body and face. The patient was admitted and treated with intravenous steroids and discharged on oral prednisone. Extensive work-up failed to find a trigger, and amlodipine was discontinued “as a precaution.” Over the next 2 years he developed multiple episodes of angioedema associated with urticaria-like lesions (erythematous, pruritic rash) lasting at least one week and sometimes longer, which resolved with steroids and antihistamines. Work-up at the time revealed monoclonal gammopathy of undetermined significance (MGUS) and normal bone marrow biopsy, skin biopsy, and flow cytometry. CT abdomen and pelvis revealed bilateral shotty inguinal lymphadenopathy, which on biopsy was noted to be reactive. He had a negative gallium scan, normal C3 and C4 levels, negative ANA, and normal CRP but elevated ESR.\n\nAbout 6 months before this admission he was seen by a rheumatologist for complaints of nonspecific polyarthralgia and pruritic rash and was treated with a course of methotrexate and prednisone for presumptive seronegative rheumatoid arthritis. Work-up done at the time was notable for normal complement levels (C3, C4, and CH50), negative Hepatitis B, Hepatitis C, and HIV serologies, negative myeloperoxidase antibodies, proteinase 3 antibodies, C- or P- antineutrophil cytoplasmic antibodies, negative HLA B27 antigen, and negative rheumatoid factor, anti-citrullinated protein antibodies, and anti-SSA and anti-SSB antibodies. A skin biopsy of the rash was suggested given the “atypical appearance” but the patient did not follow up. Later, an outside allergist diagnosed him with chronic idiopathic urticaria and placed him on chronic steroid therapy.\n\nFor the month prior to admission, the patient reported increase in frequency and severity of episodes of angioedema requiring three hospital admissions; each episode lasted about a week. Contrary to the past, these episodes had minimal response to intravenous steroids. He also noted that the urticaria-like lesions had been persistent over the last month and had not improved or resolved with treatment.\n\nPhysical examination revealed periorbital, upper lip edema without tongue involvement (Figure 1). Diffuse, elevated, blanching, red-violaceous confluent lesions were noted over the face, neck, and anterior and posterior chest, with a few scattered lesions on the torso and legs (Figure 2). There was no appreciable peripheral adenopathy. A bedside laryngoscopy revealed nonobstructive posterior pharyngeal edema.\n\nWork-up done during this admission revealed the following: normal CBC, normal ANA and RF, normal complement levels (C3, C4, and CH50), normal C1Q complement qualitative and quantitative level, normal C1 esterase inhibitor level and function, normal IgE level and normal serum specific IgE for aeroallergens and for latex, negative RAST (Northeast Panel) test, negative Mycoplasma IgM antibodies, and negative anti-thyroperoxidase antibodies. Serum protein electrophoresis revealed mild hypergammaglobulinemia and monoclonal gammopathy, with normal levels of free kappa and lambda chains in the serum. Hepatitis B, Hepatitis C, HIV, and HTLV I/II serologies were negative. Quantiferon gold was indeterminate.\n\nLDH was elevated, but AST/ALT were normal. Beta-2 microglobulin was elevated at 6.5 (normal <2.4) as was the chronic urticaria index (28.2, with normal <10). Serum tryptase level was normal (<1 ng/mL). The chest X-ray on admission was normal.\n\nThe patient was admitted with a presumptive diagnosis of refractory idiopathic angioedema and chronic urticaria and was treated with intravenous corticosteroids, H1 + H2 antihistamines, and mycophenolate mofetil, but the angioedema continued to worsen. Given the severity of the symptoms and lack of improvement, he was given a trial of two doses of Icatibant without any response. A CT Scan of the neck, chest, and abdomen obtained nine days after admission revealed diffuse lymphadenopathy (cervical, mediastinal, retroperitoneal, and pelvic) and no hepatosplenomegaly. A biopsy of the skin lesions on the posterior chest and an excisional cervical lymph node biopsy revealed angioimmunoblastic T cell lymphoma (AITL) with cutaneous involvement (Figures 3 and 4). Later, the patient went into respiratory failure. Given his deteriorating clinical status at the time of diagnosis, he was not a candidate for chemotherapy. Sadly, he died within a week from sepsis and multiorgan failure.\n\n3. Discussion\nAngioimmunoblastic T cell lymphoma is a rare but distinct type of T cell lymphomas with aggressive course and high mortality. It accounts for approximately 1% to 2% of non-Hodgkin's lymphoma, with an annual incidence of 0.05 new cases per 100,000 people in US. Most patients are diagnosed late in the disease (89%) and usually present with generalized lymphadenopathy, hepatosplenomegaly, and constitutional symptoms of fever and weight loss. Involvement of more than one extranodal site and elevation of beta-2 microglobulin portend poor prognosis [2, 4, 5].\n\nAlthough pathogenesis of AITL remains unknown, it has been associated with a number of infectious diseases including tuberculosis, Cryptococcus neoformans, and lymphotropic viruses such as EBV, HHV 6, HHV 8, HIV, and Hepatitis C [3]. The best evidence to date supports EBV infection in the pathogenesis of AITL, as EBV infected cells have been found in up to 95% of AITL cases [3, 6, 7]. In our patient EBV in situ hybridization was positive. The pathogenetic mechanism remains hypothetical and includes virus induced immunosuppression and deregulated cellular signaling [3].\n\nAutoimmune phenomena described in association with AITL include the presence of circulating immune complexes, cold agglutinins, autoimmune hemolytic anemia, positive anti-smooth-muscle antibodies and rheumatoid factor, and autoimmune thyroid disease [3]. There is no clear pathogenetic model that links malignant lymphoid transformation with the development of autoimmunity; loss of adaptive immunity through malignant transformation of B and T cells has been proposed [8]. Hypergammaglobulinemia is present in 30–50% of patients and is typically polyclonal; however, up to 10% of patients may present with monoclonal gammopathy [1]. Seropositive rheumatoid arthritis has been described as well [3]. In hindsight, our patient's polyarticular pains and the persistent MGUS were likely paraneoplastic manifestations of AITL, which preceded by months to years the histopathologic diagnosis.\n\nAITL is associated with frequent extranodal and paraneoplastic manifestations (27%). Cutaneous manifestations of AITL are rare and usually present as nonspecific maculopapular rash which resembles a viral exanthema, or a drug reaction [1, 2]. Pruritus can be a prominent symptom, as it was in our patient. Angioedema as the initial presenting symptom of AITL is exceedingly rare but has been reported before [9, 10]. The association of angioedema and chronic urticaria with AITL is even more unusual.\n\nIn our patient, the complement levels were normal, as were C1 esterase level and functional assays that are often abnormal in hereditary angioedema types I and II and in acquired angioedema; hence these diagnoses were virtually excluded [11, 12].\n\nChronic urticaria is usually classified as either inducible or spontaneous. Chronic spontaneous urticaria is defined as urticaria without any identifiable cause, lasting more than 6 weeks, with or without angioedema. H1 antihistamines are the main stay of treatment. Wheals are usually pruritic and fleeting and resolve within 24 hours, while angioedema can persist up to 72 hours [13]. Our patient's rash was pruritic but it did not resolve within 24 hours and was refractory to treatment with antihistamines, which prompted the rheumatologist to suggest a biopsy months before the admission which led to the final diagnosis (see Table 1).\n\nThe Chronic Urticaria (CU) Index is an in vitro assay that measures the histamine levels after a patient's serum is mixed with donor basophils. An elevated CU Index (greater than or equal to 10) indicates either an autoimmune cause for urticaria or the presence of an alternate histamine releasing factor [14, 15]. While the CU index was elevated in our patient, it may have been so due to histamine releasing factors secreted locally by tumor cells and not necessarily due to autoimmune causes such as antibodies against IgE, FcεRI, or anti-FcεRII.\n\nGiven the lack of response to antihistamines, steroids, mycophenolate (suppressor of T-lymphocytic and primary antibody responses to antigens), Icatibant (selective, bradykinin B2 receptor antagonist), and fresh frozen plasma (replacement of defective C1 esterase inhibitor), it is likely that the acquired angioedema and urticaria-like lesions occurred without mastocyte degranulation and systemic histamine release, activation of the complement cascade, or excessive endogenous bradykinin production, suggesting local release of vasoactive molecules by the T cells infiltrating the skin.\n\nMoreover, presence of lymphadenopathy in the setting of complement and/or bradykinin mediated angioedema is unusual and should prompt further work up to rule out malignancy. It is unclear whether our patient underwent an excisional biopsy in Puerto Rico the year before and if flow cytometry was performed on the sample; fine needle or core needle biopsies without flow cytometry make diagnosis of lymphomas difficult [16].\n\nIn conclusion, recurrent episodes of angioedema lasting for more than 3–5 days in the setting of an atypical urticaria which does not resolve with treatment within 24 hours should prompt further investigation. Presence of lymphadenopathy in the setting of angioedema is often a hallmark of underlying malignancy and should be investigated with a thorough workup until it is ruled out.\n\nAcknowledgment\nThe authors are grateful to Dr. Eugenio Capitle, M.D., for his assistance and guidance in diagnosing and managing this patient.\n\nDisclosure\nAn earlier version of this paper was presented as a poster at Society of General Internal Medicine Mid Atlantic Conference held in Hershey, PA, in March 2015.\n\nConflict of Interests\nThe authors wish to confirm that there is no known conflict of interests associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.\n\nAuthors' Contribution\nAll authors listed have contributed sufficiently to the project to be included as authors and all those who are qualified to be authors are listed in the author byline.\n\nFigure 1 Picture of the patient taken on day of admission showing upper lip edema and diffuse, elevated, blanching, red-violaceous confluent lesions over the face, neck, and anterior chest.\n\nFigure 2 Picture of the patient taken on the day of admission showing again the diffuse elevated blanching red-violaceous confluent lesions over the back.\n\nFigure 3 H&E section of skin biopsy showing a dense lymphohistiocytic dermal infiltrate composed predominantly of atypical lymphoid cells ranging in cell size (20x).\n\nFigure 4 Composite: (a) H&E section of lymph node biopsy with an atypical infiltrate that is polymorphic with scattered large cells and prominent vascularity (40x). (b) Atypical lymph node cells showing immunoreactivity to CD3 (20x). (c) Atypical lymph node cells showing weak immunoreactivity to CD4 (20x). (d) Atypical lymph node cells showing partial immunoreactivity to CD10 (20x). (e) Atypical lymph node cells showing immunoreactivity to BCL-6 (20x). (f) Atypical lymph node cells showing immunoreactivity to CD5 (20x). (g) CD21 stain highlighting the follicular dendritic cells in a pattern consistent with angioimmunoblastic T cell lymphoma (20x). (h) Atypical lymph nodes cells showing immunoreactivity to perforin (20x).\n\nTable 1 Typical features of chronic spontaneous urticaria versus features in our patient.\n\nFeatures\tChronic spontaneous urticaria\tOur patient\t\nClinical appearance\tSudden onset of wheals, angioedema, or both\tSudden onset of angioedema and wheals\t\n\n\n\t\nDuration of symptoms\tRecurrent episodes for >6 weeks\tRecurrent episodes for almost 2 years\t\nWheals resolve within 24 hours Angioedema resolves within 72 hours\tEpisodes of angioedema and wheals lasting more than one week\t\n\n\n\t\nTriggers\tNot identifiable \tNot identifiable \t\n\n\n\t\nPresence of lymphadenopathy\tNo\tYes\t\n\n\n\t\nResponse to treatment\tMost cases respond to H1 antihistamines\tInitially responded to H1 antihistamines and steroids, in time became refractory to therapy\n==== Refs\n1 Federico M. Rudiger T. Bellei M. Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project Journal of Clinical Oncology 2013 31 2 240 246 10.1200/jco.2011.37.3647 2-s2.0-84872456641 22869878 \n2 Ferran M. Gallardo F. Baena V. Ferrer A. Florensa L. Pujol R. M. The ‘deck chair sign’ in specific cutaneous involvement by angioimmunoblastic T cell lymphoma Dermatology 2006 213 1 50 52 10.1159/000092841 2-s2.0-33745204254 16778430 \n3 Dogan A. Attygalle A. D. Kyriakou C. Angioimmunoblastic T-cell lymphoma British Journal of Haematology 2003 121 5 681 691 10.1046/j.1365-2141.2003.04335.x 2-s2.0-0037495172 12780782 \n4 Yoo C. Yoon D. H. Suh C. Serum beta-2 microglobulin in malignant lymphomas: an old but powerful prognostic factor Blood Research 2014 49 3 148 153 10.5045/br.2014.49.3.148 2-s2.0-84911425092 25325033 \n5 Yun G. J. Kim K. M. Bae Y.-J. Cutaneous NK/T-cell lymphoma preceded by persistent facial angioedema Acta Dermato-Venereologica 2010 90 3 328 329 10.2340/00015555-0861 2-s2.0-77953407737 20526568 \n6 Balaraman B. Conley J. A. Sheinbein D. M. Evaluation of cutaneous angioimmunoblastic T-cell lymphoma Journal of the American Academy of Dermatology 2011 65 4 855 862 10.1016/j.jaad.2010.05.030 2-s2.0-80052790030 21550134 \n7 Ocampo-Garza J. Herz-Ruelas M. E. González-Lopez E. E. Angioimmunoblastic T-cell lymphoma: a diagnostic challenge Case Reports in Dermatology 2014 6 3 291 295 10.1159/000370302 25685133 \n8 Stern M. Buser A. S. Lohri A. Tichelli A. Nissen-Druey C. Autoimmunity and malignancy in hematology—more than an association Critical Reviews in Oncology/Hematology 2007 63 2 100 110 10.1016/j.critrevonc.2007.02.002 2-s2.0-34347218247 17391977 \n9 Harrison N. K. Twelves C. Addis B. J. Newman Taylor A. J. Souhami R. L. Isaacson P. G. Peripheral T-cell lymphoma presenting with angioedema and diffuse pulmonary infiltrates The American Review of Respiratory Disease 1988 138 4 976 980 10.1164/ajrccm/138.4.976 2-s2.0-0023719864 3264480 \n10 Chen L. Y. C. Lai E. J. Collins D. R. Ostrow D. N. Sreenivasan G. M. A young woman with episodic angioedema, papilledema, and eosinophilia American Journal of Hematology 2010 85 2 124 127 10.1002/ajh.21584 2-s2.0-75449103734 20029989 \n11 Bernstein J. A. Moellman J. Emerging concepts in the diagnosis and treatment of patients with undifferentiated angioedema International Journal of Emergency Medicine 2012 5 1 1 13 22214197 \n12 Walford H. H. Zuraw B. L. Current update on cellular and molecular mechanisms of hereditary angioedema Annals of Allergy, Asthma & Immunology 2014 112 5 413 418 10.1016/j.anai.2013.12.023 2-s2.0-84899514103 \n13 Zuberbier T. Aberer W. Asero R. The EAACI/GA2 LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update Allergy 2014 69 7 868 887 10.1111/all.12313 2-s2.0-84898022112 24785199 \n14 Altrich M. L. Halsey J. F. Altman L. C. Comparison of the in vivo autologous skin test with in vitro diagnostic tests for diagnosis of chronic autoimmune urticaria Allergy and Asthma Proceedings 2009 30 1 28 34 10.2500/aap.2009.30.3185 2-s2.0-63449096971 19026096 \n15 Biagtan M. J. Viswanathan R. K. Evans M. D. Mathur S. K. Clinical utility of the Chronic Urticaria Index Journal of Allergy and Clinical Immunology 2011 127 6 1626 1627 10.1016/j.jaci.2011.01.045 2-s2.0-79957842545 21376378 \n16 Zeppa P. Vigliar E. Cozzolino I. Fine needle aspiration cytology and flow cytometry immunophenotyping of non-Hodgkin lymphoma: can we do better? Cytopathology 2010 21 5 300 310 10.1111/j.1365-2303.2009.00725.x 2-s2.0-77956306155 20132132\n\n",
"fulltext_license": "CC BY",
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"title": "Angioimmunoblastic T Cell Lymphoma Mimicking Chronic Urticaria.",
"title_normalized": "angioimmunoblastic t cell lymphoma mimicking chronic urticaria"
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"abstract": "OBJECTIVE\nHumoral rejection is the B-cell-mediated production of immunoglobulin G antibody against the transplanted heart. Antibody-mediated rejection may be resistant to standard immunosuppressive therapy and is associated with high mortality and graft loss. Rituximab can be used to treat antibody-mediated rejection in heart transplant recipients. This retrospective study describes our experience with rituximab treatment in children with heart transplants.\n\n\nMETHODS\nWe present 7 pediatric patients with antibody-mediated rejection who were treated with plasma exchange and rituximab therapy. Rituximab was given at a dose of 375 mg/m2 by slow infusion in the intensive care unit after 5 days of plasmapheresis, in addition to a conventional regimen consisting of steroids, mycophenolate mofetil, and tacrolimus. The peripheral blood count and sodium, potassium, serum urea nitrogen, creatinine, aspartate aminotransferase, and alanine aminotransferase levels were measured in all patients before and after treatment.\n\n\nRESULTS\nSeven patients were treated with plasma exchange and rituximab. We repeated this therapy in 5 patients because of refractoriness or recurrent rejection. After diagnoses of antibody-mediated rejection, 4 patients died within 6 months (mortality rate of 57.1%). We did not observe any adverse effects or complications related to rituximab.\n\n\nCONCLUSIONS\nRituximab can be used in humoral rejection after pediatric heart transplant. However, the success of the treatment is controversial, and further study is needed to find an effective treatment for antibody-mediated rejection and steroid-resistant cellular rejection in children.",
"affiliations": "From the Department of Paediatric Cardiology, Baskent University, Ankara, Turkey.",
"authors": "Erdogan|Ilkay|I|;Varan|Birgul|B|;Sezgin|Atilla|A|;Pirat|Arash|A|;Zeyneloglu|Pinar|P|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "Turkey",
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"issue": "16(2)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D002648:Child; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D056724:Immunity, Humoral; D007166:Immunosuppressive Agents; D008297:Male; D010956:Plasmapheresis; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "199-203",
"pmc": null,
"pmid": "27210774",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rituximab Therapy for Rejection in Pediatric Heart Transplant.",
"title_normalized": "rituximab therapy for rejection in pediatric heart transplant"
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"abstract": "The long-term prognosis of HIV-2-infected patients receiving antiretroviral therapy (ART) is still challenging, due to the intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and the suboptimal response to some protease inhibitors (PI). The objective was to describe the 5-years outcomes among HIV-2 patients harboring drug-resistant viruses.\n\n\n\nA clinic-based cohort of HIV-2-patients experiencing virologic failure, with at least one drug resistance mutation was followed from January 2012 to August 2017 in Côte d'Ivoire. Follow-up data included death, lost to follow-up (LTFU), immuno-virological responses. The Kaplan-Meier curve was used to estimate survival rates.\n\n\n\nA total of 31 HIV-2 patients with virologic failure and with at least one drug resistance mutation were included. Two-third of them were men, 28(90.3%) were on PI-based ART-regimen at enrolment and the median age was 50 years (IQR = 46-54). The median baseline CD4 count and viral load were 456 cells/mm3 and 3.7 log10 c/mL respectively, and the participants have been followed-up in median 57 months (IQR = 24-60). During this period, 21 (67.7%) patients switched at least one antiretroviral drug, including two (6.5%) and three (9.7%) who switched to a PI-based and an integrase inhibitor-based regimen respectively. A total of 10(32.3%) patients died and 4(12.9%) were LTFU. The 36 and 60-months survival rates were 68.5% and 64.9%, respectively. Among the 17 patients remaining in care, six(35.3%) had an undetectable viral load (<50 c/mL) and for the 11 others, the viral load ranged from 2.8 to 5.6 log10 c/mL. Twelve patients were receiving lopinavir at the time of first genotype, five(42%) had a genotypic susceptibility score (GSS) ≤1 and 4(33%) a GSS >2.\n\n\n\nThe 36-months survival rate among ART-experienced HIV-2 patients with drug-resistant viruses is below 70%,lower than in HIV-1. There is urgent need to improve access to second-line ART for patients living with HIV-2 in West Africa.",
"affiliations": "Programme PACCI, Site de recherche ANRS de Côte d'Ivoire, Abidjan, Côte d'Ivoire.;Université de Paris, INSERM UMR 1137 IAME, Paris, France.;Département de Dermatologie et Maladies Infectieuses, Université Félix Houphouët-Boigny, UFR des Sciences Médicales, Abidjan, Côte d'Ivoire.;Centre Inserm 1219 & Institut de Santé Publique d'épidémiologie et de développement, Université de Bordeaux, Bordeaux, France.;Université de Paris, INSERM UMR 1137 IAME, Paris, France.;Département de Dermatologie et Maladies Infectieuses, Université Félix Houphouët-Boigny, UFR des Sciences Médicales, Abidjan, Côte d'Ivoire.;Centre Inserm 1219 & Institut de Santé Publique d'épidémiologie et de développement, Université de Bordeaux, Bordeaux, France.",
"authors": "Tchounga|Boris K|BK|0000-0002-8747-9610;Charpentier|Charlotte|C|;Coffie|Patrick A|PA|;Dabis|François|F|;Descamps|Diane|D|;Eholie|Serge P|SP|;Ekouevi|Didier K|DK|",
"chemical_list": "D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D019428:HIV Integrase Inhibitors; D061466:Lopinavir; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0236642",
"fulltext": "\n==== Front\nPLoS One\nPLoS ONE\nplos\nplosone\nPLoS ONE\n1932-6203 Public Library of Science San Francisco, CA USA \n\n10.1371/journal.pone.0236642\nPONE-D-19-33514\nResearch Article\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nHIV-2\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nHIV-2\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nHIV-2\nBiology and Life Sciences\nOrganisms\nViruses\nImmunodeficiency Viruses\nHIV\nHIV-2\nBiology and life sciences\nOrganisms\nViruses\nRNA viruses\nRetroviruses\nLentivirus\nHIV\nHIV-2\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nHIV-2\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nHIV-2\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nHIV-2\nBiology and Life Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nMedicine and Health Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nMedicine and Health Sciences\nPublic and Occupational Health\nPreventive Medicine\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nBiology and Life Sciences\nMicrobiology\nVirology\nViral Transmission and Infection\nViral Load\nMedicine and Health Sciences\nPharmacology\nDrugs\nAntimicrobials\nAntivirals\nAntiretrovirals\nBiology and Life Sciences\nMicrobiology\nMicrobial Control\nAntimicrobials\nAntivirals\nAntiretrovirals\nBiology and Life Sciences\nMicrobiology\nVirology\nAntivirals\nAntiretrovirals\nBiology and Life Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nProtease Inhibitor Therapy\nMedicine and Health Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nProtease Inhibitor Therapy\nMedicine and Health Sciences\nPublic and Occupational Health\nPreventive Medicine\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nProtease Inhibitor Therapy\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nImmunodeficiency Viruses\nHIV\nBiology and life sciences\nOrganisms\nViruses\nRNA viruses\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nMicrobiology\nMicrobial Mutation\nMedicine and Health Sciences\nPharmacology\nDrugs\nAntimicrobials\nAntivirals\nReverse Transcriptase Inhibitors\nBiology and Life Sciences\nMicrobiology\nMicrobial Control\nAntimicrobials\nAntivirals\nReverse Transcriptase Inhibitors\nBiology and Life Sciences\nMicrobiology\nVirology\nAntivirals\nReverse Transcriptase Inhibitors\nSurvival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d’Ivoire West Africa\nSurvival after HIV-2 treatment failurehttp://orcid.org/0000-0002-8747-9610Tchounga Boris K. ConceptualizationData curationFormal analysisFunding acquisitionMethodologyProject administrationSupervisionValidationWriting – original draftWriting – review & editing1¤a* Charpentier Charlotte Data curationFormal analysisInvestigationValidationWriting – review & editing2 Coffie Patrick A. MethodologyValidationVisualizationWriting – review & editing3 Dabis François Funding acquisitionInvestigationMethodologyVisualizationWriting – review & editing4¤b Descamps Diane MethodologySupervisionValidationVisualizationWriting – review & editing2 Eholie Serge P. Data curationInvestigationMethodologySupervisionValidationWriting – review & editing3 Ekouevi Didier K. ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationSupervisionValidationVisualizationWriting – original draft4¤c 1 \nProgramme PACCI, Site de recherche ANRS de Côte d’Ivoire, Abidjan, Côte d’Ivoire\n2 \nUniversité de Paris, INSERM UMR 1137 IAME, Paris, France\n3 \nDépartement de Dermatologie et Maladies Infectieuses, Université Félix Houphouët-Boigny, UFR des Sciences Médicales, Abidjan, Côte d’Ivoire\n4 \nCentre Inserm 1219 & Institut de Santé Publique d’épidémiologie et de développement, Université de Bordeaux, Bordeaux, France\nApetrei Cristian Editor University of Pittsburgh, UNITED STATES\nCompeting Interests: The authors have no competing interest to declare.\n\n¤a Current address: Elizabeth Glazer Pediatric AIDS Foundation Yaoundé Office, Yaounde, Cameroon\n\n¤b Current address: Agence Nationale de recherche sur le SIDA et les Hépatites, Paris, France\n\n¤c Current address: Département de santé Publique, Université de Lomé, Faculté des Sciences de la santé, Lomé, Togo\n\n* E-mail: boris.tchounga@yahoo.fr\n5 8 2020 \n2020 \n15 8 e02366424 12 2019 9 7 2020 © 2020 Tchounga et al2020Tchounga et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introduction\nThe long-term prognosis of HIV-2-infected patients receiving antiretroviral therapy (ART) is still challenging, due to the intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and the suboptimal response to some protease inhibitors (PI). The objective was to describe the 5-years outcomes among HIV-2 patients harboring drug-resistant viruses.\n\nMethods\nA clinic-based cohort of HIV-2-patients experiencing virologic failure, with at least one drug resistance mutation was followed from January 2012 to August 2017 in Côte d’Ivoire. Follow-up data included death, lost to follow-up (LTFU), immuno-virological responses. The Kaplan-Meier curve was used to estimate survival rates.\n\nResults\nA total of 31 HIV-2 patients with virologic failure and with at least one drug resistance mutation were included. Two-third of them were men, 28(90.3%) were on PI-based ART-regimen at enrolment and the median age was 50 years (IQR = 46–54). The median baseline CD4 count and viral load were 456 cells/mm3 and 3.7 log10 c/mL respectively, and the participants have been followed-up in median 57 months (IQR = 24–60). During this period, 21 (67.7%) patients switched at least one antiretroviral drug, including two (6.5%) and three (9.7%) who switched to a PI-based and an integrase inhibitor-based regimen respectively. A total of 10(32.3%) patients died and 4(12.9%) were LTFU. The 36 and 60-months survival rates were 68.5% and 64.9%, respectively. Among the 17 patients remaining in care, six(35.3%) had an undetectable viral load (<50 c/mL) and for the 11 others, the viral load ranged from 2.8 to 5.6 log10 c/mL. Twelve patients were receiving lopinavir at the time of first genotype, five(42%) had a genotypic susceptibility score (GSS) ≤1 and 4(33%) a GSS >2.\n\nConclusions\nThe 36-months survival rate among ART-experienced HIV-2 patients with drug-resistant viruses is below 70%,lower than in HIV-1. There is urgent need to improve access to second-line ART for patients living with HIV-2 in West Africa\n\nhttp://dx.doi.org/10.13039/100000060National Institute of Allergy and Infectious Diseases5U01AI069919Dabis François http://dx.doi.org/10.13039/501100001713European and Developing Countries Clinical Trials PartnershipTMA 2016 CDF 1597http://orcid.org/0000-0002-8747-9610Tchounga Boris K. The Main study was conducted under the IeDEA West Africa collaboration grants funded by the National Cancer Institute (NCI); Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD); National Institute of Allergy and Infectious Diseases (NIAID); Grant number: 5U01AI069919 awarded to Pr François Dabis. The specific analyses and results reported in this publication were conducted under the EDCTP2 Training and Mobility Action awarded to Dr Boris Kevin Tchounga as Career Development Fellowship grant. Grant number: TMA 2016 CDF 1597 EDIIMark-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityThe dataset is publicly available using the following DOI: 10.6084/m9.figshare.12659813Data Availability\nThe dataset is publicly available using the following DOI: 10.6084/m9.figshare.12659813\n==== Body\nIntroduction\nHIV-2 is responsible for a localized AIDS epidemic that mainly affects the West African region [1–3]. The therapeutic strategy for people living with HIV-2 remain challenging, due to the intrinsic resistance of this virus to non-nucleoside reverse transcriptase inhibitors (NNRTI) and fusion inhibitors, as well as the suboptimal response to some protease inhibitors (PI) [4–6].\n\nIn absence of randomized controlled trial, there is no consensus on the therapeutic care of people living with HIV-2 [7,8]. The previous national ART guidelines of West African countries, online with WHO 2010 guidelines, recommended the initiation of a boosting lopinavir/r-based regimen as the preferred option or a three-NRTI based regimen as alternative [9]. The current British, French and USA antiretroviral (ART)-guidelines recommend initiating two NRTI associated with one boosted PI or with one integrase strand-transfer inhibitor (INSTI), and excluded the use of three NRTI as first-line regimen in patients living with HIV-2 [10–12]. More recently, the 2019 WHO guidelines recommended Dolutegravir (DTG) in combination with a nucleoside reverse-transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people initiating ART, thus without any difference between those living with HIV-1 and HIV-2 [13]. However, the implementation of this recommendation in low- and middle-income countries, especially those with double circulation of HIV-1 and HIV-2 is ongoing slowly and DTG-based regimen were mainly prescribed to third-line patients in referral centers [14].\n\nIn case of virologic failure, HIV-2 patients were enrolled for three months in an enhanced adherence counselling program. If at the end of this period the viral load remained unsuppressed, the patient was eligible to switch treatment. In 2016, West African and European guidelines on the management of treatment failure recommended for HIV-2 patients initially receiving three NRTIs or a LP/r-based regimen as first line, to switch to darunavir (DRV) or raltegravir (RAL) / Dolutegravir (DTG) in combination with NRTI backbone [14]. With the recent recommendation of DTG as preferred first-line regardless of HIV type, the preferred second line recommended by WHO and currently endorsed by West African countries is now LP/r based regimen for HIV-2 patients [13].\n\nThus management of virologic failure in HIV-2 patients remain challenging despite the guidelines revision, due to the limited options (NRTI, boosted PI) available, while an increasing number of studies reported virologic failure and resistance-associated mutations to NRTIs, PIs and RAL [15–21]. These multiple resistances jeopardize the efficacy of second line HIV-2 treatment, with multidrug resistance needing boosted darunavir plus raltegravir based regimen in resource-limited settings where HIV-2 viral load and genotypic resistance tests are neither routinely available nor affordable.\n\nThere is few data reporting experience of therapeutic care and describing long-term outcome of HIV-2-infected individuals experiencing virologic failure in resource-limited settings. Such data will be useful to orient clinicians and decision makers in the management of treatment switches in HIV-2 patients with treatment failure. This survey aimed to describe the sequence of ART regimens use, and the 5-years outcomes among HIV-2 patients harboring drug-resistant viruses in Côte d’Ivoire.\n\nMaterials and methods\nStudy design, population and settings\nA clinic-based cohort study was initiated in January 2012 within the International epidemiological Database to evaluate AIDS (IeDEA) in West Africa [22]. The eligibility criteria for this cohort were assessed during a cross-sectional survey conducted to describe virologic failure and drug resistance mutations among HIV-2-infected individuals receiving ART and followed up in six HIV clinics in Abidjan, Côte d’Ivoire [15]. Based on the results of this cross-sectional survey presented elsewhere [15], adults living with HIV-2, experiencing virologic failure, and harboring at least one drug resistance mutation, were included and followed up from 2012 to 2017.\n\nEthics consideration\nThe protocol of the IeDEA west Africa collaboration cohort was reviewed and approved in Côte d’Ivoire by the National Ethic Committee for life Science and Health (CNESVS: IORG00075). Prior to the initial enrolment in the cohort, each participant was given comprehensive information on the study protocol and procedures, and had to provide a written consent before being included.\n\nHIV-2 standard of care in Côte d’Ivoire\nAccording to the national guidelines of Côte d’Ivoire at the time of study in 2012, ART was initiated in people living with HIV symptomatic stage 3–4 or asymptomatic with CD4 <350 cells/mm3. In case of HIV-2 or HIV1&2, the preferred first line option was 2 NRTI plus boosted Lopinavir. Three-NRTI-based regimen was considered as alternative option (if CD4 cell counts > 200 cells/mL or Lopinavir contraindication/intolerance) [14]. In case of virologic failure, HIV-2 patients should receive the most appropriate ART regimen available, with the guidance of the national referral center for adults living with HIV (Unit of Infectious and Tropical Diseases Treichville University teaching hospital) [14].\n\nStudy procedures\nThe follow-up consisted in the administration of a standardized questionnaire allowing collection of clinical (AIDS events and Non-AIDS severe morbidity), biological (CD4 count, viral load) and therapeutic (switches second line, salvage ART regimen) data, during routine follow-up visits.\n\nBiological procedures\nA comprehensive description of the biological procedure has been published [15]. Briefly, virologic failure was defined as plasma HIV-2 RNA above 50 copies/mL using a real-time PCR assay [23]. Genotypic resistance tests (protease and reverse transcriptase sequencing) were performed using an in-house method [15]. The interpretation was based on the HIV French resistance algorithm update of September 2017, available at http://www.hivfrenchresistance.org/index.html. A genotypic susceptibility score (GSS) was generated for each patient based on the results of genotypic analyses. In 2017, a blood sample was collected from each participant presenting at the HIV clinic, for a routine follow-up visit or returning to care after a successful tracking process. This blood samples allowed performing a viral load and an additional CD4 count.\n\nOutcomes and variables\nThe main outcomes considered were being alive, dead or LTFU. Considering LTFU like a proxy of death, a variable combining death and LTFU was defined.\n\nDeath was defined as being reported dead in the medical records of the HIV clinic or being declared dead by a close relative or a family member. A participant was considered alive if he presented for follow-up visit during the year 2017 or if he was successfully contacted during the active tracking process. The participants who did not showed up at HIV clinic for more than three months, were not known as alive, transferred out or deceased, and were not successfully tracked (phone calls and home visits when allowed in the initial consent form) were considered LTFU.\n\nStatistical analyses\nData analysis was conducted using STATA® version 14.0, Stata Corp, College Station, Texas USA. Kaplan Meier curve was used to estimate survival rate and Logrank test was used to compare survival between the two groups.\n\nResults\nBaseline characteristics\nAmong the 31 participants included in the study, 28 (90.3%) were receiving a PI-based regimen, 2 (6.5%) a three-NRTI-based regimen and 1 (3.2%) a raltegravir-based regimen. The median age at enrolment was 50 years (IQR = 46–54 years) and 20 patients were men (64.5%). At enrolment, the median baseline CD4 count and viral load were 456 cells/mm3 (IQR = 256–751) and 3,700 c/mL (IQR = 663–7797), respectively. The initial genotypic analyses retrieved PI resistance mutations (at least one) in 26 (83.9%) participants and NRTI resistance mutations in 21 (67.7%) participants. The GSS was <2 for 14 (45.2%) patients and >2 for 10 (32.3%) others (Table 1).\n\n10.1371/journal.pone.0236642.t001Table 1 Follow-up characteristics of antiretroviral-experienced HIV-2-infected patients with identified resistance mutations from 2012 to 2017.\n\tAlive\tDeath/LTFU\tTotal\tp-values\t\n\tn = 17 (55%)\tn = 14 (45%)\tn = 31\t\t\nFollow-up duration, months, Median [IQR]\t60 [58–61]\t19 [12–35]\t57 [24–60]\t0.001\t\nBaseline CD4 count cells/mm3\t\t\nMedian [IQR]\t445 [266–675]\t504 [256–855]\t456 [256–751]\t0.489\t\n≤350\t6\t(35.3)\t5\t(35.7)\t11\t(35.5)\t\t\n350–500\t4\t(23.5)\t1\t(7.2)\t5\t(16.1)\t\t\n≥500\t7\t(42.2)\t7\t(50.0)\t14\t(45.2)\t\t\nMissing\t0\t(0.0)\t1\t(7.1)\t1\t(3.2)\t\t\nLast CD4 count cells/mm3\t\t\t\nMedian [IQR]\t281 [193–321]\t150 [113–278]\t230 [120–321]\t0.202\t\n≤350\t13\t(76.4)\t11\t(78.7)\t24\t(77.4)\t\t\n350–500\t2\t(11.8)\t1\t(7.1)\t3\t(9.7)\t\t\n≥500\t2\t(11.8)\t1\t(7.1)\t3\t(9.7)\t\t\nMissing\t0\t(0.0)\t1\t(7.1)\t1\t(3.2)\t\t\nViral load at inclusion c/mL\t\t\nMedian [IQR]\t730 [372–4103]\t5992 [3700–16716]\t3700 [663–7797]\t0.007\t\nViral load at closing date c/mL\t\t\nMedian [IQR]\t859 [0–9082]\tNA\t859 [0–9082]\t\t\nARV regimen at enrollment\t\t\t\t\t\t\nPI-based\t17\t(100.0)\t11\t(78.6)\t28\t(90.3)\t0.568\t\n3 NRTI-based\t0\t(0.0)\t2\t(14.3)\t2\t(6.5)\t\t\nRaltegravir-based\t0\t(0.0)\t1\t(7.1)\t1\t(3.2)\t\t\nARV drug switch (at least one)\t12\t(70.6)\t9\t(64.3)\t21\t(67.7)\t0.270\t\nTo darunavir*\t0\t(0.0)\t2\t(14.3)\t2\t(6.5)\t\t\nTo raltegravir*\t2\t(11.8)\t1\t(7.1)\t3\t(9.7)\t\t\nGenotypic susceptibility score\t0.933\t\n<2\t8\t(47.1)\t6\t(41.9)\t14\t(45.2)\t\t\n≥2\t5\t(29.4)\t5\t(35.7)\t10\t(32.3)\t\t\nNot available\t4\t(23.5)\t3\t(21.4)\t7\t(22.5)\t\t\nIQR = interquartile range, LFTU = lost to follow-up, PI = protease inhibitor, NRTI = nucleoside reverse transcriptase inhibitor\n\n* = non-cumulative; NA = not available; ARV = antiretroviral.\n\nFollow up characteristics\nThe cumulative follow-up duration was 1327 person-months with a median duration of 52 months (IQR = 24–59). During this period, 21 (67.7%) patients switched at least one antiretroviral drug, including two (6.5%) and three (9.7%) who switched to a PI-based and an INSTI-based regimen respectively. At the censured date, 17 (55.0%) patients remained in care, while 10 (32.3%) were dead and 4 (12.9%) were LTFU. The last median CD4 count were 150 cells/mm3 (IQR = 117–218) and 143 cells/mm3 (IQR = 39–340) among patients dead and LTFU, respectively. Among those still in care during follow up, the 12, 36 and 60-months survival rates were 86.8%, 68.8% and 64.9% respectively (Fig 1). Neither gender (HR = 1.57, p = 0.484) nor age >50 years (HR = 0.59, p = 0.421) were associated with mortality.\n\n10.1371/journal.pone.0236642.g001Fig 1 Among the 17 patients remaining in care, six (35.3%) had an undetectable viral load (<50 c/mL) and for the 11 others, the median viral load was 4,334 [859–87,523] c/mL, ranging from 584 to 372,346 c/mL (Table 2). Twelve of these patients were receiving lopinavir at time of first genotyping analysis, eight (47.1%) had a GSS <2 and five (29.4%) a GSS >2. Their last median CD4 count was 281 cells/mm3 (IQR = 209–351), not significantly different to those who died or were LTFU (p = 0.20). none of participants CD4 increased after switch or after the first virologic failure.\n\n10.1371/journal.pone.0236642.t002Table 2 Five-years ART-response among HIV-2 infected patients surviving after experiencing treatment failure with identified drug resistance mutations in Côte d'Ivoire, West Africa.\nPatients demographics\tART Response in 2012\tGenotypic analyses in 2012\tART Response in 2017\t\nID\tAge(years)\tSex\tART regimen at treatment failure\tCD4(/mm3)\tVL (c/mL)\tNRTI Mutations\tPI Mutations\tGSS\tLast ART regimen\tCD4(/mm3)\tVL (c/mL)\t\nPAT-S01\t51\tM\tAZT/3TC/LPV/r\t106\t340\tM184V\tV47A, V62A\t1\tABC/3TC/LPV/r\t281\t859\t\nPAT-S02\t53\tM\tABC/3TC/LPV/r\t919\t713\tM184V\tI54M\t2\tTDF/3TC/LPV//r\t209\t4,334\t\nPAT-S03\t56\tM\tAZT/3TC/LPV/r\t675\t3085\tM184V, S215Y\tV47A, I82M, L90M\t0\tAZT/3TC/LPV/r\t351\t372,346\t\nPAT-S04\t30\tF\tAZT/3TC/LPV/r\t119\t663\tNA \tV47A,\tNA\tAZT/3TC/LPV/r\t291\t87,523\t\nPAT-S05\t58\tM\tAZT/3TC/LPV/r\t545\t149\tNA \tWild-Type\tNA\tTDF/3TC/LPV/r\t362\t-\t\nPAT-S06\t60\tF\tABC/ddI/LPV/r\t791\t4103\tM184V\tNA \tNA\tTDF/3TC/LPV/r\t79\t13,457\t\nPAT-S07\t33\tM\tSQV/LPV/r\t141\t33287\tQ151M\tI50V, I54M, L90M\t0\tTDF/3TC/DRV/r/RAL\t214\t-\t\nPAT-S08\t50\tM\tABC/3TC/SQV/r\t425\t8790\tQ151M, K65R, K70R, M184V, K223R\tV47A, I50V, I84V, L90M, L99F\t0\tTDF/3TC/DRV/r/RAL\t69\t-\t\nPAT-S09\t49\tM\tddI/ABC/LPV/r\t751\t1471\tM184V\tV47A, L99F\t2\tTDF/3TC/DRV/r\t256\t1,535\t\nPAT-S10\t54\tM\tAZT/3TC/LPV/r\t357\t5156\tWild-Type\tWild-Type\t3\tAZT/3TC/LPV/r\t103\t2,337\t\nPAT-S11\t60\tM\tABC/ddI/LPV/r\t445\t3016\tQ151M, M184V, S215F\tI54M, I84V\t0\tABC/ 3TC/ TDF/ DRV/r\t193\t9,082\t\nPAT-S12\t50\tM\tTDF/FTC/LPV/r\t606\t193\tM184I\tWild-Type\t2\tABC/3TC/LPV/r\t120\t-\t\nPAT-S13\t53\tM\tAZT/3TC/LPV/r\t157\t395\tM184V\tV47A\t1\tAZT/3TC/LPV/r\t297\t223,827\t\nPAT-S14\t43\tF\tTDF/FTC/LPV/r\t336\t91\tM184V\tWild-Type\t2\tTDF/3TC/LPV/r\t774\t-\t\nPAT-S15\t55\tM\tAZT/3TC/LPV/r\t712\t372\tNA \tV47A\tNA\tAZT/3TC/ DRV/r\t855\t-\t\nPAT-S16\t53\tM\tAZT/3TC/LPV/r\t266\t730\tM184V, S215Y\tV47A, V62AI\t0\tAZT/3TC/LPV/r\t321\t584\t\nPAT-S17\t49\tF\tTDF/FTC/LPV/r\t466\t5146\tK65R, N69S, M184V\tV47A\t0\tTDF/3TC/LPV/r\t292\t685\t\nNA: Not amplified; ID = participant identifier; ART = antiretroviral therapy; VL = viral load; NRTI = Nucleoside reverse transcriptase inhibitors; PI = protease inhibitors; GSS = genotypic susceptibility score\n\nAmong the 10 patients declared dead, 6 (60.0%) had CD4 count <200 cells/mm3, 7 (70.0%) had a boosted PI in their last known ART regimen, five (50.0%) had a GSS <2 and 7 (70.0%) changed at least one drug in their ARV regimen at least once after the diagnosis of drug resistance mutation. Regarding treatment, 5 of them switched to an unappropriated and non-effective ART regimen according to the genotypic resistance test. three of them were maintained on boosted-lopinavir as a compassionate treatment until they died. Two of them received a non-recommended regimen for HIV-2 based on Atazanavir although LPV/r-based regimen was effective.\n\nDiscussion\nIn this observational cohort study conducted in Côte d’Ivoire, we reported after 5 years of diagnosis of at least one drug resistance mutation to first-line ART regimen among HIV-2 patients, high mortality and lost to follow-up. Half of HIV-2 patients were not retained in care 5 years after the diagnosis of drug resistance mutation.\n\nThis high rate of mortality could be explained by the lack of access to second-line therapy for these patients in resource-limited settings. According to the US and French ART guidelines, only integrase inhibitors such as raltegravir, elvitegravir or dolutegravir or the CCR5 antagonist maraviroc (MVC) could be used as a second-line therapy among HIV-2 patients [24–28]. However, in most west African countries, these antiretroviral molecules are still scarcely available. In our study only three (9.3%) patients diagnosed with drug resistant viruses switched to the INSTI raltegravir, none of them received dolutegravir. Among the patients dead or LTFU, only one (7.1%) and two (14.2%) switched to an INSTI and to the PI darunavir, respectively. For these latter patients, the median last known CD4 count was 150 cells/mm3, indicating that more than half of them were in advanced HIV disease according to the immunologic definition [29]. Increase the availability of more efficient antiretroviral drugs like integrase inhibitors is critical for patients living with HIV-2 for whom the therapeutic arsenal is limited specifically for patients harboring viruses with drug resistance mutations [15].\n\nIn resource-limited settings, there was no clear sequence of ART regimen use for the treatment of HIV-2-infected individual experiencing virologic failure [14]. This lack of clear guidelines may be the consequence of limited data on the switch of treatment among HIV-2-infected patients, the lack of routine implementation of validated tool for viral load monitoring, the absence of definition of immunological failure and the paucity of data regarding drug resistance mutations [7,8,23,30–32]. Since the mortality remains high among HIV-2 patients receiving ART [33,34], it is critical to address all the gaps and need in terms of data in order to propose clear guidelines for the treatment of HIV-2 patients experiencing virologic failure.\n\nIn the present study, six of the 17 patients remaining in care had no active antiretroviral drug in their regimen. In fact, salvage regimen for those patients with a good GSS should use boosted-darunavir and DTG which remains active in some cases of resistance to the first generation of INSTI [21,35]. Thus, in this context, genotypic resistance tests are needed in order to prevent DTG from being functional monotherapy which will result to the selection of DTG resistances. Unfortunately, according to the GSS of the patients of the present study it seems that DTG will not be sufficient and additional new drugs are needed, such as maraviroc or broad-spectrum neutralizing antibodies (Ibalizumab) [36–38]. Unfortunately, in our study population, among the 10 patients with no active ARV drug (GSS = 0), four died, arguing for the need of new therapeutic options for HIV-2 infection.\n\nSince 2018, WHO guidelines recommend tenofovir plus lamivudine plus dolutegravir based regimen as the preferred first-line option according to expert opinion, pilot studies and in vitro data [39]. This will change the management of HIV-2-infected patients with the use of boosted-PI such as lopinavir or darunavir with an optimized NRTI-backbone in second-line [21,27,39–41]\n\nStudy limitations and strengths\nAlthough the study was conducted in the HIV clinics with a proper documentation of patient’s follow-up, the main limitation is the lack of documentation of the cause of death. For all the patients who were not reported dead at the HIV clinic, it was not possible to identify the clinical cause of death, as the only information available in the official death certificate was “disease”. In addition, viral load measurement was not routinely performed and only two measures (2012 and 2017) were available for the analysis, making it impossible to describe the evolution according to the switches of antiretroviral drugs during the five years of follow-up. Furthermore, this study presents data of a small population and the estimates may suffer from lack of statistic power. However, to our knowledge, this is one of the first report on treatment outcomes among HIV-2 patients who experienced virologic failure with at least one drug resistance mutation in West Africa. Data on long-term follow-up among HIV-2 patients are also limited and this study highlights the challenge to determine the sequence of ART use in this population.\n\nConclusions\nOur data call for the urgent access to second-line and third-line therapy among HIV-2 patients. Clinical trials for HIV-2-infected patients harboring multi-drug resistant viruses should be conducted in both resource-limited settings and western countries. Results from the first randomized controlled trial on HIV-2 (FIT-2) Expected in 2020, will be helpful to define a sequence of ART initiation among HIV-2 patients.\n\nWe would like to warmly thank Drs Denise Dekpanou; Albert Minga; Eugène messou; Zelika Diallo and Serge Kooley for their contribution during the implementation of the study, as well as Mr Azany Jean Claude for his strong support in data management and study monitoring and Dr Boni Simon for his support to the clinical monitoring and critical review of the manuscript.\n\nList of abbreviations\nARTAntiretroviral therapy\n\nGSSGenotypic susceptibility score\n\nHIV-2Human immune deficiency virus type 2\n\nIeDEAInternational epidemiologic database to evaluate AIDS\n\nLTFULost to follow up\n\nNNRTINon-nucleoside reverse transcriptase inhibitors\n\nNRTINucleoside reverse transcriptase inhibitors\n\nPIProtease inhibitors\n\n10.1371/journal.pone.0236642.r001\nDecision Letter 0\nApetrei Cristian Academic Editor © 2020 Cristian Apetrei2020Cristian ApetreiThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Submission Version0\n22 Jan 2020\n\n\nPONE-D-19-33514\n\nSurvival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d’Ivoire West Africa\n\nPLOS ONE\n\nDear Dr Tchounga,\n\nThank you for submitting your manuscript to PLOS ONE. 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Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. \n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n2. Has the statistical analysis been performed appropriately and rigorously? \n\nReviewer #1: No\n\nReviewer #2: Yes\n\n**********\n\n3. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n4. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n5. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: The analysis is based on 5–year outcomes of HIV-2 infected patients harboring drug resistance mutations in Cote d'Ivoire. This study included a small number of patients, compared with similar studies recently published. Many publications debated on this subject, most of them focusing on HIV-1 patients, but only a few articles discussed HIV-2 patients and the detection of drug resistance mutations.\n\nA major concern is the lack of statistical comparison in table 1 between the two categories of patients (alive and death) (ex. chi-squared test). Thus, the study has a practical utility, as it fills in information gaps concerning disease evolution under ARV therapy in this category of patients in resource-limited settings but it needs some revisions.\n\nReviewer #2: The study titled “Survival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d’lvoire West Africa” describes the various treatment modalities received by patients infected with HIV-2 experiencing virologic failure in six HIV clinics in Cote d’lvoire and the 5-year outcome of these HIV-2 patients harboring drug-resistant viruses. This study stresses on the need for clear treatment guidelines for virologic failure in HIV-2 infection and calls for an increased access to second-line and third-line drugs for HIV-2 patients in resource-limited settings.\n\nComments\n\n1. In the abstract, lines 61 and 62, the authors have mentioned that “The survival rate of HIV-2 ART-experienced patients with drug resistant viruses is somewhat low.” Please accurately describe “somewhat low” based on the study’s results. Also, please mention what this is in comparison to.\n\n2. The introduction overall is very short and not detailed. The following comments pertain to the introduction:\n\na. In the second paragraph, the authors talk about the current British, French and USA ART guidelines but for comparison with West African and WHO guidelines, the authors have utilized previous West African and 2010 WHO guidelines. Please include the current WHO and West African ART guidelines here.\n\nb. In the next paragraph, the authors go on to conclude that “ARV optimal combination in case of virologic failure is not clear.” Please elaborate on what the current guidelines are regarding virologic failure are before moving on to discuss the lack of clarity of the guidelines.\n\nc. In line 92, it is unclear what the authors mean by “sequencing of ART regimens”. Please clarify the same in all the subsequent places where this is mentioned.\n\nd. The authors may consider describing further the importance of this study and how this study may impact the field.\n\n3. In the results section, in lines 179 and 180, the authors observed that among the 17 patients, “6 had undetectable viral loads (<50 c/mL)”. However, the authors go on to note that the viral loads “for the 11 others” (implying that these 11 patients had detectable viral loads) range from “0 to 372,346 c/mL”. This is misleading as undetectable viral loads are described as <50 c/mL but the viral loads of the 11 patients that were detected ranged starting from 0 c/mL. Please clarify.\n\n4. In lines 225-228, the authors declare certain factors to be the cause for the lack of clear guidelines for the treatment of HIV-2 infected individuals experiencing virologic failure. Since these factors have not been evaluated in this study, please cite a reference or indicate how the authors reached to this conclusion. If this is a speculation and the authors are calling for further studies to evaluate these factors, please indicate so appropriately.\n\n5. In line 233, the authors have stated that 5 patients had no active antiretroviral drug in their regimen. However, in line 241, the authors have stated “4 out of 6 patients with no active ARV drug have died.” Please clarify whether it is 5 or 6 patients who had no active antiretroviral drugs in their regimen.\n\n6. The authors may consider citing outcome in HIV-2 infected patients who do not harbor drug resistant viruses, for comparison, in order to make their results more meaningful.\n\n7. There are numerous minor grammatical errors throughout the paper. Some sentences do not convey their intended meaning. Please have these edited.\n\n**********\n\n6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #1: No\n\nReviewer #2: No\n\n[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files to be viewed.]\n\nWhile revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.\n\n10.1371/journal.pone.0236642.r002\nAuthor response to Decision Letter 0\nSubmission Version1\n6 Jul 2020\n\n\nReviewer #1: \n\nThe analysis is based on 5–years outcomes of HIV-2 infected patients harboring drug resistance mutations in Cote d'Ivoire. This study included a small number of patients, compared with similar studies recently published. Many publications debated on this subject, most of them focusing on HIV-1 patients, but only a few articles discussed HIV-2 patients and the detection of drug resistance mutations.\n\nA major concern is the lack of statistical comparison in table 1 between the two categories of patients (alive and death) (ex. chi-squared test). Thus, the study has a practical utility, as it fills in information gaps concerning disease evolution under ARV therapy in this category of patients in resource-limited settings but it needs some revisions.\n\nAuthor’s response: We thank the reviewer for this encouraging comment regarding the practical utility of the study. Despite the low population size, we perform krouska wallis test to compare medians and Fischer Exact test to compare means and provide the p-values in table 1 in the revised manuscript. \n\nReviewer #2: \n\nThe study titled “Survival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d’lvoire West Africa” describes the various treatment modalities received by patients\n\ninfected with HIV-2 experiencing virologic failure in six HIV clinics in Côte d’lvoire and the 5-years outcome of these HIV-2 patients harboring drug-resistant viruses. This study stresses on the need for clear treatment guidelines for virologic failure in HIV-2 infection and calls for an increased access to second-line and third-line drugs for HIV-2 patients in resource-limited \n\nComments\n\n1. In the abstract, lines 61 and 62, the authors have mentioned that “The survival rate of HIV-2 ART-experienced patients with drug resistant viruses is somewhat low.” Please accurately describe “somewhat low” based on the study’s results. Also, please mention what this is in comparison to.\n\nAuthor’s response: We thank the reviewer for this comment, we reviewed the sentence and specified the comparison factor as follows: \n\nThe 36-months survival rate among ART-experienced HIV-2 patients with drug-resistant viruses is below 70%, lower than in HIV-1.\n\n2. The introduction overall is very short and not detailed. The following comments pertain to the introduction:\n\na. In the second paragraph, the authors talk about the current British, French and USA ART guidelines but for comparison with West African and WHO guidelines, the authors have utilized previous West African and 2010 WHO guidelines. Please include the current WHO and West African ART guidelines here.\n\nAuthor’s response: We thank the reviewer for this comment; we reviewed the section to include the current WHO and West African ART guidelines here as follows: \n\nMore recently, the 2019 WHO guidelines recommended Dolutegravir (DTG) in combination with a nucleoside reverse-transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people initiating ART, thus without any difference between those living with HIV-1 and HIV-2 (13).. However, the implementation of this recommendation in low- and middle-income countries, especially those with double circulation of HIV-1 and HIV-2 is ongoing slowly and DTG-based regimen were mainly prescribed to third-line patients in referral centers (14). \n\nb. In the next paragraph, the authors go on to conclude that “ARV optimal combination in case of virologic failure is not clear.” Please elaborate on what the current guidelines are regarding virologic failure are before moving on to discuss the lack of clarity of the guidelines.\n\nAuthor’s response: We thank the reviewer for this comment. We reviewed the section to elaborate on what the current guidelines state regarding virologic failure in the study setting and we clarified the sentence regarding clarity of guidelines. \n\nIn case of virologic failure, HIV-2 patients were enrolled for three months in an enhanced adherence counselling program. If at the end of this period the viral load remained unsuppressed, the patient was eligible to switch treatment. In 2016, West African and European guidelines on the management of treatment failure recommended for HIV-2 patients initially receiving three NRTIs or a LP/r-based regimen as first line, to switch to darunavir (DRV) or raltegravir (RAL) / Dolutegravir (DTG) in combination with NRTI backbone (14). With the recent recommendation of DTG as preferred first-line regardless of HIV type, the preferred second line recommended by WHO and currently endorsed by West African countries is now a LP/r based regimen for HIV-2 patients (13). \n\nc. In line 92, it is unclear what the authors mean by “sequencing of ART regimens”. Please clarify the same in all the subsequent places where this is mentioned.\n\nAuthor’s response: We thank the reviewer for this comment, highlighting this typo. We wanted to express the idea that the sequence of use of available ART regimens for HIV-2 patients was not clearly defined and thus admitted by the clinicians and researchers. The typo introduces a confusion between sequencing that applies for the biological genotyping procedure and the sequences meaning the treatment steps during the process of ART management. We reviewed the updated version of the manuscript to use sequencing and sequence when appropriated. \n\nd. The authors may consider describing further the importance of this study and how this study may impact the field.\n\nAuthor’s response: We thank the reviewer for this comment. We have added in the introduction a sentence describing how this study may impact the field, especially the clinical practice in African countries where HIV-2 circulates.\n\n3. In the results section, in lines 179 and 180, the authors observed that among the 17 patients, “6 had undetectable viral loads (<50 c/mL)”. However, the authors go on to note that the viral loads “for the 11 others” (implying that these 11 patients had detectable viral loads) range from “0 to 372,346 c/mL”. This is misleading as undetectable viral loads are described as <50 c/mL but the viral loads of the 11 patients that were detected ranged starting from 0 c/mL. Please clarify.\n\nAuthor’s response: We thank the reviewer for this comment. We reviewed the numerical figures and corrected the mistake. This was corrected in the updated version of the manuscript as follows: \n\nAmong the 17 patients remaining in care, six (35.3%) had an undetectable viral load (<50 c/mL) and for the 11 others, the median viral load was 4,334 [859 - 87,523] c/mL, ranging from 584 to 372,346 c/mL (Table 2).\n\n4. In lines 225-228, the authors declare certain factors to be the cause for the lack of clear guidelines for the treatment of HIV-2 infected individuals experiencing virologic failure. Since these factors have not been evaluated in this study, please cite a reference or indicate how the authors reached to this conclusion. If this is a speculation and the authors are calling for further studies to evaluate these factors, please indicate so appropriately.\n\nAuthor’s response: We thank the reviewer for this comment. The factors cited were illustrated with appropriate references inserted in the manuscript. We also reviewed the sentence to modulate the role of these factors as we did not evaluate them ourselves. \n\n5. In line 233, the authors have stated that 5 patients had no active antiretroviral drug in their regimen. However, in line 241, the authors have stated “4 out of 6 patients with no active ARV drug have died.” Please clarify whether it is 5 or 6 patients who had no active antiretroviral drugs in their regimen.\n\nAuthor’s response: We acknowledge that the two sentences were a little bit confusing. Among the 17 patients still alive by the time of this evaluation, six had a GSS =0, meaning that they had no active drug in their regimen. In the second sentence we were highlighting the fact that in our study population, 10 out of the 31 patients with virologic failure had no effective drug in their regimen (GSS=0), and among these 10 patients, four died during the 5 years of follow up. The paragraph was updated to clarify this in the revised version of the manuscript as follows: \n\nUnfortunately, in our study population, among the 10 patients with no active ARV drug (GSS=0), four died, arguing for the need of new therapeutic options for HIV-2 infection.\n\n6. The authors may consider citing outcome in HIV-2 infected patients who do not harbor drug resistant viruses, for comparison, in order to make their results more meaningful.\n\nAuthor’s response: We acknowledge the importance of a comparison with HIV-2 clients who do not harbor drug resistant viruses. We were unable to find comparable studies presenting survival or mortality data in HIV-2 patients according to the existence or the absence of viral resistance mutation after a long period of follow up. Most studies did not perform systematic viral load and resistance mutation testing for all the patients enrolled. We have taken good note of this comment and will consider the possibility of an ancillary study to document the outcome of the patients who did not harbor drug resistant viruses. We did not amend the revised version of the manuscript according to this comment as this sub--study is not planned yet. \n\n7. There are numerous minor grammatical errors throughout the paper. Some sentences do not convey their intended meaning. Please have these edited.\n\nAuthor’s response: We tried our best to improve the English and the style of the manuscript with the assistance of a native English speaker.\n\nAttachment Submitted filename: R.1 Response to reviewers.docx\n\nClick here for additional data file.\n\n 10.1371/journal.pone.0236642.r003\nDecision Letter 1\nApetrei Cristian Academic Editor © 2020 Cristian Apetrei2020Cristian ApetreiThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Submission Version1\n13 Jul 2020\n\n\nSurvival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d’Ivoire West Africa\n\nPONE-D-19-33514R1\n\nDear Dr. Tchounga,\n\nWe’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.\n\nWithin one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.\n\nAn invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.\n\nIf your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.\n\nKind regards,\n\nCristian Apetrei, MD, PhD\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments (optional):\n\nReviewers' comments:\n\n10.1371/journal.pone.0236642.r004\nAcceptance letter\nApetrei Cristian Academic Editor © 2020 Cristian Apetrei2020Cristian ApetreiThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n24 Jul 2020\n\n\nPONE-D-19-33514R1 \n\nSurvival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d’Ivoire West Africa \n\nDear Dr. Tchounga:\n\nI'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. \n\nIf your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.\n\nIf we can help with anything else, please email us at plosone@plos.org. \n\nThank you for submitting your work to PLOS ONE and supporting open access. \n\nKind regards, \n\nPLOS ONE Editorial Office Staff\n\non behalf of\n\nDr. Cristian Apetrei \n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n1 Visseaux B , Damond F , Matheron S , Descamps D , Charpentier C . Hiv-2 molecular epidemiology\n. 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Trop Med Int Health TM IH . 2016 ;21 (9 ):1124 –30\n. 10.1111/tmi.12746 \n27371814 \n30 Chang M , Gottlieb GS , Dragavon JA , Cherne SL , Kenney DL , Hawes SE , et al\nValidation for clinical use of a novel HIV-2 plasma RNA viral load assay using the Abbott m2000 platform\n. J Clin Virol Off Publ Pan Am Soc Clin Virol . 2012 \n10 ;55 (2 ):128 –33\n.\n31 Styer LM , Miller TT , Parker MM . Validation and clinical use of a sensitive HIV-2 viral load assay that uses a whole virus internal control\n. J Clin Virol Off Publ Pan Am Soc Clin Virol . 2013 \n12 ;58 Suppl 1 :e127 –133\n.\n32 Peterson K , Jallow S , Rowland-Jones SL , de Silva TI . Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings\n. AIDS Res Treat . 2011 ;2011 :463704 \n10.1155/2011/463704 \n21490779 \n33 Tchounga B , Ekouevi DK , Balestre E , Dabis F . Mortality and survival patterns of people living with HIV-2\n. Curr Opin HIV AIDS . 2016 \n5 \n31 ;\n34 Tchounga BK , Hønge BL , Eholie SP , Coffie PA , Jespersen S , Wejse C , et al\nEffect of sex and age on outcomes among hiv-2 infected patients starting antiretroviral therapy in west africa: a multicentre cohort study\n. AIDS Lond Engl . 2016 \n8 \n17 ;\n35 Charpentier C , Larrouy L , Matheron S , Damond F , Delelis O , Mouscadet J-F , et al\nLong-lasting persistence of integrase resistance mutations in HIV-2-infected patients after raltegravir withdrawal\n. Antivir Ther . 2011 ;16 (6 ):937 –40\n. 10.3851/IMP1826 \n21900727 \n36 Kong R , Li H , Bibollet-Ruche F , Decker JM , Zheng NN , Gottlieb GS , et al\nBroad and potent neutralizing antibody responses elicited in natural HIV-2 infection\n. J Virol . 2012 \n1 ;86 (2 ):947 –60\n. 10.1128/JVI.06155-11 \n22031948 \n37 Borrego P , Taveira N . HIV-2 susceptibility to entry inhibitors\n. AIDS Rev . 2013 \n3 ;15 (1 ):49 –61\n. 23449229 \n38 Caixas U , Ferreira J , Marinho AT , Faustino I , Grilo NM , Lampreia F , et al\nLong-term maraviroc use as salvage therapy in HIV-2 infection\n. J Antimicrob Chemother . 2012 \n10 ;67 (10 ):2538 –9\n. 10.1093/jac/dks240 \n22729923 \n39 Matheron S , Descamps D , Gallien S , Besseghir A , Sellier P , Blum L , et al\nFirst-line Raltegravir/Emtricitabine/Tenofovir Combination in Human Immunodeficiency Virus Type 2 (HIV-2) Infection: A Phase 2, Noncomparative Trial (ANRS 159 HIV-2)\n. Clin Infect Dis Off Publ Infect Dis Soc Am . 2018 \n28 ;67 (8 ):1161 –7\n.\n40 Ba S , Raugi DN , Smith RA , Sall F , Faye K , Hawes SE , et al\nA Trial of a Single-tablet Regimen of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate for the Initial Treatment of Human Immunodeficiency Virus Type 2 Infection in a Resource-limited Setting: 48-Week Results From Senegal, West Africa\n. Clin Infect Dis Off Publ Infect Dis Soc Am . 2018 \n30 ;67 (10 ):1588 –94\n.\n41 World Health Organization . UPDATED RECOMMENDATIONS ON FIRST-LINE AND SECOND-LINE ANTIRETROVIRAL REGIMENS AND POST-EXPOSURE PROPHYLAXIS AND RECOMMENDATIONS ON EARLY INFANT DIAGNOSIS OF HIV [Internet]. World Health Organization ; 2018 \n12 [cited 2019 Nov 1] p. 82 (Antiretroviral Treatment). Report No.: 2018. Available from: https://apps.who.int/iris/bitstream/handle/10665/277395/WHO-CDS-HIV-18.51-eng.pdf?ua=1\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "15(8)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D023241:Antiretroviral Therapy, Highly Active; D007560:Cote d'Ivoire; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D015498:HIV-2; D006801:Humans; D061466:Lopinavir; D008875:Middle Aged; D009154:Mutation; D019438:Ritonavir; D019562:Viral Load",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0236642",
"pmc": null,
"pmid": "32756581",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24920771;23824279;25690598;29672676;18718922;15456096;21900727;19143530;12386343;18832869;15040537;24342472;23028968;21490779;22064539;23571535;24583671;29590335;27371814;21507923;22190015;25808007;27536979;19420165;22729923;18784469;23449229;22832059;20961377;22031948;27254747;20827161",
"title": "Survival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d'Ivoire West Africa.",
"title_normalized": "survival among antiretroviral experienced hiv 2 patients experiencing virologic failure with drug resistance mutations in cote d ivoire west africa"
} | [
{
"companynumb": "CM-GLAXOSMITHKLINE-CI2020GSK163266",
"fulfillexpeditecriteria": "1",
"occurcountry": "CI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nRefractory status epilepticus (RSE) is associated with high morbidity and mortality. Experts recommend aggressive management with continuous intravenous infusions or inhaled anesthetics such as isoflurane. However, there is concern that MRI changes in RSE reflect isoflurane neurotoxicity. We performed a case-control study to determine whether isoflurane is neurotoxic, based on MRI signal changes.\n\n\nMETHODS\nWe performed a retrospective case-control study of the incidence of MRI changes in RSE treated with and without isoflurane. Charts were reviewed for demographic and treatment information. T1, T2, and FLAIR sequences of MRIs were reviewed independently by two neuroradiologists blinded to treatment group for presence or absence of signal change or atrophy in the meninges, cortex, white matter, basal ganglia, thalamus, hippocampus, brainstem, and cerebellum.\n\n\nRESULTS\nEight cases of RSE receiving treatment with isoflurane were identified and double-matched with 15 controls who received only intravenous anesthetics. Baseline characteristics were similar. Hippocampal signal change was observed more frequently in cases receiving isoflurane (p = 0.026).\n\n\nCONCLUSIONS\nHippocampal signal changes were associated with isoflurane use in patients with RSE. They were also associated with number of seizure days prior to MRI and the use of multiple anesthetic agents. Similar changes have been seen as a result of RSE itself, and one cannot rule out the possibility these changes represent seizure-related effects. If isoflurane-related, these hippocampal signal changes may be the result of a direct neurotoxic effect of prolonged isoflurane use or failure of isoflurane to protect the hippocampus from seizure-induced injury despite achieving electrographic burst-suppression.",
"affiliations": "Department of Clinical Neurological Sciences, London Health Sciences Centre, London, ON, Canada.;Department of Neurology, Columbia University Medical Centre, New York, NY, USA.;Department of Radiology, London Health Sciences Centre, London, ON, Canada.;Department of Radiology, Columbia University Medical Centre, New York, NY, USA.;Department of Neurology, Columbia University Medical Centre, New York, NY, USA.;Department of Clinical Neurological Sciences, London Health Sciences Centre, London, ON, Canada. bryan.young@lhsc.on.ca.",
"authors": "Ikeda|Kristin M|KM|;Connors|Robert|R|;Lee|Donald H|DH|;Khandji|Alexander G|AG|;Claassen|Jan|J|;Young|G Bryan|GB|",
"chemical_list": "D018685:Anesthetics, Inhalation; D007530:Isoflurane",
"country": "United States",
"delete": false,
"doi": "10.1007/s12028-016-0340-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1541-6933",
"issue": "26(3)",
"journal": "Neurocritical care",
"keywords": "Hippocampus; Isoflurane; MRI; Refractory status epilepticus",
"medline_ta": "Neurocrit Care",
"mesh_terms": "D000328:Adult; D018685:Anesthetics, Inhalation; D016022:Case-Control Studies; D000069279:Drug Resistant Epilepsy; D005260:Female; D006624:Hippocampus; D006801:Humans; D007530:Isoflurane; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013226:Status Epilepticus; D055815:Young Adult",
"nlm_unique_id": "101156086",
"other_id": null,
"pages": "420-427",
"pmc": null,
"pmid": "28028789",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "20068576;17197850;19293697;15805807;16931673;22075020;14980940;25572922;23294049;12651650;26362376;24614522;1527556;8385002;22192381;18329995;11843690;18723376;20885290;22510328;23787273;7824097;22119003;18769858;15313843;21914716;8346834;22343609;8828581;21190757;18156878;15105206;20841413;2817458;12131129;26380557",
"title": "Isoflurane Use in the Treatment of Super-Refractory Status Epilepticus is Associated with Hippocampal Changes on MRI.",
"title_normalized": "isoflurane use in the treatment of super refractory status epilepticus is associated with hippocampal changes on mri"
} | [
{
"companynumb": "CA-BAXTER-2013BAX030721",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOFLURANE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nLymphoma is the fourth most frequent cancer in pregnancy; however, current clinical practice is based largely on small series and case reports.\n\n\nMETHODS\nIn a multicenter retrospective analysis, we examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) occurring during pregnancy.\n\n\nRESULTS\nAmong 90 patients (NHL, n = 50; HL, n = 40), median age was 30 years (range, 18 to 44 years) and median diagnosis occurred at 24 weeks gestation. Of patients with NHL, 52% had advanced-stage versus 25% of patients with HL (P = .01). Pregnancy was terminated in six patients. Among the other 84 patients, 28 (33%) had therapy deferred to postpartum; these patients were diagnosed at a median 30 weeks gestation. This compared with 56 patients (67%) who received antenatal therapy with median lymphoma diagnosis at 21 weeks (P < .001); 89% of these patients received combination chemotherapy. The most common preterm complication was induction of labor (33%). Gestation went to full term in 56% of patients with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. At 41 months, 3-year progression-free survival (PFS) and overall survival (OS) for NHL were 53% and 82%, respectively, and 85% and 97%, respectively, for HL. On univariate analysis for NHL, radiotherapy predicted inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS. For HL patients, nulliparous status and \"B\" symptoms predicted inferior PFS.\n\n\nCONCLUSIONS\nStandard (non-antimetabolite) combination chemotherapy administered past the first trimester, as early as 13 weeks gestation, was associated with few complications and expected maternal survival with lymphoma occurring during pregnancy.",
"affiliations": "Andrew M. Evens, Tufts University School of Medicine, Boston; Aimee Kroll-Desrosiers, University of Massachusetts Medical School, Worcester, MA; Ranjana Advani and Stavroula Otis, Stanford University Medical Center, Stanford, CA; Oliver W. Press and Linda M. Parker, Fred Hutchinson Cancer Research Center, Seattle, WA; Izidore S. Lossos, Liat Nadav Dagan, and Jose Sandoval, University of Miami School of Medicine, Miami, FL; Julie M. Vose, University of Nebraska Medical Center, Omaha, NE; Francisco J. Hernandez-Ilizaliturri, Roswell Park Cancer Institute, Buffalo; Ramsey Abdallah and John P. Leonard, Weill Cornell Medical College, New York, NY; Barrett K. Robinson, Indiana University School of Medicine, Indianapolis, IN; Jessica L. Yarber and Leo I. Gordon, Northwestern University Feinberg School of Medicine, Chicago, IL; Kristie A. Blum, The Ohio State University, Columbus, OH; Christopher R. Flowers, Emory University, Atlanta, GA; Thomas M. Habermann, Mayo Clinic, Rochester, MN; and Nancy L. Bartlett, Washington University School of Medicine, St. Louis, MO.",
"authors": "Evens|Andrew M|AM|;Advani|Ranjana|R|;Press|Oliver W|OW|;Lossos|Izidore S|IS|;Vose|Julie M|JM|;Hernandez-Ilizaliturri|Francisco J|FJ|;Robinson|Barrett K|BK|;Otis|Stavroula|S|;Nadav Dagan|Liat|L|;Abdallah|Ramsey|R|;Kroll-Desrosiers|Aimee|A|;Yarber|Jessica L|JL|;Sandoval|Jose|J|;Foyil|Kelley|K|;Parker|Linda M|LM|;Gordon|Leo I|LI|;Blum|Kristie A|KA|;Flowers|Christopher R|CR|;Leonard|John P|JP|;Habermann|Thomas M|TM|;Bartlett|Nancy L|NL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2013.49.8220",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "31(32)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D005260:Female; D005333:Fetus; D006801:Humans; D053208:Kaplan-Meier Estimate; D008223:Lymphoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "4132-9",
"pmc": null,
"pmid": "24043736",
"pubdate": "2013-11-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis.",
"title_normalized": "lymphoma occurring during pregnancy antenatal therapy complications and maternal survival in a multicenter analysis"
} | [
{
"companynumb": "US-TEVA-586018USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nAlthough there have been a few studies reporting thromboembolic events (TEEs) in patients treated with immune checkpoint inhibitors (ICIs), the detailed profile of the TEEs and the prothrombotic effects of ICIs remain mostly unknown.\n\n\nMETHODS\nData from January 2004 to December 2019 in the FAERS database were retrieved. We investigated the clinical characteristics of the TEEs and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare ICIs with the full database and other anti-cancer agents.\n\n\nRESULTS\nWe identified 1855 reports of TEEs associated with ICIs. Affected patients tended to be male (59.68%) and older than 65 (47.12%). The case-fatality rate of the reported TEEs was high (38%). The median time to onset (TTO) of all cases was 42 (interquartile range [IQR] 15-96) days and the median TTO of fatal cases (31 [IQR 13-73] days) was significantly shorter than non-fatal cases (50 [IQR 20-108] days, p = 0.000002). ICIs showed increased risks of VTE (ROR 2.81, 95% CI 2.69-2.95) and ATE (ROR 1.44, 95% CI 1.37-1.52) compared with the full database. Compared with protein kinase inhibitors, ICIs showed an increased risk of VTE (ROR 1.23, 95% CI 1.17-1.29), but only anti-PD-L1 showed an increased risk of cerebral ATE (ROR 1.38, 95% CI 1.08-1.76). Compared with chemotherapy, ICIs showed an increased risk of PE (ROR 1.14, 95% CI 1.07-1.21).\n\n\nCONCLUSIONS\nOur study suggested ICIs tend to increase risks of VTE and ATE. The poor clinical outcome and early onset of these events should attract clinical attention.",
"affiliations": "Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing 100020, China. Electronic address: 1501102@ccmu.edu.cn.;Department of Pharmacy, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100020, China. Electronic address: ximu18@ccmu.edu.cn.;Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing 100020, China. Electronic address: sundan@mail.ccmu.edu.cn.;Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing 100020, China. Electronic address: jinzhao520@mail.ccmu.edu.cn.;Nirvana Intelligent (Shenzhen) Co., Ltd, Shenzhen, Guangdong Province 510810, China.;Nirvana Intelligent (Shenzhen) Co., Ltd, Shenzhen, Guangdong Province 510810, China.;Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China. Electronic address: mazhuo2013@163.com.;Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing 100020, China. Electronic address: zhangyhcy@163.com.",
"authors": "Li|Hao|H|;Sun|Ximu|X|;Sun|Dan|D|;Zhao|Jin|J|;Xu|Zhouming|Z|;Zhao|Peng|P|;Ma|Zhuo|Z|;Zhang|Yuhui|Y|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.intimp.2021.107818",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1567-5769",
"issue": "98()",
"journal": "International immunopharmacology",
"keywords": "CTLA-4; FAERS; Immune checkpoint inhibitor; PD-1; PD-L1; Thromboembolic event",
"medline_ta": "Int Immunopharmacol",
"mesh_terms": null,
"nlm_unique_id": "100965259",
"other_id": null,
"pages": "107818",
"pmc": null,
"pmid": "34130149",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thromboembolic events associated with immune checkpoint inhibitors: A real-world study of data from the food and drug administration adverse event reporting system (FAERS) database.",
"title_normalized": "thromboembolic events associated with immune checkpoint inhibitors a real world study of data from the food and drug administration adverse event reporting system faers database"
} | [
{
"companynumb": "CN-ROCHE-2939952",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATEZOLIZUMAB"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Brivaracetam is a new antiepileptic drug indicated for adjunctive treatment of focal seizures in adults at a dose of 50-200mg/day taken in two equal doses. The objective of this study was to evaluate the abuse potential of brivaracetam compared with alprazolam (positive control), placebo, and levetiracetam.\n\n\n\nThis was a randomized, double-blind, triple-dummy, crossover study in healthy male and female recreational central nervous system (CNS) depressant users aged 18-55years, who could distinguish between the subjective effects of alprazolam 2mg and placebo. All participants received single doses of brivaracetam (50 [therapeutic dose], 200, 1000mg [supratherapeutic doses]), alprazolam (1.5, 3mg), placebo, and levetiracetam (4000mg) in random order each separated by 7-10days. Subjective Visual Analogue Scales (VAS) and Addiction Research Center Inventory (ARCI) scales were completed at intervals up to 24h postdose. Primary endpoints were Drug Liking (at this moment) VAS, Overall Drug Liking VAS, Feeling High VAS, and ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG, sedation) maximum effect (Emax). Maximum effect values on each scale were analyzed using a mixed-effect model (per protocol population, N=44).\n\n\n\nThe maximum effect for both alprazolam doses was significantly greater versus placebo for six designated endpoints, confirming study validity. Drug Liking (at this moment) VAS Emax was significantly lower for brivaracetam 50mg than alprazolam (both doses); there were no significant differences between brivaracetam 200mg and alprazolam (both doses), and brivaracetam 1000mg and alprazolam 1.5mg. Brivaracetam 1000mg (supratherapeutic single dose) had significantly higher Drug Liking (at this moment) VAS Emax than alprazolam 3mg. Overall, Drug Liking VAS Emax for brivaracetam 50 and 200mg was not significantly different from alprazolam (both doses). Brivaracetam 1000mg had significantly higher Overall Drug Liking VAS Emax than alprazolam 1.5mg, but was not significantly different from alprazolam 3mg. Feeling High VAS Emax was lower versus alprazolam with brivaracetam 50 and 200mg, while brivaracetam 1000mg was comparable with alprazolam (both doses). Addiction Research Center Inventory PCAG Emax for brivaracetam (all doses) was significantly lower than alprazolam (both doses). On the secondary/supportive endpoints, compared with alprazolam, brivaracetam had fewer positive effects (ARCI Morphine Benzedrine Group [euphoria]; Good Drug Effects VAS [50mg]) and fewer negative effects (Bad Drug Effects VAS; ARCI Lysergic Acid Diethylamide [dysphoria]). Brivaracetam was not significantly different from alprazolam for Take Drug Again VAS (50, 200mg). For most endpoints, brivaracetam (50-200mg) was not significantly different from levetiracetam (4000mg).\n\n\n\nThis study in healthy recreational CNS depressant users showed that single doses of brivaracetam 50mg (therapeutic single dose) had lower sedative, positive, and negative drug effects than alprazolam, while brivaracetam 200 and 1000mg (supratherapeutic single doses) were more similar to alprazolam. The subjective profile of brivaracetam appeared to be similar to that of levetiracetam, but further evaluation using a range of levetiracetam doses would be needed to confirm similar abuse potential.",
"affiliations": "DecisionLine Clinical Research Corporation,(4) Toronto, Ontario, Canada. Electronic address: kschoedel@altreos.com.;UCB Pharma, Braine l'Alleud, Belgium. Electronic address: Armel.Stockis@ucb.com.;DecisionLine Clinical Research Corporation,(4) Toronto, Ontario, Canada.",
"authors": "Schoedel|Kerri A|KA|;Stockis|Armel|A|;Sellers|Edward M|EM|",
"chemical_list": "D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D011760:Pyrrolidinones; D000077287:Levetiracetam; C482793:brivaracetam; D000525:Alprazolam",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2017.09.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "78()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Abuse potential; Alprazolam; Antiepileptic drug; Brivaracetam; Levetiracetam; Subjective measures",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000525:Alprazolam; D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D018592:Cross-Over Studies; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005059:Euphoria; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D013287:Illicit Drugs; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones; D055815:Young Adult",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "194-201",
"pmc": null,
"pmid": "29153631",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Human abuse potential of brivaracetam in healthy recreational central nervous system depressant users.",
"title_normalized": "human abuse potential of brivaracetam in healthy recreational central nervous system depressant users"
} | [
{
"companynumb": "CA-CIPLA LTD.-2018CA12666",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Venlafaxine is a selective serotonin noradrenaline reuptake inhibitor and commonly prescribed antidepressant in adults. Most patients overdosing with venlafaxine develop only mild symptoms. Severe toxicity is reported with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities. However, lactic acidosis is an uncommon adverse effect. Here, we present the first case in the literature reporting lactic acidosis due to venlafaxine overuse in an adolescent.",
"affiliations": "Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Pediatric Intensive Care Unit, Ankara University Faculty of Medicine, Ankara, Turkey.;Pediatric Intensive Care Unit, Ankara University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.",
"authors": "Eldem|İrem|İ|;Kendirli|Tanıl|T|;Azapağası|Ebru|E|;Özdemir|Gülşah|G|;Yıldız|Çisem|Ç|;Yılmaz|Mehmet Mustafa|MM|;Karataşoğlu|Özlem|Ö|;Benderlioğlu|Elif|E|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D000069470:Venlafaxine Hydrochloride",
"country": "Turkey",
"delete": false,
"doi": "10.24953/turkjped.2016.02.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "58(2)",
"journal": "The Turkish journal of pediatrics",
"keywords": "adolescent; lactic acidosis; overdose; venlafaxine",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000140:Acidosis, Lactic; D000293:Adolescent; D062787:Drug Overdose; D005260:Female; D006801:Humans; D017367:Serotonin Uptake Inhibitors; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "200-202",
"pmc": null,
"pmid": "27976562",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Venlafaxine intoxication in an adolescent presenting with severe lactic acidosis.",
"title_normalized": "venlafaxine intoxication in an adolescent presenting with severe lactic acidosis"
} | [
{
"companynumb": "US-ENDO PHARMACEUTICALS INC-2017SCPR016317",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
... |
{
"abstract": "Takotsubo syndrome (TS) is an acute and reversible clinical syndrome characterized by transient hypokinesis of the left ventricular (LV) apex. Variant forms of LV dysfunction have been reported, including inverted Takotsubo syndrome (ITS), which represents only 5% of cases and has previously been linked to excessive use of inhaled adrenergic beta-2 agonists. The authors describe the case of a 60-year-old female patient who was diagnosed with ITS after the excessive use of inhaled adrenergic beta-2 agonists. This case highlights an uncommon variant of this syndrome that may not be obvious and must be suspected in this particular context.\nTakotsubo syndrome (TS) was initially described with a classic pattern of LV apical akinesis and accounts for around 75-80% of cases. Variants including inverted Takotsubo (also known as basal variant) can affect other areas of the myocardium.Several physiopathological mechanisms have been implicated. Catecholamine-induced cardiotoxicity is one of the most supported theories, while other triggers, including excessive use of inhaled beta-2 agonists, have also been described.Treatment of TS is mainly symptomatic and conservative and frequently leads to rapid resolution and LV function recovery.",
"affiliations": "Internal Medicine Department, Centro Hospitalar do Médio Tejo, E.P.E., Torres Novas, Portugal.;Intensive Care Unit, Hospital da Luz, Lisbon, Portugal.;Intensive Care Unit, Hospital da Luz, Lisbon, Portugal.;Cardiology Department, Hospital da Luz, Lisbon, Portugal.;Intensive Care Unit, Hospital da Luz, Lisbon, Portugal.",
"authors": "de Sousa|Marta|M|;Casado|André|A|;Marques|Alexandre Buinhas|AB|;Machado|Francisco Pereira|FP|;Esperança|Isabel|I|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2018_000831",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2018_000831831-1-5033-1-10-20180215ArticlesInverted Variant of Takotsubo Syndrome Caused by Inhaled Adrenergic Beta-2 agonists de Sousa Marta 1Casado André 2Marques Alexandre Buinhas 2Machado Francisco Pereira 3Esperança Isabel 2\n1 Internal Medicine Department, Centro Hospitalar do Médio Tejo, E.P.E., Torres Novas, Portugal\n2 Intensive Care Unit, Hospital da Luz, Lisbon, Portugal\n3 Cardiology Department, Hospital da Luz, Lisbon, Portugal2018 24 4 2018 5 4 00083122 12 2017 22 1 2018 © EFIM 20182018This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseTakotsubo syndrome (TS) is an acute and reversible clinical syndrome characterized by transient hypokinesis of the left ventricular (LV) apex. Variant forms of LV dysfunction have been reported, including inverted Takotsubo syndrome (ITS), which represents only 5% of cases and has previously been linked to excessive use of inhaled adrenergic beta-2 agonists. The authors describe the case of a 60-year-old female patient who was diagnosed with ITS after the excessive use of inhaled adrenergic beta-2 agonists. This case highlights an uncommon variant of this syndrome that may not be obvious and must be suspected in this particular context.\n\nLEARNING POINTS\nTakotsubo syndrome (TS) was initially described with a classic pattern of LV apical akinesis and accounts for around 75–80% of cases. Variants including inverted Takotsubo (also known as basal variant) can affect other areas of the myocardium.\n\nSeveral physiopathological mechanisms have been implicated. Catecholamine-induced cardiotoxicity is one of the most supported theories, while other triggers, including excessive use of inhaled beta-2 agonists, have also been described.\n\nTreatment of TS is mainly symptomatic and conservative and frequently leads to rapid resolution and LV function recovery.\n\nTakotsubo syndromecatecholaminesadrenergic beta-2 agonists\n==== Body\nCASE REPORT\nWe report the case of a 60-year-old woman with a history of chronic obstructive pulmonary disease (COPD), hypereosinophilic syndrome, hypothyroidism, rheumatoid arthritis, depression and arterial hypertension, whose treatment included fluticasone/salmeterol 50 μg/250 μg two puffs twice a day. The patient presented to the emergency room (ER) with a depressed level of consciousness after experiencing dyspnoea, cough and fever for 2 days at home. At home the patient had already overused her bronchodilator, but at the ER she received continuous nebulized salbutamol, furosemide and intravenous hydrocortisone, with no clinical improvement and a worsening of respiratory acidosis. The patient was promptly transferred to the ICU for intubation and mechanical ventilation under ketamine sedation, due to severe bronchospasm. Blood tests revealed an elevated CRP (13.17 mg/dl) and elevated NT-proBNP (11695 pg/ml), while the initial set of cardiac markers was normal but rose subsequently, with a troponin I peak of 9.18 ng/ml. The electrocardiogram showed ST depression in leads V2 and V3, while the echocardiogram showed depressed systolic function and akinesis in the mid and basal segments. A coronary angiogram demonstrated normal epicardial coronary arteries with normal TIMI 3 flow. Ventriculography revealed a mid-wall and basal ballooning pattern, suggesting the diagnosis of inverted Takotsubo syndrome (ITS) (Fig. 1).\n\nA thorax CT scan showed diffuse ground glass opacification and so antibiotherapy with piperacilin-tazobactam and azithromycin was started. Evolution was favourable, leading to extubation within 3 days. A subsequent echocardiogram, performed 3 days after the angiogram, showed complete recovery of left ventricular function with preserved ejection fraction and normal wall motion. The patient was discharged from the ICU at that point. The echocardiogram remained normal 5 months later.\n\nDISCUSSION\nWe report this clinical case because Takotsubo syndrome (TS) is a relatively recent cardiac diagnosis and remains a clinical challenge, especially in the uncommon variants like ITS. Its true prevalence remains unknown[1]. TS represents 1–2% of suspected cases of acute coronary syndrome and is a very important differential diagnosis of acute myocardial infarction[1, 2]. Prompt diagnosis is extremely important as both the treatment and prognosis of these clinical entities differ significantly. The condition predominantly affects postmenopausal women[2] (more than 90% of cases) and the major symptoms may include chest pain and dyspnoea, with electrocardiographic changes, such as ST-segment depression, as in the presented case[3, 4], but which may be indistinguishable from typical ST-elevation myocardial infarction.\n\nThe diagnosis of TS requires the exclusion of obstructive coronary artery disease, and thus an emergent angiogram is crucial in order, for instance, to avoid unnecessary thrombolysis[1], as well as other unwarranted treatments. All these features are part of the latest Takotsubo Syndrome Diagnostic Criteria adopted in 2015 by the Heart Failure Association of the European Society of Cardiology[3].\n\nThe name ‘Takotsubo’ refers to the originally described, and hence classic, form of extensive apical and/or mid-venticular akinesia or hypokinesia and basal hypercontractility (narrow base with apical ballooning), resembling the octopus-catching vases of Japanese fisherman[1, 3]. However, there are anatomical variants, including ITS which is also known as the basal variant and which represents 5% of all TS, with circumferential basal hypokinesia and apical hypercontractility[1, 3]. There are other anatomical variants, such as the mid left ventricular variant (the most frequent variant), biventricular apical dysfunction, isolated right ventricular or dysfunction sparing apical tip, with uncertain prevalence. A likely explanation for the variants is the different rates of LV segment recovery [3].\n\nPossible pathophysiological mechanisms have been discussed including coronary microvascular dysfunction, coronary artery spasm[5] and abnormalities in cardiac fatty acid metabolism, but catecholamine-induced cardiotoxicity is currently the most supported explanation[2]. Increased beta-2-adrenoreceptor stimulation has been proposed as a possible cause of this entity[6] and the task force on TS of the Heart Failure Association of the European Society of Cardiology proposed a classification as secondary TS[3] as a substantial proportion of cases occur in patients already hospitalized for another medical condition, and are a complication of the primary condition or its treatment[3]. Our patient can be diagnosed as having secondary TS since she was hospitalized due to acute exacerbation of COPD. It is probable that treatment with large doses of inhaled adrenergic beta-2 agonists, associated with activation of the sympathetic nervous system and a rise in catecholaminergic tone, precipitated acute TS. Emotional stress and illicit drug abuse were ruled out. The latest recommendations also suggest that after diagnosis, patients should be triaged according to a risk stratification algorithm; according to current recommendations, this patient would have been included in the high-risk category. All patients with TS should be monitored in a coronary care/high-dependency unit for 24 hours. After that, according to risk stratification, high-risk patients should stay in these units, while low-risk patients may be transferred to lower level monitoring units. However, this system is currently based on expert opinion (with a level of evidence of C), due to the lack of prospective studies[3].\n\nTreatment of this condition during the acute phase is mainly symptomatic and – as in the case of our patient – management should focus on the triggering underlying condition[2]. The role of beta-blockers is still controversial but may provide some protection in selected patients, such as those with recurrent TS[3]. In the ER, beta-2 agonists should be used with caution and the recommended dose should not be exceeded. Treatment of bronchospasm with beta-2 agonists can be avoided as anticholinergic agents, steroids and mast cell stabilizers can be used instead.\n\nAs in our patient, prognosis is generally good; left ventricular function starts to recover within a few days and is usually complete within 3–4 weeks[4]. The authors believe that this clinical case report contributes further to the knowledge of this entity and highlights a rare form of this syndrome.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Ventriculographic appearance showing a mid-wall and basal ballooning pattern, suggesting the diagnosis of inverted Takotsubo syndrome\n==== Refs\nREFERENCES\n1 Nóbrega S Brito D The “broken heart syndrome”: state of the art Rev Port Cardiol 2012 31 589 596 22795894 \n2 Komamura K Fukui M Iwasaku T Hirotani S Masuyama T Takotsubo cardiomyopathy: pathophysiology, diagnosis and treatment World J Cardiol 2014 6 602 609 25068020 \n3 Lyon A Bossone E Schneider B Sechtem U Citro R Underwood S Current state of knowledge on Takotsubo syndrome: a position statement from the task force on Takotsubo syndrome of the Heart Failure Association of the European Society of Cardiology Eur J Heart Fail 2016 18 8 27 \n4 Roshanzamir S Showkathali R Takotsubo cardiomyopathy a short review Curr Cardiol Rev 2013 9 191 196 23642025 \n5 Dores H Raposo L Ferreira J Andrade MJ Almeida M Mendes M Apical ballooning syndrome during diagnostic coronary angiography Arq Bras Cardiol 2013 100 e47 50 23681214 \n6 Mendonza I Novaro G Repeat recurrence of takotsubo cardiomyopathy related to inhaled beta-2-adrenoceptor agonists World J Cardiol 2012 4 211 213 22761975\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "5(4)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Takotsubo syndrome; adrenergic beta-2 agonists; catecholamines",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000831",
"pmc": null,
"pmid": "30756027",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "22761975;22795894;23642025;23681214;25068020;26548803",
"title": "Inverted Variant of Takotsubo Syndrome Caused by Inhaled Adrenergic Beta-2 agonists.",
"title_normalized": "inverted variant of takotsubo syndrome caused by inhaled adrenergic beta 2 agonists"
} | [
{
"companynumb": "PHHY2018PT186019",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
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"actiondrug": "5",
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"activesubstancename": "HYDROCORTISONE"
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"drugadditional": "3",
"d... |
{
"abstract": "Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to treat patients with various cancers. However, it is known to be associated with adverse events, such as hypertension and proteinuria. The histology of bevacizumab-induced nephropathy is known as thrombotic microangiopathy or minimal change nephrotic syndrome. Recently, however, the terms \"bevacizumab-associated glomerular microangiopathy\" and \"anti-VEGF therapy-induced glomerular microangiopathy\" have been proposed. We present a case of a 68-year-old woman who was administered postoperative chemotherapy (carboplatin, paclitaxel, and bevacizumab) for stage IV ovarian cancer. Proteinuria and hypertension appeared after three courses; however, six courses were completed. Then, gemcitabine and carboplatin were administered for recurrence of her cancer. She was diagnosed with nephrotic syndrome after eight courses. Renal biopsy showed accumulation of periodic acid-Schiff (PAS)-positive substances in the capillary walls and para-mesangial areas. Double contouring of basement membranes was also observed. Immunofluorescence microscopy revealed positive staining for IgG, IgA, IgM, C3, C4, and C1q. Immunosuppressive therapy was administered, but was ineffective. Further examination by electron microscopy and immunostaining led to a diagnosis of bevacizumab-associated glomerular microangiopathy.",
"affiliations": "Division of Nephrology, Sakai City Medical Center, 1-1-1 Ebaraji-cho, Nishi-ku, Sakai, Osaka, Japan. m_i_morimoto@sakai-hospital.jp.;Division of Nephrology, Sakai City Medical Center, 1-1-1 Ebaraji-cho, Nishi-ku, Sakai, Osaka, Japan.;Division of Nephrology, Sakai City Medical Center, 1-1-1 Ebaraji-cho, Nishi-ku, Sakai, Osaka, Japan.;Department of Pathology, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minamikoshigaya, Koshigaya, Saitama, Japan.",
"authors": "Morimoto|Madoka|M|0000-0002-4910-0278;Arai|Tatsuya|T|;Matsuura|Motoo|M|;Ono|Yuko|Y|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-020-00504-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "10(1)",
"journal": "CEN case reports",
"keywords": "Bevacizumab-associated glomerular microangiopathy; Nephrotic syndrome; Ovarian cancer",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D001706:Biopsy; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005455:Fluorescent Antibody Technique; D005920:Glomerular Mesangium; D006801:Humans; D007678:Kidney Glomerulus; D008854:Microscopy, Electron; D009365:Neoplasm Regression, Spontaneous; D009367:Neoplasm Staging; D009404:Nephrotic Syndrome; D010051:Ovarian Neoplasms; D011182:Postoperative Care; D011507:Proteinuria; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "6-11",
"pmc": null,
"pmid": "32642991",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25130034;25674232;20538785;17457362;18337603;17267332;30014486;25210627;24207130;30868298;26985375;27436855;16597608;12538598;30552416",
"title": "Bevacizumab-associated glomerular microangiopathy that occurred after postoperative chemotherapy for ovarian cancer.",
"title_normalized": "bevacizumab associated glomerular microangiopathy that occurred after postoperative chemotherapy for ovarian cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-282735",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "BACKGROUND\nAcute pancreatitis is a relatively rare but potentially lethal complication after transarterial chemotherapy. This study aimed to review the complications such as acute pancreatitis after transarterial chemotherapy with or without embolization for hepatocellular carcinoma.\n\n\nMETHODS\nA total of 1632 patients with hepatocellular carcinoma who had undergone transarterial chemoembolization from January 2000 to February 2014 in a single-center were reviewed retrospectively. We investigated the potential complications of transarterial chemoembolization, such as acute pancreatitis and acute pancreatitis-related complications.\n\n\nRESULTS\nOf the 1632 patients with hepatocellular carcinoma who had undergone 5434 transarterial chemoembolizations, 1328 were male and 304 female. The median age of these patients was 61 years. Most (79.6%) of the patients suffered from HBV-related hepatocellular carcinoma. The median tumor size was 5.2 cm. Of the 1632 patients, 145 patients underwent transarterial chemoembolization with doxorubicin eluting bead, making up a total of 538 episodes. The remaining patients underwent transarterial chemoembolization with cisplatin. Seven (0.4%) patients suffered from acute pancreatitis post-chemoembolization. Six patients had chemoembolization with doxorubicin and one had chemoembolization with cisplatin. Patients who received doxorubicin eluting bead had a higher risk of acute pancreatitis [6/145 (4.1%) vs 1/1487 (0.1%), P<0.0001]. Two patients had anatomical arterial variations. Four patients developed acute pancreatitis-related complications including necrotizing pancreatitis (n=3) and pseudocyst formation (n=1). All of the 4 patients resolved after the use of antibiotics and other conservative treatment. Three patients had further transarterial chemoembolization without any complication.\n\n\nCONCLUSIONS\nAcute pancreatitis after transarterial chemoembolization could result in serious complications, especially after treatment with doxorubicin eluting bead. Continuation of current treatment with transarterial chemoembolization after acute pancreatitis is feasible providing the initial attack is completely resolved.",
"affiliations": "Division of Hepatobiliary & Pancreatic Surgery and Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong, China. acchan@hku.hk.",
"authors": "She|Wong Hoi|WH|;Chan|Albert Cy|AC|;Cheung|Tan To|TT|;Chok|Kenneth Sh|KSh|;Chan|See Ching|SC|;Poon|Ronnie Tp|RT|;Lo|Chung Mau|CM|",
"chemical_list": "D000970:Antineoplastic Agents; D004317:Doxorubicin; D002945:Cisplatin",
"country": "Singapore",
"delete": false,
"doi": "10.1016/s1499-3872(15)60034-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "15(1)",
"journal": "Hepatobiliary & pancreatic diseases international : HBPD INT",
"keywords": null,
"medline_ta": "Hepatobiliary Pancreat Dis Int",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D002945:Cisplatin; D004317:Doxorubicin; D005260:Female; D006723:Hong Kong; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101151457",
"other_id": null,
"pages": "93-8",
"pmc": null,
"pmid": "26818549",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute pancreatitis induced by transarterial chemoembolization: a single-center experience of over 1500 cases.",
"title_normalized": "acute pancreatitis induced by transarterial chemoembolization a single center experience of over 1500 cases"
} | [
{
"companynumb": "HK-MYLANLABS-2016M1014519",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Herein the case of a patient with a prior history of heparin-induced thrombocytopenia who underwent percutaneous mitral valve edge-to-edge repair that was followed by a tricuspid edge-to-edge repair two months later is presented. Recommendations exist for systemic anticoagulant alternatives for percutaneous mitral valve edge-to-edge repair with the MitraClip device (Abbott, Chicago, IL), but minimal guidance and experience are present regarding alternative systemic anticoagulation during the performance of right-sided interventions, including tricuspid edge-to-edge repair (TriClip; Abbott). Notably, there is no clear consensus regarding the use of an alternative anticoagulant in the catheter flush solution for the delivery systems used during these procedures, particularly for right-sided interventions.",
"affiliations": "Division of Cardiothoracic Anesthesiology, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL.;Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL.;Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL.;Division of Cardiothoracic Anesthesiology, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL; Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL; University of Alabama at Birmingham Comprehensive Cardiovascular Center, Birmingham, AL. Electronic address: dylanaddis@uabmc.edu.",
"authors": "Colbaugh|Zachary|Z|;Watts|Thomas Evans|TE|;Ahmed|Mustafa I|MI|;Addis|Dylan R|DR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1053/j.jvca.2021.03.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0770",
"issue": null,
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "MitraClip; TriClip; anticoagulation; bivalirudin; heparin-induced thrombocytopenia; percutaneous valve repair",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": null,
"nlm_unique_id": "9110208",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33836962",
"pubdate": "2021-03-06",
"publication_types": "D002363:Case Reports",
"references": "20160186;32382318;11729365;30280640;18499566;24273237;26477635;1505142;28991551;31249965;17124018;29742374;16643427;31645190;28833456;19933539;3485938;31274032;28416511;31772529;21506142;27513970;10950681;32028295;26211708;16524153",
"title": "Bivalirudin as a Systemic Anticoagulant and Flush Solution Additive for Sequential Mitral and Tricuspid Valve Percutaneous Edge-to-Edge Repair in a Patient With Heparin-Induced Thrombocytopenia.",
"title_normalized": "bivalirudin as a systemic anticoagulant and flush solution additive for sequential mitral and tricuspid valve percutaneous edge to edge repair in a patient with heparin induced thrombocytopenia"
} | [
{
"companynumb": "US-MLMSERVICE-20210419-2838702-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nThe use of aspirin during in vitro fertilization (IVF) has been investigated for its effect on pregnancy rates after IVF. In most of these studies, aspirin administration was then prolonged throughout the first trimester of pregnancy. By inhibiting vasoconstriction, the use of low-dose aspirin in the first trimester could influence placentation and therefore prevent or delay development of hypertensive pregnancy complications, such as pregnancy-induced hypertension (PIH) and pre-eclampsia (PE).\n\n\nMETHODS\nThis study involved the follow-up by questionnaires and hospital records of patients with an ongoing pregnancy in a prospective, randomized, double-blind, placebo-controlled trial on the effect of low-dose aspirin during IVF. Aspirin treatment was continued throughout the first trimester of pregnancy. The primary end-point of this follow-up study was the incidence of pregnancy complications. The original trial is registered with the Dutch Trial Register and as an International Standard Randomized Clinical Trial, No. ISRNCTM97507474.\n\n\nRESULTS\nThere were 54 patients who had ongoing pregnancies in the original trial; 90.7% returned the questionnaire and all Dutch hospital records were retrieved. A significant difference was found in the incidence of hypertensive pregnancy complications: 3.6% in the aspirin group and 26.9% in the placebo group (P < 0.05), resulting in numbers-needed-to-treat (NNT) of 10.3 to prevent hypertensive complications in one pregnancy after IVF treatment.\n\n\nCONCLUSIONS\nThe incidence of hypertensive complications was significantly lower in the group of women treated with low-dose aspirin throughout IVF treatment and first trimester of pregnancy. These results suggest a potential benefit of low-dose aspirin during IVF and first trimester to prevent hypertensive pregnancy complications. The findings justify further investigation in placebo-controlled randomized trials.",
"affiliations": "Department of Obstetrics, Gynecology and Reproductive Medicine, Free University Medical Center (VUmc), PO Box 7057, 1007 MB, Amsterdam, The Netherlands. mj.lambers@vumc.nl",
"authors": "Lambers|Marieke J|MJ|;Groeneveld|Els|E|;Hoozemans|Diederik A|DA|;Schats|Roel|R|;Homburg|Roy|R|;Lambalk|Cornelis B|CB|;Hompes|Peter G A|PG|",
"chemical_list": "D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1093/humrep/dep245",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1161",
"issue": "24(10)",
"journal": "Human reproduction (Oxford, England)",
"keywords": null,
"medline_ta": "Hum Reprod",
"mesh_terms": "D000328:Adult; D001241:Aspirin; D004311:Double-Blind Method; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D015994:Incidence; D010865:Pilot Projects; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular",
"nlm_unique_id": "8701199",
"other_id": null,
"pages": "2447-50",
"pmc": null,
"pmid": "19608566",
"pubdate": "2009-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Lower incidence of hypertensive complications during pregnancy in patients treated with low-dose aspirin during in vitro fertilization and early pregnancy.",
"title_normalized": "lower incidence of hypertensive complications during pregnancy in patients treated with low dose aspirin during in vitro fertilization and early pregnancy"
} | [
{
"companynumb": "PHHY2018NL193592",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "METHODS\nA multi-centered retrospective review from five institutions.\n\n\nOBJECTIVE\nThe aim of this study was to determine whether continuing or withholding disease-modifying antirheumatoid drugs (DMARDs) in the perioperative period affect outcomes in rheumatoid arthritis (RA) patients undergoing arthrodesis at the craniovertebral junction SUMMARY OF BACKGROUND DATA.: RA is a chronic systemic inflammatory disease that affects the cervical spine and is treated with DMARDs. Some advocate withholding DMARDs in the perioperative period due to concern for the cytotoxic effects of these medications. However, the impact of DMARDs in the perioperative period is not well understood.\n\n\nMETHODS\nA multicenter retrospective study from five affiliated institutions was performed. Adult patients with RA on chronic DMARDs undergoing posterior arthrodesis of the craniovertebral junction (occipital-cervical or atlanto-axial arthrodesis) were identified. Patients were stratified based on whether DMARD therapy was continued (C group) or discontinued (DC group) in the perioperative period. The primary outcome was the need for reoperation and reason for reoperation.\n\n\nRESULTS\nThirty-nine patients met inclusion criteria, 19 in C group and 20 in DC group. Average follow-up time was 42 months. Four patients (three in DC group and one in C group) required reoperation. Two patients from the DC group required readmission secondary to RA flare-up.\n\n\nCONCLUSIONS\nOur cohort of RA patients who underwent occipital-cervical and C1/C2 posterior arthrodesis showed no significant differences in surgical complications when DMARD therapy was continued or discontinued in the perioperative period. The decision to continue or discontinue DMARD therapy in the perioperative period is at the discretion of the treating physician, but we encourage physicians to counsel patients regarding this theoretical risk and their tolerance of the medications as well as the risk of RA flare-up. Factors such as overall health, disease burden, nutrition, bone quality, smoking status, and other comorbid conditions are likely to have a larger influence on perioperative complications.\n\n\nMETHODS\n3.",
"affiliations": "Division of Neurosurgery, Riverside University Health System Medical Center,Moreno Valley, CA.;Division of Neurosurgery, Riverside University Health System Medical Center,Moreno Valley, CA.;Division of Neurosurgery, Riverside University Health System Medical Center,Moreno Valley, CA.;Division of Neurosurgery, Riverside University Health System Medical Center,Moreno Valley, CA.;Department of Neurosurgery, Kaiser Permanente, Anaheim Medical Center, Anaheim, CA.;Department of Neurosurgery, Kaiser Permanente, Fontana Medical Center, Fontana, CA.;Department of Neurosurgery, Kaiser Permanente, Fontana Medical Center, Fontana, CA.;Department of Neurosurgery, Kaiser Permanente, Sacramento Medical Center, Sacramento, CA.;Department of Neurosurgery, Kaiser Permanente, Fontana Medical Center, Fontana, CA.",
"authors": "Elia|Christopher J|CJ|;Brazdzionis|James|J|;Toor|Harjyot|H|;Takayanagi|Ariel|A|;Hariri|Omid|O|;Asgarzadie|Farbod|F|;Rao|Sanjay|S|;Guppy|Kern|K|;Tashjian|Vartan|V|",
"chemical_list": "D018501:Antirheumatic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/BRS.0000000000003402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-2436",
"issue": "45(13)",
"journal": "Spine",
"keywords": null,
"medline_ta": "Spine (Phila Pa 1976)",
"mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "7610646",
"other_id": null,
"pages": "930-936",
"pmc": null,
"pmid": "32039944",
"pubdate": "2020-07-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Impact of Chronic DMARD Therapy in Patients With Rheumatoid Arthritis Undergoing Surgery of the Craniovertebral Junction: A Multi-center Retrospective Study.",
"title_normalized": "impact of chronic dmard therapy in patients with rheumatoid arthritis undergoing surgery of the craniovertebral junction a multi center retrospective study"
} | [
{
"companynumb": "US-TEVA-2020-US-1827382",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "3",
... |
{
"abstract": "Few data exist regarding the long-term effectiveness of golimumab in ulcerative colitis. No data have been reported on real-world continuous clinical response.\n\n\n\nThis study aimed to describe the long-term outcomes in a large cohort of patients on golimumab who had ulcerative colitis.\n\n\n\nConsecutive patients with active ulcerative colitis, started on golimumab, were enrolled and prospectively followed up. The primary end point was to evaluate the long-term persistence on golimumab therapy.\n\n\n\nA total of 173 patients with ulcerative colitis were studied. Of these, 79.2% were steroid dependent, and 46.3% were naïve to anti-tumour necrosis factor alpha agents. The median duration of golimumab therapy was 52 weeks (range: 4-142 weeks). The cumulative probability of maintaining golimumab treatment was 47.3% and 22.5% at 54 and 108 weeks, respectively. Biological-naïve status (odds ratio [OR] = 3.02, 95% confidence interval [CI]: 1.44-6.29; p = 0.003) and being able to discontinue steroids at Week 8 (OR = 3.32, 95% CI: 1.34-8.30; p = 0.010) and Week 14 (OR = 2.94, 95% CI: 1.08-8.02; p = 0.036) were associated with longer persistence on therapy. At Week 54, 65/124 (52.4%) postinduction responders were in continuous clinical response. A continuous clinical response was associated with a lower likelihood of golimumab discontinuation throughout the subsequent year of therapy (p < 0.01). Overall, 40 (23.1%) patients were in clinical remission at the last follow-up visit. Twenty-six adverse events were recorded, leading to golimumab withdrawal in 9.2% of patients.\n\n\n\nBiological-naïve status and not requiring steroids at Weeks 8 and 14 seem to be associated with a longer persistence on golimumab therapy in ulcerative colitis.",
"affiliations": "CEMAD - IBD Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.;Gastroenterology Department, IBD Referral Centre, Careggi University Hospital, Florence, Italy.;IBD Unit, IRCCS Sacro Cuore Don Calabria, Negrar, Italy.;Inflammatory Bowel Disease Unit, A.O.U. Policlinico G. Martino, Messina, Italy.;CEMAD - IBD Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Inflammatory Bowel Disease Unit, A.O. Cannizzaro, Catania, Italy.;IBD Centre, Humanitas Clinical and Research Centre, Milan, Italy.;Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;AO Ordine Mauriziano, SC Gastroenterologia, Turin, Italy.;Gastroenterology and Hepatology Section, DIBIMIS, University of Palermo School of Medicine, Palermo, Italy.;Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, University Hospital of Padua, Padua, Italy.;Gastroenterology and Artificial Nutrition Department, 'San Nicola Pellegrino' Hospital, Trani, Italy.;Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy.;Gastroenterology Unit, Santa Maria degli Angeli Hospital, Pordenone, Italy.;Gastroenterology Unit, Department of Medicine, University of Verona, Policlinico G.B. Rossi, Verona, Italy.;Digestive Endoscopy Unit, ULSS7 Pedemontana, Santorso, Italy.;UOC Gastroenterologia ed Endoscopia Digestiva Ospedale Civile A, Murri, Italy.;Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Department of Internal Medicine, Gastroenterology Unit, University of Modena and Reggio Emilia, Modena, Italy.;Gastroenterology Unit, University of Pescara, Pescara, Italy.;Division of Gastroenterology, 'Brotzu' Hospital, Cagliari, Italy.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.;Gastroenterology Unit, Rho Hospital, ASST Rhodense, Garbagnate, Milanese, Italy.;IBD Unit, San Filippo Neri Hospital, Rome, Italy.;Gastroenterology and Digestive Endoscopy Department, University of Catanzaro, Catanzaro, Italy.;Gastroenterology Unit, 'Ospedale di Circolo', Varese, Italy.;Gastroenterology and Endoscopy Unit, A.R.N.A.S Civico-Di Cristina- Benfratelli Hospital, Palermo, Italy.;Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.;CEMAD - IBD Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.",
"authors": "Pugliese|Daniela|D|0000-0001-7930-5402;Privitera|Giuseppe|G|0000-0002-7020-5808;Rogai|Francesca|F|;Variola|Angela|A|;Viola|Anna|A|0000-0002-1733-6489;Laterza|Lucrezia|L|;Privitera|Antonino C|AC|;Allocca|Mariangela|M|;Bossa|Fabrizio|F|;Cappello|Maria|M|;Daperno|Marco|M|;Lorenzon|Greta|G|;Mazzuoli|Silvia|S|;Principi|Mariabeatrice|M|;Sablich|Renato|R|;Moser|Luisa|L|;Ferronato|Antonio|A|;Traini|Sara|S|;Tapete|Gherardo|G|;Bodini|Giorgia|G|;Di Girolamo|Maria|M|;Grossi|Laurino|L|;Mocci|Giammarco|G|;Ricci|Chiara|C|;Saibeni|Simone|S|0000-0001-5677-2534;Festa|Stefano|S|0000-0002-4635-3050;Spagnuolo|Rocco|R|;Cortelezzi|Claudio C|CC|;Mocciaro|Filippo|F|;Rizzello|Fernando|F|;Armuzzi|Alessandro|A|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050640620974308",
"fulltext": "\n==== Front\nUnited European Gastroenterol J\nUnited European Gastroenterol J\n10.1002/(ISSN)2050-6414\nUEG2\nUnited European Gastroenterology Journal\n2050-6406\n2050-6414\nJohn Wiley and Sons Inc. Hoboken\n\n33203342\n10.1177/2050640620974308\nUEG212022\nOriginal Article\nInflammatory Bowel Disease\nTwo‐year effectiveness and safety of golimumab in ulcerative colitis: An IG‐IBD study\nPugliese Daniela https://orcid.org/0000-0001-7930-5402\n1\nPrivitera Giuseppe https://orcid.org/0000-0002-7020-5808\n2\nRogai Francesca 3\nVariola Angela 4\nViola Anna https://orcid.org/0000-0002-1733-6489\n5\nLaterza Lucrezia 1\nPrivitera Antonino C. 6\nAllocca Mariangela 7\nBossa Fabrizio 8\nCappello Maria 9\nDaperno Marco 10\nLorenzon Greta 11\nMazzuoli Silvia 12\nPrincipi Mariabeatrice 13\nSablich Renato 14\nMoser Luisa 15\nFerronato Antonio 16\nTraini Sara 17\nTapete Gherardo 18\nBodini Giorgia 19\nDi Girolamo Maria 20\nGrossi Laurino 21\nMocci Giammarco 22\nRicci Chiara 23\nSaibeni Simone https://orcid.org/0000-0001-5677-2534\n24\nFesta Stefano https://orcid.org/0000-0002-4635-3050\n25\nSpagnuolo Rocco 26\nCortelezzi Claudio C. 27\nMocciaro Filippo 28\nRizzello Fernando 29\nArmuzzi Alessandro 1 2 alessandro.armuzzi@policlinicogemelli.it\n\nThe Italian Group for the Study of Inflammatory Bowel Disease (IG‐IBD)\n1 CEMAD ‐ IBD Unit Fondazione Policlinico Universitario A. Gemelli IRCCS Rome Italy\n2 Dipartimento Universitario di Medicina e Chirurgia Traslazionale Università Cattolica del Sacro Cuore Rome Italy\n3 Gastroenterology Department IBD Referral Centre Careggi University Hospital Florence Italy\n4 IBD Unit IRCCS Sacro Cuore Don Calabria Negrar Italy\n5 Inflammatory Bowel Disease Unit A.O.U. Policlinico G. Martino Messina Italy\n6 Inflammatory Bowel Disease Unit A.O. Cannizzaro Catania Italy\n7 IBD Centre Humanitas Clinical and Research Centre Milan Italy\n8 Gastroenterology Unit Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo Italy\n9 AO Ordine Mauriziano SC Gastroenterologia Turin Italy\n10 Gastroenterology and Hepatology Section DIBIMIS University of Palermo School of Medicine Palermo Italy\n11 Division of Gastroenterology Department of Surgery, Oncology and Gastroenterology Gastroenterology Section University Hospital of Padua Padua Italy\n12 Gastroenterology and Artificial Nutrition Department ‘San Nicola Pellegrino’ Hospital Trani Italy\n13 Emergency and Organ Transplantation Department Section of Gastroenterology AOU Policlinico Bari Italy\n14 Gastroenterology Unit Santa Maria degli Angeli Hospital Pordenone Italy\n15 Gastroenterology Unit Department of Medicine University of Verona Policlinico G.B. Rossi Verona Italy\n16 Digestive Endoscopy Unit ULSS7 Pedemontana Santorso Italy\n17 UOC Gastroenterologia ed Endoscopia Digestiva Ospedale Civile A Murri Italy\n18 Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa Pisa Italy\n19 Gastroenterology Unit Department of Internal Medicine University of Genoa Genoa Italy\n20 Department of Internal Medicine Gastroenterology Unit University of Modena and Reggio Emilia Modena Italy\n21 Gastroenterology Unit University of Pescara Pescara Italy\n22 Division of Gastroenterology ‘Brotzu’ Hospital Cagliari Italy\n23 Department of Clinical and Experimental Sciences University of Brescia Brescia Italy\n24 Gastroenterology Unit Rho Hospital ASST Rhodense Garbagnate Milanese Italy\n25 IBD Unit San Filippo Neri Hospital Rome Italy\n26 Gastroenterology and Digestive Endoscopy Department University of Catanzaro Catanzaro Italy\n27 Gastroenterology Unit ‘Ospedale di Circolo’ Varese Italy\n28 Gastroenterology and Endoscopy Unit A.R.N.A.S Civico‐Di Cristina‐ Benfratelli Hospital Palermo Italy\n29 Department of Medical and Surgical Sciences University of Bologna Bologna Italy\n* Correspondence\nAlessandro Armuzzi, IBD Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, I‐00168 Rome, Italy.\nEmail: alessandro.armuzzi@policlinicogemelli.it\n\n01 3 2021\n2 2021\n9 1 10.1002/ueg2.v9.1 102109\n16 7 2020\n16 10 2020\n© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nBackground\n\nFew data exist regarding the long‐term effectiveness of golimumab in ulcerative colitis. No data have been reported on real‐world continuous clinical response.\n\nObjective\n\nThis study aimed to describe the long‐term outcomes in a large cohort of patients on golimumab who had ulcerative colitis.\n\nMethods\n\nConsecutive patients with active ulcerative colitis, started on golimumab, were enrolled and prospectively followed up. The primary end point was to evaluate the long‐term persistence on golimumab therapy.\n\nResults\n\nA total of 173 patients with ulcerative colitis were studied. Of these, 79.2% were steroid dependent, and 46.3% were naïve to anti‐tumour necrosis factor alpha agents. The median duration of golimumab therapy was 52 weeks (range: 4–142 weeks). The cumulative probability of maintaining golimumab treatment was 47.3% and 22.5% at 54 and 108 weeks, respectively. Biological‐naïve status (odds ratio [OR] = 3.02, 95% confidence interval [CI]: 1.44–6.29; p = 0.003) and being able to discontinue steroids at Week 8 (OR = 3.32, 95% CI: 1.34–8.30; p = 0.010) and Week 14 (OR = 2.94, 95% CI: 1.08–8.02; p = 0.036) were associated with longer persistence on therapy. At Week 54, 65/124 (52.4%) postinduction responders were in continuous clinical response. A continuous clinical response was associated with a lower likelihood of golimumab discontinuation throughout the subsequent year of therapy (p < 0.01). Overall, 40 (23.1%) patients were in clinical remission at the last follow‐up visit. Twenty‐six adverse events were recorded, leading to golimumab withdrawal in 9.2% of patients.\n\nConclusions\n\n: Biological‐naïve status and not requiring steroids at Weeks 8 and 14 seem to be associated with a longer persistence on golimumab therapy in ulcerative colitis.\n\ngolimumab\nnaïve\npersistence\nremission\nulcerative colitis\nsource-schema-version-number2.0\ncover-dateFebruary 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:06.07.2021\n==== Body\n1 INTRODUCTION\n\nUlcerative colitis (UC) is a chronic inflammatory disease involving the colon, characterised by a relapsing/remitting course and requiring lifelong medical therapies. Biological drugs and, more recently, Janus kinase inhibitors such as tofacitinib are the best medical option for patients with moderate‐to‐severe disease with an inadequate response or intolerance to conventional therapies (5‐amynosalicilates, steroids and/or thiopurines). 1 golimumab, a fully human IgG1 kappa monoclonal antibody, subcutaneously administered, has now been used in clinical practice for more than five years for the treatment of adult subjects with UC. 2 , 3 The efficacy of golimumab for the induction and maintenance of clinical remission in biological‐naïve UC patients has been studied in two completed clinical trials: PURSUIT induction and PURSUIT maintenance. 4 , 5 In the second trial, a continuous clinical response (CCR) through Week 54, that is, maintenance of a clinical response through Week 54 among golimumab‐induction responders, was adopted as the primary end point, and this achieved in 47.0% of patients receiving 50 mg golimumab and in 49.7% of receiving 100 mg golimumab compared to 31.2% receiving placebo. 5 Long‐term open‐label follow‐up confirmed a good profile of effectiveness up to 4 years, more evident among patients with CCR at 54 weeks. 6 , 7 To date, few long‐term real‐life data have been reported, showing highly variable persistence on golimumab therapy in some cohorts, and particularly reduced in patients pluri‐exposed to anti‐tumour necrosis factor alpha (TNF‐α) drugs and treated with the fixed dose of 50 mg during maintenance therapy. 8 , 9 , 10 , 11 , 12\n\nThe aims of this study were to investigate the mid‐ and long‐term outcomes of patients with UC treated with golimumab in real life and to explore potential predictors for these outcomes.\n\n2 METHODS\n\nWe performed an observational retrospective/prospective study in which consecutive patients who started golimumab therapy between May 2014 and December 2015 at 29 Italian centres, affiliated with the Italian Group for the study of Inflammatory Bowel disease (IG‐IBD), were enrolled. All patients had a prospectively designed standardised follow‐up until December 2017.\n\nIn Italy, to guarantee the prescribing appropriateness, the Italian Medicine Agency (Agenzia Italiana del Farmaco [AIFA]) has instituted a computerised database system for several drugs, including golimumab, accessible to physicians and mandatory to finalise the prescription both at the beginning of and during maintenance treatment. Therefore, accessibility criteria and follow‐up visits scheduled every 8 weeks, requiring a clinical assessment through partial Mayo score (PMS), 13 are standardised for all patients on treatment with golimumab. Accordingly, we adopted a prospectively planned follow‐up protocol, with a shared common database mirroring the AIFA registry, to enrol patients and to follow them up until December 2017.\n\nAccording to the current European‐approved golimumab label, 2 all patients received golimumab induction with 200 and 100 mg at Weeks 0 and 2, respectively, followed by 50 or 100 mg every 4 weeks, depending on their weight (>80 or <80 kg). Patients were not allowed to increase the dose in case of partial response after the induction or loss of response.\n\nThe collected baseline data included: sex, age, weight, height, body mass index, duration of UC, extension of UC according to the Montreal classification, 14 clinical and endoscopic activity, previous therapies (both conventional and biological), the date of the first golimumab dose and concomitant therapies. Baseline and follow‐up clinical and endoscopic activities were determined according to PMS and endoscopic subscore, respectively. 13 Concomitant medications, new prescriptions during follow‐up, the tapering of steroids and timing of treatment discontinuation were left to the investigators' evaluation.\n\nThe primary end point of our study was to evaluate the long‐term persistence on golimumab therapy due to sustained clinical benefit.\n\nSecondary analyses looked for (a) proportion of patients achieving clinical remission at Week 54; (b) CCR through Week 54 among patients with a clinical response after induction; (c) rate of surgery for medical refractory UC; (d) effectiveness of treatment in sparing steroids among patients taking steroids at baseline; and (e) proportion of patients achieving endoscopic remission.\n\nA clinical response was defined as a reduction in the PMS of at least two points and a decrease of at least 30% from the baseline score, with a decrease of at least one point on the rectal bleeding subscale or an absolute rectal bleeding score of 1 or 0. Clinical remission was defined as a PMS of two or lower and no subscore higher than one. We adopted the same definition of CCR through Week 54 previously reported, even though the interval between each clinical assessment was set every 8 weeks. 5 Endoscopic examinations were mandatory at Week 54, but could be anticipated according to clinical judgement. Endoscopic remission was defined as an endoscopic Mayo subscore of 0 or 1. For patients undergoing two or more endoscopic assessments during the study, the last one was considered for the evaluation of endoscopic remission.\n\nReasons for golimumab discontinuation were categorised as: primary failure, defined as the absence of a clinical response at Week 8; secondary failure, defined as a relapse of clinical symptoms during maintenance treatment requiring physicians' interventions; and others, including intolerance or adverse events, lost to follow‐up and pregnancy.\n\nAll adverse events that occurred from the beginning of golimumab treatment to the date of withdrawal or last follow‐up visit on therapy were recorded and categorised as adverse events of interest (AEI) if requiring medical intervention/hospitalisation and/or treatment discontinuation (temporary or permanent).\n\n2.1 Statistical analysis\n\nData were described using means with standard deviation and medians with range for continuous data and percentages for discrete data. Categorical variables were compared using the χ2 test (or Fisher exact test). Cumulative probabilities of persistence on golimumab therapy and CCR through Week 54 were estimated by the Kaplan–Meier method. Binary logistics regression was used to estimate the association between each predictor and persistence on golimumab therapy. Variables that tested significant at binary regression (p < 0.2) were then included in a multivariate logistic regression analysis. Steroid use was updated at each available time point. Results are shown as odds ratios (ORs) and 95% confidence intervals (CIs). A p < 0.05 indicated statistical significance. All analyses were performed with IBM SPSS Statistics for Windows v24.0 (IBM Corp).\n\n2.2 Ethics approval\n\nThe protocol was approved by the ethics committee of the coordinator centre (Fondazione Policlinico Universitario A. Gemelli IRCCS‐Universita Cattolica del Sacro Cuore, Roma, Italy, protocol 1462, 26 January 2017) and of all participating centres. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. Written informed consent was obtained from each patient included in the study.\n\n3 RESULTS\n\n3.1 Patient population\n\nA total of 173 patients were included. Baseline patients' characteristics are summarised in Table 1. According to AIFA eligibility criteria, all patients had moderate to severe active disease, and all of them had showed an inadequate response or had a contraindication to steroids. In particular, 137 (79.2%) patients were steroid dependent, and 27 (15.6%) were refractory according to IG‐IBD definitions. 15 The remaining nine patients had contraindications to steroid therapy. At baseline, 60 (34.7%) patients were on concomitant steroid therapy; 52 (30.1%) and 36 (20.8%) were taking oral steroids at Weeks 8 and 14, respectively. A total of 131 (75.7%) patients weighed less than 80 kg and thus received 50 mg every 4 weeks as a maintenance dose; the remaining 42 (24.2%) weighed more than 80 kg and thus received 100 mg every 4 weeks. A total of 111 (64.2%) patients had been previously exposed to thiopurines, and 92 (53.2%) patients had been previously exposed to at least one anti‐TNF agent: 52 (30.1%) to infliximab, six (3.5%) to adalimumab and 34 (19.7%) to both.\n\nTABLE 1 Baseline patient characteristics\n\nCharacteristic\tValue (N = 173)\t\nMale, n (%)\t94 (54.3)\t\nAge (years), median (range)\t45.7 (18.0–71.1)\t\nWeight (kg), M ± SD\t68.6 ± 14.8\t\n>80 kg, n (%)\t40 (23)\t\nBMI (kg/m2), M ± SD\t23.5 ± 3.88\t\nDuration of disease (years), median (range)\t6.50 (0–58.8)\t\nDisease extent, n (%)\t\t\nE1\t6 (3.5)\t\nE2\t62 (35.8)\t\nE3\t105 (60.7)\t\nClinical severity at baseline PMS, n (%)\t\t\nModerate\t89 (51.4)\t\nSevere\t84 (48.6)\t\nEndoscopic score at baseline, n (%)\t\t\nMayo 2\t75 (43.4)\t\nMayo 3\t98 (56.6)\t\nPrevious exposure to anti‐TNF‐α, n (%)\t92 (53.2)\t\nInfliximab\t52 (30.1)\t\nAdalimumab\t6 (3.5)\t\nBoth\t34 (19.7)\t\nPrevious therapies, n (%)\t\t\nSteroids\t164 (94.7)\t\nThiopurine\t111 (64.2)\t\nCyclosporine\t3 (1.7)\t\nMethotrexate\t9 (5.2)\t\nSteroid dependence, n (%)\t137 (79.2)\t\nSteroid refractoriness, n (%)\t27 (15.6)\t\nConcomitant therapies, n (%)\t\t\nSteroids\t60 (34.7)\t\nThiopurine\t17 (9.8)\t\n5‐ASA\t107 (61.8)\t\nMethotrexate\t3 (1.7)\t\nAbbreviations: 5‐ASA, 5‐aminosalicylic acid; BMI, body mass index; PMS, partial Mayo score (5–7 = moderate, >7 = severe); SD, standard deviation; TNF‐α, tumour necrosis factor alpha.\n\n3.2 Persistency on golimumab therapy\n\nThe median time on golimumab treatment was 52 weeks (range: 4–142 weeks). The cumulative probability of maintaining golimumab treatment was 47.3% and 22.5% at 54 and 108 weeks, respectively (Figure 1). Overall, 126 (72.8%) patients withdrew from golimumab therapy after a median of 31.5 weeks (range: 4–126 weeks). Reasons for discontinuation were primary failure in 51 (40.5%) patients, secondary failure in 51 (40.5%) patients and other causes in 24 (19.1%) patients. Among the 102 patients who withdrew from treatment due to failure, 65 (63.7%) were anti‐TNF‐α experienced compared to 37 (36.3%) who were naïve (p = 0.007; Figure 2). Multivariate regression analysis showed that patients who were anti‐TNF‐α experienced were more likely to withdraw from golimumab therapy compared to patients who were anti‐TNF‐α naive (OR = 3.02, 95% CI: 1.44–6.29; p = 0.003). Moreover, not requiring steroids at Week 8 (OR = 3.32, 95% CI: 1.34–8.30; p = 0.010) and Week 14 (OR = 2.94, 95% CI: 1.088.02; p = 0.036) was associated with higher golimumab persistence. Conversely, male sex seemed to be protective from golimumab withdrawal (OR = 0.44, 95% CI: 0.21–0.94; p = 0.035; Table 2).\n\nFIGURE 1 Cumulative probability of maintaining golimumab treatment\n\nFIGURE 2 Cumulative probability of maintaining golimumab treatment. Patients split between those who were anti‐tumour necrosis factor (TNF) alpha naïve and those who were anti‐TNF alpha experienced\n\nTABLE 2 Results of binary logistic regression for persistence on golimumab therapy in 173 UC patients\n\nVariable\tUnivariate, OR (CI), p\tMultivariate, OR (CI), p\t\nSex (male vs. female)\tOR = 0.52 (CI: 0.26–1.04), p = 0.061\tOR = 0.44 (CI: 0.21–0.94), p = 0.035\t\nAge (<45 vs. >45 years)\tOR = 0.62 (CI: 0.32–1.22), p = 0.166\tOR = 1.32 (CI: 0.64–2.75), p = 0.453\t\nWeight (<80 vs. ˃80 kg)\tOR = 1.08 (CI: 0.49–2.40), p = 0.846\t–\t\nClinical activity at baseline (moderate vs. severe)\tOR = 0.88 (CI: 0.44–1.73), p = 0.701\t–\t\nEndoscopic activity at baseline (Mayo 2 vs. Mayo 3)\tOR = 0.53 (CI: 0.29–1.06), p = 0.072\tOR = 1.63 (CI: 0.79–3.35), p = 0.188\t\nPrevious anti‐TNF‐α (exposed vs. naïve)\tOR = 2.60 (CI: 1.30–5.19), p = 0.006\tOR = 3.02 (CI: 1.45–6.30), p = 0.003\t\nBMI (<25 vs. >25)\tOR = 1.02 (CI: 0.47–2.19), p = 0.970\t–\t\nDisease extension (E1–E2 vs. E3)\tOR = 1.45 (CI: 0.72–2.89), p = 0.295\t–\t\nSteroids at Week 8 (yes vs. no)\tOR = 2.45 (CI: 1.22–8.73), p = 0.006\tOR = 3.33 (CI: 1.34–8.29), p = 0.010\t\nSteroids at Week 14 (yes vs. no)\tOR = 2.14 (CI: 1.08–7.65), p = 0.048\tOR = 2.94 (CI: 1.08–8.02), p = 0.036\t\nAbbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; TNF‐α, tumour necrosis factor alpha; UC, ulcerative colitis.\n\n3.3 Secondary outcomes\n\nAmong 124 patients in clinical response after induction, 65 (52.4%) maintained CCR through Week 54. Clinical remission at Week 54 was recorded in 40 (23.1%) patients. Among the 83 patients still on therapy after 1 year, CCR through Week 54 was associated with a lower likelihood of golimumab discontinuation throughout the subsequent year of therapy (23% with CCR vs. 61% without CCR; p < 0.01). No patients required colectomy after achieving CCR at week 54 compared to six patients not in CCR at Week 54 (p < 0.05).\n\nTwenty‐two (12.7%) patients underwent total colectomy due to medical refractoriness after a median time of 28 weeks (range: 11–92 weeks) from golimumab initiation. Of these, 20 (90.9%) were anti‐TNF‐α experienced. Sixty (34.7%) patients were taking steroids at baseline: 36 (60%) were able to withdraw corticosteroids within 30 weeks. Among the remaining 24 patients, 21 (87.5%) withdrew from golimumab therapy during follow‐up.\n\nAt least one follow‐up endoscopy was performed in 119 (68.8%) patients after a median of 54 weeks (range: 8–122 weeks) from starting golimumab. Endoscopic remission was reported in 44/119 (36.9%) patients.\n\n3.4 Golimumab safety\n\nTwenty‐six AEI were reported by 21 (12.1%) patients. The most frequent AEI were infections (eight patients, 4.6%). Four patients had respiratory infections, one patient had acute gastroenteritis and one patient had genitourinary infection. Two patients experienced opportunistic infections: one experienced cytomegalovirus reactivation, and another was diagnosed with oropharyngeal candidiasis. The last two patients were on concomitant steroid therapy. Six (3.4%) patients developed skin manifestations (two psoriasis and four eczematous dermatitis). Four patients showed allergic reactions: one reaction at the injection site, and three diffuse skin rashes. One patient was diagnosed with oral condyloma, and one with basal‐cell carcinoma. Sixteen patients discontinued golimumab due to an AEI: five infections (three respiratory, one genitourinary and one candidiasis), six skin manifestation, four allergic reactions and one basal‐cell carcinoma.\n\n4 DISCUSSION\n\nThis study focused on the long‐term clinical effectiveness and safety of a large cohort of 173 patients with moderate to severe active UC treated with golimumab. Most of our patients (60.7%) had extensive colitis, and more than a half (53.2%) had already been exposed to at least one anti‐TNF‐α agent. In our cohort, the median follow‐up on golimumab therapy was 52 weeks (range: 4–142 weeks), and the cumulative probability of maintaining golimumab treatment due to sustained clinical benefit was 47.3% and 22.5% at 54 and 108 weeks, respectively. These figures are different from other real‐world experiences, showing around up to 60% of persistence at Week 54. 8 , 11 However, the higher frequency of golimumab discontinuation in our study could be partially explained by the impossibility of escalating to 100 mg early in patients with a primary nonresponse or partial response during the maintenance phase. Most of our patients (75.7%) were in fact maintained with golimumab 50 mg because of their weight (<80 kg). We recorded a primary failure rate of up to 40.5% and 30% golimumab withdrawal within the first 14 weeks.\n\nA post hoc analysis of the PURSUIT trial showed that up to 28.1% of Week 6 nonresponders who were escalated early to golimumab 100 mg achieved a clinical response at Week 14. Moreover, after 1 year, these late responders achieved similar clinical and endoscopic outcomes compared to early responders. Pharmacokinetic data showed that early Week 6 nonresponders had half the golimumab serum concentrations compared to early Week 6 responders. 16 Indeed, in their recent work, Magro et al. 17 found that Week 6 golimumab serum levels were positively correlated with clinical, endoscopic and histological remission, thus reinforcing the idea that early dose escalation could reduce the rates of primary nonresponse.\n\nIn our cohort, naive patients were more likely to maintain golimumab therapy because of a sustained clinical benefit compared to anti‐TNF‐α exposed patients. It should be noted that in about 37% of patients who were anti‐TNF‐α experienced, golimumab was used as a third‐line treatment after failure of infliximab and adalimumab. This situation has already been shown to be associated with a worse outcome compared to first‐ or second‐line utilisation. 8 Therefore, the use of golimumab should be advised at most after the failure of first‐line TNF‐α therapy. Therapeutic drug monitoring could help physicians to determine the most suitable therapeutic option in case of a loss of response to anti‐TNF‐α drugs, including switching within the class for patients with a high titre of neutralising anti‐drug antibodies or, conversely, out of class for patients with a ‘pharmacodynamics escape’ (trough levels within the therapeutic range with negative anti‐drug antibodies). 18\n\nMost patients (79.2%) included in our study were steroid dependent. For such patients, golimumab was expected to provide a clinical improvement by exerting a steroid‐sparing effect as well. Among those who were taking steroids at baseline, the inability to discontinue them after 8 and 14 weeks of golimumab therapy was indeed associated with a higher rate of treatment discontinuation. Accordingly, we might suggest that in clinical practice, patients on golimumab therapy who still need steroids after 2–3 months or, similarly, require an early reintroduction should be revaluated for a therapeutic change.\n\nCCR through Week 54 was observed in 65 (52.4%) patients comparable to those reported in the clinical trial. 5 Achieving CCR was associated with a higher rate of long‐term persistence on golimumab therapy. Moreover, none of the CCR patients underwent colectomy in the subsequent year.\n\nThe outcome of CCR, introduced for the first time in the PURSUIT study, also represents a potential goal for the treatment of UC patients in clinical practice, since it is based on the concept of tight monitoring of patients and of targeting continuous disease control. 19 Even though the evidence supporting that uncontrolled inflammation causes structural bowel damages are limited in comparison with Crohn's disease, 20 UC shows features of a progressive disease, including the proximal extension and the developing of structuring or functional disorders. 21 , 22\n\nFinally, the overall safety profile of golimumab was confirmed to be good, consistent with those reported in other real‐life experiences and of other anti‐TNF‐alpha drugs. 8 , 12 , 16 No new safety concerns about golimumab emerged during our two years of follow‐up.\n\nOur study has some limitations: as described above, including the impossibility of adapting the dose in patients with a partial or lack of response, but also a lack of data on inflammation markers (e.g., C‐reactive protein, faecal calprotectin). Conversely, the strengths of our study are the follow‐up of up to 2 years (median 52 weeks, range: 4–142 weeks), predefined standardised intervals between each clinical visit and homogeneous assessments of clinical and endoscopic activities. Moreover, we reported, for the first time to our knowledge, data on CCR in the real‐life setting and its correlation with a more favourable long‐term outcome.\n\nIn conclusion, golimumab may be considered as an effective and safe treatment option in UC patients, with higher rate of retention in therapy for biological‐naive patients and for those who are able to discontinue steroids early. CCR could potentially represent a target to pursue in clinical practice in order to improve disease control.\n\nCONFLICT OF INTERESTS\n\nThe authors declare the following conflicts of interest: Daniela Pugliese received speaker fees from AbbVie, MSD, Takeda, Janssen and Pfeizer. Giuseppe Privitera received consultancies fees from Alphasigma. Mariangela Allocca received consulting fees from Nikkiso Europe and lecture fees from Janssen, Abbvie and Pfizer. Maria Cappello served as an advisory board member for AbbVie, MSD and Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Chiesi and Takeda Pharmaceuticals. Marco Daperno received lectures, board and/or congress fees from Abbvie, Pfizer, Takeda, Mundipharma, Janssen, MS&D, SOFAR, Ferring and Chiesi. Maria Di Girolamo received speaker fees from Abbvie. Fernando Rizzello acted as consultant for Janssen, Abbvie, Takeda, MSD and Amgen, and participated in a speaker's bureau sponsored by Abbvie, Janssen, Takeda, Ferring, MSD, Sofar and Chiesi. Alessandro Armuzzi received consulting and/or advisory board fees from AbbVie, Allergan, Amgen, Biogen, Bristol‐Myers Squibb, Celgene, Celltrion, Ferring, Janssen, Lilly, MSD, Mylan, Pfizer, Samsung Bioepis, Sandoz and Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Biogen, Ferring, Janssen, MSD, Mitsubishi‐Tanabe, Nikkiso, Pfizer, Sandoz, Samsung Bioepis and Takeda; and research grants from MSD, Pfizer and Takeda. All the other authors have no conflict of interest to declare.\n\nACKNOWLEDGMENTS\n\nEnnio Sarli provided statistical consulting.\n==== Refs\nREFERENCES\n\n1 Dignass A , Eliakim R , Magro F , et al. Second European evidence‐based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis. 2012;6 :965–90.23040452\n2 European Medicines Agency . Simponi®; 2020. https://www.ema.europa.eu/en/documents/product-information/simponiepar-product-information_it.pdf. Accessed 13 July 2020.\n3 Food and Drug Administration . Simponi®; 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125289s006lbl.pdf. Accessed 13 July 2020.\n4 Sandborn WJ , Feagan BG , Marano C , et al. Sub‐cutaneous golimumab induces clinical response and remission in patients with moderate‐to‐severe ulcerative colitis. Gastroenterology. 2014;146 :85–95.23735746\n5 Sandborn WJ , Feagan BG , Marano C , et al. Subcutaneous golimumab maintains clinical response in patients with moderate‐to‐severe ulcerative colitis. Gastroenterology. 2014;146 :96–109.e1.23770005\n6 Reinisch W , Gibson PR , Sandborn WJ , et al. Long‐term benefit of golimumab for patients with moderately‐to‐ severely active ulcerative colitis: results from the PURSUIT‐maintenance extension. J Crohns Colitis. 2018;12 :1053–66.29917070\n7 Reinisch W , Colombel JF , Gibson PR , et al. Continuous clinical response is associated with a change of disease course in patients with moderate to severe ulcerative colitis treated with golimumab. Inflamm Bowel Dis. 2019;25 :163–71.29982631\n8 Taxonera C , Rodriguez C , Bertoletti F , et al. Clinical outcomes of golimumab as first, second or third anti‐ TNF agent in patients with moderate‐to‐severe ulcerative colitis. Inflamm Bowel Dis. 2017;23 :1394–402.28671873\n9 Taxonera C , Iborra M , Bosca‐Watts MM , et al. Early dose optimization of golimumab induces late response and long‐term clinical benefit in moderately to severely active ulcerative colitis. Curr Med Res Opin. 2019;35 :1297–304.30722703\n10 Bossuyt P , Baert F , D'Heygere F , et al. Early mucosal healing predicts favorable outcomes in patients with moderate to severe ulcerative colitis treated with golimumab: data from the real‐life BE‐SMART cohort. Inflamm Bowel Dis. 2019;25 :156–62.29920582\n11 Bressler B , Williamson M , Sattin B , et al. Real world effectiveness of golimumab therapy in ulcerative colitis regardless of prior TNF exposure. J Can Assoc Gastroenterol. 2018;1 :129–34.31294354\n12 Bossa F , Biscaglia G , Valvano MR , et al. Real‐life effectiveness and safety of golimumab and its predictors of response in patients with ulcerative colitis. Dig Dis Sci. 2020;65 :1767–76.31722059\n13 Schroeder KW , Tremaine WJ , Ilstrup DM . Coated oral 5‐aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317 :1625–9.3317057\n14 Silverberg MS , Satsangi J , Ahmad T , et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005;19 :5–36.\n15 Gionchetti P , Rizzello F , Annese V , et al. Use of corticosteroids and immunosuppressive drugs in inflammatory bowel disease: clinical practice guidelines of the Italian group for the study of inflammatory bowel disease. Dig Liver Dis. 2017;49 :604–17.28254463\n16 Philip G , Cornillie F , Adedokun J , et al. Early dose optimisation of golimumab in nonresponders to induction treatment for ulcerative colitis is effective and supported by pharmacokinetic data. J Crohns Colitis. 2019;13 :1257–64.30847474\n17 Magro F , Lopes S , Silva M , et al. Low golimumab trough levels at week 6 are associated with poor clinical, endoscopic and histological outcomes in ulcerative colitis patients: pharmacokinetic and pharmacodynamic sub‐ analysis of the evolution study. J Crohns Colitis. 2019;13 :1387–93.30989180\n18 Yanai H , Lichtenstein L , Assa A , Mazor Y , et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13 :522–30.e2.25066837\n19 Peyrin‐Biroulet L , Van Assche G , Armuzzi A , et al. Implementing the concept of continuous clinical response into clinical practice for ulcerative colitis. Clin Gastroenterol Hepatol. 2017;15 :1154–61.e1.27720910\n20 Pariente B , Mary JY , Danese S , et al. Development of the Liemann index to assess digestive tract damage in patients with Crohn's disease. Gastroenterology. 2015;148 :52–63.e3 25241327\n21 Torres J , Billioud V , Sachar DB , et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis. 2012;18 :1356–63.22162423\n22 Burisch J , Ungaro R , Vind I , et al. Proximal disease extension in patients with limited ulcerative colitis: a Danish population‐based inception cohort. J Crohns Colitis. 2017;11 :1200–4.28486626\n\n",
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"keywords": "golimumab; naïve; persistence; remission; ulcerative colitis",
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"title": "Two-year effectiveness and safety of golimumab in ulcerative colitis: An IG-IBD study.",
"title_normalized": "two year effectiveness and safety of golimumab in ulcerative colitis an ig ibd study"
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"abstract": "Dopamine transporter SPECT is an accurate adjunct to clinical evaluation for Parkinson disease when the diagnosis is difficult. Dopaminergic medications may significantly affect dopamine transporter availability and, thus, uptake of dopamine transporter tracers. A patient had a false-positive dopamine transporter SPECT result while she was taking dextroamphetamine and amphetamine for attention-deficit hyperactivity disorder. The SPECT findings normalized after amphetamine therapy was withheld. An accurate medication history combined with knowledge of drugs that interfere with dopamine transporter imaging is critical to ensure accuracy.",
"affiliations": "College of Medicine, University of Arizona, Tucson, Arizona jfrankl@email.arizona.edu.;Department of Neurology, University of Arizona, Tucson, Arizona.;Department of Medical Imaging, University of Arizona, Tucson, Arizona.",
"authors": "Frankl|Joseph A|JA|;Bose|Sudeshna|S|;Kuo|Phillip H|PH|",
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"journal": "Journal of nuclear medicine technology",
"keywords": "Parkinson disease; amphetamine; dopamine transporter; ioflupane; single-photon positron emission tomography",
"medline_ta": "J Nucl Med Technol",
"mesh_terms": "D000661:Amphetamine; D003913:Dextroamphetamine; D050483:Dopamine Plasma Membrane Transport Proteins; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D010300:Parkinson Disease; D015899:Tomography, Emission-Computed, Single-Photon",
"nlm_unique_id": "0430303",
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"pmid": "29273699",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "False-Positive Findings on Dopamine Transporter SPECT Due to Therapeutic Dextroamphetamine and Amphetamine.",
"title_normalized": "false positive findings on dopamine transporter spect due to therapeutic dextroamphetamine and amphetamine"
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"abstract": "We report a case of thyrotoxic periodic paralysis (TPP) in a bodybuilder who developed paralysis secondary to thyrotoxicosis factitia after taking a supplement containing thyroid hormone. Interestingly, the patient had no intrinsic thyroid disease. Prompt recognition of thyrotoxicosis is critical to avoid progression of paralysis and subsequent complications.\nWe discuss a 27-year-old body builder who presented after a 3-day bodybuilding competition with sudden upper and lower extremity paralysis. He admitted to taking anabolic steroids, a supplement containing an unknown amount of thyroid hormone for 2 weeks, and furosemide 40 mg twice daily with near-complete fluid restriction for 3 days.\nLaboratory results showed a thyroid-stimulating hormone (TSH) level of <0.010 μIU/mL (normal, 0.3 to 5.8 μIU/mL), normal total triiodothyronine level, elevated free thyroxine level of 3.6 ng/dL (normal, 0.8 to 1.9 ng/dL), and potassium level of 1.9 mEq/L (normal, 3.7 to 5.2 mEq/L). Thyroid peroxidase antibody, thyroid-stimulating immunoglobulin, and thyroglobulin antibody levels were normal. Thyroid uptake was 1% (normal, 8 to 25%) after administration of I-123 and thyroglobulin level was 9 ng/mL (normal, 1.4 to 29.2 ng/mL). The patient was treated with normal saline infusion, magnesium supplementation and a total of 230 mEq of potassium within 12 hours of hospitalization. Muscle weakness resolved within this time period and potassium level normalized. By the third day of hospitalization free thyroxine level also normalized and TSH improved to 0.1 mIU/L.\nTPP is a rare complication of thyrotoxicosis that should be considered in bodybuilders who are presenting with acute muscle weakness.",
"affiliations": "Department of Medicine, NYU Long Island School of Medicine, Mineola, New York.;Department of Medicine, NYU Long Island School of Medicine, Mineola, New York.;Department of Medicine, NYU Long Island School of Medicine, Mineola, New York.;Department of Medicine, NYU Long Island School of Medicine, Mineola, New York.",
"authors": "Patel|Amy J|AJ|;Tejera|Stephanie|S|;Klek|Stanislaw P|SP|;Rothberger|Gary D|GD|",
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"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2020-0154",
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"issue": "6(5)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
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"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e252-e256",
"pmc": null,
"pmid": "32984532",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "THYROTOXIC PERIODIC PARALYSIS IN A COMPETITIVE BODYBUILDER WITH THYROTOXICOSIS FACTITIA.",
"title_normalized": "thyrotoxic periodic paralysis in a competitive bodybuilder with thyrotoxicosis factitia"
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"activesubstancename": "TRENBOLONE"
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"abstract": "Rothia mucilaginosa is increasingly recognized as an emerging pathogen associated with endocarditis. It has mostly been reported a causative agent for prosthetic valve endocarditis. The previously reported cases of native valve endocarditis caused by this organism only required medical treatment with no surgical intervention. We report a case of R. mucilaginosa native valve endocarditis complicated by abscess formation requiring surgical intervention and review the literature of native valve endocarditis caused by this organism.",
"affiliations": "Infectious Disease division, Thomas Jefferson University Hospital, Philadelphia, PA, United States.;Department of Biology, American University of Beirut, Beirut, Lebanon.;Cardiothoracic Surgery Division, Lankenau Medical Center, Wynnewood, PA, United States.;Cardiology Division, Lankenau Medical Center, Wynnewood, PA, United States.;Infectious Disease Division, Lankenau Medical Center, Wynnewood, PA, United States.;Infectious Disease Division, Lankenau Medical Center, Wynnewood, PA, United States.",
"authors": "Haddad|S|S|;Saade|Y|Y|;Ramlawi|B|B|;Kreidieh|B|B|;Gilbert|B|B|;Rao|S|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01348",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00304-8\n10.1016/j.idcr.2021.e01348\ne01348\nCase Report\nNative valve endocarditis complicated by abscess formation caused by Rothia mucilaginosa\nHaddad S. a⁎\nSaade Y. b\nRamlawi B. c\nKreidieh B. d\nGilbert B. e\nRao S. e\na Infectious Disease division, Thomas Jefferson University Hospital, Philadelphia, PA, United States\nb Department of Biology, American University of Beirut, Beirut, Lebanon\nc Cardiothoracic Surgery Division, Lankenau Medical Center, Wynnewood, PA, United States\nd Cardiology Division, Lankenau Medical Center, Wynnewood, PA, United States\ne Infectious Disease Division, Lankenau Medical Center, Wynnewood, PA, United States\n⁎ Corresponding author.\n18 11 2021\n2021\n18 11 2021\n26 e013484 11 2021\n16 11 2021\n17 11 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nRothia mucilaginosa is increasingly recognized as an emerging pathogen associated with endocarditis. It has mostly been reported a causative agent for prosthetic valve endocarditis. The previously reported cases of native valve endocarditis caused by this organism only required medical treatment with no surgical intervention. We report a case of R. mucilaginosa native valve endocarditis complicated by abscess formation requiring surgical intervention and review the literature of native valve endocarditis caused by this organism.\n\nKeywords\n\nR.mucilaginosa\nEndocarditis\nNative valve\nAortic root abscess\n==== Body\npmcIntroduction\n\nRothia spp are gram positive pleomorphic bacteria [1], first reported to infect humans in 1975 [2]. Among the different species of Rothia, three have been described to be pathogenic for humans: R. aeria, R. dentocariosa, R. mucilaginosa [3]. The latter three species grow fast under aerobic conditions producing whitish convex colonies while they produce filamentous transparent colonies under anaerobic conditions [3].\n\nRothia mucilaginosa was formerly known as Staphylococcus salivarius, and Stomatococcus mucilaginosus [4]. It is a normal inhabitant of the human oral cavity and respiratory tract [5]. Infections with this pathogen usually affect immunocompromised hosts such as patients with cancer, HIV, diabetes mellitus and chronic liver disease [6], [7]. It can also affect immunocompetent hosts with certain risk factors such as cardiac valve disease/presence of prosthetic valves, indwelling catheters or IV drug users [4]. It is mostly reported to be involved in respiratory tract infections [8], soft tissue infections [5], meningitis [9], endocarditis [3], [4], bone and joint infections [1], central nervous system infections [10] and bacteremia [11].\n\nWhen infecting cardiac valves, this organism is mostly reported to cause prosthetic valve endocarditis with rare reports of native valve infections. A case series of infective endocarditis caused by R.mucilaginosa shows that most reported native valve infections recovered with antibiotics alone while most patient with prosthetic valve infections required surgical valve replacement [9]. We report a rare case of native valve Rothia mucilaginosa endocarditis complicated by aortic root abscess requiring surgical intervention in addition to antibiotic therapy.\n\nCase\n\nAn 80-year old man with a past medical history of coronary artery disease, mild intermittent asthma and moderate aortic stenosis presented to the emergency department for evaluation of intermittent fevers of three weeks duration. He reported that the fevers were low grade occurring randomly at no set time of the day. He had associated lethargy, generalized weakness, decreased oral intake and intermittent headache. He denied chest pain, palpitations, shortness of breath, joint pain, or rash. He reported having dental work done 2 months prior to presentation. He denied recent travel or sick contacts, intravenous drug use, recent hospitalization, or antibiotic use.\n\nOn arrival, the patient was noted to have low grade fever with a temperature of 100.4°F, tachycardia with a heart rate of 95 beats/minute and was normotensive. On exam, he was noted to have poor dentition and a loud harsh systolic murmur consistent with aortic stenosis. Lung and abdominal exams were unremarkable. No focal neurologic signs were found. He had no evidence of heart failure or stigmata suggestive of underlying endocarditis. Initial laboratory testing was pertinent for leukocytosis, abnormal liver function tests, elevated troponin and inflammatory markers [Table 1]. A urine analysis, hepatitis and viral panel were done and were negative. A chest X ray was normal. CT abdomen and pelvis with intravenous contrast revealed a 3.3 × 3.5 cm abdominal aortic aneurysm, extensive coronary artery calcification but no definite source of infection. Two sets of blood cultures were obtained, and results came back positive for non-staphylococcus gram positive cocci later identified as Rothia mucilaginosa. The patient was started on ceftriaxone 2 g daily in addition to IV vancomycin. Repeat blood cultures cleared on hospital day 2.Table 1 Laboratory workup.\n\nTable 1\tReference range\tAdmission day\tDay 2\tDischarge day\t\nHemoglobin\t11.8–15.7 g/dL\t11.6\t11.1\t9.0\t\nWhite Blood Cells\t3.80–10.50 K/uL\t13.4\t11.6\t13.3\t\nPlatelet count\t150–369 K/uL\t247\t251\t90\t\nBUN\t8–20 mg/dL\t11\t8\t11\t\nCreatinine\t0.6–1.1 mg/dL\t1.0\t0.9\t0.9\t\nSodium\t136–144 mEq/L\t136\t137\t138\t\nPotassium\t3.6–5.1 mEq/L\t3.9\t3.6\t4.5\t\nAspartate aminotransferase\t15–41 IU/L\t72\t62\t27\t\nAlanine aminotransferase\t11–54 IU/L\t111\t108\t41\t\nAlkaline phosphatase\t35–126 IU/L\t70\t68\t63\t\nC-reactive protein\t< =7.48 mg/L\t102.3\t69.4\t\t\nErythrocyte sedimentation rate\t0–20 mm/h\t77\t67\t\t\nTroponin\t< 0.05 ng/mL\t0.11\t0.06\t\t\n\nInitial transthoracic echocardiogram showed progressive mitral stenosis, regurgitation with a small mobile echo density attached to the anterior mitral annulus in addition to severe aortic stenosis. A transesophageal echocardiogram was done showing an echo dense highly mobile oscillating structure attached to the left aortic valve cusp between the noncoronary and left coronary cusp measuring 1 × 1.5 cm consistent with an aortic valve vegetation extending into the LVOT and abutting the anterior mitral leaflet in addition to an aortic root abscess with loculations and early dehiscence of the base of the aortic valve [Fig. 1]. During his stay, patient complained of recurrent headaches and an MRI brain was done showing at least two foci of septic emboli in the right occipital lobe and right parietal lobe with a focus of subarachnoid hemorrhage in the left parietal sulcus.Fig. 1 Transesophageal echocardiogram. A: Aortic valve vegetation extending into the LVOT and abutting the anterior mitral leaflet. B: Aortic valve vegetation with aortic root abscess.\n\nFig. 1\n\nOn day 10 of hospitalization, patient underwent aortic root debridement and repair with a pericardial patch, mitral valve repair with removal of vegetations noted on the anterior leaflet and aortic valve replacement with a suture-less bovine prosthetic valve [Fig. 2]. The patient had an extensive abscess cavity involving the annulus, superior aspect of the anterior leaflet of the mitral valve and extending toward the left main coronary ostium. After thorough debridement, obliteration of the abscess cavity and reconstruction was performed with bovine pericardial patch [12]. Selection of a self-expanding suture-less prosthesis was intentional to minimize suture material in the setting of infected space. Pathology of the native aortic valve showed acute inflammatory infiltrates and necrosis with tissue cultures negative to date. His course was complicated by atrial fibrillation requiring cardioversion. On post-operative day 4, he developed a blister eruption on the soles of his feet, bilateral hands, arms and abdomen [Fig. 3]. This was attributed to possible vancomycin induced IgA dermatitis and the drug was discontinued with the patient’s skin findings resolving prior to discharge. The patient was discharged on postoperative day 8 without deficits. He was continued on ceftriaxone 2 g daily for a total of 42 days.Fig. 2 A: Aortic valve vegetation with aortic root abscess. B: Aortic root repair with insertion of bovine pericardial patch. C: Aortic valve post suture-less bioprosthetic valve implantation (Corcym Perceval prosthesis).\n\nFig. 2\n\nFig. 3 Bullous eruption of patient’s left hand.\n\nFig. 3\n\nDiscussion\n\nRothia mucilaginosa is an organism often difficult to identify secondary to taxonomic confusion and misidentification with other gram-positive organisms such as staphylococcus, streptococcus or micrococcus [13]. Rothia infections are classically described as opportunistic diseases and a systematic review published in 2020 looking at Rothia spp included 61% of infected patients being immunocompromised with tooth decays reported in 28% of patients with Rothia infection [3]. In addition to underlying structural valvular disease, recent dental work was likely a major risk factor for our patient to acquire this particular infection.\n\nTable 2 describes seven patients reported in the literature with native valve infections caused by Rothia mucilaginosa [9], [14], [15], [16], [17], [18], [19] in addition to our case. Most reported cases occurred in patients with underlying valve pathologies [9], [14], [15], [16], [19] or underlying risk factors such as intravenous drug use [17], [18], [19]. Six out of seven patients were treated with antibiotics alone [9], [14], [15], [16], [17], [18] and all but one patient had a favorable outcome [18]. One of the 7 patients required surgical valve replacement [19]. We report here a rare case of native valve endocarditis secondary to Rothia mucilaginosa complicated by abscess formation and requiring two valve replacements.Table 2 Eight cases of Rothia mucilaginosa native valve endocarditis reported in the literature and our case.\n\nTable 2Reference\tAge (years)\tSex\tUnderlying disease/risk factor\tDiagnosis\tTreatment\t\n13\t63\tM\tRheumatic heart disease, Moderate MS and MR\tNative MV endocarditis\tIV PCN x 5 weeks\t\n14\t34\tF\tIVDU, MV prolapse\tNative MV endocarditis\tIV PCN x 6 weeks\t\n15\t46\tM\tMV prolapse\tNative MV endocarditis\tPCN and gentamycin x 4 weeks\t\n9\t44\tM\tMV prolapse and MR\tNative MV endocarditis\tIV PCN x 6 weeks\t\n16\t46\tM\tIVDU\tNative MV endocarditis\tIV vancomycin x 6 weeks\t\n17\t79\tM\tnone\tNative AV,MV endocarditis\tRifampin+vancomycin (expired)\t\n18\t35\tM\tIVDU,endocarditis, AI/MI\tNative AV endocarditis\tIV vancomycin x 4 weeks + valve replacement\t\nOur case\t60\tM\tAS\tNative AV,MV endocarditis\tIV CTX x 4 weeks + valve replacement\t\n\nThere are no guidelines to assist in antibiotic selection in the treatment of invasive Rothia infections [12] and the treatment regimen is not clearly determined. The organism is noted to be generally susceptible to penicillin, ampicillin, cefotaxime, imipenem, rifampin, and vancomycin [4]. In the literature, it has previously been described to be frequently resistant to clindamycin, aminoglycosides, trimethoprim sulfamethoxazole [4], [20] and occasionally to penicillin [19]. In our reported case, the organism was susceptible to penicillin (MIC<0.120), Vancomycin (MIC = 1) and levofloxacin (MIC 0.5). Our isolated strain was intermediately susceptible to clindamycin (MIC 1) and erythromycin (MIC 2) and resistant to trimethoprim sulfamethoxazole (MIC>4).\n\nRothia mucilaginosa is increasingly recognized as an emerging pathogen causing infections in both immunocompromised and immunocompetent hosts. It has mostly been described to cause prosthetic valve endocarditis [4] requiring both antibiotic therapy and surgical reconstruction. It, however, can also cause native valve endocarditis with reports of more aggressive disease emerging as is the case with our patient, requiring surgical intervention.\n\nEthical approval\n\nNo study was performed on volunteers. This is a descriptive case report.\n\nConsent\n\nInformed consent was obtained from the patient for publication of this case report and accompanying images.\n\nAuthor contribution\n\nSara Haddad: writing and editing. Youmna Saade: Literature review and background search. Basel Ramlawi: writing and editing. Bahij Kreidieh: writing and editing. Brett Gilbert: writing and editing. Shilpa Rao: writing and editing.\n\nAcknowledgments and funding\n\nB. Ramlawi is a consultant and advisory board member for Medtronic, Boston Scientific, Corcym and AtriCure. The rest of the authors report no conflict of interest. No source of funding to be declared.\n==== Refs\nReferences\n\n1 Mahobia N. Chaudhary P. Kamat Y. Rothia prosthetic knee joint infection: report and mini-review N Microbes N Infect 1 1 2013 2 5\n2 Scharfen J. Untraditional glucose fermenting actinomycetes as human pathogens. Part II: Rothia dentocariosa as a cause of abdominal actinomycosis and a pathogen for mice Zent Bakteriol Orig A 233 1 1975 80 92\n3 Franconieri F. Join-Lambert O. Creveuil C. Rothia spp. infective endocarditis: a systematic literature review Infect Dis Now 51 3 2021 228 235 33164836\n4 Bruminhent J. Tokarczyk M.J. Jungkind D. DeSimone J.A. Jr. Rothia mucilaginosa prosthetic device infections: a case of prosthetic valve endocarditis J Clin Microbiol 51 5 2013 1629 1632 23467598\n5 Tomczak H. Bilska-Stokłosa J. Osmola K. Rothia mucilaginosa, rarely isolated pathogen as an etiological factor of infection of soft tissues in young, healthy woman Post Hig Med Dosw 2013 67\n6 McWhinney P.H. Kibbler C.C. Gillespie S.H. Stomatococcus mucilaginosus: an emerging pathogen in neutropenic patients Clin Infect Dis 14 3 1992 641 646 1562654\n7 Gruson D. Hilbert G. Pigneux A. Severe infection caused by Stomatococcus mucilaginosus in a neutropenic patient: case report and review of the literature Hematol Cell Ther 40 4 1998 167 169 9766921\n8 Maraki S. Papadakis I.S. Rothia mucilaginosa pneumonia: a literature review Infect Dis J 47 3 2015 125 129 Mar 4\n9 Pérez-Vega C. Narváez J. Calvo G. Castro-Bohorquez F.J. Falgueras M.T. Vilaseca-Momplet J. Cerebral mycotic aneurysm complicating Stomatococcus mucilaginosus infective endocarditis Scand J Infect Dis 34 11 2002 863 866 12578165\n10 Goldman M. Chaudhary U.B. Greist A. Fausel C.A. Central nervous system infections due to Stomatococcus mucilaginosus in immunocompromised hosts Clin Infect Dis 27 5 1998 1241 1246 9827277\n11 Mitchell P.S. Huston B.J. Jones R.N. Holcomb L. Koontz F.P. Stomatococcus mucilaginosus bacteremias: typical case presentations, simplified diagnostic criteria, and a literature review Diagn Microbiol Infect Dis 13 6 1990 521 525 2279383\n12 Bedeir K. Reardon M. Ramlawi B. Infective endocarditis: perioperative management and surgical principles J Thorac Cardiovasc Surg 147 4 2014 1133 1141 24412256\n13 Faiad G. Singh M. Narasimhan A. Mendez M. Sharma S. Nassar N. Rothia mucilaginosa life threatening infections in non-neutropenic hosts Open J Intern Med 1 2011 68 71\n14 Rubin S.J. Lyons R.W. Murcia A.J. Endocarditis associated with cardiac catheterization due to a Gram-positive coccus designated Micrococcus mucilaginosus incertae sedis J Clin Microbiol 7 6 1978 546 549 670378\n15 Relman D.A. Ruoff K. Ferraro M.J. Stomatococcus mucilaginosus endocarditis in an intravenous drug abuser J Infect Dis 155 5 1987 1080 1081 3559282\n16 Prag J. Kjøller E. Espersen F. Stomatococcus mucilaginosus endocarditis Eur J Clin Microbiol 4 4 1985 422 424 4043062\n17 Abdelmaseih R. Abdelmasih R. Faluk M. Hasan M. Uncommon pathogen in an unexpected host: a rare case of rothia mucilaginosa infective endocarditis in an immunocompetent patient without an underlying valvular disease Cureus 13 6 2021\n18 Castaño M.A. Gascón F. Sánchez E. Bacteriemia por Stomatococcus mucilaginosus en un paciente de riesgo Rev Diag. Biol. 50 3 2001 147 148\n19 Pinsky R.L. Piscitelli V. Patterson J.E. Endocarditis caused by relatively penicillin-resistant Stomatococcus mucilaginosus J Clin Microbiol 27 1 1989 215 216 2913031\n20 Kaasch AJ, Saxler G., Seifert H. Septic arthritis due to Rothia mucilaginosa; 2011 Feb;39(1):81–82.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "26()",
"journal": "IDCases",
"keywords": "Aortic root abscess; Endocarditis; Native valve; R.mucilaginosa",
"medline_ta": "IDCases",
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"nlm_unique_id": "101634540",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "24412256;25664502;3559282;2913031;23475477;1562654;670378;33164836;12578165;21153041;1202874;34262804;23467598;25356316;4043062;2279383;9827277;9766921",
"title": "Native valve endocarditis complicated by abscess formation caused by Rothia mucilaginosa.",
"title_normalized": "native valve endocarditis complicated by abscess formation caused by rothia mucilaginosa"
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"abstract": "Previous studies have demonstrated the combination of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and other antitumor agents may delay drug resistance. In this study, we retrospectively reviewed the efficacy and safety of first-line concurrent EGFR-TKIs and platinum-based doublet chemotherapy with or without an antiangiogenic agent for advanced lung adenocarcinoma patients in the real world.\n\n\n\nA total of 30 patients with advanced lung adenocarcinoma and activating EGFR mutations concurrently received an EGFR-TKI and platinum-based doublet chemotherapy with or without bevacizumab. The safety profile and efficacy were retrospectively reviewed.\n\n\n\nAt the median follow-up time of 22.1 months, 18 patients had experienced disease progression, and six patients had died because of disease. The median progression-free survival (mPFS) was 21.2 months (95% CI: 12.631-29.798). Of the 28 patients who had measurable lesions, the objective response rate and disease control rate were 71.4% and 96.4%, respectively (one patient achieved complete remission, 19 patients had a partial response and seven patients had stable disease). Male patients had significantly longer mPFS than female patients (32.6 vs. 14.6 months, HR = 3.593, 95% CI: 1.158-11.148, p = 0.027). The most frequently seen grade 3/4 adverse events were hematological toxicities, seen in three cases (10%). Three patients ceased bevacizumab due to vascular events, including hypertension (grade 2, 6.7%) and venous thrombosis (grade 2, 3.3%), and continued EGFR-TKI and platinum-based doublet chemotherapy.\n\n\n\nThe combination of first-generation EGFR-TKIs with platinum-based chemotherapy may be a first-line treatment for advanced lung adenocarcinoma patients harboring activated EGFR mutations and is well tolerated.",
"affiliations": "Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.",
"authors": "Xu|Ziyi|Z|0000-0002-5747-5707;Hao|Xuezhi|X|;Lin|Lin|L|;Li|Junling|J|0000-0002-7361-325X;Xing|Puyuan|P|",
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"doi": "10.1111/1759-7714.14057",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n34180588\n10.1111/1759-7714.14057\nTCA14057\nOriginal Article\nOriginal Articles\nConcurrent chemotherapy and first‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) with or without an antiangiogenic agent as first‐line treatment in advanced lung adenocarcinoma harboring an EGFR mutation\nXu et al.\nXu Ziyi https://orcid.org/0000-0002-5747-5707\n1\nHao Xuezhi 1\nLin Lin 1\nLi Junling https://orcid.org/0000-0002-7361-325X\n1 lijunling@cicams.ac.cn\n\nXing Puyuan 1 xingpuyuan@cicams.ac.cn\n\n1 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China\n* Correspondence\nJunling Li and Puyuan Xing, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.\nEmail: lijunling@cicams.ac.cn and xingpuyuan@cicams.ac.cn\n\n28 6 2021\n8 2021\n12 16 10.1111/tca.v12.16 22332240\n03 6 2021\n08 4 2021\n03 6 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nBackground\n\nPrevious studies have demonstrated the combination of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) and other antitumor agents may delay drug resistance. In this study, we retrospectively reviewed the efficacy and safety of first‐line concurrent EGFR‐TKIs and platinum‐based doublet chemotherapy with or without an antiangiogenic agent for advanced lung adenocarcinoma patients in the real world.\n\nMethods\n\nA total of 30 patients with advanced lung adenocarcinoma and activating EGFR mutations concurrently received an EGFR‐TKI and platinum‐based doublet chemotherapy with or without bevacizumab. The safety profile and efficacy were retrospectively reviewed.\n\nResults\n\nAt the median follow‐up time of 22.1 months, 18 patients had experienced disease progression, and six patients had died because of disease. The median progression‐free survival (mPFS) was 21.2 months (95% CI: 12.631–29.798). Of the 28 patients who had measurable lesions, the objective response rate and disease control rate were 71.4% and 96.4%, respectively (one patient achieved complete remission, 19 patients had a partial response and seven patients had stable disease). Male patients had significantly longer mPFS than female patients (32.6 vs. 14.6 months, HR = 3.593, 95% CI: 1.158–11.148, p = 0.027). The most frequently seen grade 3/4 adverse events were hematological toxicities, seen in three cases (10%). Three patients ceased bevacizumab due to vascular events, including hypertension (grade 2, 6.7%) and venous thrombosis (grade 2, 3.3%), and continued EGFR‐TKI and platinum‐based doublet chemotherapy.\n\nConclusions\n\nThe combination of first‐generation EGFR‐TKIs with platinum‐based chemotherapy may be a first‐line treatment for advanced lung adenocarcinoma patients harboring activated EGFR mutations and is well tolerated.\n\nPrevious studies have demonstrated that the combination of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) and other antitumor agents may delay drug resistance. As results of phase III trial JMIT and NEJ009 indicated, the combination therapy of EGFR‐TKI and chemotherapy benefited NSCLC patients who harbored EGFR sensitive mutations as first‐line therapy. This study has provided further evidence for the efficacy and safety of concurrent use of EGFR‐TKI and platinum‐based chemotherapy as a first‐line therapy for advanced lung adenocarcinoma patients with EGFR 19 del or 21 L858R mutation in the real world. We also explored the relationship between EGFR mutation type and efficacy of the combination strategy. In conclusion, we determined that the combination strategy is promising as first‐line treatment for advanced lung adenocarcinoma patients harboring activated EGFR mutations, and is well‐tolerated.\n\nadvanced lung adenocarcinoma\nconcurrent therapy\nepidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI)\nfirst‐line therapy\nplatinum‐based doublet chemotherapy\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:16.08.2021\nXuZ, HaoX, LinL, LiJ, XingP. Concurrent chemotherapy and first‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) with or without an antiangiogenic agent as first‐line treatment in advanced lung adenocarcinoma harboring an EGFR mutation. Thorac Cancer. 2021;12 :2233–2240. 10.1111/1759-7714.14057\n\nZiyi Xu and Xuezhi Hao contributed equally to this manuscript as cofirst authors.\n==== Body\nIntroduction\n\nFirst‐generation oral epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, have been approved as standard first‐line therapies for non‐small cell lung cancer (NSCLC) patients harboring activating EGFR mutations, as they prolong progression‐free survival (PFS) compared to platinum‐based doublet chemotherapy according to multiple clinical studies.1, 2 Despite the related survival improvements in patients with advanced NSCLC, most develop resistance to TKIs after a median duration of 9–13 months, and about 60% of patients are found to have a p.Thr790Met (T790M) resistance mutation.3, 4 Therefore, studies are ongoing to investigate strategies, such as combining treatment with other antitumor agents to prolong the duration of response. Preclinical studies have shown that chemotherapy might have a synergistic effect with EGFR‐TKIs on the tumor growth of NSCLC in vitro.5 Clinical studies have shown controversial results, and therefore a combination strategy has not yet been proven as an effective standard first‐line treatment for advanced lung adenocarcinoma patients harboring EGFR‐activating mutations.\n\nMost previous studies have failed to demonstrate the effect of a combination of chemotherapy and EGFR‐TKIs as first‐line treatment in unselected NSCLC patients.6, 7 However, for patients with EGFR mutations, recent studies have indicated the benefit of combining chemotherapy and EGFR‐TKIs in this population. The JMIT trial compared pemetrexed plus gefitinib versus gefitinib alone as first‐line therapy for EGFR‐mutated NSCLC, and the results showed significantly improved PFS8 and a numerically higher overall survival (OS) rate in the combination therapy group than in the TKI alone group.9 For the FASTACT‐2 study, platinum‐based chemotherapy plus first‐generation TKI erlotinib showed a benefit in terms of both PFS and OS compared to chemotherapy plus placebo, not only in stage IIIB/IV NSCLC patients with targetable EGFR mutations but also in selected patients with unknown EGFR mutations.10 Based on preclinical evidence and clinical data, it is possible that the combination therapy of chemotherapy and EGFR‐TKIs could be beneficial as first‐line therapy in advanced lung adenocarcinoma patients harboring an activating EGFR mutation.\n\nHowever, the combination strategy has failed to prolong OS according to some studies. The NEJ009 study compared the efficacy of gefitinib to the concurrent strategy of gefitinib and pemetrexed plus carboplatin and found that although PFS and OS in the combination group were significantly longer than those in the monotherapy group, no significant difference was found in PFS2 considering the influence of the postprogressive disease period.11 More questions are still under investigation; for example, whether patients might benefit from maintenance treatment with chemotherapy and EGFR‐TKIs has not yet been fully studied, and whether the combination of antiangiogenic agents would increase efficacy has not yet been elucidated. In this real‐world study, we retrospectively reviewed and evaluated the effect and safety of concurrent therapy with chemotherapy and an EGFR‐TKI as first‐line therapy for patients with EGFR‐mutated advanced lung adenocarcinoma and provided more evidence of this combination regimen in clinical application.\n\nMETHODS\n\nPatients\n\nWe retrospectively reviewed the records of patients diagnosed with advanced lung adenocarcinoma according to pathology and radiological results who received their first‐line therapy at the Cancer Hospital Chinese Academy of Medical Sciences (CAMS) from May 2014 to April 2020. All patients, including two patients who underwent palliative operation, were diagnosed by cytology or histology of at least one evaluable lesion. We collected clinicopathological features, including smoking history, family history, Eastern Cooperative Oncology Group performance status (ECOG PS), and oncogene mutation type. As EGFR‐TKIs must be administered after the gene test results are obtained, some patients received chemotherapy while the gene test was being performed. Therefore, we included patients who had concurrently received EGFR‐TKIs within four cycles of chemotherapy.\n\nAll methods were carried out in accordance with the relevant guidelines and regulations.\n\nClinical assessment\n\nRadiographic assessments, including CT scans and brain MRI, were performed at baseline and after every two cycles of chemotherapy and were then performed every two to three months in the first two years and every six months thereafter until disease progression. Radiographic tests were also performed if the patient had worsening of symptoms. Further information, including survival and subsequent treatment, was collected every six months after disease progression following first‐line therapy. Response and PFS were assessed by investigators. The assessment of treatment efficacy was based on The Response Evaluation Criteria of Solid Tumors (RECIST) version 1.1.12 The tumor responses of target lesions were evaluated and categorized as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). The objective response rate (ORR) was defined as the sum of the CR and PR rates, and DCR was defined as the sum of the CR, PR, and SD rates. Progression‐free survival (PFS) was measured from the time of initiation of either treatment to PD or death from any cause, whichever came first, and overall survival (OS) was defined as the period from the initiation of treatment to death from any cause or the last follow‐up, and if lost to follow‐up, the case would be censored. Any adverse events (AEs) that occurred during treatment were recorded, and the grading of AEs was based on the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). The highest toxicity grade for each patient in all cycles of chemotherapy was considered in the toxicity analysis.\n\nStatistical analysis\n\nThe median PFS was calculated with the Kaplan–Meier product limit method. Risk factors for PFS were analyzed with the univariate Cox proportional hazards regression model. Patient clinical characteristics and responses to therapy were analyzed with descriptive methods. Continuous variables were compared using t‐tests, and categorial variables were compared using χ2 tests. All statistical analyses were performed using SPSS version 23.0, and differences with a p‐value <0.05 were considered statistically significant.\n\nRESULTS\n\nPatients\n\nIn total, 30 untreated patients with advanced adenocarcinoma who harbored sensitive EGFR mutations received platinum‐based doublet chemotherapy and an EGFR‐TKI concurrently as their first‐line therapy from May 2014 to April 2020. The median age of patients before therapy was 57 (25–70) years. Among them, 12 (40%) were male and 18 (60%) were female. Eight patients (26.7%) were current or former smokers, and 10 (33.3%) patients had a family history of cancer. Most patients (90%) had an excellent performance state (ECOG PS 0–1). Gene testing for tissue or pleural effusion indicated that 21 patients (70%) had EGFR exon 19 deletion and that the remaining nine patients (30%) had EGFR exon 21 deletion (L858R); 20 cases (66.7%) were tested by next‐generation sequencing (NGS) instead of amplification refractory mutation system (ARMS) real‐time polymerase chain reaction (PCR). In those 20 patients who underwent gene testing via NGS at baseline, analysis of a panel of at least 168 cancer‐related genes revealed that 19 patients had co‐occurring mutations in genes such as TP53, PIK3CA, and PTEN. Six patients (66.7%) harboring EGFR exon 21 deletion had known co‐occuring mutaions, and 13 patients (61.9%) harboring EGFR exon 19 deletion had co‐occuring mutations. Six patients (20%) were found to have brain metastases at baseline. No patient tested positive for the T790M mutation before treatment. The clinicopathological characteristics of these patients are listed in Table 1.\n\nTABLE 1 Clinicopathological features of all advanced lung adenocarcinoma patients harboring EGFR‐activating mutations who received first‐generation EGFR‐TKIs combined with platinum‐based doublet chemotherapy with or without an antiangiogenic agent as first‐line therapy\n\nCharacteristics\tn = 30\tCharacteristics\tn (%)\t\nAge\t\tFamily history of tumor\t\t\nMedian\t57\tYes\t10 (33.3)\t\nRange\t25–70\tNo\t20 (66.7)\t\nSex\tn (%)\tBaseline brain metastasis\t\t\nMale\t12 (40.0)\tYes\t6 (20.0)\t\nFemale\t18 (60.0)\tNo\t24 (80.0)\t\nLocation of primary tumor\tn (%)\tEGFR mutation\tn (%)\t\nLeft\t15 (50.0)\tExon 19 deletion\t21 (70.0)\t\nRight\t15 (50.0)\tExon 21 deletion (L858R)\t9 (30.0)\t\nSmoking status\tn (%)\tTreatment strategy\tn (%)\t\nNever smoker\t22 (73.3)\tEGFR‐TKI + bevacizumab + chemotherapy\t7 (23.3)\t\nCurrent/former smoker\t8 (26.7)\tEGFR‐TKI + chemotherapy\t23 (76.7)\t\nCycles of combination therapya\tn (%)\tSecond‐line therapy\tn (%)\t\n≤8\t16 (53.3)\tNo\t\t\n>8\t14 (46.7)\tFirst‐line ongoing\t12 (40.0)\t\nECOG PS\tn (%)\tDeath\t4 (13.3)\t\n0\t10 (33.3)\tYes\tn (%)\t\n1\t17 (56.7)\tThird‐generation EGFR‐TKI\t9 (30.0)\t\n2\t3 (10.0)\tChemotherapy\t5 (16.7)\t\nAbbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; n, number; TKI, tyrosine kinase inhibitors.\n\na Since the median number of combination cycles was eight, effect in those who received more than or no less than eight cycles of combination therapy (including maintenance therapy) was compared.\n\nTreatment\n\nAmong the 30 enrolled patients, 23 patients (76.7%) received a first‐generation EGFR‐TKI concurrently with platinum‐based doublet chemotherapy. In this group, 13 patients (56.5%) received icotinib, nine patients (39.1%) received gefitinib, and one patient (4.4%) received erlotinib. The remaining seven patients (23.3%) received a combination of EGFR‐TKIs and chemotherapy as well as bevacizumab, the antiangiogenic agent. In this group, six patients (85.7%) received icotinib and the other patient received gefitinib. Eighteen patients (60%) continued pemetrexed and EGFR‐TKIs with or without bevacizumab as maintenance therapy after six standard cycles of combination therapy, and the median number of combination therapy cycles was eight (range 2–24 cycles). As of the last day of follow‐up, 12 patients (40%) were still receiving first‐line treatment, and four patients (13.3%) had not received further treatment after disease progression. Among 18 patients who failed their first‐line treatment, eight patients received tissue or liquid biopsy and gene tests, and four patients (50.0%) were found to harbor EGFR T790M resistance mutations. Subsequent treatments are shown in Table 1.\n\nSurvival\n\nUntil January 21, 2021, the median follow‐up period was 22.1 months (range 4.6–76.2 months). Among the 30 patients enrolled, six patients (20%) died of disease, and 18 patients (60%) had disease progression after at least two cycles of concurrent chemotherapy and EGFR‐TKIs with or without bevacizumab. The median progression‐free survival (mPFS) was 21.2 months (95% CI: 12.631–29.798), as shown in Figure 1. The OS data had not yet matured as of the last day of follow‐up. The mPFS of 19 patients with known co‐occurring mutations was 21.2 months (95% CI: 13.023–29.397). The mPFS of other 11 patients with no co‐occuring mutations or unknown status was 21.9 months (95% CI: 12.276–31.504).\n\nFIGURE 1 Kaplan–Meier curves of progression‐free survival (PFS) for the entire population\n\nRisk factors for PFS\n\nThe relationships between PFS and clinicopathological characteristics including age, sex, smoking history, family history of cancer, ECOG PS, and EGFR mutation type, were analyzed. The impact of bevacizumab was also taken into consideration during combination therapy. Patients harboring EGFR exon 19 deletion mutation might have a longer PFS than those with EGFR exon 21 L858R mutation, although no significant difference was found (21.4 vs. 15.6 months, p = 0.343), as shown in Figure 2. The results of univariate Cox proportional hazards regression model (Cox) analysis are shown in Figure 3. The results showed that sex was an independent risk factor for PFS in patients who received concurrent EGFR‐TKIs and chemotherapy as first‐line treatment. Male patients had significantly longer PFS than female patients (32.6 vs. 14.6 months, HR = 3.593, 95% CI: 1.158–11.148, p = 0.027). Although patients who received a combination of chemotherapy and EGFR‐TKIs with an antiangiogenic agent had a longer mPFS than those who received combination therapy without an antiangiogenic agent (21.4 vs. 15.6 months, HR = 0.827, 95% CI: 0.265–2.586, p = 0.744), the difference was not significant.\n\nFIGURE 2 Progression‐free survival (PFS) curves of advanced lung adenocarcinoma patients harboring EGFR exon 19 deletion mutation or EGFR exon 21 L858R mutation using univariate analysis with the Cox proportional hazards regression model\n\nFIGURE 3 Hazard ratio of progression‐free survival in patients with different characteristics. A hazard ratio less than 1 implies a lower risk of disease progression or death in group 2 than in group 1. The number of cases that had progressive disease is shown in each group for every characteristic\n\nResponse to treatment\n\nTwo patients underwent lobe resection in palliative operations before other treatment, so 28 patients with target lesions were included for further analysis of treatment response. One patient (3.5%) had a complete response to concurrent therapy, 19 (67.9%) patients had a partial response to first‐line treatment, and seven (25%) had stable disease (SD). The ORR and DCR were 71.4% and 96.4%, respectively, as shown in Table 2, and the best overall response of each individual is shown in Figure 4.\n\nTABLE 2 Treatment outcomes of 28 advanced lung adenocarcinoma patients harboring EGFR‐activating mutations with at least one measurable lesion who received concurrent EGFR‐TKI and platinum‐based doublet chemotherapy as first‐line therapy\n\nOverall best response\tn (%)\t\nCR\t1 (3.6)\t\nPR\t19 (67.8)\t\nSD\t7 (25)\t\nPD\t1 (3.6)\t\nORR\t20 (71.4)\t\nDCR\t27 (96.4)\t\nAbbreviations: CR, complete remission; DCR, disease control rate (DCR = CR + PR + SD); n, number; ORR, objective response rate (ORR = CR + PR); PD, progressive disease; PR, partial response; SD, stable disease.\n\nFIGURE 4 Maximum tumor size change from baseline by the best overall response, as per response evaluation criteria in solid tumors (RECIST) version 1.1, in 28 patients with at least one measurable target lesion who received first‐line concurrent therapy of chemotherapy and first‐generation EGFR‐TKI treatment for advanced lung adenocarcinoma. Each bar represents the maximum change in the sum of the diameters of the target lesions of an individual patient\n\nThe ORR in patients with co‐occuring mutations and with no co‐occuring mutations or unknown status was 70.6% and 72.7%, respectively, and there was no significant difference (p = 1.000). The ORR in patients who received the regimen with an antiangiogenic agent and without an antiangiogenic agent was 85.7% and 66.7%, respectively, and no significant difference was observed (p = 0.633).\n\nSafety and tolerability\n\nTable 3 lists the incidence of hematological and nonhematological toxicities observed in the study. During combination therapy with EGFR‐TKIs and chemotherapy, with or without bevacizumab, the most frequently seen grade 3/4 AEs were hematological toxicities, including neutropenia and leukopenia, which were seen in three cases (10%). One patient had grade 4 neutropenia during chemotherapy and continued treatment after proper supportive treatment. Other grade 1/2 toxicities included hepatic toxicity (3/30, 7.4%) and diarrhea (9/30, 29.6%), fatigue (2/30, 6.7%), and rash (2/30, 6.7%). Vascular events, such as hypertension (grade 2, 2/30, 6.7%) and venous thrombosis (grade 2, 1/30, 3.3%), were seen in patients treated with the antiangiogenic agent bevacizumab, and these patients ceased bevacizumab due to toxicities.\n\nTABLE 3 Treatment‐related adverse events (AEs) in all advanced lung adenocarcinoma patients harboring EGFR‐activating mutations who received first‐generation EGFR‐TKIs combined with platinum‐based doublet chemotherapy as first‐line therapy\n\nAdverse events\tGrade 1\tGrade 2\tGrade 3\tGrade 4\t\nn (%)\tn (%)\tn (%)\tn (%)\t\nGeneral disorders\t\nFatigue\t2 (6.7)\t\t\t\t\nHematological toxicity\t\nLeukopenia\t2 (6.7)\t2 (6.7)\t2 (6.7)\t\t\nNeutropenia\t\t2 (6.7)\t2 (6.7)\t1 (3.3)\t\nVascular disorders\t\nHypertension\t\t2 (6.7)\t\t\t\nThromboembolic event\t\t1 (3.3)\t\t\t\nDermatological toxicity\t\nRash\t\t2 (6.7)\t\t\t\nGastrointestinal toxicity\t\nDiarrhea\t5 (16.7)\t4 (13.3)\t\t\t\nHepatic toxicity\t2 (6.7)\t1 (3.3)\t\t\t\nAbbreviation: n, number.\n\nDISCUSSION\n\nOur study retrospectively reviewed the efficacy and safety profile of this combined strategy as first‐line therapy in patients diagnosed with advanced lung adenocarcinoma harboring sensitive EGFR mutations in real‐world situations. The ORR and DCR values in our study were 71.4% and 96.4%, respectively. We observed a mPFS of 21.2 months, while the OS data were immature at the end of the analysis, with only six events occurring. Grade 3/4 hematological toxicities, including neutropenia and leukopenia, were most common (11.1%, seen in 3/27 patients). Other nonhematological toxicities included gastrointestinal toxicities and dermatological toxicity, which were well tolerated after local therapy.\n\nThe results showed little difference in the disease control rate from the results of EGFR‐TKI monotherapy in historic studies (73.7%–77.8%)13, 14 however, the PFS time in our study was comparable to, and even numerically longer than, that of previous trials in which combination therapy was administered (17.5–20.9 months).11, 15 Additionally, our results showed that patients who received combination therapy with an antiangiogenic agent had longer mPFS and better ORR than those who did not receive an antiangiogenic agent, although no significant difference were found. Most patients maintained EGFR‐TKIs combined with monoagent chemotherapy, such as pemetrexed, with or without bevacizumab after four to six cycles of first‐line combination therapy. Among 18 patients who progressed after first‐line combination therapy, eight patients received tissue or liquid biopsy for another oncogene test, and four (50%) showed EGFR exon 20 T790M point mutations. The incidence of the EGFR T790M resistance mutation was also parallel to that in a previous study concerning resistance to first‐ or second‐generation EGFR‐TKIs, being around 50%–60%.3 These four patients then received osimertinib, a third‐generation EGFR‐TKI targeting the resistance mutation as second‐line therapy, and had not shown disease progression as of the last follow‐up.\n\nEGFR‐TKIs have been proven to be beneficial for selected NSCLC patients who harbor sensitive EGFR mutations, such as EGFR exon 19 deletion mutation and EGFR exon 21 L858R mutation, and patients harboring EGFR 21 L858R mutation were deemed to benefit less from EGFR‐TKIs, possibly due to the higher rate of comutations, such as TP53.16 An in vivo and in vitro study has shown that first‐line EGFR‐TKI may work synergistically with pemetrexed by downregulating thymidylate synthase, the target of pemetrexed.17 On the other hand, combination therapy may prevent resistance of EGFR‐TKI mediated by EGFR T790M mutation or the epithelial‐to‐mesenthymal transition (EMT) process.18 As investigated in preclinical and clinical trials, first‐generation EGFR‐TKI therapy is inevitably followed by acquired resistance; thus, novel strategies are required to delay drug resistance. For example, the combination of EGFR‐TKIs and antiangiogenic therapy has been considered promising in prolonging PFS compared to that with monotherapy with EGFR‐TKIs.19, 20 Recently, studies showed that the combination strategy of chemotherapy and EGFR‐TKIs in treatment‐naive patients with advanced lung adenocarcinoma harboring sensitive EGFR mutations prolonged PFS and OS and also improved the response rate compared to that with chemotherapy or TKIs alone,15, 21 which indicates the promising benefit of this combination regimen. Although multiple trials have failed to present improved benefit from the concurrent use of chemotherapy and EGFR‐TKIs, these trials have not taken population selection into consideration under the circumstance that the EGFR driver gene was the essential predictor of efficacy. In subgroup studies, however, the combination strategy proved to be effective in patients harboring sensitive EGFR mutations.22 For example, in a subgroup analysis of the FASTACT‐2 trial, the mPFS of the EGFR‐TKI and chemotherapy combination group was significantly longer than chemotherapy (16.8 months vs. 6.9 months, p < 0.0001), and a significant benefit was also seen in terms of OS (31.4 months vs. 20.6 months, p = 0.0092).10 The phase III study NEJ009 also reported significantly longer PFS and OS in the EGFR‐TKI and chemotherapy combination group than in the TKI monotherapy group, with mPFS times of 20.9 months versus 11.2 months (p < 0.001) and OS times of 52.2 months versus 38.8 months (p = 0.013).11 Third‐generation osimertinib is an effective strategy as first‐line therapy, with a mPFS of 18.9 months.23 However, the mechanism of acquired resistance has proved to be more complicated than first‐ or second‐generation EGFR‐TKIs, which makes it more difficult to choose a subsequent strategy after disease progression. Since third‐generation osimertinib is also effective for EGFR‐mutated NSCLC patients with T790M mutation which exists in half of patients who progress after first‐ or second‐line therapy,24 the first‐line EGFR‐TKI combined with chemotherapy followed by osimertinib may be an optional strategy. As for other combination regimens, combining EGFR‐TKIs with antiangiogenic agents has also been reported to prolong PFS in EGFR‐mutated NSCLC patients, while no difference has been observed in OS after long‐term follow‐up.25, 26 Therefore, more randomized clinical trials should be designed to determine the optimal strategy for advanced EGFR‐mutated NSCLC patients.\n\nAccording to previous studies, the addition of EGFR‐TKIs adds to the possibility and severity of adverse events from platinum‐based therapy, especially hematological and gastrointestinal toxicity.27 Some studies altered the administration of the regimen to avoid such adverse events; for example, platinum‐based chemotherapy was administered every four weeks instead of every three weeks, and EGFR‐TKIs were administered on Days 5–21.15 Despite the positive data provided by a growing number of clinical trials, first‐line treatment with platinum‐based doublet chemotherapy combined with EGFR‐TKIs has not been widely used in clinical work; in addition, whether chemotherapy should be maintained after standard cycles of therapy and whether it is safe to maintain combination therapy remain controversial. In our study, no grade 4 nonhematological toxicity was observed, and no novel AEs or treatment‐related deaths were observed. All AEs were related to chemotherapy, EGFR‐TKIs, and the antiangiogenic drug, and had mostly been reported previously and were controllable. The longest time of maintenance therapy in our study was 28 months, which indicated that combination therapy is tolerable and that maintenance therapy with chemotherapy and EGFR‐TKIs might be beneficial.\n\nThere are several limitations to this study. First, it was retrospective with a relatively small sample size, and thus the results may not comprehensively reflect the efficacy and safety of the combination strategy in the real world. Due to the limited number of patients who received NGS gene testing, we failed to further study the relationship of comutations and the efficacy of the combination strategy. Second, since the overall survival data were not sufficient, further follow‐up of these patients is required to provide further evidence of the survival benefits of this combination regimen. Moreover, as a descriptive study, this study failed to demonstrate the optimal administration schedule, and further studies should be designed to compare the sequential, concurrent, or intercalating combination of EGFR‐TKIs and chemotherapy. A randomized, large‐sample phase III clinical trial is required in the future to further address these unknown questions.\n\nIn conclusion, combination therapy with first‐generation EGFR‐TKIs and platinum‐based chemotherapy may be a first‐line treatment for advanced lung adenocarcinoma patients harboring activating EGFR mutations and is well tolerated.\n\nCONFLICT OF INTEREST\n\nAll authors declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.\n==== Refs\nREFERENCES\n\n1 WuYL, ZhouC, LiamCK, WuG, LiuX, ZhongZ, et al. First‐line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation‐positive non‐small‐cell lung cancer: analyses from the phase III, randomized, open‐label, ENSURE study. Ann Oncol. 2015;26 :1883–9.26105600\n2 ZhouC, WuYL, ChenG, FengJ, LiuXQ, WangC, et al. Erlotinib versus chemotherapy as first‐line treatment for patients with advanced EGFR mutation‐positive non‐small‐cell lung cancer (OPTIMAL, CTONG‐0802): a multicentre, open‐label, randomised, phase 3 study. Lancet Oncol. 2011;12 :735–42.21783417\n3 SequistLV, WaltmanBA, Dias‐SantagataD, DigumarthyS, TurkeAB, FidiasP, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3 :75ra26.\n4 OxnardGR, ArcilaME, SimaCS, RielyGJ, ChmieleckiJ, KrisMG, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR‐mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17 :1616–22.21135146\n5 ChenCY, ChangYL, ShihJY, LinJW, ChenKY, YangCH, et al. Thymidylate synthase and dihydrofolate reductase expression in non‐small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer. 2011;74 :132–8.21367480\n6 GiacconeG, HerbstRS, ManegoldC, ScagliottiGV, RosellR, MillerV, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non‐small‐cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol. 2004;22 :777–84.14990632\n7 HerbstRS, PragerD, HermannR, FehrenbacherL, JohnsonBE, SandlerA, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI‐774) combined with carboplatin and paclitaxel chemotherapy in advanced non‐small‐cell lung cancer. J Clin Oncol. 2005;23 :5892–9.16043829\n8 ChengY, MurakamiH, YangPC, HeJ, NakagawaK, KangJH, et al. Randomized phase II trial of gefitinib with and without pemetrexed as first‐line therapy in patients with advanced nonsquamous non‐small‐cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016;34 :3258–66.27507876\n9 YangJCH, ChengY, MurakamiH, YangPC, HeJ, NakagawaK, et al. Gefitinib with or without pemetrexed in nonsquamous (NS) non‐small cell lung cancer (NSCLC) with EGFR mutation (Mut): final overall survival (OS) results from a randomized phase II study. Ann Oncol. 2018;29 :viii495–viii6.\n10 WuYL, LeeJS, ThongprasertS, YuCJ, ZhangL, LadreraG, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non‐small‐cell lung cancer (FASTACT‐2): a randomised, double‐blind trial. Lancet Oncol. 2013;14 :777–86.23782814\n11 HosomiY, MoritaS, SugawaraS, KatoT, FukuharaT, GemmaA, et al. Gefitinib alone versus Gefitinib plus chemotherapy for non‐small‐cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J Clin Oncol. 2020;38 :115–23.31682542\n12 TherasseP, ArbuckSG, EisenhauerEA, WandersJ, KaplanRS, RubinsteinL, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92 :205–16.10655437\n13 MaemondoM, InoueA, KobayashiK, SugawaraS, OizumiS, IsobeH, et al. Gefitinib or chemotherapy for non‐small‐cell lung cancer with mutated EGFR. N Engl J Med. 2010;362 :2380–8.20573926\n14 XuL, QiQ, ZhangY, CuiJ, LiuR, LiY. Combination of icotinib and chemotherapy as first‐line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: a randomized controlled study. Lung Cancer. 2019;133 :23–31.31200823\n15 HanB, JinB, ChuT, NiuY, DongY, XuJ, et al. Combination of chemotherapy and gefitinib as first‐line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: a randomized controlled trial. Int J Cancer. 2017;141 :1249–56.28560853\n16 HongS, GaoF, FuS, WangY, FangW, HuangY, et al. Concomitant genetic alterations with response to treatment and epidermal growth factor receptor tyrosine kinase inhibitors in patients with EGFR‐mutant advanced non‐small cell lung cancer. JAMA Oncol. 2018;4 :739–42.29596544\n17 OkabeT, OkamotoI, TsukiokaS, UchidaJ, IwasaT, YoshidaT, et al. Synergistic antitumor effect of S‐1 and the epidermal growth factor receptor inhibitor gefitinib in non‐small cell lung cancer cell lines: role of gefitinib‐induced down‐regulation of thymidylate synthase. Mol Cancer Ther. 2008;7 :599–606.18347146\n18 La MonicaS, MadedduD, TiseoM, VivoV, GalettiM, CretellaD, et al. Combination of gefitinib and pemetrexed prevents the acquisition of TKI resistance in NSCLC cell lines carrying EGFR‐activating mutation. J Thorac Oncol. 2016;11 :1051–63.27006151\n19 ZhouQ, WuYL, ChengY, LiuY, ChenG, CuiJ, et al. 1480O ‐ CTONG 1509: phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR‐mutated NSCLC. Ann Oncol. 2019;30 :v603.\n20 SaitoH, FukuharaT, FuruyaN, WatanabeK, SugawaraS, IwasawaS, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR‐positive advanced non‐squamous non‐small‐cell lung cancer (NEJ026): interim analysis of an open‐label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019;20 :625–35.30975627\n21 NoronhaV, PatilVM, JoshiA, MenonN, ChouguleA, MahajanA, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR‐mutated lung cancer. J Clin Oncol. 2020;38 :124–36.31411950\n22 HerbstRS, GiacconeG, SchillerJH, NataleRB, MillerV, ManegoldC, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non‐small‐cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol. 2004;22 :785–94.14990633\n23 SoriaJC, OheY, VansteenkisteJ, ReungwetwattanaT, ChewaskulyongB, LeeKH, et al. Osimertinib in untreated EGFR‐mutated advanced non‐small‐cell lung cancer. N Engl J Med. 2018;378 :113–25.29151359\n24 MokTS, WuYL, AhnMJ, GarassinoMC, KimHR, RamalingamSS, et al. Osimertinib or platinum‐pemetrexed in EGFR T790M‐positive lung cancer. N Engl J Med. 2017;376 :629–40.27959700\n25 MaemondoM, FukuharaT, SaitoH, FuruyaN, WatanabeK, SugawaraS, et al. NEJ026: final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR‐mutations. J Clin Oncol. 2020;38 :9506.\n26 YamamotoN, SetoT, NishioM, GotoK, OkamotoI, YamanakaT, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first‐line treatment for advanced EGFR mutation–positive non‐squamous non–small‐cell lung cancer (NSCLC): survival follow‐up results of JO25567. J Clin Oncol. 2018;36 :9007.\n27 YoshimuraN, KudohS, MitsuokaS, YoshimotoN, OkaT, NakaiT, et al. Phase II study of a combination regimen of gefitinib and pemetrexed as first‐line treatment in patients with advanced non‐small cell lung cancer harboring a sensitive EGFR mutation. Lung Cancer. 2015;90 :65–70.26238424\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "12(16)",
"journal": "Thoracic cancer",
"keywords": "advanced lung adenocarcinoma; concurrent therapy; epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI); first-line therapy; platinum-based doublet chemotherapy",
"medline_ta": "Thorac Cancer",
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"pages": "2233-2240",
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"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "18347146;21367480;31200823;29596544;20573926;27507876;29151359;21783417;21135146;31411950;16043829;30975627;34180588;28560853;27006151;14990633;26105600;23782814;27959700;26238424;21430269;10655437;14990632;31682542",
"title": "Concurrent chemotherapy and first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) with or without an antiangiogenic agent as first-line treatment in advanced lung adenocarcinoma harboring an EGFR mutation.",
"title_normalized": "concurrent chemotherapy and first generation epidermal growth factor receptor egfr tyrosine kinase inhibitors tkis with or without an antiangiogenic agent as first line treatment in advanced lung adenocarcinoma harboring an egfr mutation"
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"abstract": "Irinotecan is a cytotoxic medication used to treat various cancers. Diffuse alveolar hemorrhage (DAH) and interstitial pulmonary disease (IPD) are both serious and life-threatening complications, which are rarely reported to be associated with irinotecan. In our case, however, a pancreatic cancer patient developed both DAH and IPD after administration of irinotecan with fluorouracil (5FU).",
"affiliations": "Internal Medicine, AdventHealth Winter Park, Winter Park, USA.;Internal Medicine, AdventHealth Orlando, Orlando, USA.;Internal Medicine, AdventHealth Orlando, Orlando, USA.;Internal Medicine, AdventHealth Orlando, Orlando, USA.;Internal Medicine, AdventHealth Orlando, Orlando, USA.",
"authors": "Meng|Lingbin|L|;Deng|Bo|B|;Liu|Baoqiong|B|;Majeed|Umair|U|;Wang|Wen|W|",
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"doi": "10.7759/cureus.5041",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5041Internal MedicineOncologyA Rare Case of Irinotecan-induced Interstitial Pulmonary Disease and Diffuse Alveolar Hemorrhage in a Patient with Pancreatic Cancer Muacevic Alexander Adler John R Meng Lingbin 1Deng Bo 2Liu Baoqiong 2Majeed Umair 2Wang Wen 2\n1 \nInternal Medicine, AdventHealth Winter Park, Winter Park, USA \n2 \nInternal Medicine, AdventHealth Orlando, Orlando, USA \nWen Wang wendysqlwwb@gmail.com29 6 2019 6 2019 11 6 e504120 6 2019 28 6 2019 Copyright © 2019, Meng et al.2019Meng et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/21064-a-rare-case-of-irinotecan-induced-interstitial-pulmonary-disease-and-diffuse-alveolar-hemorrhage-in-a-patient-with-pancreatic-cancerIrinotecan is a cytotoxic medication used to treat various cancers. Diffuse alveolar hemorrhage (DAH) and interstitial pulmonary disease (IPD) are both serious and life-threatening complications, which are rarely reported to be associated with irinotecan. In our case, however, a pancreatic cancer patient developed both DAH and IPD after administration of irinotecan with fluorouracil (5FU).\n\nirinotecanchemotherapyinterstitial lung diseasediffuse alveolar hemorrhageThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nIrinotecan is a cytotoxic medication classified as a plant alkaloid and topoisomerase I inhibitor. It has been approved for treating various cancers including colorectal, gastric, lung, and brain cancers. Diffuse alveolar hemorrhage (DAH) is a serious and life-threatening condition, which can be caused by systemic autoimmune diseases, toxins, transplantation, and medications. Common culprits include antiplatelet and anticoagulant medications. DAH is rarely associated with chemotherapeutic agents. To the best of our knowledge, only one case of irinotecan-induced DAH has been documented in the literature [1]. Although interstitial lung disease is often related to the use of chemotherapeutic medications. IPD is rarely a side effect of Irinotecan [2-4]. We herein report an interesting case of the development of both DAH and IPD in a pancreatic cancer patient after the administration of irinotecan with fluorouracil (5FU). \n\nCase presentation\nA 60-year-old male with a history of pancreatic cancer presented to our emergency department with a syncopal episode. He was diagnosed with stage IV pancreatic cancer and was started on chemotherapy with a combination of 5-FU and irinotecan (FLOFRI regimen) three months ago. His last chemotherapy was one week prior to admission. On admission, he was noted to have an oxygen saturation of 75% on 5L oxygen through a nasal cannula. He was then placed on heated high flow oxygen without improvement. The patient was subsequently intubated for worsening acute hypoxic respiratory failure.\n\nThe physical examination showed diffused coarse breath sounds in bilateral lung fields. The complete blood count (CBC) revealed that the white blood cell count was 12,000 cells/L, with 12% of band cells, 81% of neutrophils, 1% of lymphocytes, 1% of monocytes, and 1% of eosinophils. A chest X-ray (CXR) showed diffuse bilateral infiltrates (Figure 1). Computed tomography (CT) of chest revealed subtle ground glass infiltrates and reticular markings suspicious for interstitial lung disease, along with two parenchymal nodules in the left lung (Figure 2). Blood cultures were negative. The urinary antigen of Legionella was negative. Bronchoscopy showed diffuse alveolar hemorrhage. Microscopic examination of the alveolar lavage sample showed large amounts of macrophages and red blood cells (Figure 3), confirming the diagnosis of DAH. Serology was negative for human immunodeficiency virus (HIV), viral hepatitis panel, anti-streptolysin O antibody (ASO), and C-reactive protein (CRP). Autoimmune panel was negative for antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), anti-citrullinated protein antibody (anti-CCP), perinuclear anti-neutrophil cytoplasmic antibodies(P-ANCA), anti-neutrophil cytoplasmic antibody (C-ANCA), anti-cardiolipin, anti-glomerular basement membrane (anti-GBM), and anti-topoisomerase antibody (anti-SCL70). Direct examination and culture of bronchoalveolar lavage fluid were negative for viruses, bacteria, fungi, mycobacteria, and Pneumocystis jirovecii. Serum polymerase chain reaction (PCR) also was negative for Aspergillus, Cytomegalovirus (CMV), P. jirovecii, and fungi. Cardiac ultrasound showed the ejection fraction of 60% to 65% with normal left ventricular diastolic function and mildly elevated right ventricular systolic pressure (RVSP) of 41 mmHg.\n\nFigure 1 CXR shows diffuse bilateral lung infiltrates (black arrows)\nCXR, chest X-ray\n\nFigure 2 CT of chest with contrast demonstrates ground glass infiltrate and increased reticular markings (black solid arrows) in the dependent portion of both lungs suspicious for interstitial lung disease and possible early fibrosis\nFigure 3 Bronchoscopy lavage smear shows scattered macrophages (black arrows) in the background of numerous red blood cells (marked with circle)\nWe held chemotherapy in light of the patient’s deteriorating condition. We started him on stress dose of steroid and broad-spectrum antibiotics, including cefepime, vancomycin, and azithromycin. The patient required prolonged ventilator support and had to receive tracheostomy as a result. His condition gradually improved after three weeks of supportive treatment. He was eventually extubated successfully. The family decided for hospice care, and the patient was transferred to the inpatient hospice service. \n\nDiscussion\nThis patient presented with sudden onset of interstitial pneumonia with diffuse alveolar hemorrhage, which was likely caused by his recent administration of the chemotherapeutic agents FLOFRI due to the time coincidence and exclusion of alternative explanations. The patient did not present with any symptoms or signs of connective tissue diseases or systemic autoimmune diseases. Laboratory data was negative for the series of auto-immunological markers. Infection workup was also negative. We did not perform biopsy because the patient was clinically ill and had a significant bleeding risk with a platelet count of 50,000 cells/L. Also, the cytology analysis of bronchial lavage revealed no evidence of cancer metastasis in the lung (Figure 3). Besides chemotherapy with 5FU and Irinotecan, the patient was not on any other medications that may have caused pulmonary toxicities. Overall, the recent chemotherapy with FLOFRI seemed to be directly associated with the development of IPD and DAH in this patient.\n\nIrinotecan was shown to cause non-specific pulmonary toxicities in previous phase II clinical trials [5]. Interstitial lung disease is a well-known side effect of various chemotherapeutic medications. But both IDP and DAH are rare complications of Irinotecan administration. Multiple recent cases of irinotecan-induced interstitial pneumonia in treating colorectal cancers were reported in the literature, demonstrating IPD as one of the potential side effects of Irinotecan [2-4]. Only one previous case of irinotecan-induced DAH has been published, suggesting DAH is an extremely rare side effect of Irinotecan [1]. 5FU could also be the potential cause; however, 5FU has almost never been accompanied by pulmonary toxicities. There has been only one report of pulmonary side effects associated with administration of 5FU [6]. Therefore, we consider irinotecan to be the cause of IPD and DAH in this patient, although the contribution of 5FU cannot be completely excluded. \n\nThe underlying mechanism of irinotecan-associated IPD and DAH is largely unknown, although direct cytotoxic effect and inflammatory response, such as hypersensitivity-mediated reaction, may play a role. It was postulated that irinotecan, as an isotopomerase inhibitor, can directly inhibit DNA synthesis or repair, inducing cytotoxic effects in pneumocytes and/or the interstitial cells. The cytology of bronchial lavage in this patient revealed the infiltration of large amounts of macrophages, suggesting the involvement of an inflammatory response. Our patient and previously published irinotecan-induced IPD or DAH patients all required systemic steroid therapy, indicating that longer duration of systemic steroids as an adjuvant therapy with Irinotecan or slower tapering of systemic steroids may reduce the incidence of irinotecan-induced IPD or DAH. Further studies are required to test this possibility and identify the exact underlying mechanisms of irinotecan-induced IPD or DAH.\n\nConclusions\nTo the best of our knowledge, our study is the first case report showing irinotecan could possibly induce both IPD and DAH in a pancreatic cancer patient. DAH is a life-threatening situation that requires immediate discontinuation of Irinotecan therapy and administration of systemic steroids. Longer duration of systemic steroids or slower tapering of systemic steroids may reduce the incidence of serious pulmonary adverse events of irinotecan. It is effective for both IPD and DAH. Further studies are required to clarify whether it is a direct toxic effect or a hypersensitivity-mediated reaction.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Diffuse alveolar hemorrhage induced by Irinotecan for a patient with metastatic thymic carcinoma: a case report and literature review Intern Med Kim S-H Minami S Ogata Y Yamamoto S Komuta K 1697 1700 56 2017 28674360 \n2 Irinotecan-induced interstitial pneumonia Lancet Oncol Michielin O Udry E Periard D Matzinger O Lobrinus J Stupp R 322 324 5 2004 15120670 \n3 A case of rectal cancer completely resected after successful treatment with irinotecan cetuximab-induced interstitial pneumonia with steroid pulse therapy Jpn J Cancer Chemother Miyake M Takeda T Haraguchi N 2334 2336 42 2015 https://www.ncbi.nlm.nih.gov/pubmed/26805355 \n4 A case of fatal interstitial pneumonia during FOLFIRI plus Cetuximab therapy for liver metastasis of colon cancer Jpn J Cancer Chemother Aoyagi H Ito H Higuchi K 51 53 45 2018 https://www.ncbi.nlm.nih.gov/pubmed/29362307 \n5 Phase II trial of Irinotecan in patients with metastatic colorectal carcinoma J Clin Oncol Pitot HC Wender DB O'Connell MJ 2910 2919 15 1997 9256135 \n6 A case of fluorouracil-induced pneumonitis Jpn J Thora Dis Andou H Itoh K Tsuda T 1080 1083 35 1997\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(6)",
"journal": "Cureus",
"keywords": "chemotherapy; diffuse alveolar hemorrhage; interstitial lung disease; irinotecan",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pmid": "31501733",
"pubdate": "2019-06-29",
"publication_types": "D002363:Case Reports",
"references": "15120670;26805355;28674360;29362307;9256135;9465619",
"title": "A Rare Case of Irinotecan-induced Interstitial Pulmonary Disease and Diffuse Alveolar Hemorrhage in a Patient with Pancreatic Cancer.",
"title_normalized": "a rare case of irinotecan induced interstitial pulmonary disease and diffuse alveolar hemorrhage in a patient with pancreatic cancer"
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"abstract": "Relapsing peritonitis in peritoneal dialysis patients is one of the complications that jeopardizes the continuity of the technique. It is often associated with the formation of biofilm in the lumen of the catheter. To date, its removal remains the only recommended attitude. Due to its antimicrobial and antifungal properties, taurolidine has been previously used for the sealing of central line catheters and hemodialysis. Despite the good results obtained, there is no evidence available regarding its utility in peritoneal dialysis. This case report describes the use of taurolidine (TauroLock™HEP500) in 5 patients with relapsing peritonitis after antibiotic treatment completion. Mean follow-up for the detection of recurrences was 13.4 months. In 4 patients with infections caused by Staphylococcus epidermidis, eradication was achieved. In the remaining case, caused by Staphylococcus aureus, the taurolidine seal was ineffective and the removal of the catheter was required.",
"affiliations": "Servicio de Nefrología, Hospital Universitario Virgen Macarena, Sevilla, España. Electronic address: klajmus@wp.pl.;Servicio de Nefrología, Hospital Universitario Virgen Macarena, Sevilla, España.;Servicio de Nefrología, Hospital Universitario Virgen Macarena, Sevilla, España.;Servicio de Nefrología, Hospital Universitario Virgen Macarena, Sevilla, España.;Servicio de Nefrología, Hospital Universitario Virgen Macarena, Sevilla, España.",
"authors": "Klimek|Kamila|K|;Aresté Fosalba|Nuria|N|;Ramírez López|Miguel Ángel|MÁ|;Gómez Castilla|Antonia Concepción|AC|;Salgueira Lazo|Mercedes|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D013829:Thiadiazines; D013654:Taurine; D014640:Vancomycin; C012566:taurolidine",
"country": "Spain",
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"issue": "40(2)",
"journal": "Nefrologia",
"keywords": "Biofilm; Diálisis peritoneal; Peritoneal dialysis; Peritonitis; Taurolidina; Taurolidine",
"medline_ta": "Nefrologia (Engl Ed)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D055499:Catheter-Related Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D010530:Peritoneal Dialysis; D010538:Peritonitis; D012008:Recurrence; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D013212:Staphylococcus epidermidis; D013654:Taurine; D013829:Thiadiazines; D014640:Vancomycin",
"nlm_unique_id": "101778581",
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"pages": "197-201",
"pmc": null,
"pmid": "31208832",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Taurolidine as adjuvant treatment of relapsing peritonitis in peritoneal dialysis patients.",
"title_normalized": "taurolidine as adjuvant treatment of relapsing peritonitis in peritoneal dialysis patients"
} | [
{
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"abstract": "OBJECTIVE\nTo assess the feasibility of acute thrombolysis for ischaemic stroke in clinical practice.\n\n\nMETHODS\nProspective.\n\n\nMETHODS\nOn July 1st, 1998 thrombolytic therapy for ischaemic stroke was introduced in the University Hospital Maastricht, the Netherlands. All patients admitted with ischaemic stroke were prospectively registered during the first year. Of all patients with ischaemic stroke, it was determined how many were potentially eligible for thrombolysis within 3 hours of stroke symptom onset, and how many of these patients were actually treated with thrombolysis. Furthermore, the reasons for exclusion from thrombolytic therapy were assessed. Several baseline and clinical patient characteristics were noted.\n\n\nRESULTS\nDuring the first year 18 ischaemic stroke patients were treated with thrombolysis within 3 hours of stroke onset. These 18 patients constituted 7% of all 256 ischaemic stroke patients and 18% of the potentially eligible patients who arrived in the hospital within 3 hours. More than 40% of the ischaemic stroke patients were not eligible for thrombolysis due to late arrival in the hospital. There were no major complications in the 18 treated patients: 3 patients developed an asymptomatic haemorrhagic transformation of the infarct.\n\n\nCONCLUSIONS\nAcute thrombolysis for ischaemic stroke within 3 hours from stroke onset is feasible, and can under specific conditions be applied in clinical practice. Only 7% of all ischaemic stroke patients underwent thrombolysis. This percentage of patients could be increased by an earlier presentation of patients to the hospital.",
"affiliations": "Afd. Neurologie: dr.J.Boiten, Academisch Ziekenhuis, Maastricht.",
"authors": "Boiten|J|J|;Wilmink|J T|JT|;Lodder|J|J|;Troost|J|J|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator",
"country": "Netherlands",
"delete": false,
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"issue": "144(22)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D000075202:Contraindications; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010960:Plasminogen Activators; D011446:Prospective Studies; D020127:Recovery of Function; D020521:Stroke; D016019:Survival Analysis; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D015599:Trauma Severity Indices; D016896:Treatment Outcome",
"nlm_unique_id": "0400770",
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"title": "Thrombolytic therapy in patients with acute brain infarction: favorable preliminary results in Maastricht.",
"title_normalized": "thrombolytic therapy in patients with acute brain infarction favorable preliminary results in maastricht"
} | [
{
"companynumb": "NL-ROCHE-1940287",
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{
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"activesubstancename": "ALTEPLASE"
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{
"abstract": "We report a case of early onset schizophrenia that responded favourably to paliperidone but experienced hyperprolactinaemia, tremors, and weight gain, with impaired fasting glycaemia. Addition of bromocriptine helped with both hyperprolactinaemia and tremors, but also brought about euglycaemia and, strikingly, ameliorated negative symptoms.",
"affiliations": "a Department of Child and Adolescent Psychiatry , Kuwait Centre for Mental Health , Kuwait ;;b Neuromodulation Unit, Department of General Adult Psychiatry , Kuwait Centre for Mental Health , Kuwait.",
"authors": "Naguy|Ahmed|A|;Al-Tajali|Ali|A|",
"chemical_list": "D014150:Antipsychotic Agents; D001971:Bromocriptine; D000068882:Paliperidone Palmitate",
"country": "England",
"delete": false,
"doi": "10.3109/08039488.2015.1094127",
"fulltext": null,
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"issn_linking": "0803-9488",
"issue": "70(4)",
"journal": "Nordic journal of psychiatry",
"keywords": "Bromocriptine; Hyperprolactinaemia; Metabolic syndrome; Negative domain; Paliperidone; Schizophrenia.",
"medline_ta": "Nord J Psychiatry",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D001971:Bromocriptine; D006801:Humans; D006966:Hyperprolactinemia; D008297:Male; D000068882:Paliperidone Palmitate; D012559:Schizophrenia; D016896:Treatment Outcome; D014202:Tremor; D015430:Weight Gain",
"nlm_unique_id": "100927567",
"other_id": null,
"pages": "318-9",
"pmc": null,
"pmid": "26573387",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bromocriptine mitigated paliperidone metabolic and neuro-hormonal side effects and improved negative domain in a case of early onset schizophrenia.",
"title_normalized": "bromocriptine mitigated paliperidone metabolic and neuro hormonal side effects and improved negative domain in a case of early onset schizophrenia"
} | [
{
"companynumb": "KW-MYLANLABS-2016M1020075",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PALIPERIDONE"
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... |
{
"abstract": "BACKGROUND\nCancer-related neuropathic pain is resistant to treatment with multiple medications and results in reduced patient quality of life.\n\n\nOBJECTIVE\nThe aim was to find a new curative to treat neuropathic pain without using adjuvant analgesics.\n\n\nMETHODS\nThis was a retrospective study that used the FACES Pain Scale (FPS) to measure pain intensity and pain relief.\n\n\nMETHODS\nTwenty-eight inpatients who were treated with other strong opioids and who consulted the palliative care team about their pain relief.\n\n\nRESULTS\nIn 22 (78.6%) out of 28 patients who successfully switched to methadone from other strong opioids, such as oxycodone and fentanyl, within two weeks, the mean FPS score was significantly reduced from 4.43 to 1.86, and methadone switching either reduced the number of prescriptions or stopped them entirely in 12 out of 17 (70.5%) patients who had used adjuvant analgesics before switching to methadone.\n\n\nCONCLUSIONS\nThese results suggest that opioid switching to oral methadone not only achieves pain relief but also curtails substantial adjuvant analgesic use.",
"affiliations": "1 Division of Psycho-oncology and Palliative Care, Nagoya City University Hospital , Nagoya, Japan .;1 Division of Psycho-oncology and Palliative Care, Nagoya City University Hospital , Nagoya, Japan .;3 Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University , Nagoya, Japan .;1 Division of Psycho-oncology and Palliative Care, Nagoya City University Hospital , Nagoya, Japan .;1 Division of Psycho-oncology and Palliative Care, Nagoya City University Hospital , Nagoya, Japan .;1 Division of Psycho-oncology and Palliative Care, Nagoya City University Hospital , Nagoya, Japan .;3 Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University , Nagoya, Japan .;4 Division of Respiratory Medicine, Juntendo Tokyo Koto Geriatric Medical Center , Tokyo, Japan .;5 Department of Respiratory Medicine, Allergy and Clinical Immunology, Graduate School of Medical Sciences, Nagoya City University , Nagoya, Japan .;6 Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Nagoya City University , Nagoya, Japan .;1 Division of Psycho-oncology and Palliative Care, Nagoya City University Hospital , Nagoya, Japan .;2 Department of Pharmacy, Nagoya City University Hospital , Nagoya, Japan .",
"authors": "Sugiyama|Yosuke|Y|;Sakamoto|Nobuhiro|N|;Ohsawa|Masahiro|M|;Onizuka|Mami|M|;Ishida|Kyoko|K|;Murata|Yuki|Y|;Iio|Ayaka|A|;Sugano|Koji|K|;Maeno|Ken|K|;Takeyama|Hiromitsu|H|;Akechi|Tatsuo|T|;Kimura|Kazunori|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2015.0303",
"fulltext": null,
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"issn_linking": "1557-7740",
"issue": "19(10)",
"journal": "Journal of palliative medicine",
"keywords": null,
"medline_ta": "J Palliat Med",
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"nlm_unique_id": "9808462",
"other_id": null,
"pages": "1051-1059",
"pmc": null,
"pmid": "27404399",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Retrospective Study on the Effectiveness of Switching to Oral Methadone for Relieving Severe Cancer-Related Neuropathic Pain and Limiting Adjuvant Analgesic Use in Japan.",
"title_normalized": "a retrospective study on the effectiveness of switching to oral methadone for relieving severe cancer related neuropathic pain and limiting adjuvant analgesic use in japan"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1051467",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nCastleman's disease is a rare lymphoproliferative disorder which occurs in localized and multicentric forms and can mimic lymphoma. Despite its well-known association with certain autoimmune diseases, including paraneoplastic pemphigus and myasthenia gravis, Castleman's disease has not previously been associated with limbic encephalitis.\n\n\nMETHODS\nWe report the case of a 47-year old Caucasian man who presented with subacute onset of constitutional symptoms, diffuse lymphadenopathy, and stereotyped spells involving olfactory aura, nausea, disorientation, and unresponsiveness. He was found to have focal dyscognitive seizures of temporal lobe origin, cerebrospinal fluid with lymphocytic pleocytosis, hyponatremia, and serum positive for voltage-gated potassium channel antibodies, consistent with limbic encephalitis. An extensive infectious workup was unrevealing, but lymph node biopsy revealed multicentric Castleman's disease. His symptoms improved with antiepileptic drugs and immunotherapy.\n\n\nCONCLUSIONS\nThis case highlights the clinical diversity of voltage-gated potassium channel autoimmunity and expands the association of Castleman's disease and autoimmune syndromes to include limbic encephalitis. Clinicians should be aware that paraneoplastic disorders of the central nervous system can be related to underlying hematologic disorders such as Castleman's disease.",
"affiliations": "Department of Neurology, University of California, San Francisco, 400 Parnassus Ave, 8th Floor, San Francisco, CA, 94143, USA. vikram.rao@ucsf.edu.;Neurology Service, Department of Veteran Affairs, Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304, USA. leland.lim@va.gov.;Pathology and Laboratory Medicine Service, Department of Veteran Affairs, Palo Alto Health Care System (113), 3801 Miranda Avenue, Palo Alto, CA, 94304, USA. dean.fong@va.gov.;Epilepsy Center of Excellence, San Francisco Veteran Affairs Medical Center, 4150 Clement Street, Box 127E, San Francisco, CA, 94121, USA. nina.garga@va.gov.;Epilepsy Center of Excellence, San Francisco Veteran Affairs Medical Center, 4150 Clement Street, Box 127E, San Francisco, CA, 94121, USA. karen.parko@va.gov.",
"authors": "Rao|Vikram R|VR|;Lim|Leland E|LE|;Fong|Dean|D|;Garga|Nina I|NI|;Parko|Karen L|KL|",
"chemical_list": "D000906:Antibodies; D024642:Potassium Channels, Voltage-Gated",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-015-0266-8",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 2564843126610.1186/s12883-015-0266-8Case ReportMulticentric Castleman’s disease with voltage-gated potassium channel antibody-positive limbic encephalitis: a case report Rao Vikram R vikram.rao@ucsf.edu Lim Leland E leland.lim@va.gov Fong Dean dean.fong@va.gov Garga Nina I nina.garga@va.gov Parko Karen L karen.parko@va.gov Department of Neurology, University of California, San Francisco, 400 Parnassus Ave, 8th Floor, San Francisco, CA 94143 USA Neurology Service, Department of Veteran Affairs, Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304 USA Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 USA Pathology and Laboratory Medicine Service, Department of Veteran Affairs, Palo Alto Health Care System (113), 3801 Miranda Avenue, Palo Alto, CA 94304 USA Epilepsy Center of Excellence, San Francisco Veteran Affairs Medical Center, 4150 Clement Street, Box 127E, San Francisco, CA 94121 USA 4 2 2015 4 2 2015 2015 15 412 9 2014 21 1 2015 © Rao et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCastleman’s disease is a rare lymphoproliferative disorder which occurs in localized and multicentric forms and can mimic lymphoma. Despite its well-known association with certain autoimmune diseases, including paraneoplastic pemphigus and myasthenia gravis, Castleman’s disease has not previously been associated with limbic encephalitis.\n\nCase presentation\nWe report the case of a 47-year old Caucasian man who presented with subacute onset of constitutional symptoms, diffuse lymphadenopathy, and stereotyped spells involving olfactory aura, nausea, disorientation, and unresponsiveness. He was found to have focal dyscognitive seizures of temporal lobe origin, cerebrospinal fluid with lymphocytic pleocytosis, hyponatremia, and serum positive for voltage-gated potassium channel antibodies, consistent with limbic encephalitis. An extensive infectious workup was unrevealing, but lymph node biopsy revealed multicentric Castleman’s disease. His symptoms improved with antiepileptic drugs and immunotherapy.\n\nConclusion\nThis case highlights the clinical diversity of voltage-gated potassium channel autoimmunity and expands the association of Castleman’s disease and autoimmune syndromes to include limbic encephalitis. Clinicians should be aware that paraneoplastic disorders of the central nervous system can be related to underlying hematologic disorders such as Castleman’s disease.\n\nKeywords\nCastleman’s diseaseLymphoproliferativeLimbic encephalitisVoltage-gated potassium channelVGKCParaneoplasticSeizureissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nCastleman’s disease (CD) is a rare lymphoproliferative disorder characterized by enlarged, hyperplastic lymph nodes that can mimic lymphoma. First described in 1954 [1], CD occurs in several histologic variants, including hyaline-vascular, plasma cell, and mixed types. Two clinical presentations can be distinguished: a localized or unicentric form, which is typically indolent and treated with local excision, and a systemic or multicentric form (MCD), which usually involves the plasma cell variant and portends a worse prognosis. MCD presents with diffuse lymphadenopathy, hepatosplenomegaly, fevers, night sweats, and fatigue. The pathogenesis of MCD is thought to be driven by human herpesvirus 8 (HHV8), which latently infects B cells in healthy individuals but can reactivate in the setting of immune system compromise, such as human immunodeficiency virus (HIV) infection. Reactivated HHV8 promotes production of interleukin-6 (IL-6), which stimulates B cell proliferation and lymphoid hyperplasia, and treatment of MCD can be directed at lowering levels of this cytokine [2].\n\nCD most commonly presents with lymphadenopathy in the neck, chest, and/or abdomen. Central nervous system (CNS) involvement is rare, but intracranial, extra-axial lesions mimicking meningiomas have been reported in CD and can present with seizures [3,4], presumably due to their direct impingement on cortex. CD has been associated with several autoimmune diseases [5], including paraneoplastic pemphigus, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, but only a single report describes a paraneoplastic CNS syndrome in the setting of CD [6]. Limbic encephalitis (LE), a classic CNS autoimmune disorder, presents with cognitive changes and focal seizures of mesial temporal lobe origin. LE can occur with or without identifiable underlying malignancy and can be seronegative or associated with specific antibodies. Malignant hemopathies—including leukemia [7] and, more commonly, lymphomas [8]—have been associated with paraneoplastic LE, but, to our knowledge, CD has not.\n\nHere we report the case of a patient who presented with subacute onset of constitutional symptoms and seizures and was found to have MCD, LE, and voltage-gated potassium channel (VGKC) antibodies. This case illustrates novel linkage of two rare clinical entities through an antibody well-known to mediate paraneoplastic neurological syndromes.\n\nCase presentation\nA 47-year old Caucasian man with history of depression and remote polysubstance abuse presented to his primary care physician with two months of cough, dyspnea, and asthenia. Chest radiography demonstrated patchy, diffuse interstitial infiltrates. Chest computed tomography (CT) disclosed diffuse lymphadenopathy, splenomegaly, and bilateral bronchiectatic changes (Figure 1). Body positron emission tomography (PET)/CT showed diffuse, hypermetabolic (mild-moderate 18 F-fluorodeoxyglucose (FDG) uptake) lymphadenopathy without other evidence of malignancy. The initial differential diagnosis included atypical respiratory infection, granulomatous disease, and lymphoproliferative disorder. He underwent bronchoscopy with bronchoalveolar lavage, with negative staining for acid-fast bacilli, no malignant cells on cytology, and no growth in bacterial and fungal cultures. Transbronchial lung biopsy revealed non-specific chronic inflammation, and fine needle aspirate of a left neck lymph node was non-diagnostic. A repeat bronchoscopic evaluation nine months later was similarly unrevealing. Serum protein electrophoresis showed no evidence of monoclonal gammopathy, and angiotensin-converting enzyme levels were within normal limits. Serum inflammatory markers were elevated (erythrocyte sedimentation rate 111 mm/hr, C-reactive protein 7.28 mg/dL), but an extensive biochemical evaluation for infectious etiologies, including HIV, tuberculosis, coccidioidomycosis, aspergillosis, cryptococcosis, blastomycosis, and histoplasmosis, was negative. Due to an elevated Strongyloides IgG antibody titer, he was treated with ivermectin but had no improvement in his symptoms.Figure 1 \nLymphadenopathy on chest CT. Chest CT demonstrating enlarged lymph nodes (arrows) involving the right axillary (a), paratracheal (b), subcarinal (c), and cardiophrenic (d) regions.\n\n\n\nWhile this workup was in progress, the patient described progressive memory difficulty and recurrent, stereotyped spells involving perception of an unpleasant odor followed by nausea and dizziness. The spells lasted about one minute, occurred up to seven times per day, and coincided with episodic confusion noticed by his girlfriend. A routine electroencephalogram (EEG) was normal, and the patient was treated empirically with levetiracetam without benefit.\n\nHis neurological exam was notable for short-term memory impairment (1 out of 3 object recall after 5-minute delay) and hyporeflexia with length-dependent sensory loss in the lower extremities. Routine bloodwork revealed hyponatremia, with serum sodium of 131 mmol/L. Lumbar puncture was performed, and cerebrospinal fluid (CSF) analysis revealed glucose 55 mg/dL, total protein 33 mg/dL, and 12/mm3 white blood cells (88% lymphocytes, 11% monocytes) and 15/mm3 red blood cells. CSF cytology was negative. Gadolinium-enhanced brain magnetic resonance imaging (MRI) at 3.0 Tesla was normal. Video-EEG monitoring performed over two days captured twelve electrographic seizures—most were subclinical but some had associated dyscognitive features—with ictal onset over the left temporal region (Figure 2). Electrographic features of the seizures, including early emergence of rhythmic theta- and alpha-range frequencies, suggested mesial temporal origin. Levetiracetam was substituted with divalproex, which led to complete resolution of the patient’s seizures based both on his report and on repeat video-EEG monitoring one month later. His cognitive deficits also improved subjectively, though formal neuropsychological testing was not pursued.Figure 2 \nIctal EEG. EEG during a seizure (red bar) arising from light sleep. Initially, there is emergence of theta/alpha range frequencies broadly over the left temporal region, maximal at electrodes F7 and T3 (a). Left temporal waveforms become rhythmic (b) and evolve in frequency and amplitude while acquiring sharpened elements (c) before return to interictal background (d). Clinically, the patient was observed to have lip-smacking automatisms during this seizure.\n\n\n\nThe constellation of subacute encephalopathy, temporal lobe seizures, and mild lymphocytic CSF pleocytosis raised the possibility of autoimmune encephalitis. Serological analysis revealed elevated voltage-gated potassium channel (VGKC) antibodies (850 pmol/L; Athena Diagnostics, reference range 31–88 pmol/L). Testing for N-methyl-D-aspartate receptor and glutamic acid decarboxylase antibodies was negative. VGKC antibodies can be associated with underlying neoplastic disease, and, to further evaluate this possibility, excisional biopsy of a level V lymph node in the right neck was performed.\n\nHistologic sections revealed lymph nodes with variable sized follicles, some with atrophic germinal centers (Figure 3a). Germinal centers with penetrating vessels were present, conferring a “lollipop” appearance (Figure 3b). Mantle zone lymphocytes were arranged in concentric rings (“onion-skinning”). The interfollicular areas and medulla were expanded by large sheets of mature plasma cells. No granulomas were seen. Immunohistochemistry demonstrated the presence of polytypic plasma cells. Flow cytometry provided no evidence for a clonal lymphocyte population or aberrant antigen expression. IL-6 concentration in undiluted serum was 7.12 pg/mL (reference range 0.31-5.00 pg/mL) but the level was 174.08 pg/mL when tested in serial dilutions, suggesting prozone effect. Taken together, these results were most consistent with MCD, plasma cell variant. Of note, HHV8 staining of lymphoid tissue and serum HHV8 immunofluorescence assay were both negative. Repeat HIV antibody testing was also negative.Figure 3 \nLymph node biopsy pathology. 10x (a) and 20x (b) images of lymph node tissue sections were captured on an Olympus BX40 microscope with Olympus SC100 camera and Olympus analySIS getIT software. (a) Atrophic germinal centers with mantle zone lymphocytes arranged in concentric rings create an “onion-skinning” appearance. Note that the interfollicular areas are expanded by sheets of plasma cells. (b) Germinal center with penetrating vessels and a “lollipop” appearance.\n\n\n\nThe patient was treated with two four-week cycles of weekly rituximab infusions followed by maintenance rituximab infusions every two months for a planned two-year course. Antiepileptic drug therapy with divalproex was continued with some dose adjustment required for breakthrough seizures. Serum IL-6 levels were not monitored to track response to therapy, but serial PET scans have shown decreased size and FDG-avidity of diffuse lymphadenopathy without complete resolution. A repeat VGKC antibody titer six months after initiation of rituximab was lower but remained elevated at 656 pmol/L. At last follow-up, the patient’s cough was persistent, now being managed with prednisone, but the constitutional symptoms that led to initial presentation had resolved.\n\nDiscussion\nThis case illustrates the typical features of MCD: onset in middle age, non-specific constitutional symptoms suggestive of inflammatory disease, diffuse lymphadenopathy and hepatosplenomegaly mimicking lymphoma, and, often, cough or dyspnea, which is more common in HIV-positive patients and may relate to a non-infectious pulmonary interstitial lymphocytic infiltrate. Mild sensory polyneuropathy, as found in our patient, can occur in 20% of patients with MCD [9]. Manifestations of MCD are thus non-specific and diagnosis is made by histopathology, which most commonly reveals the plasma cell variant. Although HHV8 is central to the pathogenesis of HIV-positive CD, its role in HIV-negative disease remains controversial [9] because HHV8 is found in only 50% of these patients [10]. Our patient was found to be HIV-negative and HHV8-negative, which may represent a nosologically-distinct disease entity, termed idiopathic MCD, whose pathogenesis is speculated to involve autoimmune mechanisms [11]. Thus, this case raises the intriguing possibility that VGKC antibodies might be important for the pathogenesis of certain forms of MCD.\n\nOur patient also developed cardinal features of LE associated with VGKC antibodies, including subacute encephalopathy, temporal lobe seizures, CSF lymphocytic pleocytosis, and hyponatremia [12]. Brain MRI was normal, as is the case in up to 45% of patients with LE and VGKC antibodies [13]. VGKC antibodies are thought to be pathogenic in LE, but the antibodies are actually directed against epitopes in the extracellular domains of proteins tightly complexed with VGKCs in vivo; the most common target in LE is the leucine-rich glioma-inactivated 1 (LGI-1) protein [12]. Although we did not test specifically for this immunoreactivity, our patient did not demonstrate the faciobrachial dystonic seizure semiology that often precedes onset of LE in LGI-1 antibody-positive patients [14].\n\nPrevious reports have described patients with intracranial CD lesions presenting with seizures [3,4], presumably due to mass effect and irritation of adjacent cortex. CD is also known to be associated with paraneoplastic syndromes affecting the peripheral nervous system (PNS), including myasthenia gravis and POEMS syndrome [5]. One reported case of cerebellar degeneration in the setting of CD may represent an autoimmune CNS syndrome, but no antibody was identified [6]. Only 30% of patients with antibodies against VGKC have tumors, but VGKC antibodies have been reported in association with thymoma and lung cancer [15]. To our knowledge, this is the first report of CD associated with either LE or VGKC antibodies.\n\nLE associated with VGKC antibodies is frequently responsive to immunotherapy, and reduction in antibody titer correlates with clinical improvement [16]. Our patient’s seizures were relatively easily controlled with antiepileptic drug monotherapy, though we cannot exclude the possibility that steroids used later for pulmonary indications also contributed to seizure control. Rituximab was initiated primarily for treatment of MCD. That only modest decrease in VGKC antibody titer was seen following treatment with rituximab, however, may indicate that paraneoplastic LE in the setting of MCD is more treatment-resistant than other forms of LE. Three-year disease-free survival in HIV-negative patients with plasma cell variant MCD is 45% [17], so our patient’s prognosis remains guarded. Other treatment options, including the anti-IL-6 monoclonal antibody, siltuximab [2], are being considered.\n\nThe range of autoimmune disorders associated with CD is broader than previously known, and VGKC antibodies may play an important pathogenic role. In addition to paraneoplastic syndromes affecting the PNS, clinicians should be aware that CD can be associated with LE and other CNS manifestations even in the absence of overt intracranial disease.\n\nConclusions\nCastleman’s disease can be associated with voltage-gated potassium channel antibodies and paraneoplastic syndromes involving the central nervous system. Although rare, Castleman’s disease should be considered in patients presenting with features of limbic encephalitis and evidence of an underlying lymphoproliferative disorder.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nVRR interpreted the patient data regarding the neurological disease and was a major contributor in writing the manuscript. DF analyzed the histopathology and contributed to writing the manuscript. LEL, NIG, and KLP interpreted the patient data regarding the neurological disease. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors thank Dr. Charlotte Jacobs for helpful discussions and expert oncological management of this patient.\n==== Refs\nReferences\n1. Castleman B Towne VW Case records of the Massachusetts general hospital: case No. 40231 N Engl J Med 1954 250 23 1001 1005 10.1056/NEJM195406102502308 13165944 \n2. van Rhee F Wong RS Munshi N Rossi JF Ke XY Fossa A Siltuximab for multicentric Castleman's disease: a randomised, double-blind Placebo-Controlled Trial Lancet Oncol 2014 15 9 966 974 10.1016/S1470-2045(14)70319-5 \n3. Sotrel A Castellano-Sanchez AA Prusmack C Birchansky S Brathwaite C Ragheb J Castleman's disease in a child presenting with a partly mineralized solitary meningeal mass Pediatr Neurosurg 2003 38 5 232 237 10.1159/000069821 12686765 \n4. Matsumura K Nakasu S Tanaka T Nioka H Matsuda M Intracranial localized Castleman's disease. Case report Neurol Med Chir (Tokyo) 2005 45 1 59 65 10.2176/nmc.45.59 15699624 \n5. Muskardin TW Peterson BA Molitor JA Castleman disease and associated autoimmune disease Curr Opin Rheumatol 2012 24 1 76 83 10.1097/BOR.0b013e32834db525 22157415 \n6. Lee S Le S Paraneoplastic cerebellar degeneration with castleman disease: a case report Neurology 2014 82 P1.027 10.1212/WNL.0000000000000152 \n7. Alcantara M Bennani O Verdure P Lepretre S Tilly H Jardin F Voltage-gated potassium channel antibody paraneoplastic limbic encephalitis associated with acute myeloid leukemia Case Rep Oncol 2013 6 2 289 292 10.1159/000351835 23898271 \n8. Graus F Arino H Dalmau J Paraneoplastic neurological syndromes in Hodgkin and Non-Hodgkin lymphomas Blood 2014 123 21 3230 3238 10.1182/blood-2014-03-537506 24705493 \n9. van Rhee F Stone K Szmania S Barlogie B Singh Z Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy Clin Adv Hematol Oncol 2010 8 7 486 498 20864917 \n10. Soumerai JD Sohani AR Abramson JS Diagnosis and management of castleman disease Cancer Control 2014 21 4 266 278 25310208 \n11. Fajgenbaum DC van Rhee F Nabel CS Hhv-8-negative, idiopathic multicentric castleman disease: novel insights into biology, pathogenesis, and therapy Blood 2014 123 19 2924 2933 10.1182/blood-2013-12-545087 24622327 \n12. Irani SR Gelfand JM Al-Diwani A Vincent A Cell-Surface Central Nervous System Autoantibodies: Clinical Relevance and Emerging Paradigms Ann Neurol 2014 76 2 168 84 10.1002/ana.24200 24930434 \n13. Vincent A Bien CG Irani SR Waters P Autoantibodies associated with diseases of the Cns: New developments and future challenges Lancet Neurol 2011 10 8 759 772 10.1016/S1474-4422(11)70096-5 21777830 \n14. Irani SR Michell AW Lang B Pettingill P Waters P Johnson MR Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis Ann Neurol 2011 69 5 892 900 10.1002/ana.22307 21416487 \n15. Tan KM Lennon VA Klein CJ Boeve BF Pittock SJ Clinical spectrum of voltage-gated potassium channel autoimmunity Neurology 2008 70 20 1883 1890 10.1212/01.wnl.0000312275.04260.a0 18474843 \n16. Vincent A Buckley C Schott JM Baker I Dewar BK Detert N Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis Brain 2004 127 Pt 3 701 712 14960497 \n17. Talat N Schulte KM Castleman's disease: systematic analysis of 416 patients from the literature Oncologist 2011 16 9 1316 1324 10.1634/theoncologist.2011-0075 21765191\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "15()",
"journal": "BMC neurology",
"keywords": null,
"medline_ta": "BMC Neurol",
"mesh_terms": "D000906:Antibodies; D005871:Castleman Disease; D006801:Humans; D020363:Limbic Encephalitis; D008297:Male; D008875:Middle Aged; D024642:Potassium Channels, Voltage-Gated; D012640:Seizures",
"nlm_unique_id": "100968555",
"other_id": null,
"pages": "4",
"pmc": null,
"pmid": "25648431",
"pubdate": "2015-02-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18474843;22157415;23898271;24705493;14960497;21777830;20864917;12686765;24930434;25310208;25042199;24622327;13165944;15699624;21416487;21765191",
"title": "Multicentric Castleman's disease with voltage-gated potassium channel antibody-positive limbic encephalitis: a case report.",
"title_normalized": "multicentric castleman s disease with voltage gated potassium channel antibody positive limbic encephalitis a case report"
} | [
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"companynumb": "US-APOTEX-2017AP019557",
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"abstract": "<p>BACKGROUND: Treatment of vitiligo is aimed at repigmentation and often consists of multiple modalities, none of which are universally or rapidly successful. Extensive cases are most often treated with ultraviolet light therapy, which can be both costly and time-consuming. Though vitiligo is an autoimmune disease, there is no current data to support systemic immunosuppressive monotherapy.</p> <p>CASE SUMMARY: Here we present a case series of 3 patients with vitiligo treated for 11-16 months with low-dose methotrexate (12.5-25 mg per week) with folic acid supplementation with clinically significant skin repigmentation, with response within 6 months in one case. There were no severe adverse effects reported.</p> <p>CONCLUSION: These cases demonstrate an unexplored effective and steroid-sparing therapeutic alternative in patients with vitiligo for whom topical therapy has failed and phototherapy is cost-prohibitive or ineffective.</p> <p><em>J Drugs Dermatol. 2017;16(7):705-706.</em></p>.",
"affiliations": null,
"authors": "Garza-Mayers|Anna Cristina|AC|;Kroshinsky|Daniela|D|",
"chemical_list": "D007166:Immunosuppressive Agents; D005492:Folic Acid; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "16(7)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000328:Adult; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D014820:Vitiligo",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "705-706",
"pmc": null,
"pmid": "28697225",
"pubdate": "2017-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low-dose Methotrexate for Vitiligo.",
"title_normalized": "low dose methotrexate for vitiligo"
} | [
{
"companynumb": "US-AMGEN-USASP2017146296",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"activesubstancename": "ETANERCEPT"
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{
"abstract": "OBJECTIVE\nThe present study evaluated the safety and efficacy of neoadjuvant chemotherapy with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab in clinical stage III rectal cancer with KRAS wild-type.\n\n\nMETHODS\nWe conducted a prospective multicenter phase II trial. KRAS wild-type clinical stage III rectal cancer patients were enrolled. Patients received 6 cycles of mFOLFOX6 with 6 mg/kg panitumumab as neoadjuvant chemotherapy. The primary outcome was the response rate (RR) defined by RECIST. Lateral lymph node dissection (LLDN) was performed when patients had a locally advanced tumor < 9 cm from the anal margin.\n\n\nRESULTS\nA total of 50 patients were enrolled. Twelve (24.0%) experienced grade 3-4 adverse events during neoadjuvant chemotherapy. The RR was 88.0% (complete response 2.0%, partial response 86.0%), which met the primary outcome. All patients underwent laparoscopic surgery and achieved R0 resection. Seven patients underwent resection of other adjacent organs, and 43 underwent LLND. Twelve patients (24.0%) experienced grade 3-4 postoperative complications, and 4 (8.0%) had pathological complete response (pCR). Thirteen patients (26.0%) had lymph node metastasis. Forty-five patients (90.0%) received postoperative adjuvant chemotherapy. The 3-year relapse-free survival (RFS) and overall survival (OS) rates were 79.0% and 93.7%, respectively.\n\n\nCONCLUSIONS\nNeoadjuvant chemotherapy of mFOLFOX6 plus panitumumab without radiotherapy resulted in a low pCR rate but a high PR rate, low local recurrence rate, and good long-term outcome, suggesting that this treatment strategy may be a viable option for patients unable or unwilling to receive radiotherapy. The trial was registered with the UMIN Clinical Trials Registry, number 000006039.",
"affiliations": "Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. nabe-jun@comet.ocn.ne.jp.;Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, 4-57, Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.;Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Surgery, Yokosuka Kyosai Hospital, Yokosuka, Japan.;Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Surgery, Yokohama Minato Red Cross hospital, Yokohama, Japan.;Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, 4-57, Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.;Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan.;Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.",
"authors": "Toritani|Kenichiro|K|https://orcid.org/0000-0001-5184-8819;Watanabe|Jun|J|https://orcid.org/0000-0002-7187-3664;Suwa|Yusuke|Y|;Nakagawa|Kazuya|K|;Suwa|Hirokazu|H|;Ishibe|Atsushi|A|;Ota|Mitsuyoshi|M|;Kunisaki|Chikara|C|;Yamanaka|Takeharu|T|;Endo|Itaru|I|",
"chemical_list": "D000077544:Panitumumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00384-020-03693-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-1958",
"issue": "35(12)",
"journal": "International journal of colorectal disease",
"keywords": "Laparoscopic surgery; Neoadjuvant chemotherapy; Panitumumab; Rectal cancer; mFOLFOX6",
"medline_ta": "Int J Colorectal Dis",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D000077544:Panitumumab; D011446:Prospective Studies; D012004:Rectal Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8607899",
"other_id": null,
"pages": "2197-2204",
"pmc": null,
"pmid": "32725346",
"pubdate": "2020-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A prospective, single-arm, multicenter trial of neoadjuvant chemotherapy with mFOLFOX6 plus panitumumab without radiotherapy for locally advanced rectal cancer.",
"title_normalized": "a prospective single arm multicenter trial of neoadjuvant chemotherapy with mfolfox6 plus panitumumab without radiotherapy for locally advanced rectal cancer"
} | [
{
"companynumb": "JP-AMGEN-JPNNI2020130118",
"fulfillexpeditecriteria": "2",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Pembrolizumab is a monoclonal antibody directed towards programmed cell death protein 1 (PD-1) and is an antineoplastic drug which has a growing variety of oncologic uses. Pembrolizumab is commonly associated with immune-related adverse events (IRAEs) but is infrequently noted to cause cardiotoxicities such as myocarditis, arrhythmias, and heart failure. The following case report illustrates the clinical course of a 67-year-old female patient with stage IV non-small-cell lung cancer who developed Mobitz type 2 second-degree atrioventricular block three weeks after receiving her first infusion of pembrolizumab. Within a few hours of presentation, she progressed to symptomatic complete heart block requiring emergent placement of a temporary transvenous pacemaker. The article further discusses proposed mechanisms to explain IRAEs and management of IRAEs. We conclude by recommending a higher degree of caution and awareness among all physicians when treating patients on immunotherapy and a multidisciplinary approach when considering resumption of immune checkpoint inhibitor therapy.",
"affiliations": "Department of Medicine, SUNY Upstate Medical University, USA.;Department of Medicine, SUNY Upstate Medical University, USA.;Department of Cardiology, SUNY Upstate Medical University, USA.",
"authors": "Khan|Alisha|A|https://orcid.org/0000-0001-5379-6645;Riaz|Sana|S|;Carhart|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/8428210",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 3204767410.1155/2020/8428210Case ReportPembrolizumab-Induced Mobitz Type 2 Second-Degree Atrioventricular Block https://orcid.org/0000-0001-5379-6645Khan Alisha khanali@upstate.edu\n1\nRiaz Sana \n1\nCarhart Robert Jr.\n2\n\n1Department of Medicine, SUNY Upstate Medical University, USA\n2Department of Cardiology, SUNY Upstate Medical University, USAAcademic Editor: Kathleen Ngu\n\n2020 28 1 2020 2020 842821012 9 2019 14 12 2019 Copyright © 2020 Alisha Khan 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.Pembrolizumab is a monoclonal antibody directed towards programmed cell death protein 1 (PD-1) and is an antineoplastic drug which has a growing variety of oncologic uses. Pembrolizumab is commonly associated with immune-related adverse events (IRAEs) but is infrequently noted to cause cardiotoxicities such as myocarditis, arrhythmias, and heart failure. The following case report illustrates the clinical course of a 67-year-old female patient with stage IV non-small-cell lung cancer who developed Mobitz type 2 second-degree atrioventricular block three weeks after receiving her first infusion of pembrolizumab. Within a few hours of presentation, she progressed to symptomatic complete heart block requiring emergent placement of a temporary transvenous pacemaker. The article further discusses proposed mechanisms to explain IRAEs and management of IRAEs. We conclude by recommending a higher degree of caution and awareness among all physicians when treating patients on immunotherapy and a multidisciplinary approach when considering resumption of immune checkpoint inhibitor therapy.\n==== Body\n1. Introduction\nSince its initial approval by the Food and Drug Administration in the United States in 2014, the indications for the use of the antineoplastic drug pembrolizumab have steadily continued to increase in the world of oncology. The drug is an immune checkpoint inhibitor most commonly used in the treatment of melanoma and non-small-cell lung cancer (NSCLC).\n\nPembrolizumab is an IgG4-kappa humanized monoclonal antibody directed towards programmed cell death protein 1 (PD-1). PD-1, also known as CD 274 or B7-H1, is a costimulation receptor expressed by activated T cells. Binding of pembrolizumab to the PD-1 receptor prevents two immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1. Blocking of the PD-1 receptor by pembrolizumab thereby leads to inhibition of effector T cell proliferation, reduces cytotoxic activity, and induces apoptosis in tumor-infiltrating T cells and regulatory T cell expression [1].\n\nThis immunotherapy may now be used as a first-line agent for patients whose malignant cells have a PD-L1 expression or tumor proportion score (TPS) ≥ 1% and who do not harbor EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) mutations [2]. Overall survival with the use of pembrolizumab correlates with increasing levels of PD-L1 expression [2].\n\nDespite its survival benefits, it is also known for its immune-related adverse events, which affect various organ systems. Immune-related cardiotoxicity is a rare but often fatal complication. Cardiotoxicities associated with pembrolizumab include myocarditis, heart failure, sick sinus syndrome, cardiomyopathy, cardiac fibrosis, and cardiac arrest [3–7]. The following case describes a patient who developed complete heart block which appears to be temporally related to the use of the anti-PD-1 antibody, pembrolizumab.\n\n2. Case Presentation\nWe provided care for a 67-year-old female with a past medical history of stage IV NSCLC metastatic to the adrenal gland, lymph nodes, and brain, complicated by a prior seizure for which she was on levetiracetam, hypertension on amlodipine, hyperlipidemia on simvastatin, hypothyroidism on levothyroxine, and depression on trazodone who presented to our Emergency Department as a transfer from the Cancer Center for bradycardia which was noted on routine vital sign assessment as she was about to get her second immunotherapy dose.\n\nHer recent PET scan showed progression of her cancer in the mediastinum and supraclavicular area. Lymph node biopsy revealed a PD-L1 expression of 90%, and hence, she received her first infusion of pembrolizumab 200 mg intravenously three weeks prior to our encounter, as it is usually administered.\n\nIn the Emergency Department, she was initially asymptomatic with a heart rate of 30 beats per minute (bpm) as noted on telemetry monitoring and blood pressure of 121/63 mmHg. On admission, her EKG depicted Mobitz type 2 second-degree atrioventricular block (Figure 1). The electrophysiologist was immediately consulted with plans to place a permanent pacemaker the following morning. However, approximately three hours later, as she shifted in bed in order to place the bedpan beneath her, she began to feel lightheaded and her blood pressure dropped to 64/42 mmHg. Repeat EKG at this time showed complete heart block with a ventricular rate of 22 bpm (Figure 2). At this point, she was given a 500 cc bolus and dobutamine drip was initiated. EKG at this time showed complete heart block and idioventricular rhythm with a heart rate of 25 bpm (Figure 3), following which a temporary transvenous pacemaker was emergently placed overnight.\n\nHer labs including a basic metabolic panel and complete metabolic panel were unremarkable. Her magnesium level was 2.2 mg/dL and phosphorus level was 3.2 mg/dL. Troponin T was trended and was negative throughout her admission. Thyroid stimulating hormone level on admission was within normal range at 1.270 mU/mL. Her echocardiogram showed a LVEF of 60-65%. Her baseline EKG obtained approximately a year and a half prior to presentation showed a left anterior fascicular block and a right bundle branch block (Figure 4).\n\nShe underwent permanent pacemaker placement the following morning without complication. Prior to discharge, a chest X-ray, electrocardiogram, and device interrogation were performed. She was discharged home in a hemodynamically stable condition.\n\n3. Discussion\nPembrolizumab is commonly associated with immune-related adverse events and is infrequently associated with cardiotoxicities such as myocarditis and heart failure. Conduction disease can be isolated or associated with coexisting myocarditis [8]. However, there are only two case reports in the literature so far in which patients presented with complete heart block. Interestingly, similar to the article by Katsume et al., our patient was receiving pembrolizumab after initial prior treatment with pemetrexed and bevacizumab for NSCLC. Katsume et al.'s patient was also found to have a high PD-L1 expression of >95% and received pembrolizumab at 200 mg 16 days prior to admission [7]. In other words, both patients were highly susceptible to the effects of pembrolizumab with their tumor cells having a high degree of expression (90% or greater), and both patients developed heart block the second time they received the immunotherapy, approximately 3 weeks after the first infusion. Our patient's prior chemotherapy with bevacizumab, a VEGF-A inhibitor, is also a recognized risk factor for immune checkpoint inhibitor-related cardiotoxicity [8].\n\nMoreover, in the second published case of pembrolizumab-induced complete heart block by Jang and Stream, their patient who was being treated for metastatic renal cell carcinoma also presented with worsening exertional dyspnea precisely 3 weeks after his first infusion [9]. His PD-L1 expression level was not documented. Of note, the median interval from the initial administration of other commonly used immune checkpoint inhibitors, ipilimumab and nivolumab, to the development of myocarditis is 17 days [10].\n\nIt is also worthwhile to note that the patients in the two other cases were concurrently diagnosed with other immune-related adverse events such as biopsy-proven hepatitis (as presented by Katsume et al.) and myasthenia gravis (as presented by Jang and Stream), whereas our patient was asymptomatic on presentation and her laboratory testing was negative for elevations in troponin, creatine kinase, or liver enzymes. Thus, physicians should be mindful of immune-related adverse events in patients, irrespective of their symptoms and findings on blood work. Since pembrolizumab is administered every three weeks for a variety of indications, increased awareness of possible cardiotoxicity around the time of the second infusion is advised.\n\nThere are various proposed mechanisms attempting to explain immune checkpoint inhibitor-mediated arrythmias. Some of these theories include ventricular myocarditis with inflammation and fibrosis or inflammation of the His-Purkinje conduction system, both leading to reentry arrythmias [8]. Atrial or ventricular arrythmias secondary to inflammation without myocarditis, as well as atrial and ventricular arrythmias from functional cardiotoxicity without inflammation, are other possibilities [8]. Interestingly, genetic deletion of PD-1 in mice leads to cardiomyopathy that is caused by autoantibiodies against cardiac troponin I, which may be contributing to the cardiotoxicity caused by immune checkpoint inhibitors [10–12].\n\nUltimately, we recommend a higher degree of caution among all physicians when dealing with patients on immunotherapy. According to the clinical practice guidelines provided in the American Society of Clinical Oncology Journal for the management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy, holding checkpoint inhibitor therapy is recommended for all grades of cardiac complications and the appropriateness of rechallenging remains unknown [13]. Discontinuation of the immunotherapy with or without steroid treatment (1 to 2 mg/kg of prednisone) should be considered depending on the grade of toxicity as a therapeutic option [13]. In patients who do not immediately respond to high-dose corticosteroids, methylprednisolone 1 g daily can be attempted [13]. In some cases, further adding mycophenolate, infliximab, or antithymocyte globulin can be considered [13]. Cardiology consultation should always be obtained and transfer to the coronary care unit should be performed in the case of conduction abnormalities or troponemia [13].\n\nResuming immune checkpoint inhibitor therapy should be considered following multidisciplinary evaluation between cardiology, oncology, and cardiooncology if possible. In the case of our patient, her pembrolizumab was eventually restarted and she has so far tolerated nine additional cycles without any further discernable cardiac toxicities.\n\nConflicts of Interest\nWe declare that we do not have any conflict of interest with regard to this publication.\n\nFigure 1 Progression of electrocardiogram tracings from the time of admission to immediately prior to transvenous pacer wire placement. Our patient was noted to have a heart rate of 31 bpm on admission, with initial EKG showing 2nd-degree AV block.\n\nFigure 2 Progression of electrocardiogram tracings from the time of admission to immediately prior to transvenous pacer wire placement. Approximately three hours later, repeat EKG revealed complete heart block with ventricular rate of 22 bpm.\n\nFigure 3 Progression of electrocardiogram tracings from the time of admission to immediately prior to transvenous pacer wire placement. EKG was repeated a few minutes later, showing complete heart block and idioventricular rhythm with a heart rate of 25 bmp immediately after starting a dobutamine infusion, at which point a transvenous pacer wire was emergently placed.\n\nFigure 4 Baseline EKG which was obtained approximately a year and a half prior to presentation showed a left anterior fascicular block and a right bundle branch block.\n==== Refs\n1 Toor S. M. Syed Khaja A. S. Alkurd I. Elkord E. In-vitro effect of pembrolizumab on different T regulatory cell subsets Clinical and Experimental Immunology 2018 191 2 189 197 10.1111/cei.13060 2-s2.0-85032896039 28963773 \n2 Mok T. S. K. Wu Y.-L. Kudaba I. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial The Lancet 2019 393 10183 1819 1830 10.1016/S0140-6736(18)32409-7 2-s2.0-85064607320 30955977 \n3 Mahmood S. S. Fradley M. G. Cohen J. V. Myocarditis in patients treated with immune checkpoint inhibitors Journal of the American College of Cardiology 2018 71 16 1755 1764 10.1016/j.jacc.2018.02.037 2-s2.0-85043452821 29567210 \n4 Varricchi G. Marone G. Mercurio V. Galdiero M. R. Bonaduce D. Tocchetti C. G. Immune checkpoint inhibitors and cardiac toxicity: an emerging issue Current Medicinal Chemistry 2018 25 11 1327 1339 10.2174/0929867324666170407125017 2-s2.0-85047796335 28403786 \n5 Hsu C.-Y. Su Y.-W. Chen S.-C. Sick sinus syndrome associated with anti-programmed cell death-1 Journal for ImmunoTherapy of Cancer 2018 6 1 p. 72 10.1186/s40425-018-0388-9 2-s2.0-85050123684 \n6 Heinzerling L. Ott P. A. Hodi F. S. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy Journal for Immunotherapy of Cancer 2016 4 p. 50 10.1186/s40425-016-0152-y 2-s2.0-84997633422 \n7 Katsume Y. Isawa T. Toi Y. Complete atrioventricular block associated with pembrolizumab-induced acute myocarditis: the need for close cardiac monitoring Internal Medicine 2018 57 21 3157 3162 10.2169/internalmedicine.0255-17 2-s2.0-85055791764 29877257 \n8 Lyon A. R. Yousaf N. Battisti N. M. L. Moslehi J. Larkin J. Immune checkpoint inhibitors and cardiovascular toxicity The Lancet Oncology 2018 19 9 e447 e458 10.1016/S1470-2045(18)30457-1 2-s2.0-85052477987 30191849 \n9 Jang J. Stream S. A Case of Pembrolizumab-induced Complete Heart Block and Myasthenia Gravis 2018 Orlando, FL, USA Hospital Medicine Abstract 869, https://www.shmabstracts.com/abstract/a-case-of-pembrolizumab-induced-complete-heart-block-and-myasthenia-gravis/ \n10 Johnson D. B. Balko J. M. Compton M. L. Fulminant myocarditis with combination immune checkpoint blockade The New England Journal of Medicine 2016 375 18 1749 1755 10.1056/NEJMoa1609214 2-s2.0-84994144982 27806233 \n11 Nishimura H. Okazaki T. Tanaka Y. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice Science 2001 291 5502 319 322 10.1126/science.291.5502.319 2-s2.0-0035846991 11209085 \n12 Okazaki T. Tanaka Y. Nishio R. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice Nature Medicine 2003 9 12 1477 1483 10.1038/nm955 2-s2.0-10744220884 14595408 \n13 Brahmer J. R. Lacchetti C. Schneider B. J. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline Journal of Clinical Oncology 2018 36 17 1714 1768 10.1200/JCO.2017.77.6385 2-s2.0-85048283183 29442540\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2020()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
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"pages": "8428210",
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"pmid": "32047674",
"pubdate": "2020",
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"title": "Pembrolizumab-Induced Mobitz Type 2 Second-Degree Atrioventricular Block.",
"title_normalized": "pembrolizumab induced mobitz type 2 second degree atrioventricular block"
} | [
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"companynumb": "US-009507513-2003USA000416",
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"abstract": "OBJECTIVE\nOxcarbazepine (OXC) is an antiepileptic drug. Patients suffering from chronic kidney disease with an estimated glomerular filtration rate below 30 ml/min/1.73 m2 require dose adjustments for OXC.\n\n\nMETHODS\nA 31-year-old man was admitted with a history of diplopia, ataxia and dizziness attacks that had disappeared after a regular haemodialysis sessions for three months. Medical history was remarkable for primary antiphospholipid syndrome (APS). However, no signs of new-onset APS-related neurological involvement were present. Then, it was revealed that the patient had been using 2400 mg/day of OXC for four months, despite the prescription of half of this dose. Serum OXC level was 50 mcg/ml (reference: 3-35 mcg/ml) before a regular haemodialysis session. All symptoms disappeared in a few days after reducing to 1200 mg/day and never recurred.\n\n\nCONCLUSIONS\nWe reported a chronic OXC intoxication in a patient on maintenance haemodialysis. To the best of our knowledge, it is the first chronic OXC intoxication case in the literature. It could be related to episodic removal of OXC and its metabolites via haemodialysis. Consequently, dose modification of drugs is a pivotal point in haemodialysis patients. Chronic drug intoxications must be kept in mind in haemodialysis patients with unexplained symptoms.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Dirim|Ahmet Burak|AB|https://orcid.org/0000-0003-2262-8627;Mirioglu|Safak|S|;Yesilot|Nilufer|N|;Oguz|Emin|E|;Yazici|Halil|H|;Inanc|Murat|M|;Artim-Esen|Bahar|B|",
"chemical_list": null,
"country": "England",
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"doi": "10.1111/jcpt.13504",
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"issue": null,
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "haemodialysis; intoxication; oxcarbazepine",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34322888",
"pubdate": "2021-07-28",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Chronic oxcarbazepine intoxication in a patient with primary antiphospholipid syndrome on maintenance haemodialysis.",
"title_normalized": "chronic oxcarbazepine intoxication in a patient with primary antiphospholipid syndrome on maintenance haemodialysis"
} | [
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"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-307382",
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"abstract": "Fluoroquinolone is recommended as a prophylactic antibiotic for high-risk patients with profound neutropenia. We previously reported that multiple myeloma (MM) patients who received bortezomib-based regimens were at higher risk of severe infections (30.9%) associated with lymphocytopenia. In the study, we evaluated whether severe infectious complications can be prevented by prophylactic administration of oral levofloxacin in MM patients treated with bortezomib-based regimens. A total of 80 patients received oral levofloxacin 500 mg daily during the median four cycles of treatment. The prophylactic group (n = 80) with levofloxacin showed significantly decreased severe infections compared to a historical control group (n = 139) without levofloxacin prophylaxis during treatment of bortezomib-based regimens (17.5 vs. 30.9%, P = 0.037). In the prophylactic group, two patients (2.5%) died of pneumonia and septic shock. Four patients (5%) stopped levofloxacin due to side effects that consisted of gastrointestinal discomfort (2.5%), itching sense (1.25%), and QTc prolongation (1.25%). In conclusion, prophylaxis with levofloxacin may be effective in the prevention of severe infection in MM patients receiving bortezomib-based regimens. A prospective randomized study is needed to test the prophylactic effect of levofloxacin in MM patients treated with bortezomib-based regimens.",
"affiliations": "Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo, 519-763, Republic of Korea.",
"authors": "Jung|Sung-Hoon|SH|;Kang|Seung-Ji|SJ|;Jang|Hee-Chang|HC|;Ahn|Jae-Sook|JS|;Yang|Deok-Hwan|DH|;Lee|Seung-Shin|SS|;Kim|Yeo-Kyeoung|YK|;Kim|Hyeoung-Joon|HJ|;Lee|Je-Jung|JJ|",
"chemical_list": "D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D064704:Levofloxacin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-014-1672-1",
"fulltext": null,
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"issn_linking": "0925-5710",
"issue": "100(5)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents; D019072:Antibiotic Prophylaxis; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D015897:Comorbidity; D005260:Female; D006801:Humans; D015994:Incidence; D007239:Infections; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "473-7",
"pmc": null,
"pmid": "25212681",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": "16138816;17938978;6976144;15791505;8686975;20645430;22678167;14615441;8678082;10530434;16148283;10722520;23355264;17975015;15968013;9649209;21258094;3532328;16275935;9322345;19769539;7730490;9508206;7063164;10405706;8092175",
"title": "Effect of levofloxacin prophylaxis for prevention of severe infections in multiple myeloma patients receiving bortezomib-containing regimens.",
"title_normalized": "effect of levofloxacin prophylaxis for prevention of severe infections in multiple myeloma patients receiving bortezomib containing regimens"
} | [
{
"companynumb": "KR-TAKEDA-2014MPI002546",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
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"abstract": "BACKGROUND\nAnimal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight.\n\n\nOBJECTIVE\nTo calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight.\n\n\nMETHODS\nData were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM.\n\n\nRESULTS\nFrom December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5-32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0-15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both).\n\n\nCONCLUSIONS\nThese data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.",
"affiliations": "Department of Neurology, Royal Victoria Hospital (Belfast Health and Social Care Trust), Grosvenor Road, Belfast BT12 6BA, United Kingdom.;Department of Neurology, Royal Victoria Hospital (Belfast Health and Social Care Trust), Grosvenor Road, Belfast BT12 6BA, United Kingdom.;Scottish Epilepsy Centre, Glasgow, United Kingdom.;Department of General Practice, University College Cork, Cork, Ireland.;Neurology Department, Luton & Dunstable Hospitals NHS Trust, Luton, United Kingdom.;Department of Medical Genetics, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, United Kingdom.;Royal Manchester Children's Hospital, Central Manchester University Foundation NHS Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom; Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom.;Women's Centre. Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.;Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom.;Department of Neurology, Beaumont Hospital, Dublin, Ireland.;Department of Neurology, Beaumont Hospital, Dublin, Ireland.;Department of Neurology, Beaumont Hospital, Dublin, Ireland; Department of Neurology, Beaumont Hospital, and FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.;Department of Neurology, Royal Victoria Hospital (Belfast Health and Social Care Trust), Grosvenor Road, Belfast BT12 6BA, United Kingdom.;Department of Neurology, Royal Victoria Hospital (Belfast Health and Social Care Trust), Grosvenor Road, Belfast BT12 6BA, United Kingdom.;Department of Neurology, Royal Victoria Hospital (Belfast Health and Social Care Trust), Grosvenor Road, Belfast BT12 6BA, United Kingdom.;Department of Neurology, Royal Victoria Hospital (Belfast Health and Social Care Trust), Grosvenor Road, Belfast BT12 6BA, United Kingdom.;Department of Neurology, Royal Victoria Hospital (Belfast Health and Social Care Trust), Grosvenor Road, Belfast BT12 6BA, United Kingdom. Electronic address: john.craig@belfasttrust.hscni.net.",
"authors": "McCluskey|G|G|;Kinney|M O|MO|;Russell|A|A|;Smithson|W H|WH|;Parsons|L|L|;Morrison|P J|PJ|;Bromley|R|R|;MacKillop|L|L|;Heath|C|C|;Liggan|B|B|;Murphy|S|S|;Delanty|N|N|;Irwin|B|B|;Campbell|E|E|;Morrow|J|J|;Hunt|S J|SJ|;Craig|J J|JJ|",
"chemical_list": "D000927:Anticonvulsants; D000078305:Zonisamide",
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2021.07.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "91()",
"journal": "Seizure",
"keywords": "Epilepsy; Major congenital malformation; Pregnancy; Teratogenicity; Zonisamide",
"medline_ta": "Seizure",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007494:Ireland; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012042:Registries; D006113:United Kingdom; D000078305:Zonisamide",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "311-315",
"pmc": null,
"pmid": "34273670",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register.",
"title_normalized": "zonisamide safety in pregnancy data from the uk and ireland epilepsy and pregnancy register"
} | [
{
"companynumb": "GB-GLAXOSMITHKLINE-GB2022GSK028997",
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"activesubstancename": "LAMOTRIGINE"
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"abstract": "Empyema thoracis is a serious condition characterized by the accumulation of purulent fluid in the pleural cavity, typically following a pneumonia, subdiaphragmatic abscess, or esophageal rupture. Fungal empyema thoracis is a rare form of this condition with especially high mortality, in which the most frequently isolated fungus is Candida spp. This article presents a 74-year-old female with Candida krusei pneumonia and a complicated hospital course, initially presenting with nausea, vomiting, and dysphagia. She was initially suspected to have community-acquired pneumonia and was started on azithromycin and ceftriaxone. Worsening respiratory function led to the diagnosis of hydropneumothorax. Pleural fluid and an independent sample of pus and pleural tissue grew Candida krusei, giving the diagnosis of fungal empyema. With further respiratory deterioration, the patient was intubated and switched to piperacillin/tazobactam and micafungin. Decortication with extensive pleural peel and removal of foul-smelling pus and food particles within the chest was performed. This further lead to confirmation of esophageal perforation, and she was started on voriconazole and meropenem. After developing septic shock, the patient was managed with phenylephrine and vasopressin. Finally, after improving she was weaned off pressors and extubated, followed by an esophagogastroduodenoscopy (EDG) with pneumatic balloon dilation and WallFlex stent placement. This patient's case demonstrated an example of empyema thoracis, which required a high index of suspicion since the presentation was with a community-acquired infection. Candida empyema thoracis may be a complication of operation, gastroesophageal fistula, and spontaneous esophageal rupture. On the other hand, the course of this patient's hospital stay progressed from esophageal perforation to Candida krusei pneumonia, empyema, and pneumothorax. Thus, community-acquired fungal empyema should be considered in patients with respiratory symptoms and suspected esophageal perforation; nevertheless, after a diagnosis of fungal empyema, esophageal perforation should also be ruled out in addition to other causes like pneumonia, subphrenic abscess, and hematogenous spread. Improved communication between clinicians and microbiologists can lead to early diagnosis and a reduction in the morbidity and mortality of this condition.",
"affiliations": "Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.",
"authors": "Bukamur|Hazim|H|0000-0002-6494-249X;Ahmed|Waseem|W|;Numan|Yazan|Y|;Shahoub|Ibrahim|I|;Zeid|Fuad|F|0000-0001-5287-5691",
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"doi": "10.1155/2018/8039803",
"fulltext": "\n==== Front\nCase Rep Infect DisCase Rep Infect DisCRIIDCase Reports in Infectious Diseases2090-66252090-6633Hindawi 10.1155/2018/8039803Case Report\nCandida krusei Empyema Thoracis: A Community-Acquired Infection Requiring a High Index of Suspicion http://orcid.org/0000-0002-6494-249XBukamur Hazim Bukamur@marshall.eduAhmed Waseem Numan Yazan Shahoub Ibrahim http://orcid.org/0000-0001-5287-5691Zeid Fuad Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USAAcademic Editor: Raul Colodner\n\n2018 18 2 2018 2018 80398038 10 2017 10 1 2018 28 1 2018 Copyright © 2018 Hazim Bukamur et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Empyema thoracis is a serious condition characterized by the accumulation of purulent fluid in the pleural cavity, typically following a pneumonia, subdiaphragmatic abscess, or esophageal rupture. Fungal empyema thoracis is a rare form of this condition with especially high mortality, in which the most frequently isolated fungus is Candida spp. This article presents a 74-year-old female with Candida krusei pneumonia and a complicated hospital course, initially presenting with nausea, vomiting, and dysphagia. She was initially suspected to have community-acquired pneumonia and was started on azithromycin and ceftriaxone. Worsening respiratory function led to the diagnosis of hydropneumothorax. Pleural fluid and an independent sample of pus and pleural tissue grew Candida krusei, giving the diagnosis of fungal empyema. With further respiratory deterioration, the patient was intubated and switched to piperacillin/tazobactam and micafungin. Decortication with extensive pleural peel and removal of foul-smelling pus and food particles within the chest was performed. This further lead to confirmation of esophageal perforation, and she was started on voriconazole and meropenem. After developing septic shock, the patient was managed with phenylephrine and vasopressin. Finally, after improving she was weaned off pressors and extubated, followed by an esophagogastroduodenoscopy (EDG) with pneumatic balloon dilation and WallFlex stent placement. This patient's case demonstrated an example of empyema thoracis, which required a high index of suspicion since the presentation was with a community-acquired infection. Candida empyema thoracis may be a complication of operation, gastroesophageal fistula, and spontaneous esophageal rupture. On the other hand, the course of this patient's hospital stay progressed from esophageal perforation to Candida krusei pneumonia, empyema, and pneumothorax. Thus, community-acquired fungal empyema should be considered in patients with respiratory symptoms and suspected esophageal perforation; nevertheless, after a diagnosis of fungal empyema, esophageal perforation should also be ruled out in addition to other causes like pneumonia, subphrenic abscess, and hematogenous spread. Improved communication between clinicians and microbiologists can lead to early diagnosis and a reduction in the morbidity and mortality of this condition.\n==== Body\n1. Introduction\nEmpyema thoracis is a serious condition characterized by the accumulation of purulent fluid in the pleural cavity, typically following a pneumonia, subdiaphragmatic abscess, or esophageal rupture. Fungal empyema thoracis is a rare form of this condition with especially high mortality, in which the most frequently isolated fungus is Candida spp [1]. A high index of suspicion is required to diagnose this condition, as it may present as a community-acquired infection [2].\n\n2. Case Presentation\nA 74-year-old female with a history of schizophrenia, dementia, COPD, and a CVA presented to the Emergency Department with nausea and vomiting for 3 days, as well as dysphagia for 2 weeks, which all began after drinking hot water. Her vital signs on presentation were BP of 122/77 millimeter of mercury (mmHg), HR of 75 beats per minute (bpm), RR of 16 breaths/minute (br/min), oxygen saturation of 95% on room air, and temperature of 97.7°F. The chest examination revealed decreased air entry and diffuse rhonchi bilaterally. The remainder of physical examination was unremarkable. Her labs showed WBCs of 10,300/mm3, creatinine of 0.77 mg/dl, and a negative urine analysis. The chest X-ray (CXR) revealed left lower lobe consolidation with a left-sided pleural effusion. The abdominal X-ray exhibited dilation of the esophagus. The patient refused a modified barium swallow and a CT of the abdomen. She was started on azithromycin and ceftriaxone for community-acquired pneumonia.\n\nOn the third day of admission, she became short of breath, with vitals of HR 130 bpm, BP 86/43 mmHg, RR 38 br/min, temperature 98.6°F, and oxygen saturation 93% on 3 L/min of oxygen. On examination, the patient was cyanotic, using accessory muscles, taking rapid shallow breaths, with decreased air entry and hyperresonance to percussion on the right side of the chest. The CXR showed a large right-sided hydropneumothorax, and the esophagus was air-filled down to the distal segment (Figure 1). Surgery was consulted, and a chest tube was inserted on the right side, which removed 1.85 liters of pleural fluid. Analysis of the pleural fluid showed WBCs 17424/cmm, RBCs 1728/cmm, neutrophils 95%, lymphocytes 3%, macrocytes 2%, albumin 1.2, amylase 816, glucose < 1, LDH 1559, pH 7.41, and protein 2.7. The pleural fluid grew Lactobacillus, and the pleural fluid and sputum culture then grew Candida krusei, which was isolated again from a second confirmatory sample of pus, indicating its clinical significance and satisfying the criteria for fungal empyema [2]. Susceptibility testing revealed intermediate sensitivity to 5-flucytosine with minimal inhibitory concentration (MIC) 16.0 mg/L and good sensitivity to itraconazole with MIC of 0.25 mg/L (sensitivity was not done for micafungin). Three sets of blood cultures were negative.\n\nThereafter, the patient was intubated and transferred to the ICU. The antibiotics were switched to piperacillin/tazobactam and micafungin. CT of the chest without contrast showed bilateral pleural fluid collections, which were larger and more complex appearing on the right (Figure 2). Cardiothoracic surgery was consulted, after which right decortication was performed, with extensive pleural peel and removal of foul-smelling pus and food particles within the chest. Pleural tissue culture grew C. Krusei. To further confirm the diagnosis of esophageal rupture, a limited Gastrografin swallow was done through the preexisting NG tube while it was pulled back into the distal esophagus. This revealed a leak in the right distal esophagus, after which a barium swallow exposed esophageal perforation with contrast extravasation into the right pleural cavity (Figure 3), that was confirmed by CT scan.\n\nInfectious diseases was consulted, who then switched the medications to voriconazole and meropenem. Subsequently, the patient developed septic shock during the course of her ICU stay and was started on phenylephrine and vasopressin. After two weeks, the patient improved, was weaned off pressors, and was extubated. An EGD was performed, with pneumatic balloon dilation to 20 mm and WallFlex stent placement. Finally, the patient improved and was discharged from the ICU to the general medical floor.\n\n3. Discussion\nEmpyema is, by definition, pus in the pleural space. Pus is a thick, viscous, yellowish fluid formed in infected tissue, composed of WBCs, tissue debris, necrotic tissue, and pathogens [3]. Fungal empyema thoracis is a rare but severe form of invasive candidiasis with high mortality. The most frequently isolated microorganisms in this condition are Candida species, whereas other filamentous fungi are rare, as only sporadic cases have been reported. Interestingly, Candida empyema thoracis has been reported as a complication of operation, gastropleural fistula, and spontaneous esophageal rupture [4].\n\nIn a retrospective analysis of 128 cases of culture-positive pleural effusion, Ishiguro et al. demonstrated that isolation of Candida species could be an important clue for empyema due to gastrointestinal perforation [5]. In this case presentation, the patient presented with dysphagia and was diagnosed with esophageal perforation complicated by C. krusei pneumonia, empyema, and pneumothorax.\n\nThe diagnosis of fungal bronchopulmonary infection is difficult to confirm because fungi isolated from the sputum may represent either pathogens or saprophytes, and invasive diagnostic procedures such as bronchoscopy or lung biopsy are usually necessary [6]. The diagnosis of fungal empyema thoracis requires that the following criteria be met: (1) isolation of fungal species from exudative thoracentesis fluid, (2) significant signs of infection, such as fever (body temperature > 38.3°C) and leukocytosis (WBCs > 10,000/µL), and (3) isolation of the same fungus from pleural fluid and other specimens, including blood, sputum, or surgical wounds, that showed evidence of tissue invasion [2]. The patient in our case presentation was afebrile, with leukocytosis, and Candida krusei was isolated from the thoracentesis fluid as well as sputum and tissue cultures from the thoracotomy, thus satisfying two of the criteria mentioned above.\n\nAlthough the prevalence of C. krusei remains low among yeast infections, its intrinsic resistance to fluconazole raises epidemiological and therapeutic concerns. Echinocandins have in vitro activity against most Candida spp. and are the first-line agents in the treatment of candidemia. Although resistance to echinocandins is still rare, individual cases of C. krusei resistance have been reported in recent years, especially with strains that have been under selective pressure [7]. Review of 25,470 isolates of yeasts and 3,216 isolates of filamentous fungi showed voriconazole to have broad-spectrum activity against pathogenic yeasts including intrinsically fluconazole-resistant isolates such as C. krusei, dimorphic fungi, opportunistic molds like Aspergillus spp., and amphotericin-B-resistant Aspergillus terreus, Fusarium spp., and Scedosporium apiospermum. It displays excellent clinical efficacy in patients with fluconazole-resistant and fluconazole-susceptible Candida infections, invasive bone and central nervous system aspergillosis, and various refractory fungal infections [8]. In our case presentation, the patient was first treated empirically with micafungin and then switched to voriconazole after receiving susceptibility testing results.\n\nThere are several surgical options available for management of the pleural fluid in patients with empyema, including tube thoracostomy, intrapleural instillation of fibrinolytics, thoracoscopy with breakdown of adhesions or decortication, thoracotomy with breakdown of adhesions and decortication, and open drainage procedures [3]. Some physicians recommend a formal thoracotomy when the patient's condition allows it, since it may lead to an early discharge without tubes and open draining wounds. Pothula and Krellenstein retrospectively studied 90 patients with this hypothesis, which resulted in low morbidity (10%) and very low mortality (8%). The mortalities in the formal thoracotomy group were mostly related to underlying disease and age [9]. The patient in our case presentation had chest tube insertion and bilateral pleural fluid collections shown on CT of the chest, after which right decortication was performed.\n\n4. Conclusion\nInfections of the pleural cavity remain an important cause of morbidity and mortality despite advances in diagnostic modalities and therapy. We are presenting this case and are confident that it will be a valuable addition to medical literature in raising awareness about community-acquired fungal empyema in patients presenting with respiratory symptoms and suspected esophageal perforation. Additionally, in the presence of a fungal empyema, esophageal rupture should also be considered and ruled out in addition to other causes like pneumonia, subphrenic abscess, and hematogenous spread [10]. In our case, we think that the fungal empyema happened secondary to esophageal rupture as other causes had been excluded with negative blood culture, no subphrenic abscess in CT abdomen, and no recent trauma or thoracic surgical intervention. In order to accurately diagnose fungal empyema, a high level of suspicion is required, as it may be due to a community-acquired infection. Furthermore, there is a need for improved communication between clinicians and microbiologists for early decision making, which will reduce the morbidity and mortality [11]. Finally, empirical systemic antimycotic therapy should always be considered in an ideal multidisciplinary approach to the management of patients with esophageal rupture [10].\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 CXR showing a large right-sided hydropneumothorax, and the esophagus was air-filled down to the distal segment.\n\nFigure 2 CT of the chest without contrast showing bilateral pleural fluid collections, which were larger and more complex appearing on the right.\n\nFigure 3 A barium swallow showing contrast extravasation into the right pleural cavity confirming esophageal perforation.\n==== Refs\n1 Pal N. De A. Mondal M. Maiti P. K. \nCandida albicans as a rare causative agent of pyopneumothorax International Journal of Current Microbiology and Applied Sciences 2015 4 7 716 719 \n2 Bardkar V. P. Mathur M. Kulkarni S. D. Kumar S. Thoracic empyema due to Candida albicans : case report Indian Journal of Pathology and Microbiology 2008 51 2 286 288 10.4103/0377-4929.41699 2-s2.0-46949093826 18603712 \n3 Light R. W. Parapneumonic effusions and empyema Proceedings of the American Thoracic Society 2006 3 1 78 80 10.1513/pats.200510-113jh 2-s2.0-33644501812 \n4 Bauer T. M. Dupont V. Zimmerli W. Invasive candidiasis complicating spontaneous esophageal perforation (Boerhaave syndrome) American Journal of Gastroenterology 1996 91 6 1248 1250 8651181 \n5 Ishiguro T. Takayanagi N. Ikeva T. Isolation of Candida species is an important clue for suspecting gastrointestinal tract perforation as a cause of empyema Internal Medicine 2010 49 18 1957 1964 10.2169/internalmedicine.49.3667 2-s2.0-77957965195 20847498 \n6 Ko S. C. Chen K. Y. Hsueh P. R. Luh K. T. Yang P. C. Fungal empyema thoracis Chest 2000 117 6 1672 1678 10.1378/chest.117.6.1672 10858401 \n7 Forastiero A. Gil V. G. Menendez O. R. Rapid development of Candida krusei echinocandin resistance during caspofungin therapy Antimicrobial Agents and Chemotherapy 2015 59 11 6975 6982 10.1128/aac.01005-15 2-s2.0-84946219497 26324281 \n8 Pemán J. Salavert M. Cantón E. Voriconazole in the management of nosocomial invasive fungal infections Therapeutics and Clinical Risk Management 2006 2 2 129 158 18360588 \n9 Pothula V. Krellenstein D. J. Early aggressive surgical management of parapneumonic empeymas Chest 1994 105 3 832 836 10.1378/chest.105.3.832 8131548 \n10 Cascio A. Barone M. Micali V. On a fatal case of Candida krusei pleural empiema in a pregnant woman with spontaneous esophageal perforation Mycopatholgia 2010 169 6 451 455 10.1007/s11046-010-9277-6 2-s2.0-77952672645 \n11 Srinivasnakshatri V. K. Subramani P. Venkateshwaraprasad K. N. Varma P. A fatal case of fungal empeyma due to Candida krusei and Candida tropicalis : a rare occurrence with an atypical presentation Journal of Clinical and Diagnostic Research 2014 8 11 DD01 DD02\n\n",
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"title": "Candida krusei Empyema Thoracis: A Community-Acquired Infection Requiring a High Index of Suspicion.",
"title_normalized": "candida krusei empyema thoracis a community acquired infection requiring a high index of suspicion"
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"abstract": "A 62-year-old Japanese female with primary lung adenocarcinoma received seven cycles of nivolumab as an eighth line of chemotherapy until she presented with hemoptysis. After transcatheter arterial embolization therapy, she received subsequent chemotherapy with paclitaxel and S-1. Four weeks later, a chest computed tomography examination revealed infiltrative shadows mainly in the right lung field, in addition to enlargement of the lung metastasis in the right middle lung lobe. Bronchofiberscopic examination revealed infiltration of lymphocytes without any malignant cells in the right segment 1 of the lung, which suggested interstitial lung disease. Corticosteroid therapy not only improved the infiltrative shadows but also reduced the lung metastasis. Even after the infiltrative shadows improved, the lung metastasis reduced further. This phenomenon resembles manifestation of pseudoprogression during treatments with immune checkpoint inhibitors, such as nivolumab.",
"affiliations": "Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.;Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.",
"authors": "Kumagai|Toru|T|;Kimura|Madoka|M|;Inoue|Takako|T|;Tamiya|Motohiro|M|;Nishino|Kazumi|K|;Imamura|Fumio|F|",
"chemical_list": "D000911:Antibodies, Monoclonal; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D000077594:Nivolumab; D010094:Oxonic Acid; D017239:Paclitaxel",
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"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 2837139710.1111/1759-7714.12431TCA12431Case ReportCase ReportsDelayed pseudoprogression of lung adenocarcinoma accompanied with interstitial lung disease during chemotherapy after nivolumab treatment Delayed pseudoprogressionT. Kumagai et al.Kumagai Toru torukumagai@ybb.ne.jp \n1\nKimura Madoka \n1\nInoue Takako \n1\nTamiya Motohiro \n1\nNishino Kazumi \n1\nImamura Fumio \n1\n1 Department of Thoracic OncologyOsaka Medical Center for Cancer and Cardiovascular DiseasesOsakaJapan* Correspondence\n\nToru Kumagai, Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1‐3‐3 Nakamichi Higashinari‐ku, Osaka 537‐8511, Japan.\n\nTel: +81 6 6972 1181\n\nFax: +81 6 6971 7636\n\nEmail: torukumagai@ybb.ne.jp\n30 3 2017 5 2017 8 3 10.1111/tca.2017.8.issue-3275 277 09 1 2017 12 2 2017 12 2 2017 © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.A 62‐year‐old Japanese female with primary lung adenocarcinoma received seven cycles of nivolumab as an eighth line of chemotherapy until she presented with hemoptysis. After transcatheter arterial embolization therapy, she received subsequent chemotherapy with paclitaxel and S−1. Four weeks later, a chest computed tomography examination revealed infiltrative shadows mainly in the right lung field, in addition to enlargement of the lung metastasis in the right middle lung lobe. Bronchofiberscopic examination revealed infiltration of lymphocytes without any malignant cells in the right segment 1 of the lung, which suggested interstitial lung disease. Corticosteroid therapy not only improved the infiltrative shadows but also reduced the lung metastasis. Even after the infiltrative shadows improved, the lung metastasis reduced further. This phenomenon resembles manifestation of pseudoprogression during treatments with immune checkpoint inhibitors, such as nivolumab.\n\nInterstitial lung diseaselung adenocarcinomanivolumabpseudoprogression source-schema-version-number2.0component-idtca12431cover-dateMay 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:18.05.2017\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICIs), such as nivolumab or pembrolizumab, which are antibodies against programmed cell death protein 1, have become key drugs against advanced non‐small cell lung cancers.1, 2, 3, 4, 5, 6 While pseudoprogression is occasionally observed during nivolumab therapy,7 interstitial lung disease (ILD) is also observed at a ratio of 3–5% as an immune‐related adverse event,3, 4 and ILDs caused during nivolumab therapy generally show a radiologic pattern of cryptogenic organizing pneumonia and exhibit a good response against corticosteroid therapy.8 In addition, nivolumab may enhance the risk of ILD when osimertinib is used after novolumab.9 Interestingly, some melanoma cases of ILD induced by nivolumab or ipilimumab show both improvement of ILD and reduction of tumor size by corticosteroid therapy, and antitumor immunity might partially contribute to these phenomena.10, 11\n\n\nHere we report a case of lung adenocaricinoma with pseudoprogression and ILD during chemotherapy after nivolumab treatment.\n\nCase report\nA 62‐year‐old Japanese female with a 32 pack‐year smoking history was diagnosed with primary lung adenocarcinoma lacking epidermal growth factor receptor‐mutation in the right lower lobe, with a clinical stage of T2N2M0, stage IIIA. It was unknown whether her lung cancer harbored anaplastic lymphoma kinase‐rearrangement. She received chemoradiotherapy as first line therapy. A year later, her lung cancer relapsed with a single brain metastasis and multiple lung metastases. She subsequently received gamma knife radiotherapy and six regimens of chemotherapy for six years and three months, followed by nivolumab treatment. After receiving seven cycles of nivolumab (12 weeks later), she presented with hemoptysis. Chest computed tomography (CT) revealed that the lung metastasis in the middle lobe had slightly enlarged within the range of stable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1 (Fig 1a,b).12 Bronchofiberscopic examination revealed that her right basal bronchus was responsible for hemoptysis (Fig 1c). She received transcatheter arterial embolization therapy against the right lower lobe bronchial artery. In addition to the endoscopic gross view, positron emission tomography‐CT revealed accumulation of 18F‐fluorodeoxyglucose in the lung metastasis, and her carcinoembryonic antigen serum level was increased (Fig 1b,d). Based on these factors, we considered her lung cancer to be clinically progressive. The patient subsequently received chemotherapy with paclitaxel and S−1.13 Four weeks later, when 20 weeks had passed since the initiation of nivolumab, she visited our hospital with a fever and cough. CT examination revealed infiltrative shadows in the bilateral lung fields mainly in the right, in addition to enlargement of the lung metastasis (Fig 2c), which suggested ILD with a radiologic pattern of cryptogenic organizing pneumonia and progressive disease by RECIST v1.1. Chemotherapy was discontinued. She was admitted to our hospital, and bronchofiberscopic examination revealed infiltration of the lymphocytes without any cancer cells or bacteria in the right lung segment 1. We diagnosed grade III ILD, and 1000 mg of methylprednisolone was administered daily for three days. She then received 60 mg of prednisolone daily, which was altered to dexamethasone because of hypokalemia induced by prednisolone. The corticosteroid therapy improved the infiltrative shadow (Fig 2d). Surprisingly, during the tapering of dexamethasone, the lung metastasis also decreased in size, and reduced even further after the infiltrative shadows improved (Fig 2a–e). The anti‐tumor effect was considered a partial response through pseudoprogression. Her carcinoembryonic antigen serum level also decreased (Fig 2e). Nineteen weeks after the initiation of paclitaxel and S−1, her lung cancer became progressive disease (Fig 2e).\n\nFigure 1 Chest computed tomography and carcinoembryonic antigen serum level (normal upper limit of 5 ng/ml). After (a) three and (b) seven cycles of nivolumab. (c) The right intermediate bronchus of the patient. (d) Positron emission tomography‐computed tomography after transcatheter arterial embolization therapy.\n\nFigure 2 Chest computed tomography and carcinoembryonic antigen (CEA) serum level during a ninth chemotherapy regimen with paclitaxel and S−1. (a) Prior to the ninth chemotherapy and (b–f) two, four, six, 11 and 19 weeks later, respectively.\n\nDiscussion\nIt is well known that ICIs, such as nivolumab or pembrolizumab, occasionally induce pseudoprogression.7, 14 Although not completely clarified, one possible mechanism for pseudoprogression is an increase of tumor volume via lymphocytic infiltration.15 In our case, corticosteroid therapy might have induced early tumor reduction, probably through a rapid decrease of lymphocytic infiltration, which might also have occurred in the region of ILD. While almost all instances of pseudoprogression are reported to appear during treatment with an immune‐checkpoint‐inhibitor (ICI), our case indicates that pseudoprogression may also occur after cessation of ICI treatment. Therefore, paclitaxel + S‐1 appeared to have triggered both pseudoprogression and ILD. The improved immune responses from nivolumab and increased antigen presentation from destructed cancer cells after chemotherapy might have been responsible for these two phenomena. The reduction in tumor size may resemble an abscopal effect, in which radiation enhances ICIs responses, although we cannot exclude the possibility of a direct cytotoxic effect of paclitaxel and S−1.16, 17\n\n\nDisclosure\nNo authors report any conflict of interest.\n\nAcknowledgment\nWe thank the radiographic examination staff of Osaka Medical Center for Cancer and Cardiovascular Diseases for their assistance with diagnosis.\n==== Refs\nReferences\n1 \n\nPardoll \nDM \n. The blockade of immune checkpoints in cancer immunotherapy . Nat Rev Cancer \n2012 ; 12 : 252 –64 .22437870 \n2 \n\nGuibert \nN \n, \nMazières \nJ \n. Nivolumab for treating non‐small cell lung cancer . Expert Opin Biol Ther \n2015 ; 15 : 1789 –97 .26574148 \n3 \n\nBrahmer \nJ \n, \nReckamp \nKL \n, \nBaas \nP \n\net al.\nNivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer . N Engl J Med \n2015 ; 373 : 123 –35 .26028407 \n4 \n\nBorghaei \nH \n, \nPaz‐Ares \nL \n, \nHorn \nL \n\net al.\nNivolumab versus docetaxel in advanced nonsquamous non‐small‐cell lung cancer . N Engl J Med \n2015 ; 373 : 1627 –39 .26412456 \n5 \n\nGaron \nEB \n, \nRizvi \nNA \n, \nHui \nR \n\net al.\nPembrolizumab for the treatment of non‐small‐cell lung cancer . N Engl J Med \n2015 ; 372 : 2018 –28 .25891174 \n6 \n\nReck \nM \n, \nRodríguez‐Abreu \nD \n, \nRobinson \nAG \n\net al.\nPembrolizumab versus chemotherapy for PD‐L1‐positive non‐small‐cell lung cancer . N Engl J Med \n2016 ; 375 : 1823 –33 .27718847 \n7 \n\nChiou \nVL \n, \nBurotto \nM \n. Pseudoprogression and immune‐related response in solid tumors . J Clin Oncol \n2015 ; 33 : 3541 –3 .26261262 \n8 \n\nNishino \nM \n, \nRamaiya \nNH \n, \nAwad \nMM \n\net al.\nPD‐1 inhibitor‐related pneumonitis in advanced cancer patients: Radiographic patterns and clinical course . Clin Cancer Res \n2016 ; 22 : 6051 –60 .27535979 \n9 \n\nKotake \nM \n, \nMurakami \nH \n, \nKenmotsu \nH \n, \nNaito \nT \n, \nTakahashi \nT \n. High incidence of interstitial lung disease following practical use of osimertinib in patients who had undergone immediate prior nivolumab therapy . Ann Oncol \n2017 ; 28 : 669 –70 .27993813 \n10 \n\nSano \nT \n, \nUhara \nH \n, \nMikoshiba \nY \n, \net al. \n\nNivolumab‐induced organizing pneumonia in a melanoma patient . Jpn J Clin Oncol \n2016 ; 46 : 270 –2 .26759348 \n11 \n\nBerthod \nG \n, \nLazor \nR \n, \nLetovanec \nI \n\net al.\nPulmonary sarcoid‐like granulomatosis induced by ipilimumab . J Clin Oncol \n2012 ; 30 : e156 –9 .22547608 \n12 \n\nEisenhauer \nEA \n, \nTherasse \nP \n, \nBogaerts \nJ \n\net al.\nNew response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) . Eur J Cancer \n2009 ; 45 : 228 –47 .19097774 \n13 \n\nAono \nN \n, \nIto \nY \n, \nNishino \nK \n\net al.\nA retrospective study of the novel combination of paclitaxel and S1 for pretreated advanced non‐small cell lung cancer . Chemotherapy \n2012 ; 58 : 454 –60 .23392470 \n14 \n\nHodi \nFS \n, \nHwu \nWJ \n, \nKefford \nR \n\net al.\nEvaluation of immune‐related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab . J Clin Oncol \n2016 ; 34 : 1510 –7 .26951310 \n15 \n\nRibas \nA \n, \nChmielowski \nB \n, \nGlaspy \nJA \n. Do we need a different set of response assessment criteria for tumor immunotherapy? \nClin Cancer Res \n2009 ; 15 : 7116 –8 .19934296 \n16 \n\nSeyedin \nSN \n, \nSchoenhals \nJE \n, \nLee \nDA \n\net al.\nStrategies for combining immunotherapy with radiation for anticancer therapy . Immunotherapy \n2015 ; 7 : 967 –80 .26310908 \n17 \n\nRibeiro Gomes \nJ \n, \nSchmerling \nRA \n, \nHaddad \nCK \n\net al.\nAnalysis of the abscopal effect with anti‐PD1 therapy in patients with metastatic solid tumors . J Immunother \n2016 ; 39 : 367 –72 .27741091\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1759-7706",
"issue": "8(3)",
"journal": "Thoracic cancer",
"keywords": "Interstitial lung disease; lung adenocarcinoma; nivolumab; pseudoprogression",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077594:Nivolumab; D010094:Oxonic Acid; D017239:Paclitaxel; D005641:Tegafur; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "275-277",
"pmc": null,
"pmid": "28371397",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports",
"references": "26412456;26759348;27535979;23392470;26574148;22437870;27993813;19934296;27718847;19097774;22547608;26028407;25891174;26261262;26310908;26951310;27741091",
"title": "Delayed pseudoprogression of lung adenocarcinoma accompanied with interstitial lung disease during chemotherapy after nivolumab treatment.",
"title_normalized": "delayed pseudoprogression of lung adenocarcinoma accompanied with interstitial lung disease during chemotherapy after nivolumab treatment"
} | [
{
"companynumb": "JP-BAUSCH-BL-2017-010587",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "We aimed to identify risk factors that predict functional imaging (FI) response to salvage chemotherapy and evaluate outcomes following autologous stem cell transplant (ASCT) in primary refractory Hodgkin Lymphoma (HL). From 1 October 1994 to 10 July 2015, 192 primary refractory HL patients were treated on sequential second line protocols. Event-free survival (EFS) and overall survival (OS) were calculated from the date of histological confirmation of refractory disease. Covariates were analysed for relationship with FI response and EFS. By intent-to-treat, the median EFS was 8·9 years and OS 10·4 years with 41% having positive post-salvage FI. On multivariate analysis, the presence of B symptoms and bulk ≥5 cm predicted for positive FI, with odds ratios of 2·15 and 2·03, respectively. For the 167 (87%) transplanted patients, 60% had a negative pre-ASCT FI. Median EFS and OS were not reached with at a median follow-up of 3·6 years in surviving patients. Both stage IV refractory disease and persistent FI abnormality pre- ASCT were associated with worse outcomes: 3-year EFS was 84%, 54% and 28% for zero, 1 and 2 risk factors, respectively (P < 0·001). Further studies are needed to validate our prognostic model and to determine optimal therapy for patients with multiple risk factors.",
"affiliations": "Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. shahg@mskcc.org.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"authors": "Shah|Gunjan L|GL|http://orcid.org/0000-0002-9977-0456;Yahalom|Joachim|J|;Matasar|Matthew J|MJ|;Verwys|Stephanie L|SL|;Goldman|Debra A|DA|;Bantilan|Kurt S|KS|;Zhang|Zhigang|Z|;McCall|Susan J|SJ|;Moskowitz|Alison J|AJ|;Moskowitz|Craig H|CH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.14245",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "175(3)",
"journal": "British journal of haematology",
"keywords": "autologous stem cell transplant; hodgkin lymphoma; positron emission tomography; primary refractory",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D049268:Positron-Emission Tomography; D011379:Prognosis; D019233:Retreatment; D012189:Retrospective Studies; D012307:Risk Factors; D016879:Salvage Therapy; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "440-447",
"pmc": null,
"pmid": "27377168",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": "18809615;22473680;20197102;23394351;24628515;19344403;2809679;11157476;25796459;21601641;17084370;17497648;23128322;16943528;23749108;23617324;14871252;20733154;22184409;21699377;12888816",
"title": "Risk factors predicting outcomes for primary refractory hodgkin lymphoma patients treated with salvage chemotherapy and autologous stem cell transplantation.",
"title_normalized": "risk factors predicting outcomes for primary refractory hodgkin lymphoma patients treated with salvage chemotherapy and autologous stem cell transplantation"
} | [
{
"companynumb": "US-JNJFOC-20161127253",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Amiodarone (Cordarone®, Pfizer Inc) is an antiarrhythmic medication with a well-known toxicity profile, including rare cases of hyponatremia as a result of syndrome of inappropriate antidiuretic hormone (SIADH). We report on such a case in which a patient was found to be hyponatremic after evaluation. An 88-year-old male who presented to the emergency department was found to be hyponatremic secondary to amiodarone-induced SIADH following a fall, with possible seizure and traumatic brain injury. He had a history of hypertension, paroxysmal atrial fibrillation, emphysema, myocardial infarction, benign prostatic hyperplasia, chronic kidney disease, Meniere's disease, anemia, and gastroesophageal reflux. Upon admission, his urine sodium level was elevated, and his serum sodium, urine osmolality, and anion gap were below normal. In the setting of hyponatremia, the patient's amiodarone was held: he had been taking amiodarone 200 mg once daily for nine months prior to admission. He was treated with intravenous (IV) normal saline over four days. He was fluid-restricted and his sodium levels were closely monitored every two hours. Within 19 hours, his serum sodium levels had improved. Amiodarone was restarted approximately three days later. Upon follow-up after discharge, the patient remained on amiodarone for the next two months. His serum sodium level ranged from 126 mEq/L to 131 mEq/L over a two-week period. He was supplemented with sodium chloride tablets and has been otherwise stable. Amiodarone may cause acute or chronic SIADH, with a wide range of symptoms. Seizures have not been reported in the literature but our patient had a witnessed seizure, although his electroencephalogram (EEG) was negative. Syndrome of inappropriate antidiuretic hormone can occur with any formulation of amiodarone in a dose-dependent fashion. Our patient's sodium levels stabilized within two weeks after amiodarone was resumed. The mechanism of amiodarone-induced SIADH remains unclear.",
"affiliations": null,
"authors": "Marcelino|Gretchen P|GP|;Collantes|Cyril Manuel C|CMC|;Oommen|Jomi K|JK|;Wang|Shan|S|;Baldassari|Heather|H|;Muralidharan|Rajanandini|R|;Hanna|Adel|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-1372",
"issue": "44(7)",
"journal": "P & T : a peer-reviewed journal for formulary management",
"keywords": "SIADH; amiodarone; arrhythmia; hyponatremia; seizure; side effect",
"medline_ta": "P T",
"mesh_terms": null,
"nlm_unique_id": "9015516",
"other_id": null,
"pages": "416-423",
"pmc": null,
"pmid": "31258313",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "10522906;10573050;10871966;12000975;12013366;1474169;15189547;17904459;18199281;19881933;21314679;21426247;2293761;23687510;24712668;24818037;25822386;26584969;26754778;28039863;28168757",
"title": "Amiodarone-Induced Syndrome of Inappropriate Antidiuretic Hormone: A Case Report and Review of the Literature.",
"title_normalized": "amiodarone induced syndrome of inappropriate antidiuretic hormone a case report and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-2019292969",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "1",
"... |
{
"abstract": "Outcomes of pregnancies after kidney transplantation were evaluated. Thirty-one pregnancies in 26 women were noted. The mean maternal age at pregnancy was 31 ± 5 years (range, 23-44 years). The interval between transplantation and conception was 54 ± 51 months (range, 7-213 months). The mean serum creatinine concentration before conception was 1.28 ± 0.4 mg/dL (range, 0.8-2.45 mg/dL), and mean estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration) was 62 ± 18 mL/min/1.73 m2 (range, 27-106 mL/min/1.73 m2). There were no maternal deaths. There was 1 case of suspected acute rejection after delivery. There was 1 case of graft loss during pregnancy. Maternal complications included edema (6/26), hypertension (7/26), increase of (2/26) or appearance of proteinuria (5/26), and preeclampsia (4/26). Mean creatinine increase during pregnancy was 0.02 mg/dL. Mean creatinine 1 year after pregnancy was 1.54 mg/dL (±0.8 mg/dL). There were 19 cesarean sections. Fetal outcomes included 25 live births, 4 abortions, and 2 stillbirths. Out of 25 live births, 22 children were considered healthy, 2 children had congenital defects, and there were 2 deaths at neonatal age. Mean pregnancy age was 35 ± 4 weeks (range, 24-40 weeks). The rate of premature deliveries was 15 of 25. Mean neonate birth weight was 2363 ± 1029 grams (range, 490-4100 grams). The rate of babies small for gestational age was 19%. During follow-up (range, 0.5-30 years) 5 of 26 patients lost grafts (between 3 and 15 years after pregnancy); most (20) of the children previously considered healthy had good long-term development. Our results confirm that risk of pregnancy in kidney transplant recipients can be accepted, and children considered healthy at delivery develop well.",
"affiliations": "Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland. Electronic address: jgalgowska@gumed.edu.pl.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Obstetrics, Medical University of Gdańsk, Poland.;Department of Obstetrics, Medical University of Gdańsk, Poland.;Department of Occupational and Internal Medicine, Medical University of Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland.;Department of General, Endocrinological and Transplant Surgery.;Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdańsk, Poland.",
"authors": "Dębska-Ślizień|Alicja|A|;Gałgowska|Joanna|J|;Bułło-Piontecka|Barbara|B|;Bzoma|Beata|B|;Chamienia|Andrzej|A|;Król|Ewa|E|;Lichodziejewska-Niemierko|Monika|M|;Lizakowski|Sławomir|S|;Pankrac|Zofia|Z|;Preis|Krzysztof|K|;Renke|Marcin|M|;Rutkowski|Przemysław|P|;Śledziński|Zbigniew|Z|;Zdrojewski|Zbigniew|Z|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.01.122",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D016030:Kidney Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2430-2435",
"pmc": null,
"pmid": "32444125",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy After Kidney Transplantation With Maternal and Pediatric Outcomes: A Single-Center Experience.",
"title_normalized": "pregnancy after kidney transplantation with maternal and pediatric outcomes a single center experience"
} | [
{
"companynumb": "PL-ROCHE-2739134",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "Vemurafenib is increasingly being used to treat nonmelanoma tumors that are positive for the BRAF V600E mutation. We report three children who presented with panniculitis induced by vemurafenib while undergoing treatment for central nervous system tumors and review the literature.",
"affiliations": "Department of Dermatology, Hofstra Northwell School of Medicine, New Hyde Park, New York.;Division of Pediatric Hematology, Oncology, Neuro-Oncology and Stem Cell Transplant, Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois.;Division of Pathology, Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois.;Division of Dermatology, Texas Children's Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Division of Pediatric Hematology-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Division of Pediatric Hematology-Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Division of Dermatology, Texas Children's Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Division of Dermatology, Texas Children's Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.;Division of Dermatology, Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois.",
"authors": "Finelt|Nika|N|http://orcid.org/0000-0002-1418-976X;Lulla|Rishi R|RR|;Melin-Aldana|Hector|H|;Ruth|Jennifer Shuley|JS|;Lin|Frank Y|FY|;Su|Jack M|JM|;Pourciau|Crystal Y|CY|;Hunt|Raegan D|RD|;Kenner-Bell|Brandi M|BM|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13148",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "34(3)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D016543:Central Nervous System Neoplasms; D002648:Child; D006801:Humans; D007211:Indoles; D008297:Male; D015434:Panniculitis; D013449:Sulfonamides; D000077484:Vemurafenib",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "337-341",
"pmc": null,
"pmid": "28523881",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Bumps in the Road: Panniculitis in Children and Adolescents Treated with Vemurafenib.",
"title_normalized": "bumps in the road panniculitis in children and adolescents treated with vemurafenib"
} | [
{
"companynumb": "US-ROCHE-1941870",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nCardiopulmonary bypass causes a series of inflammatory events that have adverse effects on the outcome. The release of cytokines, including interleukins, plays a key role in the pathophysiology of the process. Simultaneously, cessation of ventilation and pulmonary blood flow contribute to ischaemia-reperfusion injury in the lungs when reperfusion is maintained. Collapse of the lungs during cardiopulmonary bypass leads to postoperative atelectasis, which correlates with the amount of intrapulmonary shunt. Atelectasis also causes post-perfusion lung injury. In this study, we aimed to document the effects of continued low-frequency ventilation on the inflammatory response following cardiopulmonary bypass and on outcomes, particularly pulmonary function.\n\n\nMETHODS\nFifty-nine patients subjected to elective coronary bypass surgery were prospectively randomised to two groups, continuous ventilation (5 ml/kg tidal volume, 5/min frequency, zero end-expiratory pressure) and no ventilation, during cardiopulmonary bypass. Serum interleukins 6, 8 and 10 (as inflammatory markers), and serum lactate (as a marker for pulmonary injury) levels were studied, and alveolar- arterial oxygen gradient measurements were made after the induction of anaesthesia, and immediately, one and six hours after the discontinuation of cardiopulmonary bypass.\n\n\nRESULTS\nThere were 29 patients in the non-ventilated and 30 in the continuously ventilated groups. The pre-operative demographics and intra-operative characteristics of the patients were comparable. The serum levels of interleukin 6 (IL-6) increased with time, and levels were higher in the nonventilated group only immediately after discontinuation of cardiopulmonary bypass. IL-8 levels significantly increased only in the non-ventilated group, but the levels did not differ between the groups. Serum levels of IL-10 and lactate also increased with time, and levels of both were higher in the non-ventilated group only immediately after the discontinuation of cardiopulmonary bypass. Alveolar-arterial oxygen gradient measurements were higher in the non-ventilated group, except for six hours after the discontinuation of cardiopulmonary bypass. The intubation time, length of stay in intensive care unit and hospital, postoperative adverse events and mortality rates were not different between the groups.\n\n\nCONCLUSIONS\nDespite higher cytokine and lactate levels and alveolar-arterial oxygen gradients in specific time periods, an attenuation in the inflammatory response following cardiopulmonary bypass due to low-frequency, low-tidal volume ventilation could not be documented. Clinical parameters concerning pulmonary and other major system functions and occurrence of postoperative adverse events were not affected by continuous ventilation.",
"affiliations": "Department of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, Turkey.",
"authors": "Durukan|Ahmet Baris|AB|;Gurbuz|Hasan Alper|HA|;Salman|Nevriye|N|;Unal|Ertekin Utku|EU|;Ucar|Halil Ibrahim|HI|;Yorgancioglu|C E M|CE|",
"chemical_list": "D015415:Biomarkers; C508606:CXCL8 protein, human; C508609:IL10 protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D016753:Interleukin-10; D019344:Lactic Acid",
"country": "South Africa",
"delete": false,
"doi": "10.5830/CVJA-2013-041",
"fulltext": "\n==== Front\nCardiovasc J AfrCardiovasc J AfrTBCCardiovascular Journal of Africa1995-18921680-0745Clinics Cardive Publishing 10.5830/CVJA-2013-041Cardiovascular TopicsVentilation during cardiopulmonary bypass did not attenuate inflammatory response or affect postoperative outcomes Durukan Ahmet Baris MDbarisdurukan@yahoo.comDepartment of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, TurkeyGurbuz Hasan Alper MDDepartment of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, TurkeyUcar Halil Ibrahim MDDepartment of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, TurkeyYorgancioglu Cem MDDepartment of Cardiovascular Surgery, Medicana International Ankara Hospital, Ankara, TurkeySalman Nevriye MDDepartment of Anesthesia, Medicana International Ankara Hospital, Ankara, TurkeyUtku Unal Ertekin MDDepartment of Cardiovascular Surgery, Ankara Yuksek Ihtisas Hospital, Ankara, Turkey8 2013 24 6 224 230 www.cvja.co.za28 3 2013 24 5 2013 Copyright © 2010 Clinics Cardive Publishing2010This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nCardiopulmonary bypass causes a series of inflammatory events that have adverse effects on the outcome. The release of cytokines, including interleukins, plays a key role in the pathophysiology of the process. Simultaneously, cessation of ventilation and pulmonary blood flow contribute to ischaemia–reperfusion injury in the lungs when reperfusion is maintained. Collapse of the lungs during cardiopulmonary bypass leads to postoperative atelectasis, which correlates with the amount of intrapulmonary shunt. Atelectasis also causes post-perfusion lung injury. In this study, we aimed to document the effects of continued low-frequency ventilation on the inflammatory response following cardiopulmonary bypass and on outcomes, particularly pulmonary function.\n\nMethods\nFifty-nine patients subjected to elective coronary bypass surgery were prospectively randomised to two groups, continuous ventilation (5 ml/kg tidal volume, 5/min frequency, zero end-expiratory pressure) and no ventilation, during cardiopulmonary bypass. Serum interleukins 6, 8 and 10 (as inflammatory markers), and serum lactate (as a marker for pulmonary injury) levels were studied, and alveolar–arterial oxygen gradient measurements were made after the induction of anaesthesia, and immediately, one and six hours after the discontinuation of cardiopulmonary bypass.\n\nResults\nThere were 29 patients in the non-ventilated and 30 in the continuously ventilated groups. The pre-operative demographics and intra-operative characteristics of the patients were comparable. The serum levels of interleukin 6 (IL-6) increased with time, and levels were higher in the non-ventilated group only immediately after discontinuation of cardiopulmonary bypass. IL-8 levels significantly increased only in the non-ventilated group, but the levels did not differ between the groups. Serum levels of IL-10 and lactate also increased with time, and levels of both were higher in the non-ventilated group only immediately after the discontinuation of cardiopulmonary bypass. Alveolar–arterial oxygen gradient measurements were higher in the non-ventilated group, except for six hours after the discontinuation of cardiopulmonary bypass. The intubation time, length of stay in intensive care unit and hospital, postoperative adverse events and mortality rates were not different between the groups.\n\nConclusion\nDespite higher cytokine and lactate levels and alveolar–arterial oxygen gradients in specific time periods, an attenuation in the inflammatory response following cardiopulmonary bypass due to low-frequency, low-tidal volume ventilation could not be documented. Clinical parameters concerning pulmonary and other major system functions and occurrence of postoperative adverse events were not affected by continuous ventilation.\n\ncardiopulmonary bypassrespirationartificiallactic acidinterleukins\n==== Body\nAbstract\nSince the development of the first heart–lung machine in the 1950s, cardiopulmonary bypass (CPB) has been the only way to provide a motionless and bloodless field. During CPB, circulation is maintained by mechanical pumps and venous blood is artificially oxygenated.1\n\nCardiopulmonary bypass is a non-physiological state where blood is exposed to artificial surfaces; laminar flow is employed instead of pulsatile flow, the heart is exposed to cold cardioplegic arrest and the body temperature is lowered. These key derangements lead to a series of inflammatory events involving the endothelium, leukocytes, platelets, complement system and the coagulation cascade, with the release of various cytokines.2 Surgical trauma, blood product transfusion and haemodilution also participate in this inflammatory process.3\n\nDuring CPB, pulmonary arterial circulation and alveolar ventilation are ceased and only bronchial arterial circulation supply oxygen to the lungs.3 After weaning from CPB, pulmonary reperfusion leads to ischaemia–reperfusion injury (I/R), with the release of oxygen free radicals and the resultant lipid peroxidation and endothelial damage.4 Maintaining ventilation and pulmonary flow during CPB attenuates the inflammatory response.3,5\n\nIn this study, we aimed to compare ventilation and non-ventilation regimes during CPB in patients undergoing on-pump coronary artery bypass grafting (CABG). Its influence on pulmonary injury was evaluated using lactate levels and measurement of alveolar–arterial oxygen gradients, and on postoperative cardiopulmonary functions using clinical parameters.\n\nMethods\nA prospective, randomised study was carried out. The study was approved by the local ethics committee and written informed consent was obtained from every patient. The study followed the Declaration of Helsinki 2008 on medical protocol.\n\nBetween October 2011 and February 2012, patients subjected to elective CABG surgery were studied. Patients undergoing redo surgery, and those with pre-operative renal failure (serum creatinine > 1.3 mg/dl) or hepatic dysfunction (serum aspartate/alanine amino transferase > 40 U/l), myocardial infarction within six weeks prior to surgery, any kind of pulmonary disease, pre-operative use of steroids and ejection fraction below 30% were excluded from the study.\n\nA total of 59 patients were prospectively randomised into two groups as follows: in the operation room, each patient was numbered chronologically by the same perfusionist. He reviewed the patient’s file prior to the induction of anaesthesia, based on a form explaining the inclusion and exclusion criteria, and the anesthesiologist was informed about the proposed regimen. Odd-numbered patients (n = 30) were ventilated during CPB and the even-numbered patients (n = 29) were not ventilated.\n\nPeri-operative management and anaesthesia\nPre-operative acetylsalicylic acid 100 mg/day was continued in all patients prior to the day of surgery. All patients were pre-medicated with 10 mg of oral diazepam. Anaesthesia was induced with etomidate 2 mg/kg, fentanyl 1μg/kg, vecuronium 1 mg/kg, isofluorane 1 MAC with 50% oxygen and 50% air, and remifentanyl 1μg/kg bolus, followed by a 0.5-μg/kg/min infusion. Intra-operative arterial (through the radial artery catheter) and central venous pressure (through the right internal jugular vein catheter) monitoring was done.\n\nThe CPB circuit was primed with 1 500 ml Isolyte-S® (Eczacibaşi-Baxter, Istanbul), which is a balanced electrolyte solution, and 5 000 units of heparin were added. After anticoagulation with heparin (300 U/kg), CPB was established using a roller pump with a membrane oxygenator (Dideco Compactflo Evo, Sorin group, Mirandola Modena, Italy). The average flow rate varied from 2.3 to 2.4 l/min/m2. Surgery was performed under mild hypothermia (33°C). Mean arterial pressure was kept between 45 and 70 mmHg. All patients were rewarmed to 37°C (nasopharayngeal temperature) before weaning from CPB. Heparin was neutralised with 1:1 protamine sulfate.\n\nCold (4–8°C) blood cardioplegia (1 000 ml, 25 mEq/l potassium) was administered after aortic cross clamping, and 500-ml repeat doses were given every 15 to 20 minutes (antegrade and from the venous bypass grafts; retrograde in the case of left main stenosis). Terminal warm blood cardioplegia (36–37°C) was given prior to aortic clamp release. The operating room temperature was kept at 20–21°C.\n\nFollowing surgery, the patients were taken to the intensive care unit (ICU), intubated, and intravenous propofol (1–2 mg/kg/h) and morphine (0.01–0.02 mg/kg/h) were given for the maintenance of analgesia and sedation.\n\nAtrial fibrillation (AF) was diagnosed based on an electrocardiogram. All patients were ECG monitored continuously during the ICU stay and for the first 24 hours in the ward. An ECG was immediately performed in cases of irregular pulse, palpitations or symptoms related to possible AF.\n\nPrimary outcome variables included mean time to extubation, length of stay in ICU and postoperative hospital stay, incidence of renal dysfunction (based on the finding that the peak creatinine value was ≥ 1.5 times the pre-operative value), postoperative stroke, total amount of blood loss postoperatively, postoperative exploration for haemorrhage, amount of blood and blood products used, and in-hospital mortality.\n\nVentilation strategy\nAfter intubation, before and after CPB, all patients were ventilated with FiO2 of 0.4 to 0.5, at a tidal volume of 7 ml/kg and respiratory rate of 12/min. Positive end-expiratory pressure was not used, and no requirement for FiO2 over 0.5 was required to maintain adequate oxygen saturation. The variability in ventilation parameters was to maintain a partial arterial carbon dioxide pressure between 35 and 40 mmHg.\n\nIn the non-ventilated group (NV), following establishment of CPB, ventilation was stopped (open to atmospheric pressure). In the ventilated group (V) mechanical ventilation with 0.5 FiO2 at 5 ml/kg tidal volume and 5/min respiratory rate with zero end-expiratory pressure was maintained. In the ICU, patients had volume-controlled ventilation and were extubated when their haemodynamics were stable, and neurological and respiratory functions were noted.\n\nBlood sampling and measurements\nPeripheral arterial blood samples were collected from the radial artery catheter after the induction of anaesthesia (T0), and immediately after (T1), one (T2) and six hours (T3) after the discontinuation of CPB. The blood samples were put into citrated and EDTA anti-coagulated tubes, centrifuged, and the plasma was separated and stored at –70°C until the assay.\n\nPlasma levels of IL-6, -8 and -10 were measured by commercially available enzyme-linked immunosorbent assays (AssayMax Human ELISA Kit, Assaypro, Missouri, USA). Plasma lactate levels were measured by blood gas analyser (ABL 700 series, Radiometer®, Brønshøj, Denmark).\n\nAlveolar–arterial oxygen gradient (ΔA–aO2) was calculated as follows:6\n\nΔA–aO2 = PAO2 – PaO2\n\nPAO2 = PiO2 – (PACO2/R)\n\nPiO2 = (PB – PH2O) – FiO2\n\nwhere PAO2 = alveolar oxygen tension; PaO2 = partial arterial oxygen pressure; PiO2 = partial pressure of inspired oxygen; PACO2 = alveolar carbon dioxide tension (assumed to equal the partial arterial CO2 pressure due to the ease of exchange of CO2); R = respiratory quotient (assumed at 0.8); PB = barometric pressure; PH2O = water pressure (6.2 kPa, as inspired air is fully saturated at the level of the carina); and FiO2 = fractional concentration of inspired oxygen.\n\nStatistical analysis\nStatistical analyses were performed using SPSS software for Windows version 17.0 (Statistical Package for the Social Sciences Inc, Chicago, IL, USA). Continuous variables were expressed as mean values ± standard deviation (SD). Categorical variables were expressed as number and percentages. Demographic characteristics and outcomes of the groups were compared using independent samples t-test for continuous variables, and chi-square and Fisher’s exact tests for categorical variables. Statistical significance was set as p < 0.05.\n\nThe changes in cytokine levels, lactate and ΔA–aO2 within the groups were compared using the Friedman test. In cases of significant difference, Wilcoxon signed ranks test was used to define the groups that made the difference. Comparison between the groups was done using the Mann-Whitney U-test.\n\nResults\nFifty-nine patients were included in the study. There were 29 patients in the NV group and 30 in the V group. The mean ages of the patients were 62.48 ± 6.42 in the NV group and 59.40 ± 11.10 in the V group (p = 0.19). The pre-operative demographic data and intra-operative characteristics of the patients are given in Table 1. The groups were comparable.\n\nTable 1 Pre-Operative Demographic Characteristics Of Patients\nVariable\tNV group (n = 29) mean ± SD\tV group (n = 30) mean ± SD\tp-value*\t\nAge\t62.48 ± 6.42\t59.40 ± 11.10\t0.19\t\nBMI (kg/m2)\t32.51 ± 12.22\t29.17 ± 3.44\t0.15\t\nLVEF (%)\t52.48 ± 11.77\t52.57 ± 10.14\t0.97\t\nCross-clamp time (min)\t54.66 ± 13.97\t54.67 ± 13.11\t0.99\t\nCPB time (min)\t83.41 ± 22.72\t80.83 ± 22.23\t0.66\t\nNo of grafts\t3.21 ± 0.77\t3.03 ± 0.85\t0.41\t\n\tn (%)\tn (%)\tp-value**\t\nMale\t23 (79.3)\t26 (86.7)\t0.45\t\nCurrent/ex-smoker\t22 (75.9)\t22 (73.3)\t0.82\t\nDiabetes mellitus\t16 (55.2)\t12 (40.0)\t0.24\t\nInsulin dependenta\t7 (46.7)\t8 (58.3)\t0.22\t\nHypertension\t22 (75.9)\t16 (53.3)\t0.07\t\nDyslipidaemia\t23 (79.3)\t21 (70)\t0.41\t\nStatin therapyb\t14 (60.9)\t16 (76.2)\t0.27\t\nPre-operative β-blocker use\t17 (58.6)\t12 (40.0)\t0.15\t\nPeripheral arterial diseasec\t2 (6.9)\t0\t0.23***\t\nStroke\t2 (6.9)\t1(3.3)\t0.49***\t\nCarotid diseased\t0\t2 (6.7)\t0.61***\t\nSD: standard deviation, NV: non-ventilated, V: ventilated, BMI: body mass index, LVEF: left ventricular ejection fraction, CPB: cardiopulmonary bypass.\n\n*Independent samples t-test, **Chi-square test, ***Fisher’s exact test.\n\naThe percentage values were calculated in diabetic patients.\n\nbThe percentage values were calculated in dyslipidaemic patients.\n\ncHistory of therapeutic vascular intervention, history of claudication, aniography/non-invasive proven peripheral arterial disease.\n\ndHistory of carotid intervention or angiographic/non-invasive proven > 40% stenosis of either carotid artery.\n\nIL-6 levels were increased after induction of anaesthesia in both groups and remained higher than baseline levels six hours after discontinuation of CPB. When the two groups were compared, only IL-6 levels were higher immediately after discontinuation of CPB in the NV group than in the V group (p = 0.049) (Table 2, Fig. 1).\n\nTable 2 Comparison Of Two Groups With Cytokine Levels And Alveolar–Arterial Oxygen Gradient\nVariable\tNV group (n = 29) mean ± SD\tV group (n = 30) mean ± SD\tp-value*\t\nIL-60 (pg/ml)\t8.28 ± 1.06\t8.03 ± 0.18\t0.51\t\nIL-61 (pg/ml)\t16.0 ± 9.04\t15.37 ± 17.21\t0.049\t\nIL-62 (pg/ml)\t17.31 ± 10.34\t13.97 ± 6.57\t0.22\t\nIL-63 (pg/ml)\t22.83 ± 12.91\t19.50 ± 6.88\t0.38\t\np-value**\t< 0.001\t< 0.001\t\t\nIL-80 (pg/ml)\t24.86 ± 48.30\t25.03 ± 25.53\t0.14\t\nIL-81 (pg/ml)\t30.79 ± 44.50\t26.07 ± 30.35\t0.85\t\nIL-82 (pg/ml)\t31.72 ± 44.71\t21.67 ± 21.18\t0.62\t\nIL-83 (pg/ml)\t20.34 ± 29.47\t24.20 ± 23.63\t0.33\t\np-value**\t0.005\t0.997\t\t\nIL-100 (pg/ml)\t15.30 ± 7.31\t15.58 ± 9.36\t0.87\t\nIL-101 (pg/ml)\t142.03 ± 55.20\t85.74 ± 61.65\t0.002\t\nIL-102 (pg/ml)\t120.00 ± 41.73\t108.45 ± 68.13\t0.62\t\nIL-103 (pg/ml)\t24.20 ± 24.98\t26.16 ± 37.41\t0.98\t\np-value**\t< 0.001\t< 0.001\t\t\nLactate0 (mmol/l)\t1.56 ± 0.73\t1.38 ± 0.47\t0.55\t\nLactate1 (mmol/l)\t4.07 ± 1.68\t2.95 ± 1.49\t0.003\t\nLactate2 (mmol/l)\t4.10 ± 1.90\t4.04 ± 4.04\t0.21\t\nLactate3 (mmol/l)\t3.96 ± 2.16\t4.10 ± 1.37\t0.34\t\np-value**\t< 0.001\t< 0.001\t\t\nΔA–aO2(0) (kPa)\t20.60 ± 6.16\t11.84 ± 5.39\t< 0.001\t\nΔA–aO2(1) ( kPa)\t24.91 ± 3.98\t14.15 ± 5.77\t< 0.001\t\nΔA–aO2(2) (kPa)\t26.47 ± 5.13\t19.54 ± 4.05\t< 0.001\t\nΔA–aO2(3) (kPa)\t18.95 ± 7.59\t17.19 ± 6.77\t0.31\t\np-value**\t< 0.001\t< 0.001\t\t\nSD: standard deviation, NV: non-ventilated, V: ventilated, IL: interleukin, ΔA–aO2: alveolar–arterial oxygen gradient.\n\n*Mann-Whitney U-test, **Friedman test.\n\n0After induction of anaesthesia, 1Immediately after discontinuation of CPB, 2One hour after discontinuation of CPB, 3Six hours after discontinuation of CPB.\n\nFig. 1. Serum IL-6 levels.\n\nInterleukin-8 levels were increased in the NV group, they peaked one hour after discontinuation of CPB and decreased at six hours to baseline levels (p = 0.005). In the V group, IL-8 levels increased, peaked immediately after discontinuation of CPB, decreased at one hour and increased again at six hours, but the change in IL-8 concentrations in this group was not significant (p = 0.99). When the two groups were compared, there was no statistically significant difference at any time period (Table 2, Fig. 2).\n\nFig. 2. Serum IL-8 levels.\n\nIL-10 levels were increased in the NV group, peaked immediately after discontinuation of CPB, decreased soon after and returned to baseline levels (p < 0.001). In the V group, IL-10 levels were increased following induction of anaesthesia, peaked at one hour after discontinuation of CPB, and decreased soon after (p < 0.001). When the two groups were compared, only IL-10 levels were higher immediately after discontinuation of CPB in the NV group than in the V group (p = 0.001) (Table 2, Fig. 3).\n\nFig. 3. Serum IL-10 levels.\n\nPulmonary function\nLactate release was significantly increased after the induction of anaesthesia in both groups; it peaked at one hour after discontinuation of CPB in the NV group and decreased at six hours, but remained higher than baseline levels (p < 0.001). In the ventilated group, levels of lactate progressively increased with time (p < 0.001) (Table 2, Fig. 4). However, in each time period there was no significant difference in lactate levels between the groups.\n\nFig. 4. Serum lactate levels.\n\nThe alveolar–arterial oxygen gradient widened after the induction of anaesthesia, peaked at one hour after discontinuation of CPB, and decreased at six hours, but remained higher than baseline levels in both groups (p < 0.001). When the two groups were compared, the gradient was higher in the non-ventilated group after induction, and immediately after and at one hour after discontinuation of CPB (p < 0.001) (Table 2, Fig. 5).\n\nFig. 5. Alveolar–arterial oxygen gradient measurements.\n\nIn the ICU, the intubation time for the NV group was 9.67 ± 3.29 h and 9.27 ± 2.86 h in the V group (p = 0.61) (Table 3). Prolonged intubation was not required in any patient.\n\nTable 3 Comparison Of Two Groups By Postoperative Variables\n\tNV group (n = 29) mean ± SD\tV group (n = 30) mean ± SD\tp-value*\t\nICU intubation time (h)\t9.67 ± 3.29\t9.27 ± 2.86\t0.61\t\nLength of stay\t\nICU (h)\t47.90 ± 14.16\t45.83 ± 2.15\t0.43\t\nPostoperative (days)\t5.45 ± 0.87\t6.07 ± 1.66\t0.08\t\nDrainage tubes removed (h)\t36.03 ± 9.22\t36.93 ± 20.64\t0.94\t\nTotal amount of drainage (ml)\t709.66 ± 541.21\t720.00 ± 540.37\t0.83\t\nNumber of FFP used\t1.07 ± 2.18\t1.10 ± 1.34\t0.94\t\nNumber of packed RBC used\t1.79 ± 1.67\t1.60 ± 1.67\t0.66\t\nNumber of PC used\t0.45 ± 1.32\t0.37 ± 1.21\t0.80\t\n\tn (%)\tn (%)\tp-value**\t\nPostoperative exploration for haemorrhage\t0\t1 (3.3)\t1.00\t\nPostoperative AF\t6 (20.7)\t3 (10.0)\t0.29\t\nRenal dysfunctiona\t5 (17.2)\t4 (13.3)\t0.73\t\nPostoperative stroke\t0\t0\t-\t\nSD: standard deviation, NV: non-ventilated, V: ventilated, ICU: intensive care unit, FFP: fresh frozen plasma, RBC: red blood cells, PC: platelet concentrate, AF: atrial fibrillation.\n\n*Independent samples t-test, ** Fisher’s exact test.\n\naDefined when peak creatinine value was ≥ 1.5 times the pre-operative value.\n\nClinical parameters\nLength of stay in ICU and postoperative hospital length of stay were not statistically different in both groups. There was no significant difference when amount of drainage, amount of blood and blood products used, and incidence of postoperative exploration for haemorrhage were compared. Renal failure was defined as peak creatinine value ≥ 1.5 times the pre-operative value and there was no significant difference between the groups (Table 3).\n\nWhen postoperative AF was studied, there were six patients (20.7%) with AF in the NV group, and three (10.0%) in the V group (p = 0.29). Normal sinus rhythm was maintained in all patients except one in the V group. There was no statistically significant difference when maintenance of sinus rhythm was compared. There was no postoperative stroke and mortality noted throughout the study.\n\nDiscussion\nThe inflammatory response to CPB is acute, complex and can lead to significant morbidity and mortality. It involves the release of cytokines, which may have an impact on postoperative outcomes. The release of cytokines [tumour necrosis factoralpha (TNF-α), interleukins and interferons] may negatively affect cardiac, renal and pulmonary functions.2 Cytokine release was shown to correlate with outcome after cardiac surgery. During and after CPB, serum levels of IL-6, IL-8 and TNF-α were increased.\n\nTNF-α is a proximal mediator in the inflammatory cascade.7 It induces endothelial cells to produce cell adhesion molecules (Eand P-selectins), which bind to ligands on activated leukocytes to mediate ‘rolling’ of the leukocytes, and intracellular and vascular cell adhesion molecules, which facilitate leukocyte migration from the endothelium to the extravascular space.1 TNF-α also induces a second wave of cytokines such as IL-6, which is an important regulator of the hepatic acute-phase response, and IL-8, a cytokine with important neutrophil-activating and chemo-attractant properties.7 The neutrophilic effects of IL-8 lead to local release of proteolytic enzymes, with resultant pulmonary injury.8\n\nIncreased levels of IL-6 and IL-8 were also related to regional wall motion abnormalities following on-pump cardiac surgery.2 The release of IL-6 and -8 during CPB led to neutrophil entrapment in pulmonary capillaries. This in turn led to endothelial cell swelling, plasma and protein extravasation into the pulmonary interstitial tissue, together with the release of proteolytic enzymes and the resultant congestion of the alveoli.9 The clinical result was decreased PaO2 and increased PaCO2, indicating pulmonary injury.10\n\nThe negative effects of these cytokines are limited by the anti-inflammatory cytokine IL-10, which has protective effects against organ dysfunction following CPB.11 In a study of 13 patients, Deblier et al.12 reported increased IL-10 release, with a peak at the end of CPB in both ventilated and non-ventilated groups, but ventilation did not influence this increase and there was no significant difference between the groups. They failed to document a significant increase in IL-6 in both groups. Beer et al.13 conducted a similar study and indicated that continued ventilation during CPB attenuated pro-inflammatory IL-6 concentrations and anti-inflammatory IL-10 concentrations. The levels of IL-6 and IL-10 peaked at the end of surgery (which corresponds to T2 in our study) in both groups.\n\nNg et al.3 documented higher IL-10 levels one hour after declamping the aorta in the ventilated group (which corresponds to sometime between T1 and T2 in our study). In our study, the levels of IL-6 were highest six hours after discontinuation of CPB in both groups, but there was no significant difference at any time interval between the ventilated and non-ventilated groups. In the NV group, IL-10 levels peaked immediately after discontinuation of CPB, and one hour after discontinuation of CPB in the V group. The serum IL-10 levels were only significantly higher in the NV group immediately after discontinuation of CPB.\n\nMiranda et al.7 compared different ventilation strategies during CPB in their randomised, controlled clinical study: continuous ventilation, early and open-lung concepts. They observed that CPB caused a significant increase in IL-6, IL-8 and IL-10 levels. IL-6 levels did not differ significantly between the groups. The decrease in IL-10 levels was more pronounced in the early open-lung group. After discontinuation of CPB, they observed a more rapid decrease in IL-8 in the open-lung groups. They concluded that the open-lung concept attenuates the inflammatory response. It is not wise to compare our results with theirs since the design of the studies were completely different, but we can conclude that we did not observe an objective attenuation of the inflammatory response with ventilation.\n\nMost of the studies comparing the effects of ventilation on the inflammatory response after CPB did not study serum IL-8 levels.12,13 IL-8 is a very important cytokine in the pathophysiology of myocardial ischaemia. Its levels correlate with complications following myocardial infarction, and anti-IL-8 antibodies prevented injury in experimental models.7 Its levels also correlated well with left ventricular wall motion abnormalities in the postoperative period.4 Furthermore, it was reported that cyclic alveolar stress due to mechanical ventilation led to increased IL-8 levels.14\n\nNg et al.3 studied IL-8 levels. They reported IL-8 levels were higher in the non-ventilated group four hours after declamping. In our study, in the ventilated group, we did not observe any significant change in IL-8 concentrations. They peaked at one hour after discontinuation of CPB in the non-ventilated group and then decreased to baseline levels. However, there was no statistically significant difference between the groups at any given time interval.\n\nLamarche et al.15 reported that CPB with reperfusion without aortic clamping induced a selective decrease in endothelial relaxation to acetylcholine, and normal ventilation during CPB prevented changes in endothelium-dependent relaxation of the endothelium. Similarly Gagnon et al.4 documented that continued ventilation during CPB correlated with an attenuated inflammatory and proteolytic process and better preserved pulmonary function. It was suggested that maintaining ventilation and pulmonary flow during CPB attenuated the inflammatory response.3,5,16 The continuation of pulmonary blood flow during CPB also led to reduction in serum IL-6 and -8 levels.10\n\nThe lungs depend on three separate sources of oxygen delivery: bronchial arterial and pulmonary arterial circulations, and alveolar ventilation.3 Two of these cease during CPB because in standard CPB surgery, the lungs are deflated and pulmonary blood flow is shunted. After weaning from CPB, pulmonary reperfusion leads to I/R injury with the release of oxygen free radicals and the resultant lipid peroxidation and endothelial damage.4 As a consequence of I/R injury, pulmonary vascular endothelial dysfunction results in secondary vasoconstriction and increased vascular permeability, and finally pulmonary hypertension, oedema and hypoxia.15\n\nThe alveolar–arterial oxygen gradient is widened and lactate is released as a result of lung injury. The levels of pulmonary lactate release correlate well with systemic lactate levels. This lactate release is increased in procedures employing CPB and correlates with prolonged respiratory support.6 Furthermore, deflated/unventilated lungs during CPB induce atelectasis,12 which may further induce pro-inflammatory cytokine production.17 Atelectasis is also blamed for post-CPB pulmonary injury. Moreover, the degree of intrapulmonary shunt and atelectasis was found to be correlated.\n\nComputed tomography studies also showed a correlation between atelactatic areas and intrapulmonary shunt.18 Based on this finding ventilation was suggested to protect lungs from ischaemic damage.\n\nGasparovic et al.6 studied pulmonary lactate release and changes in ΔA–aO2 during CPB. They reported that the lungs were a significant source of lactate release and there was a correlation between pulmonary lactate release and peripheral lactate concentrations. The duration of CPB correlated with increased pulmonary lactate release and widened ΔA–aO2. We also observed that lactate release was increased with CPB and ΔA–aO2 was widened in both groups, but unlike their study, we studied the effects of continued ventilation on ΔA–aO2 and peripheral lactate levels in order to document its effects on pulmonary functions.\n\nThe lactate levels were significantly lower only immediately after discontinuation of CPB in the ventilated group; in other determined time periods there was no difference. In each group, ΔA–aO2 widened with time. When the two groups were compared, ΔA–aO2 was lower in the ventilated group in all time periods, except for six hours following discontinuation of CPB, when there was no difference. We also report that ΔA–aO2 was higher following induction of anesthaesia in the non-ventilated group, and this may be the cause of differences in the following time periods.\n\nIn an experimental porcine study, Imura et al.19 documented that low-frequency ventilation caused reduction of ischaemic changes and lower rates of atelectasis. They also observed that lactate levels were lower in the ventilated group compared to the control. We also documented similar results with regard to ΔA–aO2, but lactate levels were higher only in the non-ventilated group immediately after discontinuation of CPB.\n\nSchreiber et al.20 revealed that to date, there have been three trials that investigated the effects of continued ventilation during CPB on pulmonary functions. Gagnon et al.4 determined a tidal volume of 3 ml/kg during CPB and John et al.21 5 ml/kg. Boldt et al.22 continued normal ventilation during CPB. They all failed to document a significant difference with regard to ΔA–aO2. Only John et al.21 reported less extravascular lung fluid accumulation and a decreased period of ventilation.\n\nIn our study, we employed a modified ventilation strategy, the tidal volume was 5 ml/kg, but frequency was 5/min to avoid an uncomfortable operating field. Different from these studies, we documented higher ΔA–aO2 in the non-ventilated group, except for six hours after discontinuation of CPB.\n\nThe effects of continued ventilation during CPB on pulmonary function are still controversial. This controversy is very briefly summarised by Schreiber et al.20 in a recent systematic review and meta-analysis comprising 814 participants of 16 randomised trials. They concluded that continued ventilation was beneficial when serum levels of inflammatory cytokines were considered. Moreover, oxygenation parameters were improved and shunt fraction was decreased. However, all these documented effects were short-lived, questionable, and did not influence the clinical course and final outcomes.\n\nA similar review reported by Vohra et al.23 also concluded that no convincing results of any ventilation strategies were available. In our study, aside from the cytokine levels and other formula measurements, the clinical outcomes were not affected by continuous ventilation during CPB. The intubation time, length of stay in ICU and hospital, and occurrence of postoperative adverse events were not different between the groups.\n\nConclusion\nWe did not document an objective finding that continuous, low-frequency ventilation attenuated the inflammatory response and positively affected postoperative pulmonary functions, adverse events and outcomes. We believe that further studies with increased numbers of patients and more detailed investigation of inflammatory markers should be done to be able to draw any conclusions.\n\nThe IL kits were provided by Sanovel Pharmaceutical Company, Istanbul, Turkey.\n==== Refs\nReferences\n1 Warren OJ Smith AJ Alexiou C Rogers PL Jawad N Vincent C et al. The inflammatory response to cardiopulmonary bypass: Part 1-Mechanisms of pathogenesis. J Cardiothorac Vasc Anesth 2009 23 223 231 18930659 \n2 Larmann J Inflammatory response to cardiac surgery: Cardiopulmonary bypass vs. non-cardiopulmonary bypass surgery. Best Pract Res Clin Anesthesiol 2004 18 425 438 \n3 Ng CS Arifi AA Wan S Ho AM Wan IY Wong EM et al. Ventilation during cardiopulmonary bypass: Impact on cytokine response and cardiopulmonary function. Ann Thorac Surg 2008 85 154 162 18154801 \n4 Gagnon J Laporta D Beique F Langlois Y Morin JF Clinical relevance of ventilation during cardiopulmonary bypass in the prevention of postoperative lung dysfunction. Perfusion 2010 25 205 210 20605871 \n5 De Perrot M Liu M Waddell TK Keshavjee S Ischemia reperfusion-induced lung injury. Am J Respir Crit Care Med 2003 167 490 511 12588712 \n6 Gasparovic H Plestina S Sutlic Z Husedzinovic I Coric V Ivancan V et al. Pulmonary lactate release following cardiopulmonary bypass. Eur J Cardiothorac Surg 2007 32 882 887 17904857 \n7 Reis Miranda D Gommers D Struijs A Dekker R Mekel J Feelders R et al. Ventilation according to open lung concept attenuates pulmonary inflammatory response in cardiac surgery. Eur J Cardiothorac Surg 2005 28 889 895 16271479 \n8 Ng CS Wan S Yim AP Arifi AA Pulmonary dysfunction after cardiac surgery. Chest 2002 121 1269 1277 11948063 \n9 Zhang R Wang Z Wang H Song H Zhang N Fang M Effective pulmonary artery perfusion mode during cardiopulmonary bypass. Heart Surg Forum 2011 14 18 21 \n10 Yewei X Liya D Jinghao Z Rufang Z Li S Study of the mechanism of pulmonary protection strategy on pulmonary injury with deep hypothermia low flow. Eur Rev Med Pharmacol Sci 2013 17 879 885 23640433 \n11 Wan S Izzat MB Lee TW Wan IY Tang NL Yim AP Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999 68 52 57 10421114 \n12 Deblier I Sadowska AM Janssens A Rodrigus I Backer WA Markers of inflammation and oxidative stress in patients undergoing CABG with CPB with and without ventilation of the lungs: a pilot study. Interact Cardiovasc Thorac Surg 2006 5 387 391 17670599 \n13 Beer L Szerafin T Mitterbauer A Debreceni T Maros T Dworschak M et al. Continued mechanical ventilation during coronary artery bypass graft operation attenuates the systemic immune response. Eur J Cardiothorac Surg 2012 \n14 Yamamoto H Teramoto H Uetani K Igawa K Shimizu E Cyclic stretch upregulates interleukin-8 and transforming growth factor-beta1 production through a protein kinase C-dependent pathway in alveolar epithelial cells. Respirology 2002 7 103 109 11985731 \n15 Lamarche Y Gagnon J Malo O Blaise G Carrier M Perrault L Ventilation prevents pulmonary endothelial dysfunction and improves oxygenation after cardiopulmonary bypass without aortic cross clamping. Eur J Cardiothorac Surg 2004 26 554 563 15302051 \n16 Hasegawa A Iwasaka H Hagiwara S Koga H Hasegawa R Kudo K et al. Anti-inflammatory effects of perioperative intensive insulin therapy during cardiac surgery with cardiopulmonary bypass. Surg Today 2011 41 1385 1390 21922361 \n17 Kotani N Hashimoto H Sessler DI Muraoka M Wang JS O’Connor MF et al. Cardiopulmonary bypass produces greater pulmonary than systemic proinflammatory cytokines. Anesth Analg 2000 90 1039 1045 10781450 \n18 Verheiji J van Lingen A Raijmakers PG Spijkstra JJ Girbes AR Jansen EK et al. Pulmonary abnormalities after cardiac surgery are better explained by atelectasis than increased permeability oedema. Acta Anaesthesiol Scand 2005 49 1302 1310 16146467 \n19 Imura H Caputo M Lim K Suleiman M Shimizu K Angelini G Pulmonary injury after cardiopulmonary bypass: Beneficial effects of low frequency ventilation. J Thorac Cardiovasc Surg 2009 137 1530 1537 19464476 \n20 Schreiber JU Lancé MD de Korte M Artmann T Aleksic I Kranke P The effect of different lung-protective strategies in patients during cardiopulmonary bypass: a meta-analysis and semiquantitative review of randomized trials. J Cardiothorac Vasc Anesth 2012 26 448 454 22459933 \n21 John LCH, Ervine IM A study assessing the potential benefit of continued ventilation during cardiopulmonary bypass. Interact Cardiovasc Thorac Surg 2008 7 14 17 17933836 \n22 Boldt J King D Scheld HH Hempelmann G Lung management during cardiopulmonary bypass: influence on extravascular lung water. J Cardiothorac Anesth 1990 4 73 79 2131860 \n23 Vohra HA Levine A Dunning J Can ventilation while on cardiopulmonary bypass improve post-operative lung function for patients undergoing cardiac surgery. Interact Cardiovasc Thorac Surg 2005 4 442 446 17670453\n\n",
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"mesh_terms": "D000368:Aged; D015415:Biomarkers; D002315:Cardiopulmonary Bypass; D001026:Coronary Artery Bypass; D017558:Elective Surgical Procedures; D005260:Female; D006801:Humans; D018836:Inflammation Mediators; D016753:Interleukin-10; D015850:Interleukin-6; D016209:Interleukin-8; D019344:Lactic Acid; D008168:Lung; D055370:Lung Injury; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012119:Respiration; D012121:Respiration, Artificial; D018746:Systemic Inflammatory Response Syndrome; D013997:Time Factors; D016896:Treatment Outcome; D014421:Turkey",
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"title": "Ventilation during cardiopulmonary bypass did not attenuate inflammatory response or affect postoperative outcomes.",
"title_normalized": "ventilation during cardiopulmonary bypass did not attenuate inflammatory response or affect postoperative outcomes"
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"abstract": "A 67-year-old man presented at our hospital with severe edema on the left side of his neck, chest and brachial regions. He had a history of right radical nephrectomy due to renal cell carcinoma (RCC, clear cell subtype, stage II) 15 years earlier. Thereafter, metastases to the pancreatic tail and right lung, and left lung metastasis were removed at 8 years and 11 years, respectively, after the nephrectomy. Four years earlier, he had also undergone total gastrectomy for gastric carcinoma (poorly differentiated adenocarcinoma, stage IV) and subsequent maintenance chemotherapy for gastric carcinoma. Follow-up computed tomography (CT) disclosed bilateral lung metastases and a pancreatic head metastasis. Cytology of pleural effusion on admission suggested pleuritis carcinomatosa from RCC. Clinical diagnosis was bilateral lung and pancreatic head metastases, pleuritis carcinomatosa and left subclavian vein thrombosis due to RCC metastasis. Maintenance chemotherapy for gastric carcinoma was replaced by Sunitinib 50 mg for RCC but he died of progressive disease 20 days later. Immunohistochemical study of the tissue from autopsy revealed lung metastasis and pancreatic head metastasis from both RCC and gastric carcinoma as well as multiple visceral metastases, pleuritis carcinomatosa and left subclavian vein thrombosis due to gastric carcinoma. Cause of death was acute respiratory failure due to pulmonary tumor embolism and pulmonary edema. Immunohistochemical study from autopsy was able to reveal the exact diagnosis, and immunohistochemical studies may be helpful in diagnosing the exact origin of metastasis and selecting appropriate treatmentsin patientswith multiple cancers.",
"affiliations": "The Department of Urology, Shiga University of Medical Science.;The Department of Urology, Shiga University of Medical Science.;The Department of Urology, Shiga University of Medical Science.;The Department of Urology, Shiga University of Medical Science.;The Department of Molecular and Diagnostic Pathology, Shiga University of Medical Science.;The Department of Molecular and Diagnostic Pathology, Shiga University of Medical Science.;The Department of Molecular and Diagnostic Pathology, Shiga University of Medical Science.;The Department of Urology, Yasu Hospital.",
"authors": "Fujiwara|Ryo|R|;Narita|Mitsuhiro|M|;Kageyama|Susumu|S|;Kawauchi|Akihiro|A|;Nakayama|Takahisa|T|;Nishi|Natsumi|N|;Sugihara|Hiroyuki|H|;Okada|Yusaku|Y|",
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"mesh_terms": "D000368:Aged; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D013274:Stomach Neoplasms; D014057:Tomography, X-Ray Computed",
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"title": "A Case of Synchronous Multiple Metastases in which the Origin Could Not Be Identified by Routine Examination.",
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"abstract": "BACKGROUND: Second as well as higher-line therapies have a significant influence on progression-free and overall survival of metastatic colorectal cancer patients. However, treatment of late-stage disease remains suboptimal. Therefore, the introduction of new, effective and well-tolerated agents is of major importance. Case Reports: Here we describe the cases of 2 patients with metastatic KRAS wild-type colorectal cancer who received a fourth-line monotherapy with panitumumab after failure of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab. RESULTS: Both patients achieved a partial remission, and for 11.5 and 18 months, respectively, they had a stable disease with initial reduction in the tumor marker carcinoembryonic antigen. Both patients reported a good tolerability of the treatment with improved quality of life (compared to receiving combined chemotherapy). CONCLUSION: Panitumumab monotherapy is an effective and well tolerated treatment of metastatic colorectal cancer in extensively pretreated KRAS wild-type patients. Our data have shown a response to panitumumab monotherapy for more than 11 months.",
"affiliations": "Department for Gastroenterology and Endocrinology, University Medicine Göttingen, Göttingen, Germany.",
"authors": "Ramadori|G|G|;Cameron|S|S|;Tschechne|B|B|",
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"fulltext": "\n==== Front\nCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 2074018910.1159/000312107cro0003-0154Published: May 2010Long-Lasting Tumor Response in Patients with Panitumumab Monotherapy for Chemorefractory Metastatic Colorectal Carcinoma – A Report of Two Cases Ramadori G. a*Cameron S. aTschechne B. baDepartment for Gastroenterology and Endocrinology, University Medicine Göttingen, Göttingen, GermanybPrivate Practice for Hemato-Oncology, Lehrte, Germany*Prof. Dr. med. Giuliano Ramadori, University Medicine Göttingen, Center for Internal Medicine Department for Gastroenterology and Endocrinology, Robert-Koch-Strasse 40, DE–37075 Göttingen (Germany), Tel. +49 551 39 6301, Fax +49 551 39 6921, E-Mail gramado@med.uni-goettingen.deApr-Aug 2010 07 5 2010 07 5 2010 3 2 154 159 Copyright © 2010 by S. Karger AG, Basel2010This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Background\nSecond as well as higher-line therapies have a significant influence on progression-free and overall survival of metastatic colorectal cancer patients. However, treatment of late-stage disease remains suboptimal. Therefore, the introduction of new, effective and well-tolerated agents is of major importance. Case Reports: Here we describe the cases of 2 patients with metastatic KRAS wild-type colorectal cancer who received a fourth-line monotherapy with panitumumab after failure of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab.\n\nResults\nBoth patients achieved a partial remission, and for 11.5 and 18 months, respectively, they had a stable disease with initial reduction in the tumor marker carcinoembryonic antigen. Both patients reported a good tolerability of the treatment with improved quality of life (compared to receiving combined chemotherapy).\n\nConclusion\nPanitumumab monotherapy is an effective and well tolerated treatment of metastatic colorectal cancer in extensively pretreated KRAS wild-type patients. Our data have shown a response to panitumumab monotherapy for more than 11 months.\n\nKey Words\nMetastatic colorectal carcinomaPanitumumab monotherapyFourth-line therapy\n==== Body\nIntroduction\nDuring the previous 10 years, a significant improvement has been observed in the treatment of metastatic colorectal cancer patients, which is largely due to the introduction of new cytotoxic drugs (irinotecan, oxaliplatin) and targeted therapies (bevacizumab, cetuximab, panitumumab). As therapeutic options expanded, overall survival improved incrementally from a median of approximately 12 months (achievable with 5-fluorouracil/folinic acid monotherapy) [1] to more than 20 months in patients who are given 2 or more effective drugs in combination or sequentially [2, 3]. It has become increasingly clear that combination therapy is effective in treating advanced disease [4,5,6]. However, in cases with progression under modern chemotherapy, the development and introduction of new effective agents is of major importance. This is especially true for agents like the approved epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab that have demonstrated efficacy in the management of late-stage disease.\n\nPanitumumab is the first fully human anti-EGFR monoclonal antibody and is a very promising new treatment option for patients with KRAS wild-type metastatic colorectal carcinoma. The efficacy of panitumumab monotherapy has been demonstrated in the pivotal open label phase III study [7, 8] in which panitumumab significantly prolonged progression-free survival versus best supportive care in patients with wild-type KRAS tumors refractory to standard chemotherapeutic agents.\n\nHere we present two patients who benefited from fourth-line treatment with panitumumab.\n\nCase Reports\nCase 1\nA 68-year-old man with good performance status was diagnosed with a tumor in the colon sigmoideum (June 2006). Thoracic CT-scan revealed lung-metastases, and PET-scan suggested additional liver metastases. While the primary sigmoid tumor was left in situ, first-line treatment with FOLFIRI/bevacizumab was initiated in July 2006 and pursued until July 2007. Meanwhile, the treatment was interrupted three times on the patient's request to regain a quality of life without chemotherapy. In July 2007, the treatment was switched to second-line therapy with FOLFOX because of local tumor progression.\n\nIn February 2008, third-line treatment with FOLFIRI was introduced and terminated in May 2008 as a result of side effects such as nausea, vomiting, loss of appetite and general weakness. After wild-type KRAS tumor status was confirmed, monotherapy with panitumumab (6 mg/kg every 2 weeks) was initiated (June 2008) and administered for 23 cycles (until May 2009). Treatment with panitumumab resulted in a good partial response of the primary tumor (fig. 1). Concomitantly, a decline of the carcinoembryonic antigen (CEA) serum levels to normal was observed from 7.6 μg/l in July 2008 to 3.4 μg/l in March 2009 (normal values =3.4 μg/l) (fig. 2). The size of the lung metastases had not changed significantly until then. However, from April 2009, CEA-values increased successively to 5.0 μg/l, and follow-up staging resulted in a size increase of the oligotope lung metastases (index metastasis from 1.6 × 2.5 cm to 2.6 × 3.4 cm) leading to the re-introduction of FOLFIRI as combination therapy with panitumumab in May 2009 for another 6 cycles, when FOLFIRI was continued without the antibody.\n\nTolerability of panitumumab monotherapy proved to be very good, the quality of life improved and the patient gained weight (5 kg). The patient experienced neither emesis nor vomiting and did no longer suffer from oxaliplatin-induced neuropathy. The only treatment-related side effect was skin toxicity (WHO grade 2), which was treated with a greasy ointment containing paraffinum liquidum and glycerin and a nadifloxacin-containing anti-acne ointment. Under panitumumab monotherapy, the patient had regained his quality of life with an improvement of the Karnofsky index from initially 70-80% to now 100%. The patient is up to now (04/2010) in a good health state and continues to receive combination therapy.\n\nCase 2\nA male patient aged 79 years was diagnosed in October 2003 with an adenocarcinoma of the rectum, massive lymphangiosis carcinomatosa, and infiltration of regional lymph nodes (stage IIIC). Between December 2003 and May 2005 the patient was treated with deep anterior resection of the rectum (R0) and received adjuvant chemoradiation with 5-fluorouracil/folinic acid. In August 2005, new lymphogenic infiltration and metastases in the lung were diagnosed. First-line treatment with 5-fluorouracil/folinic acid and bevacizumab was initiated and pursued until June 2006 when chest X-ray and abdominal CT revealed pulmonary progression. Second-line treatment with FOLFOX was started in October 2006 and terminated in May 2007 as a result of renewed progression (abdominal CT and ultrasound). From July 2007 the patient received third-line treatment with FOLFIRI. In January 2008, a metastasis of the liver was detected by CT-scan, which was shown to be KRAS wild-type by biomarker testing on metastasis material after fine-needle biopsy. In February 2008, panitumumab monotherapy (6 mg/kg every 2 weeks, with one interruption) was initiated which resulted (August 2008) in a decrease of lymphatic lesions, in particular in a reduction of the beforehand enlarged abdominal lymph nodes, as well as a partial remission of the liver metastases (fig. 3). In addition, a reduction in CEA levels from 369.0 μg/l (February 2008) to 108.7 μg/l (August 2008) was observed. In January 2009 CEA levels had risen to 283.3 μg/l. The lung metastases remained unchanged.\n\nTreatment with panitumumab was very well tolerated, with mild skin reactions (grade 1) which were treated with a metronidazole-containing cream. After 34 cycles of panitumumab monotherapy, the treatment was again changed to combination therapy. The patient has a stable partial remission and stays continuously under treatment. The patient has unremarkable liver counts and does not suffer from hematological toxicity. Due to the very good efficacy and tolerability of the therapy, the patient now still has a high quality of life.\n\nDiscussion\nBoth our patients had visceral metastases and failed prior treatment with 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab. In spite of extensive pretreatment, stable disease was observed after switching treatment to panitumumab monotherapy for 11.5 and 18 months, respectively, when combination therapy was re-introduced in both patients. These progression-free intervals are remarkably good for patients who receive a fourth-line therapy. Both patients benefited from good tolerability of the treatment and an improved quality of life. The good experience with panitumumab treatment in these 2 heavily pretreated patients is in line with the results of the pivotal studies [7, 8].\n\nThe EGFR inhibitors cetuximab and panitumumab were found to be significantly superior over best supportive care in randomized trials when given to patients who had already received two or more lines of chemotherapy [7, 9]. However, the real potential of EGFR inhibitors was not fully recognized until KRAS-mutation status was confirmed as a predictive marker [8]. A subgroup analysis of the pivotal study showed [8] that patients with wild-type KRAS tumors refractory to standard chemotherapy achieved a marked and significant prolongation of progression-free survival when treated with panitumumab as compared with best supportive care (median 12.3 vs. 7.3 months, p < 0.0001). Disease control was also improved with 51% versus 12% benefiting from treatment (PR, SD). Furthermore, panitumumab proved to be safe and well tolerated. In the pivotal trial less than 2% of patients had potential infusion reactions (grade 3 in 0.1% of patients) [10]. The main treatment-related toxicity was skin related (=5% grade 3) and consisted of erythema, acneiform dermatitis or pruritus. Recent evidence suggests that prophylactic treatment may reduce the incidence of treatment-related skin toxicity by more than 50% [11].\n\nThe optimal use of panitumumab in the treatment of metastatic colorectal cancer is yet to be determined. Currently, combinations of panitumumab with standard chemotherapies are being evaluated as first or second-line strategies in phase III randomized clinical studies. Based on currently available data and our current experience, it can be concluded that panitumumab is an effective and well tolerated monotherapy of metastatic colorectal cancer even in extensively pretreated patients. Moreover, panitumumab treatment may allow to bridge treatment breaks when chemotherapy has to be temporarily interrupted because of side effects.\n\nAcknowledgements\nFinancial support for medical writing was provided by Amgen Germany. Both patients gave their written informed consent for the publication of this article.\n\nFig. 1 Colonoscopic images of the primary carcinoma of the colon sigmoideum (case 1). a Before starting therapy with panitumumab; b after 12 cycles; c after 23 cycles.\n\nFig. 2 Serum CEA levels during fourth-line treatment with panitumumab (case 1).\n\nFig. 3 CT scans of liver metastases in a patient with an adenocarcinoma of the rectum: a at diagnosis of the metastases (January 2008) and b after 6 months (August 2008) of fourth-line treament with panitumumab (case 2).\n==== Refs\nReferences\n1 The Meta-Analysis Group in Cancer Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis J Clin Oncol 2004 22 3766 3775 15365073 \n2 Tournigand C André T Achille E Lledo G Flesh M Mery-Mignard D Quinaux E Couteau C Buyse M Ganem G Landi B Colin P Louvet C de Gramont A FOLFIRI followed by FOLFOX6 or the reverse sequence in colorectal cancer: a randomized GERCOR study J Clin Oncol 2004 22 229 237 14657227 \n3 Hurwitz H Fehrenbacher L Novotny W Cartwright T Hainsworth J Heim W Berlin J Baron A Griffing S Holmgren E Ferrara N Fyfe G Rogers B Ross R Kabbinavar F Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med 2004 350 2335 2342 15175435 \n4 Folprecht G Seymour MT Saltz L Douillard JY Hecker H Stephens RJ Maughan TS Van Cutsem E Rougier P Mitry E Schubert U Köhne CH Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: combined analysis of 2,691 patients in randomized controlled trials J Clin Oncol 2008 26 1443 1451 18349394 \n5 Emmanouilides C Sfakiotaki G Androulakis N Kalbakis K Christophylakis C Kalykaki A Vamvakas L Kotsakis A Agelaki S Diamandidou E Touroutoglou N Chatzidakis A Georgoulias V Mavroudis D Souglakos J Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study BMC Cancer 2007 7 91 17537235 \n6 Cameron S Hünerbein D Mansuroglu T Armbrust T Scharf JG Schwörer H Füzesi L Ramadori G Response of the primary tumor in symptomatic and asymptomatic stage IV colorectal cancer to combined interventional endoscopy and palliative chemotherapy BMC Cancer 2009 9 218 19570230 \n7 Van Cutsem E Peeters M Siena S Humblet Y Hendlisz A Neyns B Canon JL Van Laethem JL Maurel J Richardson G Wolf M Amado RG Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer J Clin Oncol 2007 25 1658 1664 17470858 \n8 Amado RG Wolf M Peeters M Van Cutsem E Siena S Freeman DJ Juan T Sikorski R Suggs S Radinsky R Patterson SD Chang DD Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer J Clin Oncol 2008 26 1626 1634 18316791 \n9 Jonker DJ O'Callaghan CJ Karapetis CS Zalcberg JR Tu D Au HJ Berry SR Krahn M Price T Simer RJ Tebbutt NC van Hazel G Wierzbicki R Langer C Moore MJ Cetuximab for the treatment of colorectal cancer N Engl J Med 2007 357 2040 2048 18003960 \n10 Hecht JR Peeters M Van Cutsem E Berlin J Visonneau S Navale L Ruiz R Amado R Meropol NJ Safety and tolerability of panitumumab: a fully human monoclonal antibody, in patients with metastatic colorectal cancer Ann Oncol 2007 17 suppl 9 ix124 abstract 361P. \n11 Mitchell EP LaCouture M Shearer H Iannotti N Piperdi B Pillai MV Xu F Yassine M Updated results of STEPP, a phase II, open-label study of pre-emptive versus reactive skin toxicity treatment in metastatic colorectal cancer patients receiving panitumumab + FOLFIRI or irinotecan-only chemotherapy as second-line treatment Ann Oncol 2008 19 suppl 6 vi14 O-021.\n\n",
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"title": "Long-Lasting Tumor Response in Patients with Panitumumab Monotherapy for Chemorefractory Metastatic Colorectal Carcinoma - A Report of Two Cases.",
"title_normalized": "long lasting tumor response in patients with panitumumab monotherapy for chemorefractory metastatic colorectal carcinoma a report of two cases"
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"abstract": "OBJECTIVE\nThe aim of this study was to determine the safety and efficacy of Mitomycin C (MMC) infusion in a large cohort of advanced liver metastatic breast cancer patients (LMBC) and to determine factors influencing overall survival (OS).\n\n\nMETHODS\nWe retrospectively analysed LMBC patients, treated with MMC infusion between 2000 and 2017. Hepatic response was measured with baseline CT scans and first available CT scan after MMC infusion by RECIST 1.1 criteria. Adverse events were registered by the CTCAE version 5.0. OS and hepatic progression free survival (hPFS) were evaluated using Kaplan-Meier estimates. After univariable analysis, a stepwise forward multivariable (MV) prediction analysis was developed to select independent pre-treatment factors associated with OS.\n\n\nRESULTS\nWe included 176 patients with a total of 599 MMC infusions, mostly heavily pre-treated patients with a median time from diagnosis of MBC to MMC infusion of 36.9 months. RECIST evaluation of liver lesions (n = 132) showed a partial response rate of 15%, stable disease of 43% and progressive disease in 17%. Adverse events grade 3 and 4 were reported in 17.5%. Median PFS was 5.5 months and median OS was 7.8 months. Significant independent baseline predictors of worse OS included number of prior systemic chemotherapy lines, prior liver ablation, higher liver tumour burden and elevated levels of bilirubin and ALT.\n\n\nCONCLUSIONS\nMMC infusion is safe and effective in advanced LMBC patients. An increased number of prior therapies, a higher liver tumour burden and elevated levels of bilirubin and ALT were associated with a worse OS.",
"affiliations": "Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.;Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.;Department of Radiology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Department of Biostatistics and Statistical Bioinformatics, KU Leuven Universiteit Hasselt, Kapucijnenvoer 35, 3000, Leuven, Belgium.;Department of Radiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.;Department of General Medical Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Department of General Medical Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Department of General Medical Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Department of Radiology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. geert.maleux@uzleuven.be.",
"authors": "Aarts|B M|BM|;Klompenhouwer|E G|EG|;Dresen|R C|RC|;Laenen|A|A|;Beets-Tan|R G H|RGH|;Punie|K|K|;Neven|P|P|;Wildiers|H|H|;Maleux|G|G|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D016685:Mitomycin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-019-05254-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6806",
"issue": "176(3)",
"journal": "Breast cancer research and treatment",
"keywords": "Chemo resistant; Intra-arterial therapy; Liver metastases; Metastatic breast cancer; Mitomycin C infusion",
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic; D001943:Breast Neoplasms; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007261:Infusions, Intra-Arterial; D053208:Kaplan-Meier Estimate; D008111:Liver Function Tests; D008113:Liver Neoplasms; D008875:Middle Aged; D016685:Mitomycin; D011379:Prognosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "597-605",
"pmc": null,
"pmid": "31065871",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intra-arterial Mitomycin C infusion in a large cohort of advanced liver metastatic breast cancer patients: safety, efficacy and factors influencing survival.",
"title_normalized": "intra arterial mitomycin c infusion in a large cohort of advanced liver metastatic breast cancer patients safety efficacy and factors influencing survival"
} | [
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"abstract": "BACKGROUND Strongyloidiasis, caused by infection with Strongyloides stercoralis parasitic nematodes, is most prevalent in tropical regions of the world, such as South America, Southeast Asia, and sub-Saharan Africa, but its incidence has increased in nonendemic areas of the United States due to immigration. The majority of patients remain asymptomatic or have only mild gastrointestinal, respiratory, or dermatologic symptoms. Unrecognized strongyloidiasis can progress to Strongyloides hyperinfection syndrome, a highly fatal complication that can occur in response to immunosuppressive therapy. This rare complication is easily misdiagnosed because of its similar presentation to asthma or exacerbation of chronic obstructive pulmonary disease. CASE REPORT We report a case of worsening therapeutic response to systemic corticosteroids in an elderly Colombian man who presented with symptoms of acute exacerbation of asthma. His history was positive for residence in a region endemic to S. stercoralis, and he had undergone multiple hospitalizations over the past few years for pulmonary, gastrointestinal, and dermatologic complaints. Laboratory results were significant for increased eosinophilia, and chest radiography showed blunting of the left costophrenic angle. The patient was found to have S. stercoralis hyperinfection after parasitic larvae were detected in a bronchoalveolar lavage sample. Symptoms improved after a course of ivermectin, and the patient was subsequently discharged. CONCLUSIONS This unusual presentation of Strongyloides hyperinfection syndrome showcases the dangers of corticosteroid therapy in individuals with undiagnosed Strongyloides infection who present with a presumed diagnosis of asthma exacerbation. Clinicians should maintain a high level of suspicion when treating patients from S. stercoralis endemic regions presenting with pulmonary, gastrointestinal, and/or dermatologic symptoms. Ivermectin is the current standard of care for both asymptomatic and complicated strongyloidiasis.",
"affiliations": "Department of Pulmonary Medicine, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Pulmonary Medicine, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Pulmonary Medicine, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Pulmonary Medicine, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Surgery, St. Joseph's University Medical Center, Paterson, NJ, USA.",
"authors": "Salam|Reshad|R|;Sharaan|Ahmed|A|;Jackson|Stephanie M|SM|;Solis|Roberto A|RA|;Zuberi|Jamshed|J|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007559:Ivermectin",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.925221",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33347427\n10.12659/AJCR.925221\n925221\nArticles\nStrongyloides Hyperinfection Syndrome: A Curious Case of Asthma Worsened by Systemic Corticosteroids\nSalam Reshad ABCDEF1 Sharaan Ahmed ABCDEF1 Jackson Stephanie M. ABCDEF1 Solis Roberto A. E1 Zuberi Jamshed E2 \n1 Department of Pulmonary Medicine, St. Joseph’s University Medical Center, Paterson, NJ, U.S.A.\n\n2 Department of Surgery, St. Joseph’s University Medical Center, Paterson, NJ, U.S.A.\nCorresponding Author: Reshad Salam, e-mail: rsalam@sgu.eduAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n21 12 2020 \n21 e925221-1 e925221-6\n17 4 2020 11 8 2020 04 11 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 84-year-old\n\nFinal Diagnosis: Strongyloides hyperinfection syndrome\n\nSymptoms: Acute respiratory failure • dyspnea\n\nMedication: —\n\nClinical Procedure: Bronchoalveolar lavage\n\nSpecialty: Pulmonology\n\nObjective:\nUnusual clinical course\n\nBackground:\nStrongyloidiasis, caused by infection with Strongyloides stercoralis parasitic nematodes, is most prevalent in tropical regions of the world, such as South America, Southeast Asia, and sub-Saharan Africa, but its incidence has increased in nonendemic areas of the United States due to immigration. The majority of patients remain asymptomatic or have only mild gastrointestinal, respiratory, or dermatologic symptoms. Unrecognized strongyloidiasis can progress to Strongyloides hyperinfection syndrome, a highly fatal complication that can occur in response to immunosuppressive therapy. This rare complication is easily misdiagnosed because of its similar presentation to asthma or exacerbation of chronic obstructive pulmonary disease.\n\nCase Report:\nWe report a case of worsening therapeutic response to systemic corticosteroids in an elderly Colombian man who presented with symptoms of acute exacerbation of asthma. His history was positive for residence in a region endemic to S. stercoralis, and he had undergone multiple hospitalizations over the past few years for pulmonary, gastrointestinal, and dermatologic complaints. Laboratory results were significant for increased eosinophilia, and chest radiography showed blunting of the left costophrenic angle. The patient was found to have S. stercoralis hyperinfection after parasitic larvae were detected in a bronchoalveolar lavage sample. Symptoms improved after a course of ivermectin, and the patient was subsequently discharged.\n\nConclusions:\nThis unusual presentation of Strongyloides hyperinfection syndrome showcases the dangers of corticosteroid therapy in individuals with undiagnosed Strongyloides infection who present with a presumed diagnosis of asthma exacerbation. Clinicians should maintain a high level of suspicion when treating patients from S. stercoralis endemic regions presenting with pulmonary, gastrointestinal, and/or dermatologic symptoms. Ivermectin is the current standard of care for both asymptomatic and complicated strongyloidiasis.\n\nMeSH Keywords:\nGlucocorticoidsIvermectinNematode InfectionsStrongyloides stercoralisStrongyloidiasis\n==== Body\nBackground\nStrongyloides stercoralis is an intestinal nematode that can establish a chronic parasitic infection in the human host through its potential for autoinfection. The parasite can cause reinfection through its cyclical migratory pathway, which includes the gastrointestinal tract, vasculature, lungs, trachea, and esophagus.\n\nStrongyloidiasis is a common condition primarily found in tropical regions of the world, such as South America, Southeast Asia, and sub-Saharan Africa. The estimated prevalence is reported to be 100 million worldwide [1]. Although strongyloidiasis primarily occurs in underdeveloped countries, its incidence has increased in nonendemic areas of the United States due to immigration [2]. Presentation of S. stercoralis infection varies from asymptomatic to symptomatic with multisystem involvement. Most chronically infected patients remain asymptomatic, although a sizable minority can present with persistent abdominal, pulmonary, and dermatologic symptoms [1].\n\nIn patients with an underlying immunocompromised status or in patients undergoing immunosuppressive therapy (e.g., systemic glucocorticosteroids), unrecognized strongyloidiasis carries an increased risk for hyperinfection syndrome and disseminated strongyloidiasis. These conditions have a high mortality rate and represent the primary causes of death due to Strongyloides infection [1,3].\n\nPatients with hyperinfection syndrome may develop signs of acute dyspnea that mimic an exacerbation of asthma or chronic obstructive pulmonary disease (COPD) [4,5].\n\nWe present an unusual case of S. stercoralis hyperinfection syndrome mimicking acute asthma exacerbation, with pulmonary symptoms worsening upon glucocorticoid administration. We review the presentation, course, and treatment of this case to highlight the need for screening and preemptive treatment of strongyloidiasis in immigrants or travelers from endemic regions who present with respiratory symptoms.\n\nCase Report\nAn 84-year-old Colombian man who was a nonsmoker presented to the Emergency Department (ED) reporting a worsening shortness of breath and a productive cough with green-colored sputum. He reported having intermittent shortness of breath for the past 2 months. The patient had a past medical history of coronary artery disease, coronary artery bypass grafting, pacemaker implant, hypertension, dyslipidemia, and adult-onset asthma that was diagnosed several years earlier in his home country. The patient was not immunosuppressed or on any long-term immunosuppressive medications. Due to the worsening shortness of breath and increased sputum production, he decided to visit the ED. The patient arrived in the United States 7 years ago and had a remarkable history of multiple asthma exacerbations and hospitalizations since then. He did not see a respiratory specialist before his ED visit and thus clear information about his diagnosis was not available. The patient’s home medication for asthma consisted of combination therapy with an inhaled long-acting beta-adrenergic agonist, inhaled corticosteroids, and an oral leukotriene inhibitor. The patient’s admission history indicated multiple instances of asthma exacerbations; interestingly, at least one of those exacerbations occurred shortly after treatment with corticosteroids for respiratory distress. In addition, he received treatment 1 month earlier for a pruritic rash and acute pancreatitis of unknown etiology. These symptoms developed shortly after being treated with corticosteroids in the ED for asthma exacerbation. Oral prednisone at 40 mg daily for 5 days was prescribed for acute exacerbation of asthma at our ED about 1 week prior to presentation.\n\nSystemic review was negative for rash, abdominal pain, nausea, vomiting, diarrhea, or constipation. Physical examination on admission revealed a frail-appearing elderly man in moderate respiratory distress. His temperature was 36.9°C, and he had a pulse of 78 beats/min and a respiratory rate of 19 breaths/min. Bilateral expiratory wheezes and diffuse rhonchi were noted on physical examination, and no skin lesions or urticaria was observed.\n\nBased on laboratory testing, the patient’s hematocrit was 29.3%, the white blood cell count was 16.2×103/mm3 (59% segs, 14% bands, 10% lymphocytes, 7% monocytes, 7% eosinophils, 3% myelocytes), the platelet count was 381×103/mm3, and the absolute eosinophil count was 1100 cells/mm3. The patient experienced respiratory failure and developed significant respiratory distress. Oxygen saturation was measured at 89% on admission and was decreasing. Given the patient’s deteriorating condition, the decision was made to commence bi-level positive airway pressure (BiPAP). The patient was placed on BiPAP with FiO2 60%, inspiratory positive airway pressure 10 cmH2O, and expiratory positive airway pressure 5 cmH2O. Arterial blood gas analysis revealed a pH of 7.45, PaCO2 of 39 mmHg, PaO2 of 212 mmHg, and bicarbonate of 27.1 mmHg. The patient’s condition improved, and he was transitioned to nasal cannula, saturating at 93%. Chest radiography showed blunting of the left costophrenic angle, but it was negative for any focal infiltrates (Figure 1). This result combined with the laboratory finding of 14% bands left us unable to rule out a possible small pleural effusion with underlying pneumonia. The patient was diagnosed with acute asthma exacerbation and acute respiratory failure.\n\nTreatment consisted of intravenous (IV) methylprednisolone (40 mg daily), empiric antibiotic treatment with IV vancomycin (1000 mg) and IV piperacillin-tazobactam (3.375 g), combination therapy with nebulized short-acting beta-adrenergic agonist and nebulized corticosteroids, and an anticholinergic agent. Nevertheless, the patient continued to report worsening dyspnea and a productive cough over the next couple days. This unusual course prompted us to employ a more invasive approach.\n\nBronchoscopy was performed and revealed a normal nasopharynx/oropharynx, larynx, vocal cords, and subglottic space. The trachea was of normal caliber but appeared mildly inflamed. The carina was sharp. The tracheobronchial tree was examined to at least the first subsegmental level. Bronchial mucosa throughout appeared inflamed. Copious amounts of thick, mucoid secretions were found throughout the tracheobronchial tree, particularly on the left side. A mucus plug was obstructing the left lower lobe bronchi and was suctioned. Washings were obtained in the left upper lobe and in the left lower lobe and sent for cell count (differential and bacterial) and acid-fast bacilli (AFB), fungal, and viral analysis. The return was mucoid. Protected brushings were obtained in the lateral and posterior basal segments of the left lower lobe and sent for bacterial, AFB, and fungal analysis. There were no mucus plugs after washing, and no endobronchial lesions were seen in the visualized portion of the airway.\n\nBronchial washings exhibited S. stercoralis larvae under microscopy (Figure 2), which suggested Strongyloides infection. The patient was consequently prescribed oral ivermectin 9 mg (200 μg/kg) daily for 2 weeks by the infectious disease team and weaned off systemic corticosteroids. The patient reported feeling better in the following days with improvement of his cough as well as decreased sputum production. He was discharged with instructions to complete the oral ivermectin course.\n\nDiscussion\nStrongyloidiasis is a parasitic infection caused by the multicellular helminth S. stercoralis of the phylum Nematoda. There are over 50 species of Strongyloides, but the most common species in human infections is S. stercoralis. This species has a worldwide distribution and is found mostly in rural regions of tropical and subtropical countries. In the United States, some southeastern states are endemic areas; however, sporadic cases are reported throughout the United States, with patients mostly being immigrants, travelers, and military personnel with a travel history to endemic regions of the world [2,6,7].\n\nChronic strongyloidiasis is characterized by the parasite’s ability to autoinfect the human host and remain undetected for decades [5]. Figure 3 shows the parasitic cycle of the S. stercoralis nematode [8]. Strongyloides infection is established initially through direct skin penetration by the infective filariform larvae present in contaminated soil [1]. After entering the skin, the larvae travel via the bloodstream to the alveoli in the lungs. The migratory larvae in the lungs cause the pulmonary symptoms, which are often misdiagnosed as new-onset asthma or an exacerbation of asthma or COPD [5,6,9,10]. From the lungs, the larvae ascend the trachea and are eventually swallowed and descend down the esophagus into the gastrointestinal tract. Molting of the infective filariform larvae into the adult parthenogenetic female form allows them to produce eggs that are either excreted or remain in the gastrointestinal tract. The eggs then hatch into the noninvasive and noninfectious rhabditiform larvae [5]. These rhabditiform larvae can transform into filariform larvae, which have the ability to penetrate the intestinal mucosa and restart the parasitic cycle [6]. Our patient was from Colombia, a country where S. stercoralis is endemic. Thus, it is likely that he was infected before arrival to the United States.\n\nChronic infection by S. stercoralis can be asymptomatic or present with cutaneous, pulmonary, or gastrointestinal symptoms [1,6]. Gastrointestinal symptoms include diarrhea, abdominal discomfort, nausea, and anorexia [1,5,6]. Dermatologic manifestations of strongyloidiasis include pruritus or a pathognomonic rash called larva currens, which is an urticarial wheal with a tortuous track created by migrating larvae [6,10]. Pulmonary symptoms include cough, shortness of breath, wheezing, and hemoptysis [1,4,6]. These symptoms can mimic acute exacerbation of COPD or asthma [9]. Some of these symptoms were apparent in our patient’s history of dyspnea, cough, dermal pruritus, and acute pancreatitis. The patient’s history of asthma might actually have been an overlooked indicator of strongyloidiasis, which was erroneously attributed to adult-onset asthma.\n\nAcute pancreatitis is a rare complication of Strongyloides hyperinfection syndrome, with only 5 prior cases being reported in the literature [11]. The exact mechanism has not been established, but it has been theorized that inflammation of the duodenal ampulla and pancreatic duct plays a role in its pathogenesis [11]. As stated above, our patient had an episode of acute pancreatitis that developed shortly after treatment of respiratory distress with corticosteroids. A possible explanation is that the glucocorticoids caused immunosuppression, which then incited hyperinfection leading to acute pancreatitis. However, this possibility cannot be proved without serology or stool samples taken at the time.\n\nBecause the symptoms of strongyloidiasis are nonspecific and the disease has a low incidence in the United States, the diagnosis can be challenging. This circumstance explains why there is a delay in the diagnosis of chronic strongyloidiasis of about 5 years in the United States [5].\n\nThe worsening of pulmonary symptoms in our patient could be explained by hyperinfection brought on by the systemic glucocorticoids he had been prescribed a week prior. Hyperinfection syndrome involves the phenomena of accelerated autoinfection and increased parasite load [1,4,10]. Autoinfection and hyperinfection are distinguished by the development or exacerbation of gastrointestinal and pulmonary symptoms and an increase in the number of larvae found in sputum or stool samples [10]. These phenomena differ from disseminated infection, which occurs when larvae migrate away from the organs normally involved in the autoinfection cycle to infect additional organ systems such as the brain and skin [1,4,10].\n\nHyperinfection or disseminated strongyloidiasis can occur in individuals who are immunocompromised or those undergoing immunosuppressive therapy. Such situations include steroid therapy, chemotherapy, HIV or HTLV-1 infection, organ transplants, or hematologic malignancy [9,10]. Disseminated strongyloidiasis has a high mortality rate (up to 87%) and is commonly the cause of death in chronic Strongyloides infection [1,3]. The complications of dissemination and hyperinfection have been well documented and are accompanied by a high mortality rate if left untreated [1,4,6,9,10].\n\nComplications include disseminated bacterial and fungal infections, septicemia, pneumonia, meningitis, paralytic ileus, and mucosal ulceration [1,9]. Chronic strongyloidiasis has also been associated with reactive arthritis, nephrotic syndrome, chronic malabsorption duodenal obstruction, and hepatic lesions [10]. Penetration of the mucosal wall by a large number of infective filariform larvae introduces gut bacteria to the bloodstream. The larvae are also able to carry bacteria that are linked to bacterial septicemia such as Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas species, Enterococcus faecalis, Candida species, and group D streptococci [9,10]. It is therefore crucial for clinicians to be aware of the possibility of Strongyloides infection in patients with the aforementioned symptoms who have ever visited endemic regions. Corticosteroid use carries the greatest risk of hyperinfection syndrome, and disseminated Strongyloides infection has been reported as early as 1 week after corticosteroid initiation [10]. Some reports encourage screening patients with possible exposure to the parasite before corticosteroid or immunosuppressive treatment is initiated to prevent severe infection [6,12]. In a cross-sectional study by Ostera et al. [13], a combined enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) diagnostic technique detected a prevalence of 5% in a sample of 117 immigrants from Latin American countries residing in Washington, DC. This result highlights the need for screening of individuals from endemic regions [13].\n\nEosinophilia is a common presentation in people with chronic strongyloidiasis; for example, our patient showed an increase in eosinophil count, with an absolute count of 1100 cells/mm3 [4]. Interestingly, an absence of eosinophilia is associated with a worse prognosis in strongyloidiasis [14]. Other studies have reported a similar absence of eosinophilia, possibly due to suppression of eosinophils caused by administration of systemic corticosteroids [6]. In a systematic review of case reports of 244 cases of hyperinfection syndrome and dissemination, only 22.4% of cases were found to have reported eosinophilia [12]. In addition, Newberry et al. [4] conducted a retrospective study in which they analyzed chart data of patients with complicated Strongyloides infection in 2 metropolitan hospitals in Minnesota. The study included 9 patients who had emigrated from Southeast Asia to the United States prior to presentation. Only 2 of the 9 patients had increased absolute eosinophil counts >500 cells/L [4]. Therefore, a strong suspicion must be maintained for S. stercoralis infection even in the absence of an increase in the eosinophil count.\n\nStrongyloides infection can be diagnosed using multiple modalities. Some methods include microscopic examination of samples obtained through bronchoalveolar lavage, bronchial brushings, lung biopsies, or stool samples [6]. However, a single stool examination was found to have a specificity of only 75.9%, which increased to 92% when 3 stool samples were examined [9]. Detection of larvae in hyperinfection syndrome or dissemination is made easier by the increased parasite load [1]. Less laborious and time-intensive techniques are being developed and might offer a more reliable diagnostic potential. These include real-time PCR, ELISA, and luciferase immunoprecipitation systems, but these tests have limitations due to cross-reactivity with other parasitic infections and the inability to distinguish between current and past infections [1,6].\n\nOur patient’s chest X-ray showed blunting of the left costophrenic angle, consistent with the abnormal radiographic chest findings seen in most patients. However, normal chest radiographs have also been reported [6]. Radiological findings of pulmonary strongyloidiasis can present as focal or bilateral pulmonary infiltrates, lung consolidation, lung cavitation, acute respiratory distress syndrome, mediastinal lymphadenopathy, or pleural effusion [1,15].\n\nElimination of S. stercoralis is a challenge due the relative resistance of the infectious form of the larvae to antiparasitic agents [6]. Ivermectin is widely accepted to be the current criterion standard due to its superior efficacy and tolerability [1,10,12]. Consequently, the World Health Organization has officially designated ivermectin as one of the essential drugs for the treatment of strongyloidiasis [1]. However, there is currently no consensus on the treatment duration or dose of ivermectin [12]. Some studies have reported 200 μg/kg/day to be an effective ivermectin dosage [9,16]. Hyperinfection syndrome is considered a medical emergency, and medication should be started immediately if clinical evidence suggests the diagnosis. Although there is no established treatment regimen for hyperinfection syndrome, ivermectin for a minimum of 2 weeks is considered the de facto treatment [9].\n\nOur patient received oral ivermectin at 200 μg/kg/day for 2 weeks as recommended by the infectious disease team, and he was weaned off systemic glucocorticosteroids. This drug regimen was intended to ensure that all remaining infectious larvae were eliminated and to prevent the cycle of endogenous reinfection. Although stool ova and parasite testing would have been useful to strengthen the diagnosis and confirm clearance of infection, it was not performed after diagnosis in this case.\n\nThiabendazole and albendazole are alternatives that can be used if ivermectin is not available. Thiabendazole efficacy is limited by a high relapse rate and an unfavorable adverse-effect profile including gastrointestinal symptoms, pruritus, headache, dizziness, visual disturbances, and neuropsychiatric symptoms [1,6,16]. Albendazole is an acceptable alternative in patients who have accompanying high levels of Loa loa microfilaremia because of the risk of encephalopathy when treated with ivermectin [10].\n\nConclusions\nClinicians should employ a high level of caution when administering glucocorticoids for symptoms of an asthma exacerbation in patients with a history of travel or prior residence in an area endemic for S. stercoralis. Possible complications include Strongyloides hyperinfection syndrome and dissemination, both of which can be fatal. Screening efforts should be encouraged in those at risk before commencing immunosuppressive treatment. Ivermectin is the current standard of care for both asymptomatic and complicated strongyloidiasis.\n\nFigure 1. Posteroanterior view of the patient’s chest showing the blunting of the left lateral costophrenic angle.\n\nFigure 2. Bronchial lavage examination and gram stain showing larva of Strongyloides stercoralis (original magnification, ×100).\n\nFigure 3. This image depicts the various stages in the life cycle of the Strongyloides stercoralis nematode in the human host [8].\n==== Refs\nReferences:\n1. Ericsson CD Steffen R Siddiqui AA Berk SL Diagnosis of Strongyloides stercoralis infection Clin Infect Dis 2001 33 7 1040 47 11528578 \n2. Vasquez-Rios G Pineda-Reyes R Ruiz EF Strongyloides stercoralis infection after the use of emergency corticosteroids: A case report on hyper-infection syndrome J Med Case Rep 2019 13 1 121 31030665 \n3. Muennig P Pallin D Challah C Khan K The cost-effectiveness of ivermectin vs . albendazole in the presumptive treatment of strongyloidiasis in immigrants to the United States Epidemiol Infect 2004 132 6 1055 56 15635962 \n4. Newberry AM Williams DM Stauffer WM Strongyloides hyperinfection presenting as acute respiratory failure and gram-negative sepsis Chest 2005 128 5 3681 84 16304332 \n5. Junior KN Zaman R Zaman MH Zaman T Twenty-five years of chronic strongyloidiasis in an immigrant Clin Med Insights Case Rep 2017 10 1179547616684828 28469498 \n6. Mokhlesi B Shulzhenko O Garimella PS Pulmonary strongyloidiasis: The varied clinical presentations Clin Pulm Med 2004 11 1 6 13 20111672 \n7. Barros N Montes M Infection and hyperinfection with Strongyloides stercoralis : Clinical presentation, etiology of disease, and treatment options Curr Trop Med Rep 2014 1 223 28 \n8. Public Health Image Library (PHIL) Life cycle of Strongyloides stercoralis Public-use data file and documentation 2020. https://phil.cdc.gov/Detailsaspx?pid=5223 . \n9. Liu H Hsu J Chang K Strongyloides stercoralis hyperinfection presenting with symptoms mimicking acute exacerbation of chronic obstructive pulmonary disease J Chin Med Assoc 2009 72 8 442 45 19687002 \n10. Mejia R Nutman TB Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis Curr Opin Infect Dis 2012 25 4 458 63 22691685 \n11. Makker J Balar B Niazi M Daniel M Strongyloidiasis: A case with acute pancreatitis and a literature review World J Gastroenterol 2015 21 11 3367 75 25805946 \n12. Buonfrate D Requena-Mendez A Angheben A Severe strongyloidiasis: A systematic review of case reports BMC Infect Dis 2013 13 78 23394259 \n13. Ostera G Blum J Cornejo C Strongyloidiasis in Latin American immigrants: A pilot study J Helminthol 2017 91 2 262 66 27121364 \n14. Lim S Katz K Krajden S Complicated and fatal Strongyloides infection in Canadians: Risk factors, diagnosis and management CMAJ 2004 171 5 479 84 15337730 \n15. Dogan C Gayaf M Ozsoz A Pulmonary Strongyloides stercoralis infection Respir Med Case Rep 2014 11 12 15 26029521 \n16. Suputtamongkol Y Premasathian N Bhumimuang K Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis PLoS Negl Trop Dis 2011 5 5 e1044 21572981\n\n",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000818:Animals; D001249:Asthma; D006801:Humans; D007559:Ivermectin; D008297:Male; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis",
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"pubdate": "2020-12-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21572981;20111672;19687002;15635962;26029521;28469498;11528578;22691685;25805946;27121364;16304332;15337730;31030665;23394259",
"title": "Strongyloides Hyperinfection Syndrome: A Curious Case of Asthma Worsened by Systemic Corticosteroids.",
"title_normalized": "strongyloides hyperinfection syndrome a curious case of asthma worsened by systemic corticosteroids"
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... |
{
"abstract": "Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786.",
"affiliations": "Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Unité Hémopathies Lymphoïdes, Créteil, France.;Service d'Hématologie Clinique, Hospices Civils de Lyon, Pierre-Bénite, and Université Lyon 1, Lyon, France.;Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France.;Département de Médecine Nucléaire, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France.;Service d'Hématologie Clinique, Hospices Civils de Lyon, Pierre-Bénite, and Université Lyon 1, Lyon, France.;Département d'Hématologie Clinique, Centre Hospitalo-Universitaire de Montpellier, Unité Mixte de Recherche-Centre National de Recherche Scientifique 5535, Université de Montpellier, Montpellier, France.;Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France.;Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France.;Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France.;Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland.;Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland.;Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France.;Service d'Hématologie, Centre Hospitalier Universitaire, Angers, France.;Service d'Hématologie, Centre Hospitalier Universitaire, Reims, France.;Service d'Hématologie, Institut Paoli-Calmette, Marseille, France.;Service d'Hématologie, Centre Hospitalier, Chalon, France.;Service de Médecine Nucléaire, Centre de Lutte Contre le Cancer Becquerel, Rouen, France.;Université de Nantes, Center Hospitalier Universitaire Nantes, Département de Pathologie, INSERM Centre de Recherche en Cancérologie et Immunologie Nantes Angers, Nantes, France.;Département de Pathologie, Hôpital Haut-Lévêque, Pessac, INSERM U1053, Université de Bordeaux, Bordeaux, France.;Service d'Hématologie, Centre Hospitalier Universitaire, Dijon, France.;Service d'Hématologie, Centre Hospitalier Universitaire, Clermont Ferrand, France.;Service d'Hématologie, Centre Hospitalier Universitaire, Grenoble, France.;Département d'Hématologie, Centre Henri Becquerel, Rouen, France; and.;Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France.;LYSA Image, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Institut de Pathologie, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland.;Université Paris Est Créteil, INSERM, Institut Médical de Recherche Biomédicale, Créteil, France.;Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Unité Hémopathies Lymphoïdes, Créteil, France.",
"authors": "Lemonnier|François|F|;Safar|Violaine|V|;Beldi-Ferchiou|Asma|A|;Cottereau|Anne-Ségolène|AS|;Bachy|Emmanuel|E|;Cartron|Guillaume|G|;Fataccioli|Virginie|V|;Pelletier|Laura|L|;Robe|Cyrielle|C|;Letourneau|Audrey|A|;Missiaglia|Edoardo|E|;Fourati|Slim|S|;Moles-Moreau|Marie-Pierre|MP|;Delmer|Alain|A|;Bouabdallah|Reda|R|;Voillat|Laurent|L|;Becker|Stéphanie|S|;Bossard|Céline|C|;Parrens|Marie|M|;Casasnovas|Olivier|O|;Cacheux|Victoria|V|;Régny|Caroline|C|;Camus|Vincent|V|;Delfau-Larue|Marie-Hélène|MH|;Meignan|Michel|M|;de Leval|Laurence|L|;Gaulard|Philippe|P|;Haioun|Corinne|C|",
"chemical_list": "D000069283:Rituximab; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2020003081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "5(2)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D000077269:Lenalidomide; D016399:Lymphoma, T-Cell; D008875:Middle Aged; D011446:Prospective Studies; D000069283:Rituximab",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "539-548",
"pmc": null,
"pmid": "33496747",
"pubdate": "2021-01-26",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29398449;24584070;31471376;24345752;27841873;21723201;30410035;20572046;27956631;23731832;28082343;25355245;8778336;23161606;19961485;24413734;22371178;18626005;22216861;25113753;26045291;28337768;24413737;30952970;28157189;30172345;22215888;25736312;17242396;22915641;30279227;22760778;17284527;25135992;14645001;28459613;26787236;30670535;27369867;24570094;8141877",
"title": "Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma.",
"title_normalized": "integrative analysis of a phase 2 trial combining lenalidomide with chop in angioimmunoblastic t cell lymphoma"
} | [
{
"companynumb": "FR-CELGENEUS-FRA-20210201513",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Tuberculous ventriculitis is an inflammatory infection of the ventricular system of the brain, and is caused by Mycobacterium tuberculosis. We herein present the case of an immunocompromised patient with brain tuberculomas who developed ventriculitis during treatment. The patient was successfully treated with a high dose of steroid, long-term antituberculosis drugs, and aggressive supportive care.",
"affiliations": "Department of Infectious Diseases, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Infectious Diseases Research Center, AJA University of Medical Sciences, Tehran, Iran. Electronic address: dr.saeed.meigooni@gmail.com.;Department of Infectious Diseases, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.;Department of Infectious Diseases, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.",
"authors": "Vaziri|Siavash|S|;Soleiman-Meigooni|Saeed|S|;Rajabi|Jalil|J|;Asgari|Ali|A|",
"chemical_list": "D000995:Antitubercular Agents; D013256:Steroids",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5531",
"issue": "5(2)",
"journal": "International journal of mycobacteriology",
"keywords": "Tuberculoma; Tuberculosis; Ventriculitis",
"medline_ta": "Int J Mycobacteriol",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D058565:Cerebral Ventriculitis; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis; D013256:Steroids; D020306:Tuberculosis, Central Nervous System",
"nlm_unique_id": "101615660",
"other_id": null,
"pages": "231-4",
"pmc": null,
"pmid": "27242238",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tuberculous ventriculitis: A rare complication of central nervous system tuberculosis.",
"title_normalized": "tuberculous ventriculitis a rare complication of central nervous system tuberculosis"
} | [
{
"companynumb": "IR-BAUSCH-BL-2020-005474",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPerioperative oncologic treatments provide a survival benefit for junctional and gastric adenocarcinoma (JGA) and esophageal cancer (EC). Whether neoadjuvant therapy toxicity (NTT) correlates with increased perioperative risk remains unclear. We aimed to evaluate the impact of grade III/IV NTT on postoperative and oncologic outcomes in resected upper gastrointestinal malignancies.\n\n\nMETHODS\nA multicenter retrospective analysis was performed on consecutive patients who benefited from neoadjuvant chemo(radio)therapy followed by surgery between 1997 and 2010 for JGA (first cohort, n = 653) and for EC (second cohort, n = 640). Data between patients who experienced NTT were compared to those who did not.\n\n\nRESULTS\nNTT was associated with higher postoperative mortality after resection of JGA (P = 0.001) and after esophagectomy (P < 0.001), more non-R0 resections (JGA P = 0.019, EC P = 0.024), a decreased administration of adjuvant treatment among the JGA cohort (P = 0.012), and higher surgical morbidity (JGA P = 0.005, EC P = 0.020). Median survival was reduced in patients who experienced NTT in both cohorts (JGA P = 0.018, EC P = 0.037). After adjustment on confounding variables, NTT was independently associated with postoperative mortality in both cohorts (P ≤ 0.007).\n\n\nCONCLUSIONS\nNTT is a predictor of postoperative mortality, correlates with higher postoperative morbidity, and negatively affects oncologic outcomes for upper gastrointestinal carcinomas.",
"affiliations": "Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France.;Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France.;Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France.;Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France.;Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France.;Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France.;Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France. christophe.mariette@chru-lille.fr.",
"authors": "Robb|William B|WB|;Messager|Mathieu|M|;Gronnier|Caroline|C|;Tessier|Williams|W|;Hec|Flora|F|;Piessen|Guillaume|G|;Mariette|Christophe|C|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1245/s10434-015-4423-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1068-9265",
"issue": "22(11)",
"journal": "Annals of surgical oncology",
"keywords": null,
"medline_ta": "Ann Surg Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D059186:Chemoradiotherapy, Adjuvant; D003967:Diarrhea; D019583:Dose Fractionation, Radiation; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D004943:Esophagogastric Junction; D005260:Female; D005743:Gastrectomy; D017052:Hospital Mortality; D006801:Humans; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D052016:Mucositis; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D015996:Survival Rate; D013921:Thrombocytopenia; D016896:Treatment Outcome; D014839:Vomiting; D055815:Young Adult",
"nlm_unique_id": "9420840",
"other_id": null,
"pages": "3632-9",
"pmc": null,
"pmid": "25676845",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "High-Grade Toxicity to Neoadjuvant Treatment for Upper Gastrointestinal Carcinomas: What is the Impact on Perioperative and Oncologic Outcomes?",
"title_normalized": "high grade toxicity to neoadjuvant treatment for upper gastrointestinal carcinomas what is the impact on perioperative and oncologic outcomes"
} | [
{
"companynumb": "FR-ROCHE-1639307",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nAdult-onset still disease (AOSD) and hemophagocytic syndrome (HPS) are two inflammatory diseases with very similar clinical manifestations. HPS is one of the most serious complications of AOSD and its risk of death is very high. It is difficult to identify HPS early in patients with AOSD, but early identification and proper treatment directly affects the prognosis.\n\n\nMETHODS\nA 39-year-old male showed a high spiking fever and myalgia. Laboratory data revealed elevated white blood cell, serum ferritin, and neutrophil percentage. However, his fever failed to relieve after a clear diagnosis of AOSD caused by pulmonary infection and treatment by antibiotics and corticosteroids; further laboratory data showed elevated serum ferritin, C-reactive protein, erythrocyte sedimentation rate and triglyceride, as well as liver abnormalities. Bone marrow smear showed hemophagocytosis. Secondary HPS was definitely diagnosed. The high fever disappeared and the laboratory findings returned to normal values after treatment by high-dose intravenous methylprednisolone and methotrexate.\n\n\nCONCLUSIONS\nFor AOSD patients with high suspicion of HPS, active examination needs to be considered for early diagnosis, and timely using of adequate amount of corticosteroids is the key to reducing risk of HPS death.",
"affiliations": "Beijing University of Chinese Medicine, Beijing 100029, China.;Rheumatism and Immunology Department, Seventh Medical Center of PLA General Hospital, Beijing 100700, China.;Rheumatism and Immunology Department, Seventh Medical Center of PLA General Hospital, Beijing 100700, China. jiangdx1@163.com.",
"authors": "Wang|Gui|G|;Jin|Xiao-Rong|XR|;Jiang|De-Xun|DX|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v8.i3.560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2307-8960",
"issue": "8(3)",
"journal": "World journal of clinical cases",
"keywords": "Adult-onset still disease; Case report; Hemophagocytic syndrome; Hemophagocytosis",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "560-567",
"pmc": null,
"pmid": "32110667",
"pubdate": "2020-02-06",
"publication_types": "D002363:Case Reports",
"references": "22536541;29742693;25386930;16937360;29983666;22272648;18782855;25767156;30214327;16540551;24290661;24657513;7668903;14558048;20075703;30992265;25183244;1578458",
"title": "Successful treatment of adult-onset still disease caused by pulmonary infection-associated hemophagocytic lymphohistiocytosis: A case report.",
"title_normalized": "successful treatment of adult onset still disease caused by pulmonary infection associated hemophagocytic lymphohistiocytosis a case report"
} | [
{
"companynumb": "CN-SGP-000011",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nWith the introduction of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel therapy for unresectable pancreatic cancer, erlotinib plus gemcitabine therapy is now occasionally used as late-line therapy. This study investigates outcomes of treatment with erlotinib plus gemcitabine for unresectable pancreatic cancer.\n\n\nMETHODS\nWe retrospectively analysed consecutive patients with unresectable pancreatic cancer treated with erlotinib plus gemcitabine as the third or later-line chemotherapy between March 2014 and December 2020 in our hospital.\n\n\nRESULTS\nA total of 56 patients were included (third line/fourth or later line = 42/14). All patients were previously treated with gemcitabine plus nab-paclitaxel and 45 patients were previously treated with modified FOLFIRINOX. The median progression-free survival (PFS) and overall survival (OS) were 1.6 and 4.6 months, respectively. The disease control rate was 21.4%. Performance status, modified Glasgow prognostic score and carcinoembryonic antigen level were independently associated with survival. Our prognostic model using these parameters could classify patients into good (n = 32) and poor (n = 24) prognostic groups. The median PFS and OS were longer in good than in poor prognostic group, but the difference in PFS was very small (PFS: 2.1 vs. 1.4 months, P = 0.01. OS: 6.8 vs. 2.4 months, P < 0.01). Interstitial pneumonia occurred in one patient (1.8%).\n\n\nCONCLUSIONS\nBenefits of erlotinib plus gemcitabine as late-line chemotherapy were limited, particularly with respect to PFS. Development of more effective third-line treatment options is desirable in the future.",
"affiliations": "Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.",
"authors": "Mie|Takafumi|T|0000-0002-7561-5558;Sasaki|Takashi|T|;Takeda|Tsuyoshi|T|0000-0002-0786-8166;Okamoto|Takeshi|T|;Mori|Chinatsu|C|;Furukawa|Takaaki|T|;Yamada|Yuto|Y|;Kasuga|Akiyoshi|A|;Matsuyama|Masato|M|;Ozaka|Masato|M|;Sasahira|Naoki|N|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D000069347:Erlotinib Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyab091",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "51(9)",
"journal": "Japanese journal of clinical oncology",
"keywords": "erlotinib plus gemcitabine; pancreatic cancer; prognostic factor",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D006801:Humans; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "1416-1422",
"pmc": null,
"pmid": "34128055",
"pubdate": "2021-08-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment outcomes of erlotinib plus gemcitabine as late-line chemotherapy in unresectable pancreatic cancer.",
"title_normalized": "treatment outcomes of erlotinib plus gemcitabine as late line chemotherapy in unresectable pancreatic cancer"
} | [
{
"companynumb": "JP-ACCORD-229923",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nPALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients.\n\n\nMETHODS\nThe induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm.\n\n\nRESULTS\nIn the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n = 33) or the observational arm (n = 33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (P = .028). The multivariate Cox model indicated that del17p (P = .006) and elevated beta-2-microglobulin (P = .015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (P = .013) significantly decreased it; maintenance therapy with rituximab (P < .0001) significantly decreased the HR of disease progression.\n\n\nCONCLUSIONS\nThe study confirmed the high efficacy and acceptable safety profile of induction therapy with RCC and maintenance therapy with rituximab in previously untreated patients with CLL.",
"affiliations": "Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Lodz, Poland.;Department of Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Lodz, Poland.;Department of Hematology, Jagiellonian University, Kraków, Poland.;Department of Hematology, Jagiellonian University, Kraków, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.;Department of Hematology, Medical University of Białystok, Białystok, Poland.;Department of Hematology, Medical University of Białystok, Białystok, Poland.;Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.;Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.;City Clinical Hospital No. 9, Minsk, Belarus.;Roche Poland, Warsaw, Poland.;Department of Experimental Hematology, Copernicus Memorial Hospital, Medical University of Lodz, Lodz, Poland.",
"authors": "Robak|Tadeusz|T|http://orcid.org/0000-0003-1744-4145;Błoński|Jerzy|J|;Skotnicki|Aleksander Bartłomiej|AB|;Piotrowska|Magdalena|M|;Wróbel|Tomasz|T|;Rybka|Justyna|J|;Kłoczko|Janusz|J|;Bołkun|Łukasz|Ł|;Budziszewska|Bożena Katarzyna|BK|;Walczak|Urszula|U|;Uss|Anatoly|A|;Fidecka|Marta|M|;Smolewski|Piotr|P|",
"chemical_list": "D015415:Biomarkers; D017338:Cladribine; D000069283:Rituximab; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "100(5)",
"journal": "European journal of haematology",
"keywords": "RCC regimen; chronic lymphocytic leukemia; first line; maintenance; rituximab",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D017338:Cladribine; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D060046:Maintenance Chemotherapy; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "465-474",
"pmc": null,
"pmid": "29427355",
"pubdate": "2018-05",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial.",
"title_normalized": "rituximab cladribine and cyclophosphamide rcc induction with rituximab maintenance in chronic lymphocytic leukemia palg cll4 ml21283 trial"
} | [
{
"companynumb": "PL-ROCHE-2110441",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
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"abstract": "Interstitial lung disease (ILD) accompanied by anti-melanoma differentiation-associated gene 5 (anti-MDA-5)-positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti-MDA-5-positive DM patients with ILD.\n\n\n\nAdult Japanese patients with new-onset anti-MDA-5-positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high-dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6-month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti-MDA-5-positive DM patients with ILD who received step-up treatment (high-dose GC and stepwise addition of immunosuppressant). Secondary end points were 12-month survival rate, adverse events, and changes in laboratory data.\n\n\n\nThe combined immunosuppressive regimen group showed significantly higher 6-month survival rates than the step-up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti-MDA-5 titers, serum ferritin levels, vital capacity, and chest high-resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step-up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks.\n\n\n\nA combined immunosuppressive regimen is effective for anti-MDA-5-positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment.",
"affiliations": "Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.;Kitano Hospital, Osaka, Japan.;Kitano Hospital, Osaka, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Hiroshima University Hospital, Hiroshima, Japan.;Hiroshima University Hospital, Hiroshima, Japan.;Hiroshima University Hospital, Hiroshima, Japan.;Tenri Hospital, Tenri, Japan.;Tenri Hospital, Tenri, Japan.;Osaka Red Cross Hospital, Osaka, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.",
"authors": "Tsuji|Hideaki|H|;Nakashima|Ran|R|0000-0001-6247-0647;Hosono|Yuji|Y|;Imura|Yoshitaka|Y|;Yagita|Masato|M|;Yoshifuji|Hajime|H|;Hirata|Shintaro|S|0000-0002-2474-9943;Nojima|Takaki|T|;Sugiyama|Eiji|E|;Hatta|Kazuhiro|K|;Taguchi|Yoshio|Y|;Katayama|Masaki|M|0000-0002-0773-7238;Tanizawa|Kiminobu|K|;Handa|Tomohiro|T|;Uozumi|Ryuji|R|0000-0002-9546-9869;Akizuki|Shuji|S|;Murakami|Kosaku|K|;Hashimoto|Motomu|M|;Tanaka|Masao|M|;Ohmura|Koichiro|K|;Mimori|Tsuneyo|T|",
"chemical_list": "D001323:Autoantibodies; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/art.41105",
"fulltext": null,
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"issn_linking": "2326-5191",
"issue": "72(3)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D003520:Cyclophosphamide; D003882:Dermatomyositis; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D000072640:Interferon-Induced Helicase, IFIH1; D007564:Japan; D017563:Lung Diseases, Interstitial; D008297:Male; D011446:Prospective Studies; D015996:Survival Rate; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "488-498",
"pmc": null,
"pmid": "31524333",
"pubdate": "2020-03",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multicenter Prospective Study of the Efficacy and Safety of Combined Immunosuppressive Therapy With High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Diseases Accompanied by Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis.",
"title_normalized": "multicenter prospective study of the efficacy and safety of combined immunosuppressive therapy with high dose glucocorticoid tacrolimus and cyclophosphamide in interstitial lung diseases accompanied by anti melanoma differentiation associated gene 5 positive dermatomyositis"
} | [
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"abstract": "Anti-phospholipid syndrome (APS) is an autoimmune prothrombotic disorder characterised by the predisposition to venous and/or arterial thrombosis and obstetric morbidity. Management of APS centres on attenuating the procoagulant state whilst balancing the risks of anticoagulant therapy. Cases of recurrent thromboses and obstetric complications occur despite optimum therapy. Alternative therapies for refractory cases are subject to disparity among clinicians due to the current lack of clinical evidence present. This review aims to address the current management strategies for refractory thrombotic and obstetric cases and future therapeutic interventions. The role and current clinical evidence of using long term low molecular weight heparin (LMWH) as an alternative to warfarin therapy for refractory thromboses is evaluated. Potential alternatives for thromboses including statins, hydroxychloroquine, Rituximab are reviewed as well as the additional avenues to target in the future as the pathogenic mechanisms of APS are unveiled. The optimal management for refractory obstetric APS cases is subject to controversy. This review focuses and assesses the current evidence for the uses of low dose prednisolone, intravenous immunoglobulin and hydroxycholoroquine in obstetric cases. The treatment modalities for the management of refractory APS require further clinical evidence.",
"affiliations": "Lupus Research Unit, The Rayne Institute, King's College London School of Medicine, London, UK.",
"authors": "Scoble|Tina|T|;Wijetilleka|Sonali|S|;Khamashta|Munther A|MA|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D006495:Heparin, Low-Molecular-Weight; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016756:Immunoglobulins, Intravenous; D000069283:Rituximab; D006886:Hydroxychloroquine; D014859:Warfarin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.autrev.2011.04.030",
"fulltext": null,
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"issn_linking": "1568-9972",
"issue": "10(11)",
"journal": "Autoimmunity reviews",
"keywords": null,
"medline_ta": "Autoimmun Rev",
"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D016736:Antiphospholipid Syndrome; D002986:Clinical Trials as Topic; D019317:Evidence-Based Medicine; D005260:Female; D005313:Fetal Death; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D006886:Hydroxychloroquine; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016756:Immunoglobulins, Intravenous; D011247:Pregnancy; D000069283:Rituximab; D055502:Secondary Prevention; D013927:Thrombosis; D014859:Warfarin",
"nlm_unique_id": "101128967",
"other_id": null,
"pages": "669-73",
"pmc": null,
"pmid": "21558021",
"pubdate": "2011-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Management of refractory anti-phospholipid syndrome.",
"title_normalized": "management of refractory anti phospholipid syndrome"
} | [
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"activesubstancename": "RIVAROXABAN"
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"abstract": "Ventricular standstill (VS) is a potentially fatal arrhythmia that is usually associated with syncope, if prolonged and is rarely asymptomatic[1]. Its mechanism involves either a lack of supraventricular impulse or an interruption in the transmission of these signals from the atria to the ventricles, resulting in a sudden loss of cardiac output[2]. Although rare, ventricular arrhythmias have been associated with intravenous (IV) erythromycin. However, to our knowledge, VS has not been reported following the administration of IV erythromycin. The Authors describe a rare case of asymptomatic VS and subsequent third-degree atrioventricular block, following the administration of IV erythromycin in a 49-year-old woman with borderline hypokalemia. Through this case, the Authors highlight the importance of cardiac monitoring and electrolyte replacement when administering IV erythromycin, as well as discuss several other mechanisms that contribute to ventricular arrhythmias.\nIntravenous erythromycin is associated with prolongation of the QTc interval and ventricular arrhythmias.Ventricular standstill is a rare but potentially fatal arrhythmia, and may have an association with the administration of intravenous erythromycin.Cardiac monitoring in patients with baseline QTc prolongation and correction of electrolyte disturbances are important when administering intravenous erythromycin.",
"affiliations": "Department of Gastroenterology, Peninsula Health, Frankston, Australia.;Department of Medicine, Eastern Health, Box Hill, Australia.;Department of Medicine, St Vincent's Health, Fitzroy, Australia.;Department of Gastroenterology, Peninsula Health, Frankston, Australia.;Department of Gastroenterology, Peninsula Health, Frankston, Australia.",
"authors": "Khan|Saad|S|;Ramzy|John|J|;Papachristos|Danae|D|;George|Nayana|N|;Fisher|Leon|L|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2016_000375",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2016_000375375-1-2575-1-10-20160217ArticlesVentricular Standstill Following Intravenous Erythromycin and Borderline Hypokalemia Khan Saad 1Ramzy John 2Papachristos Danae 3George Nayana 1Fisher Leon 1\n1 Department of Gastroenterology, Peninsula Health, Frankston, Australia\n2 Department of Medicine, Eastern Health, Box Hill, Australia\n3 Department of Medicine, St Vincent’s Health, Fitzroy, Australia2016 17 2 2016 3 3 00037504 1 2015 14 1 2015 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseVentricular standstill (VS) is a potentially fatal arrhythmia that is usually associated with syncope, if prolonged and is rarely asymptomatic[1]. Its mechanism involves either a lack of supraventricular impulse or an interruption in the transmission of these signals from the atria to the ventricles, resulting in a sudden loss of cardiac output[2]. Although rare, ventricular arrhythmias have been associated with intravenous (IV) erythromycin. However, to our knowledge, VS has not been reported following the administration of IV erythromycin. The Authors describe a rare case of asymptomatic VS and subsequent third-degree atrioventricular block, following the administration of IV erythromycin in a 49-year-old woman with borderline hypokalemia. Through this case, the Authors highlight the importance of cardiac monitoring and electrolyte replacement when administering IV erythromycin, as well as discuss several other mechanisms that contribute to ventricular arrhythmias.\n\nLEARNING POINTS\nIntravenous erythromycin is associated with prolongation of the QTc interval and ventricular arrhythmias.\n\nVentricular standstill is a rare but potentially fatal arrhythmia, and may have an association with the administration of intravenous erythromycin.\n\nCardiac monitoring in patients with baseline QTc prolongation and correction of electrolyte disturbances are important when administering intravenous erythromycin.\n\nArrhythmiasventricular standstillerythromycin\n==== Body\nCASE REPORT\nA 49-year-old woman with a past medical history of type 2 diabetes, hypertension and migraines presented to a regional hospital with symptoms suggestive of viral gastroenteritis and secondary atypical pneumonia. She did not have any known drug allergies. The patient described a five-day history of generalized abdominal pain, associated diarrhea and vomiting, as well as a two-day history of productive cough, mild dyspnea, and coryzal symptoms.\n\nHer vital signs on admission were as follows: temperature 36.8°C; heart rate 80/min regular; oxygen saturation 97% on room air; and blood pressure 120/75 mmHg. Her body mass index (BMI) was 26.2 kg/m2. Abdominal examination revealed mild generalised tenderness, but was soft with normal bowel sounds. Cardiovascular and respiratory examinations were unremarkable. Baseline 12-lead electrocardiogram (ECG) showed normal sinus rhythm. There was evidence of bilateral peri-hilar and infra-hilar opacities on chest x-ray, suggestive of atypical pneumonia. Initial biochemistry was unremarkable except for an elevated c-reactive protein of 89.6 mg/L (reference range [RR], < 10 mg/L). In particular, her electrolytes were within normal parameters, though a borderline hypokalemia was noted (magnesium 0.72mmol/L [RR, 0.6–1.1 mmol/L], potassium 3.5mmol/L [RR, 3.5–5 mmol/L). Fecal culture and clostridium difficile toxin were negative.\n\nShe was initially commenced on regulation doses of oral amoxicillin and doxycycline for a mild community-acquired pneumonia. These were ceased on day 1 of her admission. She was subsequently commenced on IV erythromycin 500mg 6-hourly and was monitored with telemetry for significant QT prolongation. She received three doses in total, at the times 10:00, 16:00 and 22:00. During sleep, at 00:34 on day 2 of admission (approximately 2.5 hours after her third dose of IV erythromycin), a seven second period of VS was noted on cardiac monitoring (Fig. 1). This rhythm then progressed to a third-degree atrioventricular (AV) block (Fig. 2). This persisted for approximately 2 minutes then returned to normal sinus rhythm. The patient remained hemodynamically stable and asleep throughout this entire period.\n\nShe was in normal sinus rhythm leading up to VS, with no variations in the PR-interval. The rate-corrected QT interval (QTc) prior to erythromycin administration was 410 milliseconds (ms). The QTc following erythromycin administration and immediately prior to the period of VS was 420 ms.\n\nErythromycin was discontinued following this event and a specialist cardiology opinion was sought. Magnesium and potassium were replaced intravenously. A further 36-hour period of cardiac monitoring did not reveal any further episodes of VS and thus no further action was taken. There was significant improvement in the patient’s gastrointestinal and respiratory symptoms and she was subsequently discharged home with oral doxycycline. Outpatient holter monitor did not reveal any cardiac arrhythmias. She remained well at six-month follow-up.\n\nDISCUSSION\nThe mechanism of VS involves either a lack of supraventricular impulse or an interruption in the transmission of these signals from the atria to the ventricles, resulting in a sudden loss of cardiac output[2]. The usual ECG appearance of VS is the absence of QRS complexes despite the presence of regular p-waves, with or without occasional ventricular escape rhythms[1]. This was observed in our patient during cardiac monitoring. VS is commonly associated with dizziness, syncope and cardiac arrest, if prolonged; however asymptomatic VS, as in our case, is extremely rare.\n\nRapid eye movement (REM) sleep has been associated with transient bradyarrhythmias and AV blockade. It has, thus, been postulated that episodes of VS may be attributable to the vagotonic effects of REM sleep[3]. This may have been a contributing factor in our case; however, this mechanism is not well understood or documented. Transient AV blockade secondary to increased vagal tone has also been described in many situations, including vomiting[4]. Our patient had not vomited for over 12 hours prior to the time of her VS with prolonged AV block and thus, it is unlikely to have been a factor. Obstructive sleep apnea (OSA) has also been associated with cardiac arrhythmias and conduction disturbances. While our patient had a BMI slightly in the overweight range, she did not describe any symptoms suggestive of OSA.\n\nAlthough rare, ventricular arrhythmias associated with IV erythromycin have been well documented. However, these usually occur in the setting of abnormal cardiac electrophysiology, such as electrolyte disturbances or bradycardia[5]. Our patient was found to be borderline hypokalemic prior to the event, and though it is unclear if she was hypokalemic at the time of VS, this may have been a contributing factor. An important mechanism of transient hypokalemia in an acutely ill patient is the intracellular shift of potassium caused by endogenous catecholamines acting on beta-2 adrenergic receptors[6]. In conjunction with vomiting and diarrhea, this mechanism may have contributed to our patient’s hypokalemia.\n\nIV erythromycin is well known to be associated with prolongation of the rate-corrected QT interval (QTc) on ECG, as well as its potential consequence, polymorphic ventricular tachycardia (torsades de pointes). This effect appears to be further associated with infusion rate[7] and its arrhythmogenic potential appears to be greater than other QTc prolonging antibiotics, such as fluoroquinolones[8]. The Authors estimate from the rhythm strip of the cardiac monitoring that the patient’s QTc prolonged by approximately 10 ms as a result of erythromycin; however, the QTc remained within normal limits at all times.\n\nWe feel that given the onset of VS and subsequent prolonged third-degree AV blockade following administration, as well as the lack of recurrence after cessation, IV erythromycin may have played a role in the mechanism of this patient’s ventricular arrhythmia. Cardiac arrhythmias secondary to antibiotics in the absence of QTc prolongation is extremely rare, and to our knowledge, VS following IV erythromycin has not previously been reported. Patients with baseline QTc prolongation should, however, be stratified as higher risk and prioritized for cardiac monitoring. Further investigation is required to better outline any potential association between IV erythromycin and VS. Our case also highlights the importance of electrolyte correction when administering medications that are associated with cardiac arrhythmias.\n\nHer vital signs on admission were as follows: temperature 36.8°C; heart rate 80/min regular; oxygen saturation 97% on room air; and blood pressure 120/75 mmHg. Her body mass index(BMI) was 26.2 kg/m2. Abdominal examination revealed mild generalised tenderness, but was soft with normal bowel sounds. Cardiovascular and respiratory examinations were unremarkable. Baseline 12-lead electrocardiogram (ECG) showed normal sinus rhythm. There was evidence of bilateral peri-hilar and infra-hilar opacities on chest x-ray, suggestive of atypical pneumonia. Initial biochemistry was unremarkable except for an elevated c-reactive protein of 89.6 mg/L (reference range [RR], < 10 mg/L). In particular, her electrolytes were within normal parameters, though a borderline hypokalemia was noted (magnesium 0.72mmol/L [RR, 0.6–1.1 mmol/L], potassium 3.5mmol/L [RR, 3.5–5 mmol/L). Fecal culture and clostridium difficile toxin were negative.\n\nShe was initially commenced on regulation doses of oral amoxicillin and doxycycline for a mild community-acquired pneumonia. These were ceased on day 1 of her admission. She was subsequently commenced on IV erythromycin 500mg 6-hourly and was monitored with telemetry for significant QT prolongation. She received three doses in total, at the times 10:00, 16:00 and 22:00. During sleep, at 00:34 on day 2 of admission (approximately 2.5 hours after her third dose of IV erythromycin), a seven second period of VS was noted on cardiac monitoring (Fig. 1). This rhythm then progressed to a third-degree atrioventricular (AV) block (Fig. 2). This persisted for approximately 2 minutes then returned to normal sinus rhythm. The patient remained hemodynamically stable and asleep throughout this entire period.\n\nShe was in normal sinus rhythm leading up to VS, with no variations in the PR-interval. The rate-corrected QT interval (QTc) prior to erythromycin administration was 410 milliseconds (ms). The QTc following erythromycin administration and immediately prior to the period of VS was 420 ms.\n\nErythromycin was discontinued following this event and a specialist cardiology opinion was sought. Magnesium and potassium were replaced intravenously. A further 36-hour period of cardiac monitoring did not reveal any further episodes of VS and thus no further action was taken. There was significant improvement in the patient’s gastrointestinal and respiratory symptoms and she was subsequently discharged home with oral doxycycline. Outpatient holter monitor did not reveal any cardiac arrhythmias. She remained well at six-month follow-up.\n\nConflicts of Interests: The authors declare that there are no competing interests.\n\nFigure 1 Printout from cardiac monitor showing normal sinus rhythm, and then sudden onset of ventricular standstill lasting approximately 7 seconds (between arrows), characterized by regular p-waves but the absence of subsequent QRS complexes.\n\nFigure 2 Printout from cardiac monitor showing progression of VS into third-degree AV block. This is characterized by the presence of p-waves with regular p- to p-intervals (arrowheads), and independent QRS complexes with regular R- to R-intervals (arrows), but no apparent relationship between p-waves and QRS complexes.\n==== Refs\nREFERENCES\n1 Vassalle M On the mechanisms underlying cardiac standstill: factors determining success or failure of escape pacemakers in the heart J Am Coll Cardiol 1985 5 35B 42B \n2 Lynch RM Ballesty L Maicoo R Be still my beating heart: Ventricular standstill occurring in difference age groups Afr J Emerg Med 2014 4 e12 e15 \n3 Serafini A Dolso P Gigli GL Fratticci Cancelli I Facchin D REM sleep brady-arrhythmias: An indication to pacemaker implantation? Sleep Med 2012 13 759 62 22521310 \n4 Jaiswal S Aldave APN Wool KJ Ventricular standstill: An uncommon electrophysiological abnormality caused by profound vagal tone N Am J Med Sci 2014 6 178 24843851 \n5 Oberg KC Bauman JL QT interval prolongation and torsades de pointes due to erythromycin lactobionate Pharmacotherapy 1995 15 687 692 8602374 \n6 Brown MJ Brown DC Murphy MB Hypokalemia from beta2-receptor stimulation by circulating epinephrine N Engl J Med 1983 309 1414 1419 6314140 \n7 Haefeli WE Schoenenberger RA Weiss PH Ritz R Possible risk of cardiac arrhythmia related to intravenous erythromycin Intensive Care Med 1992 18 469 473 1289371 \n8 Wisialowski T Crimin K Engtrakul J O’Donnell J Fermini B Fossa AA Differentiation of arrhythmia risk of the antibacterials moxifloxacin, erythromycin, and telithromycin based on analysis of monophasic action potential duration alternans and cardiac instability J Pharmacol Exp Ther 2006 318 352 359 16614168\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "3(3)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Arrhythmias; erythromycin; ventricular standstill",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
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"pages": "000375",
"pmc": null,
"pmid": "30755864",
"pubdate": "2016",
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"title": "Ventricular Standstill Following Intravenous Erythromycin and Borderline Hypokalemia.",
"title_normalized": "ventricular standstill following intravenous erythromycin and borderline hypokalemia"
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"abstract": "The term refeeding syndrome (RFS) refers to the metabolic perturbations and its attendant complications in subjects who are refed after fasting. The syndrome is characterized by profound shifts of electrolytes and fluids. Its consequences are widespread and sometimes fatal. Patients with malignancies are especially vulnerable due to the presence of multiple comorbidities. We report the course of four patients with malignant or hematological disorders who developed RFS while being treated for their underlying illness. All physicians caring for susceptible patients should be cognizant of the risks of refeeding and treat RFS appropriately to reduce patient morbidity as well as mortality.",
"affiliations": "Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.;Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.;Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.;Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.;Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.;Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.;Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria.",
"authors": "Windpessl|Martin|M|;Mayrbaeurl|Beate|B|;Baldinger|Christian|C|;Tiefenthaller|Gernot|G|;Prischl|Friedrich C|FC|;Wallner|Manfred|M|;Thaler|Josef|J|",
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"doi": "10.14740/wjon1007w",
"fulltext": "\n==== Front\nWorld J OncolWorld J OncolElmer PressWorld Journal of Oncology1920-45311920-454XElmer Press 10.14740/wjon1007wCase ReportRefeeding Syndrome in Oncology: Report of Four Cases Refeeding in OncologyWindpessl Martin abMayrbaeurl Beate aBaldinger Christian aTiefenthaller Gernot aPrischl Friedrich C. aWallner Manfred aThaler Josef aa Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austriab Corresponding Author: Martin Windpessl, Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Grieskirchnerstrasse 42, 4600 Wels, Austria. Email: martin.windpessl@klinikum-wegr.at2 2017 23 2 2017 8 1 25 29 13 2 2017 Copyright 2017, Windpessl et al.2017This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The term refeeding syndrome (RFS) refers to the metabolic perturbations and its attendant complications in subjects who are refed after fasting. The syndrome is characterized by profound shifts of electrolytes and fluids. Its consequences are widespread and sometimes fatal. Patients with malignancies are especially vulnerable due to the presence of multiple comorbidities. We report the course of four patients with malignant or hematological disorders who developed RFS while being treated for their underlying illness. All physicians caring for susceptible patients should be cognizant of the risks of refeeding and treat RFS appropriately to reduce patient morbidity as well as mortality.\n\nRefeedingHypophosphatemiaCancerOncologyMalnutrition\n==== Body\nIntroduction\nNot widely known outside nutritional support circles, the term refeeding syndrome (RFS) denotes a cascade of metabolic disturbances and clinical symptoms that may develop when previously malnourished patients are refed carbohydrates, whether this is by the oral, enteral or parenteral route [1]. The syndrome is characterized by profound shifts of electrolytes and fluids, with hypophosphatemia constituting the cardinal biochemical feature. Serious cardiac, respiratory and neurologic complications may occur; in extreme cases, these complications may prove fatal [2]. This notwithstanding, protocols aimed at its prevention and management are lacking in many hospitals.\n\nWhile anorexia nervosa is the modern prototypical predisposing condition, there are many clinical situations in which RFS may occur [1, 3]. Cancer patients undergoing chemotherapy seem particularly vulnerable due to the presence of several comorbidities, both disease- and treatment-related [4, 5]. Therefore, RFS represents an important aspect of supportive oncology. Given its non-specific symptoms, recognizing RFS can be a difficult task. As such, it remains “underdiagnosed and undertreated” [6].\n\nIn this case series, we present the clinical course of four patients with malignant or hematological disorders who experienced RFS while being treated for their underlying illness. We aim to raise awareness of this syndrome in physicians involved in nutritional support, provide suggestions for the prevention of RFS and outline treatment strategies, according to the evidence in the literature. We believe that local guidelines should be established. Hospital nutrition teams, where available, may help in this regard.\n\nCase Reports\nCase 1\nA 35-year-old woman with longstanding rheumatoid arthritis was admitted because of febrile neutropenia, presumably drug-related. Her body mass index (BMI) was 18.3 kg/m2. On examination, severe mucositis was apparent. Laboratory results showed an absolute neutropenia and a significant inflammatory response. Electrolytes and renal function were normal on admission (Table 1). A diagnosis of methotrexate-induced neutropenia was made. The patient was isolated and commenced on broad spectrum antibiotic treatment (piperacillin-tazobactam) and a granulocyte-colony stimulating factor was given. As she remained unable to eat, a central line was placed and intravenous nutrition was started at a rate of 18 kcal/kg/day after 10 days of negligible food intake. B-multivitamins were added. The infusion rate was not altered, but within the next 3 days phosphate plummeted to 0.15 mmol/L (normal: 0.7 - 1.3 mmol/L). Edema developed and the patient complained of diffuse abdominal pain. In view of her electrolyte disturbance and fluid retention, a diagnosis of RFS was made. Parenteral phosphate supplementation was prescribed. Nutrition was withheld temporarily and restarted at a slower rate. By hospital day 10, electrolytes had normalized. In parallel, the blood count had recovered and the patient was discharged after 3 weeks.\n\nTable 1 Laboratory Findings of Four Consecutive Patients With the Refeeding Syndrome\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nA1\tB5\tC8\tD13\tA1\tB13\tC19\tD22\tA1\tB8\tC10\tD15\tA1\tB4\tC7\tD20\t\nNa+ (mmol/L)\t137\t142\t141\t143\t136\t127\t128\t129\t139\t129\t127\t134\t151\t157\t136\t140\t\nK+ (mmol/L)\t3.7\t3.1\t3.7\t3.7\t4.6\t3.7\t3.4\t3.6\t3.7\t3.0\t3.5\t3.7\t2.9\t2.7\t3.2\t3.1\t\nCa2+ (mmol/L)\t2.47\t2.08\t2.04\t2.33\t2.35\t2.00\t1.75\t1.64\t2.40\t2.13\t2.00\t2.30\t2.63\t1.99\t2.06\t1.83\t\nMg2+ (mmol/L)\t0.75\t0.67\t0.71\t0.84\t0.59\t0.58\t0.37\t0.40\t0.75\t0.69\t0.54\t0.66\t0.81\t0.65\t0.45\t0.63\t\nCl- (mmol/L)\t99\t110\t110\t108\t101\t94\t94\t98\t1.22\t90\t92\t96\t116\t127\t107\t107\t\nPO43- (mmol/L)\t0.88\t0.65\t0.15\t1.05\t0.97\t0.56\t0.27\t0.61\t0.76\t0.73\t0.27\t0.68\t0.94\t0.14\t0.24\t0.63\t\nA: admission; B: start of nutritional support; C: phosphate nadir; D: last lab result before discharge. Numbers denote hospital day.\n\nCase 2\nA 69-year-old man with advanced squamous cell carcinoma of the tonsil was admitted for palliative chemotherapy. Within the preceding 6 months, he had lost 30% of his usual body weight. His current BMI was 16.9 kg/m2. On admission, mild hypomagnesemia was present, otherwise electrolytes were in the normal range (Table 1). A percutaneous endoscopic gastrostomy (PEG) was placed because of dysphagia. On day 5, cetuximab and docetaxel were administered as scheduled. Due to poor wound healing, the feeding tube could not be used immediately and parenteral nutrition via a pre-existing port-a-cath was introduced for 3 days at a daily rate of 24 kcal/kg/day. At that point, he had not eaten properly for 9 days. Subsequently, enteral nutrition was commenced via the PEG at a rate of 24 kcal/kg/day for 5 days. Profound hypophosphatemia developed (nadir 0.27 mmol/L; normal: 0.7 - 1.3 mmol/L) and hypomagnesemia and hypocalcemia worsened concurrently. Within 12 days from admission, marked fluid retention had occurred amounting to a gain of weight of 10 kg. Nutrition was withheld intermittently, parenteral phosphate was administered and feeding was restarted at a slower rate. Except for magnesium, his electrolytes normalized within the following 4 days and he was discharged after 2 weeks.\n\nCase 3\nA 66-year-old woman was diagnosed with metastasized squamous cell cancer of the anus and admitted for initiation of palliative chemotherapy. Over the last 4 months, she had lost 12% of weight and her BMI was 20.8 kg/m2. After implantation of a port-a-cath, 5-fluorouracil and cisplatin were administered as per protocol. Despite supportive measures, the treatment was poorly tolerated and complicated by prolonged anorexia. Due to severe gingivitis, she had barely eaten for 5 days and parenteral nutrition was prescribed at a rate of 18 kcal/kg/day and left unaltered for the following 4 days. Electrolytes showed typical features of the RFS (Table 1) and the patient complained of generalized languor. After electrolyte supplementation, salt restriction and cautious switch to oral nutrition, her symptoms slowly abated.\n\nCase 4\nFive days after his third cycle of chemotherapy (5-fluorouracil/cisplatin) for adenocarcinoma of the esophagus, a 72-year-old man was admitted with severe mucositis. Within 3 months, he had lost 18% of his usual weight and his BMI was 21.9 kg/m2 on admission. He had had negligible oral intake for 8 days. Electrolytes were normal but marked hyperglycaemia was present, deemed due to high dose dexamethasone (Table 1). Insulin sliding-scale was commenced and glucose normalized subsequently. On hospital day 4, the patient became septic and was transferred to the intensive care unit (ICU) for inotropic support and broad cover antibiotic treatment (piperacillin-tazobactam). Whilst on ICU, parenteral nutrition was commenced at a rate of 15 kcal/kg/day for 2 days which triggered a precipitous drop in phosphate. Parenteral phosphate substitution improved values to some extent. After 3 days, he could be transferred back to the normal ward. Parenteral nutrition was restarted at the same rate and continued unchanged for 6 days. In parallel, electrolytes decreased again. Within 1 week, he had gained 9 kg in weight. Edema was present. A diagnosis of RFS was made, possibly aggravated by concurrent sepsis and sodium-containing antibiotics. Electrolytes were substituted aggressively and salt and fluid restriction was implemented. The patient was finally discharged after 3 weeks with normal electrolytes.\n\nThe salient laboratory results of all cases are summarized in Table 1. The course of individual serum phosphate levels is depicted in Figure 1.\n\nFigure 1 Courses of individual serum phosphate levels. The red diamond depicts the start of nutrition. \n\nDiscussion\nThe perils of reinstituting nutrition after periods of starvation have been recognized since World War II, with victims of famine being the first documented cases. However, it was only with the advent of widespread nutritional support that this phenomenon has garnered renewed attention. More than 30 years ago, reporting the death of two malnourished patients who were fed “overzealously”, Weinsier and Krumdieck coined the term “refeeding syndrome” [7].\n\nFrom a pathophysiological view, malnourished patients gradually develop a total body depletion of phosphorous. Insulin levels fall during starvation as the body switches from carbohydrate to fat metabolism. Following the delivery of glucose as part of a feeding regimen, the sudden mount in insulin secretion reverses catabolism to anabolism [8]. Due to the associated transcellular flux of electrolytes and the increased cellular demands, the serum concentration of these agents can fall dramatically. Hypophosphatemia, which constitutes the biochemical hallmark of RFS, is almost universally present [9]. Not surprisingly, in the treatment of diabetic ketoacidosis, analogous metabolic perturbations occur. The insulin surge also enhances fluid and sodium retention, further contributing to morbidity [10]. Concomitant thiamine deficiency can occur and may present as Wernicke encephalopathy [1].\n\nWhile RFS is typically presented as a single entity, in practice it constitutes a spectrum disorder that occurs under particular circumstances within a high-risk population, i.e., malnourished patients with negligible food intake for several days at the time of refeeding. No unanimously agreed definition exists [11]. Clinical manifestations are related directly to electrolyte and vitamin deficiency but are variable and unpredictable [12]. Cardiac arrhythmias and heart failure are the most-dreaded aspects of the RFS. Fluid retention, respiratory failure and neuromuscular problems such as paralysis, seizures and rhabdomyolysis may also occur. Case reports have emphasized the potentially fatal nature of this condition [2, 7].\n\nThere is a paucity of data about the incidence of RFS in patients with cancer. However, in a Mexican study, it was reported to be as high as 25% [13]. Individuals with head and neck cancer (HNC) are particularly vulnerable for this phenomenon. A Danish report found an incidence of 20% in HNC patients referred for surgery (n = 54), with a history of previous radiation therapy among the predisposing factors [14]. Likewise, in a Dutch cohort of internal medicine patients (n = 178), sepsis and malignancy conferred the highest risk for the development of RFS [10]. Disease-related malnutrition reportedly occurs in approximately half of oncology patients and is associated with negative outcomes [4, 12, 15]. Pre-existing electrolyte disorders are common in these patients, whether this is paraneoplastic, associated with chemotherapeutic regimens or other compounds frequently used in this clinical setting, as exemplified by case 2 [16, 17]. Hypophosphatemia can be frequently found in patients with sepsis, especially in Gram-negative bacteremia and its extent correlates with illness severity [18]. Electrolyte disorders such as hypokalemia can also arise as a consequence of antibiotic therapy. Moreover, sodium-containing antibiotic regimens such as piperacillin-tazobactam can lead to fluid retention [19]. Therefore, it is often difficult if not impossible to ascribe biochemical and clinical complications to one of several causative factors. As illustrated by case 4, these events often occur in parallel and should be seen as potentiating each other rather than causing the RFS singularly.\n\nTimely recognition of patients at risk is crucial before initiating nutritional support. Any patients with negligible food intake for more than 5 days should be deemed at risk of developing refeeding problems [20]. The short nutritional assessment questionnaire (SNAQ) had a high negative predictive value for the diagnosis of RFS in one observational study [10]. In 2006, the British National Institute for Clinical Excellence (NICE) came up with criteria for identifying patients at risk and offered treatment strategies and is still considered a useful tool in daily practice [10, 21]. Of note, a history of recent chemotherapy is one of several risk factors cited for RFS. In 2013, the Irish Society for Clinical Nutrition & Metabolism followed suit with detailed instructions for electrolyte replacement [22]. Both guidelines could serve as templates for local protocols as shown in Table 2 [5, 21, 22]. By using these criteria, all patients presented could have been found to be at high risk of RFS before the start of nutrition (Table 3) [21]. At first glance, refeeding was started rather carefully, with only 1,000 kcal/day (ranging from 15 to 24 kcal/kg/day in the respective cases) being delivered. However, in such high-risk patients, starting nutrition support at a maximum of 10 kcal/kg/day is recommended, increasing levels slowly to meet full needs within 1 week [21].\n\nTable 2 Guideline for the Management of the RFS (Adapted From Refs. [5, 21, 22])\nIdentify patients at risk (“Discussion”)\t\nCheck electrolytes prior to re-alimentation and correct deficiencies\t\nAdminister thiamine 200 - 300 mg daily\t\nLimit salt and fluid intake\t\nStart feeding 10 kcal/kg/day and slowly increase over the first week\t\nMonitor electrolytes and weight daily\t\nIf severe hypophosphatemia (< 0.3 mmol/L) develops: give phosphate parenterally*\t\n*Assuming normal renal function, parenteral phosphate repletion is generally safe with doses up to 45 mmol with infusion rates up to 20 mmol per hour. Individualized frequent checks are recommended (e.g. after 6 and 12 h on day 1) [25].\t\nFor detailed recommendations regarding electrolyte substitution, see particularly Ref. [22].\n\nTable 3 NICE Criteria for Identifying Patients at High Risk of Refeeding Problems (Adapted From [21])\n\t1\t2\t3\t4\t\nOne or more of the following:\t\t\t\t\t\n BMI < 16 kg/m2\t-\t-\t-\t-\t\n Weight loss > 15% within the last 3 - 6 months\tn/a\t+\t-\t+\t\n Little or no nutritional intake for more than 10 days\t+\t-\t-\t-\t\n Low levels of electrolytes prior to feeding\t+\t+\t+\t+\t\nTwo or more of the following:\t\t\t\t\t\n BMI < 18.5 kg/m2\t+\t+\t-\t-\t\n Weight loss > 10% within the last 3 - 6 months\tn/a\t+\t+\t+\t\n Little or no nutritional intake for more than 5 days\t+\t+\t+\t+\t\n History of alcohol abuse or drugs including chemotherapy\t-\t+\t+\t+\t\nNumbers 1 - 4: individual patients. +/- denotes presence/absence of a risk factor. n/a: not available.\n\nPrior to refeeding, electrolytes should be checked. Thiamine is recommended upfront realimentation in at-risk patients. Gradual introduction of calories particularly over the first week of refeeding is prudent until the patient is metabolically stable (“start low and go slow”). Initially, fluid and salt intake should be conservative because of the propensity to retain these [23]. As noted, attention needs to be paid to biochemical indices, and electrolytes should be measured daily. Once overt RFS has developed, caloric intake should be reduced, electrolyte abnormalities treated aggressively and extra B vitamins given.\n\nDespite considerable progress in our understanding of its pathophysiology over the last decades, RFS remains underdiagnosed, causing avoidable morbidity in core patient groups at risk. The present case series illustrates that cancer patients are particularly prone for this phenomenon. Because disease- and treatment-related complications such as electrolyte disturbances and infections often occur in parallel, diagnosis of RFS can be delayed. Moreover, it is not unusual for chemistry panels not to include phosphate unless specifically ordered and it is partly therefore that phosphate has been dubbed a “neglected electrolyte” [24]. Our experience emphasizes the need for better recognition and monitoring.\n\nTo summarize, clinical diagnosis of RFS requires vigilance. As stated by Marinella, physicians involved with providing supportive care to cancer patients ought to be familiar with this syndrome and its attendant complications to prevent morbidity and mortality [25].\n\nConflicts of Interest\nThe authors have no conflicts of interest.\n==== Refs\nReferences\n1 Crook MA Hally V Panteli JV The importance of the refeeding syndrome Nutrition 2001 17 7-8 632 637 10.1016/S0899-9007(01)00542-1 11448586 \n2 Boateng AA Sriram K Meguid MM Crook M Refeeding syndrome: treatment considerations based on collective analysis of literature case reports Nutrition 2010 26 2 156 167 10.1016/j.nut.2009.11.017 20122539 \n3 Mehanna HM Moledina J Travis J Refeeding syndrome: what it is, and how to prevent and treat it BMJ 2008 336 7659 1495 1498 10.1136/bmj.a301 18583681 \n4 Marinella MA Refeeding syndrome: an important aspect of supportive oncology J Support Oncol 2009 7 1 11 16 19278172 \n5 Stanga Z Brunner A Leuenberger M Grimble RF Shenkin A Allison SP Lobo DN Nutrition in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention and treatment Eur J Clin Nutr 2008 62 6 687 694 10.1038/sj.ejcn.1602854 17700652 \n6 Gariballa S Refeeding syndrome: a potentially fatal condition but remains underdiagnosed and undertreated Nutrition 2008 24 6 604 606 10.1016/j.nut.2008.01.053 18359196 \n7 Weinsier RL Krumdieck CL Death resulting from overzealous total parenteral nutrition: the refeeding syndrome revisited Am J Clin Nutr 1981 34 3 393 399 6782855 \n8 Walmsley RS Refeeding syndrome: screening, incidence, and treatment during parenteral nutrition J Gastroenterol Hepatol 2013 28 Suppl 4 113 117 10.1111/jgh.12345 24251716 \n9 Kagansky N Levy S Koren-Morag N Berger D Knobler H Hypophosphataemia in old patients is associated with the refeeding syndrome and reduced survival J Intern Med 2005 257 5 461 468 10.1111/j.1365-2796.2005.01457.x 15836663 \n10 Kraaijenbrink BV Lambers WM Mathus-Vliegen EM Siegert CE Incidence of refeeding syndrome in internal medicine patients Neth J Med 2016 74 3 116 121 27020991 \n11 Miller SJ Death resulting from overzealous total parenteral nutrition: the refeeding syndrome revisited Nutr Clin Pract 2008 23 2 166 171 10.1177/0884533608314538 18390784 \n12 Palesty JA Dudrick SJ Cachexia, malnutrition, the refeeding syndrome, and lessons from Goldilocks Surg Clin North Am 2011 91 3 653 673 10.1016/j.suc.2011.02.007 21621702 \n13 Gonzalez Avila G Fajardo Rodriguez A Gonzalez Figueroa E [The incidence of the refeeding syndrome in cancer patients who receive artificial nutritional treatment] Nutr Hosp 1996 11 2 98 101 8695716 \n14 Rasmussen SO Kristensen MB Wessel I Andersen JR Incidence and Risk Factors of Refeeding Syndrome in Head and Neck Cancer Patients-An Observational Study Nutr Cancer 2016 68 8 1320 1329 10.1080/01635581.2016.1225103 27682582 \n15 Vandebroek AJ Schrijvers D Nutritional issues in anti-cancer treatment Ann Oncol 2008 19 Suppl 5 v52 55 10.1093/annonc/mdn311 18611901 \n16 Rosner MH Dalkin AC Electrolyte disorders associated with cancer Adv Chronic Kidney Dis 2014 21 1 7 17 10.1053/j.ackd.2013.05.005 24359982 \n17 Miltiadous G Christidis D Kalogirou M Elisaf M Causes and mechanisms of acid-base and electrolyte abnormalities in cancer patients Eur J Intern Med 2008 19 1 1 7 10.1016/j.ejim.2007.04.016 18206594 \n18 Geerse DA Bindels AJ Kuiper MA Roos AN Spronk PE Schultz MJ Approach to hypophosphataemia in intensive care units - a nationwide survey Neth J Med 2012 70 9 425 430 23123542 \n19 Zietse R Zoutendijk R Hoorn EJ Fluid, electrolyte and acid-base disorders associated with antibiotic therapy Nat Rev Nephrol 2009 5 4 193 202 10.1038/nrneph.2009.17 19322184 \n20 Crook MA Refeeding syndrome: problems with definition and management Nutrition 2014 30 11-12 1448 1455 10.1016/j.nut.2014.03.026 25280426 \n21 National Institute for Clinical Excellence. Nutrition Support for Adults. Clinical Guideline CG32. 2006 Feb 1; 1-176. Cited December 2016. Available from URL: http://www.nice.org.uk/nicemedia/live/10978/29981/29981.pdf \n22 Irish Society for Clinical Nutrition & Metabolism. Prevention and Treatment of Refeeding Syndrome in the Acute Care Setting. IrSPEN Guideline 1. November 2013; 1-31. Cited December 2016. Available from URL: http://www.irspen.ie/wp-content/uploads/2013/12/Refeeding-Syndome-Guideline-Doc.pdf \n23 Brooks MJ Melnik G The refeeding syndrome: an approach to understanding its complications and preventing its occurrence Pharmacotherapy 1995 15 6 713 726 8602378 \n24 Workman ML Magnesium and phosphorus: the neglected electrolytes AACN Clin Issues Crit Care Nurs 1992 3 3 655 663 10.4037/15597768-1992-3012 1524936 \n25 Marinella MA Refeeding syndrome in cancer patients Int J Clin Pract 2008 62 3 460 465 10.1111/j.1742-1241.2007.01674.x 18218007\n\n",
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"title": "Refeeding Syndrome in Oncology: Report of Four Cases.",
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"abstract": "We describe a 22-year-old woman with cutaneous polyarteritis nodosa in whom dapsone hypersensitivity syndrome (DHS) developed 5 weeks after initiation of dapsone therapy. She had fever and cervical lymphadenopathy, and later a widespread erythematous eruption studded with pustules developed. She also had liver involvement with mixed hepatocellular and cholestatic features. The patient was treated with prednisone 60 mg daily. Once the patient's liver function normalized, prednisone dosage was reduced by 5 mg weekly. The clinical features and treatment of DHS are reviewed. We encourage immediate discontinuation of the drug in a patient in whom a fever or flu-like illness develops, especially 4 or more weeks after the treatment is started. We also suggest routine thyroid function testing 3 months after recovery because of the possible risk of hypothyroidism.",
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"abstract": "Insulinomas are uncommon tumors, and in patients with diabetes mellitus they are extremely rare. We describe a patient with type 1 diabetes who developed malignant insulinoma. When hypoglycemic episodes persist in a patient with diabetes and treatment-induced and other causes of hypoglycemia have been ruled out, an insulin-producing tumor should be considered.",
"affiliations": "Department of Pathology Haukeland University Hospital Bergen Norway.;Department of Gastrointestinal Surgery Haukeland University Hospital Bergen Norway.;Institute of Clinical Medicine University of Oslo Oslo Norway.;Department of Pathology Haukeland University Hospital Bergen Norway.;Department of Medicine Stavanger University Hospital Stavanger Norway.;Department of Pathology Haukeland University Hospital Bergen Norway.",
"authors": "Gjelberg|Hilde K|HK|;Hoem|Dag|D|;Verbeke|Caroline S|CS|;Eide|Johan|J|;Cooper|John G|JG|;Molven|Anders|A|0000-0003-1847-3079",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.927CCR3927Case ReportCase ReportsHypoglycemia and decreased insulin requirement caused by malignant insulinoma in a type 1 diabetic patient: when the hoof beats are from a zebra, not a horse H. K. Gjelberg et al.Gjelberg Hilde K. \n1\nHoem Dag \n2\nVerbeke Caroline S. \n3\n\n4\nEide Johan \n1\nCooper John G. \n5\nMolven Anders http://orcid.org/0000-0003-1847-3079anders.molven@uib.no \n1\n\n6\n\n7\n1 Department of PathologyHaukeland University HospitalBergenNorway2 Department of Gastrointestinal SurgeryHaukeland University HospitalBergenNorway3 Institute of Clinical MedicineUniversity of OsloOsloNorway4 Department of PathologyOslo University Hospital, RikshospitaletOsloNorway5 Department of MedicineStavanger University HospitalStavangerNorway6 Gade Laboratory for PathologyDepartment of Clinical MedicineUniversity of BergenBergenNorway7 KG Jebsen Center for Diabetes ResearchFaculty of Medicine and DentistryUniversity of BergenBergenNorway* Correspondence\n\nAnders Molven, Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, N‐5021 Bergen, Norway. Tel: 0047 55 973169; Fax: 0047 55 973158; E‐mail: anders.molven@uib.no\n06 4 2017 6 2017 5 6 10.1002/ccr3.2017.5.issue-6761 768 03 2 2017 05 3 2017 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nInsulinomas are uncommon tumors, and in patients with diabetes mellitus they are extremely rare. We describe a patient with type 1 diabetes who developed malignant insulinoma. When hypoglycemic episodes persist in a patient with diabetes and treatment‐induced and other causes of hypoglycemia have been ruled out, an insulin‐producing tumor should be considered.\n\nChromogranindiabeteshypoglycemiainsulin secretioninsulinomaNovo Nordisk FondenNNF16OC0021050 source-schema-version-number2.0component-idccr3927cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.0 mode:remove_FC converted:05.06.2017\n==== Body\nIntroduction\nInsulinomas are insulin‐producing neuroendocrine neoplasms. They comprise the most common functional neuroendocrine tumor of the pancreas despite being rare, with an estimated incidence of only 0.7–4 cases per 1 million persons per year 1. Most insulinomas occur sporadically, but up to 10% are associated with the multiple endocrine neoplasia type 1 (MEN1) syndrome 2. The tumor occurs at any age with a median age at diagnosis of around 50 years, and there is a slight female preponderance 2. Approximately 5–10% of insulinomas are malignant 3; these tumors tend to be larger and have a higher mitotic count. A diagnosis of malignancy is reached by identification of metastatic disease, usually in lymph nodes or the liver.\n\nClinically, insulinomas are characterized by Whipple's triad 4, that is, the following three criteria: (1) presence of central nervous system or vasomotor symptoms of hypoglycemia; (2) low laboratory‐measured concentration of plasma glucose at the time of symptoms; and (3) prompt resolution of symptoms when the plasma glucose level returns to the normal range. The symptoms may be provoked by a 72‐h monitored fast. Upon confirmation of hypoglycemia, further laboratory investigations are necessary to establish its etiology. Inappropriately elevated insulin levels (>3 mIU/L) at the time of hypoglycemia (<2.5 mmol/L), together with elevated C‐peptide (>0.2 nmol/L) and proinsulin (≥25% or ≥22 pmol/L) levels 5, and the absence of plasma sulfonylurea are consistent with endogenous hyperinsulinism. When the diagnosis is established, different pre‐ and/or intraoperatively imaging modalities are used to localize the insulin‐producing tumor, which typically is solitary, small, and intrapancreatic 6, 7. Surgical resection is the treatment of choice. When possible, enucleation or segmental resection is performed to preserve endocrine and exocrine pancreatic function. The mean cure rate has been reported to be 93% in a review of more than 6000 insulinoma cases 8. The clinical course of metastatic insulinoma is variable, 25–35% of patients surviving longer than 5 years 6.\n\nThe incidence of insulinoma in patients with diabetes is considered to be lower than in the general population 9, and reported cases have been almost exclusively in type 2 diabetes mellitus (T2DM). Furthermore, hypoglycemia due to treatment with a hypoglycemic agent is not uncommon among patients with diabetes, and the detection of an insulinoma therefore represents a diagnostic challenge. We describe the clinical history and management of a malignant insulinoma diagnosed in a patient who had suffered from type 1 diabetes mellitus (T1DM) for 20 years. The patient has previously been included in summary tables describing 16 insulinoma cases referred to Haukeland University Hospital between 1986 and 2006 10.\n\nCase Report\nA 43‐year‐old woman was referred to our hospital with a three‐year history of decreasing insulin requirements and frequent hypoglycemic episodes. Diabetes mellitus had been diagnosed when the patient was 23 years old and, initially, she was treated by diet only. Islet antibodies and C‐peptide were not measured at the time of diagnosis. At age 24, after a weight loss of 14 kg accompanied by polydipsia and polyuria, a diagnosis of T1DM was established and insulin treatment started. The patient's body mass index (BMI) at that time was 17.6 (height 170 cm, weight 51 kg). In the following years, her diabetes was well controlled, and there were no microvascular complications. She was also treated for hypothyroidism and hypertension from age 38.\n\nThe patient's family history included a sister with primary hyperparathyroidism, another sister with breast cancer diagnosed at age 43, a father who had T2DM, hypothyroidism and cardiovascular disease, a mother with vitamin B12 deficiency, and a cousin with hypothyroidism and celiac disease. The patient had two children, and her son developed T1DM at the age of 20. No cases of MEN1 syndrome were known in the family.\n\nThe patient was treated with an insulin pump during pregnancy when she was 31 years old. Otherwise her insulin requirements were stable, requiring approximately 42–50 international units (IU) of insulin daily, given as four bolus doses at mealtimes and one basal dose at bedtime. However, at age 40, her total daily insulin requirement started to decrease and was recorded as 28 IU at age 41 (Fig. 1). During the next year, intermediate‐acting (NPH) insulin was discontinued, and mealtime bolus doses were gradually reduced to a total of 8 IU per day. Despite these measures, the patient was experiencing frequent and long‐lasting hypoglycemic episodes, especially during the night. She also had detectable insulin C‐peptide level at 0.7 nmol/L (normal range, NR: 0.17–1.0 nmol/L). Chromogranin A was elevated at 6.6 nmol/L (NR: 0.4–2.0). However, the patient had been taking esomeprazole for abdominal discomfort, which may cause increased chromogranin A.\n\nFigure 1 Time line illustrating major events in the patient's medical history, with age shown along the x‐axis. Insulin requirements and serum chromogranin A levels are indicated by open blue and solid red dots, respectively.\n\nOn admission at age 43, the patient reported a weight gain of 10 kg during the last 2 years, (current weight: 75 kg; BMI: 26.0). She looked fit and well. Her blood pressure was 140/80 mm Hg. There was no abdominal tenderness or palpable abdominal tumor. HbA1c was only slightly elevated at 7.0% (NR: 4.0–6.4%). Insulin treatment was discontinued, and the patient underwent a prolonged fast. After 24 h, she had symptoms of hypoglycemia, a bedside glucometer showed a blood glucose level of 1.9 mmol/L, and the fast was terminated. Laboratory‐measured plasma glucose was 2.8 mmol/L, C‐peptide was 0.58 nmol/L, and plasma insulin 3.8 mIU/L. The concurrent plasma insulin and glucose values were interpreted to be within normal limits, and therefore an insulinoma was considered to be less likely. A diagnosis of T2DM was also considered as the patient had been treated with diet only for the first year after her diabetes diagnosis, C‐peptide was measurable, and there was a family history of T2DM and cardiovascular disease. The patient was discharged without insulin treatment and advised to return to the hospital if hypoglycemia recurred.\n\nTwo months later, she was readmitted after a protracted hypoglycemic episode. Laboratory investigations revealed elevated glutamic acid decarboxylase (GAD) autoantibodies at 4 U/mL (NR: <1) and slightly elevated plasma glucagon at 84 pmol/L (NR: 7.2–72). The values for islet antigen‐2 autoantibodies, hemoglobin, erythrocyte sedimentation rate, C‐reactive protein, calcium, parathyroid hormone, prolactin, gastrin, human chorionic gonadotropin, alpha‐fetoprotein, pancreas polypeptide, adrenocorticotropic hormone, calcitonin, and liver tests were all within normal ranges. A new fast was then performed until hypoglycemia could be verified by the hospital laboratory. Sixteen hours after food intake, plasma glucose was 2.5 mmol/L, C‐peptide 0.56 nmol/L and plasma insulin 9.7 mIU/L. Two hours later, plasma glucose was 2.0 mmol/L, C‐peptide 0.60 nmol/L, and plasma insulin 8.2 mIU/L.\n\nEndogenous hyperinsulinism was now considered to be the cause of the patient's hypoglycemia. Abdominal ultrasound examination showed a hypoechoic lesion with a diameter of around 10 cm in the pancreatic tail. CT examination (Fig. 2A) confirmed the presence of a large retroperitoneal tumor and also revealed enlarged retroperitoneal lymph nodes as well as two possible liver metastases. Octreotide scintigraphy demonstrated increased uptake in the large tumor, but none in the liver or other organs. The patient underwent surgery, and the pancreatic lesion was removed. The surgical specimen (Fig. 2B) consisted of the body and tail of the pancreas with a well‐circumscribed, large central tumor measuring 11 × 7 × 5.5 cm, the spleen, hilar and peripancreatic fat, lymph nodes, and left adrenal. Also resected were two liver metastases, each measuring 1 × 0.5 × 0.5 cm. The tumor was partly demarcated by a thin pseudocapsule of connective tissue and showed a light gray‐yellowish cut surface with a variegated, mainly soft consistency.\n\nFigure 2 (A) Preoperative computed tomography image at the level of cauda pancreatis, portal venous contrast phase. A large tumor (T) is seen in the pancreatic tail. (B) The surgical specimen consisting of the pancreatic tail with a large, circumscribed tumor (T), the spleen (S), and hilar and peripancreatic fat. An incision has been made in the tumor to expose the inner surface. The asterisk indicates the resection margin toward the residual pancreas. (C) Similar image as A, 11 years after surgery. Two hypervascular liver metastases are evident (arrows).\n\nHistological examination (Fig. 3A–D) revealed an epithelial tumor with varying histological growth pattern, including nested, trabecular, gyriform, and solid areas. There was a varying amount of fibrous stroma, focally with a marked sclerotic quality. The tumor cells showed a varying degree of slightly granular eosinophilic to amphophilic cytoplasm and moderately pleomorphic round to oval nuclei with coarsely clumped chromatin and one or more centrally placed distinct nucleoli. Mitoses were nearly undetectable; <1 mitosis per 10 high‐power fields on average. There was no inflammatory response.\n\nFigure 3 (A–D) Hematoxylin/eosin histological images of the tumor illustrating its varying growth patterns. (A and B) Nested growth pattern with various amounts of sclerotic stroma. (C) Solid diffuse growth pattern. (D) Trabecular pattern. (E–H) Immunohistological profile of the tumor tissue. (E) Synaptophysin. (F) Glucagon. (G) Insulin. (H) Proliferation marker Ki‐67. Scale bars: 200 μm (A, C, E, F, G); 75 μm (B, D, H).\n\nRoutine immunohistochemistry (Fig. 3E–H) showed diffuse and strong positivity for chromogranin A and synaptophysin. Insulin expression was diffuse and moderate, with smaller areas exhibiting strong positivity. Staining for somatostatin showed diffuse positivity with varying intensity. A minority of the tumor cells exhibited positivity for glucagon. Staining for vimentin, calcitonin, gastrin, human growth hormone, ACTH, and thyroid transcription factor was negative. Ki‐67 proliferation index was <1%. Two peripancreatic lymph node metastases and two liver metastases showed the same morphological pattern and immunohistochemistry profile as the primary tumor (Fig. 4), that is, diffuse and strong immunoreactivity for chromogranin A and synaptophysin, although only focal immunoreactivity for insulin. The left adrenal was unremarkable.\n\nFigure 4 Liver tissue with metastatic tumor deposits (right part of image) resected during the surgical removal of the primary tumor. Consecutive sections. (A) Hematoxylin/eosin. (B) Synaptophysin. (C) Insulin. (D) Proliferation marker Ki‐67. Scale bars: 200 μm.\n\nIslets in the nontumorous pancreatic tissue of the resection specimen (Fig. 5) consisted almost exclusively of glucagon‐positive cells. There was no positivity for insulin. Neither the islets nor the exocrine parenchyma showed significant infiltration of inflammatory cells. Taken together, the clinical, morphological, and immunohistochemical findings were those of a malignant insulinoma.\n\nFigure 5 Nontumorous pancreatic tissue showing an islet of Langerhans (arrow) and a small pancreatic duct (arrowhead). Consecutive sections. (A) Hematoxylin/eosin. (B) An islet highlighted by immunohistochemical staining for synaptophysin. (C) Glucagon. (D) No immunoreactivity for insulin. Scale bars: 80 μm.\n\nImmediately after surgery, the plasma glucose concentration increased, C‐peptide became undetectable, and chromogranin A fell to 0.8 nmol/L (Fig. 1). Insulin therapy was reintroduced. The patient was discharged on a basal/bolus regime of 34 IU insulin daily. Chromogranin A and C‐peptide were undetectable, and it was decided not to give adjuvant treatment with a somatostatin analog (octreotide) or other chemotherapy as all known tumor tissue had been removed.\n\nFive months after surgery, a CT examination revealed two new liver metastases, while C‐peptide and chromogranin A remained undetectable. Because the patient was asymptomatic, further treatment was not initiated at this point. Six months later, numerous liver and regional lymph node metastases had emerged, giving rise to pleiotropic symptoms, mainly weight loss and night sweats, but not those of hyperinsulinemia. Liver function tests were normal, and C‐peptide and chromogranin A were undetectable. Due to multifocal metastatic disease, the patient was not eligible for surgery and was treated palliatively with 5‐fluorouracil and streptozocin. Initially, there was remarkable alleviation of symptoms, and the patient's performance status was close to normal. Follow‐up CT scans showed regression of the largest liver metastasis, and there was no sign of disease progression for almost 2 years. She then developed icterus and a marked elevation of liver enzymes ascribed to chemotherapy‐induced hepatotoxicity. Streptozocin and 5‐fluorouracil were therefore discontinued.\n\nSubsequently, liver enzymes normalized, but the size and number of liver metastases increased. There was reoccurrence of night sweats and slightly elevated chromogranin A (3.2 nmol/L). Hypoglycemic episodes were not recorded. A biopsy from one of the liver metastases showed strong immunoreactivity for synaptophysin and chromogranin A, but none for insulin. Attempted treatment with octreotide and interferon had to be terminated because of hepatotoxicity.\n\nFour and half years after the initial surgery, the patient underwent whole‐body [11C]5‐hydroxytryptophan positron emission tomography at Uppsala University Hospital. There was uptake in the liver and in para‐aortic lymph nodes. Due to the risk of liver failure and the existence of extrahepatic disease, the patient was not considered to be a candidate for treatment with radioactive lutetium or liver transplantation. During the following months, further disease progression occurred with multiple liver metastases and ascites, and the patient was treated with liver embolization (transarterial embolization with microspheres) at Rikshospitalet, Oslo. In three subsequent sessions over a 1.5‐year period, a large part of the right liver lobe and segments 2, 3, and 4 of the left lobe were embolized. This procedure and spironolactone treatment alleviated symptoms for a period of time.\n\nFive years after the insulinoma diagnosis, at age 48, the patient was diagnosed with lobular carcinoma of the right breast. She was treated with curative intent, and two foci (5 and 11 mm) of a grade 2 lobular carcinoma were completely resected. Estrogen and progesteron receptors were positive and HER2 negative. A sentinel node revealed one micrometastasis. The patient was given postoperative locoregional radiation therapy (2 Gy × 25) and antiestrogen treatment with tamoxifen. Follow‐up showed no breast cancer recurrence.\n\nSeven years after pancreatic surgery, and following several months of stable disease, there was again progression of the residual liver metastases, and chromogranin A levels were rising. The patient was given second‐line treatment with temozolomide and capecitabine for nearly 2 years. During this time, she developed portal vein thrombosis, which was treated with injections of low‐molecular‐weight heparin. She did not have any hypoglycemic episodes, and her diabetes was well regulated with stable insulin requirements. She was then observed for 1 year without treatment.\n\nTen years postsurgery, temozolomide and capecitabine were reintroduced, but had to be discontinued due to intractable side effects (diarrhea, abdominal pain, general weakness). However, the patient's diarrhea and abdominal pain did not improve, and celiac disease was diagnosed based on elevated tissue transglutaminase‐immunoglobulin A, positive HLA DQ2/DQ8 and typical findings in duodenal biopsies. The abdominal symptoms improved with a gluten‐free diet. Abdominal CT showed slow progression of the liver metastases (Fig. 2C).\n\nDuring this period, chromogranin A levels started to rise rapidly, and 11.5 years postsurgery, the patient was admitted to hospital with acute confusion and in poor general condition. Octreotide scintigraphy showed, in addition to multiple liver and lymph node metastases, uptake in the peritoneum, suspicious for peritoneal carcinomatosis. A CT scan of the head did not reveal any specific pathological findings. There were no hypoglycemic episodes. The patient died a few days later. A postmortem examination was not permitted by the relatives.\n\nDiscussion\nIn diabetes mellitus, hypoglycemic episodes are relatively common and then usually associated with the use of exogenous insulin or insulin secretagogues. The co‐occurrence of diabetes and insulinoma poses diagnostic challenges and is sufficiently rare to deserve individual case reports. In a series of 313 confirmed cases of insulinoma at the Mayo Clinic from 1927 to 1992, there was only one case of a functioning insulinoma in a patient with established T2DM diagnosis 9. In 1996, a review of the literature retrieved 17 documented case reports of insulinomas in patients with T2DM 11. We have found only two published case reports of insulinoma in patients with a pre‐existing diagnosis of T1DM 11, 12, although it should be noted that tumor immunoreactivity to insulin was documented in only one of the patients 12. Moreover, two insulinoma patients have been diagnosed with T1DM soon after surgical resection of the tumor, including one case with documented insulitis and the absence of beta cells in the nontumorous pancreatic tissue 13.\n\nFor the patient presented here, the evidence for an autoimmune etiology of her diabetes is strong. A need for insulin treatment within 1 year of diagnosis in a nonobese young person is in itself suggestive of T1DM. Moreover, elevated GAD autoantibodies were detected, and there was no sign of insulin expression in the islets of the nontumorous pancreatic tissue removed during surgery. C‐peptide was undetectable postoperatively and insulin requirement re‐emerged immediately. Finally, the patient had two other autoimmune disorders (hypothyroidism, celiac disease) known to be associated with T1DM as well as a son with this disease.\n\nThe histological appearance of the tumor together with the immunoprofile (strong, diffuse positivity for chromogranin A and synaptophysin) confirmed the diagnosis of a neuroendocrine tumor. The focal distribution of tumor cells intensely positive for insulin together with clinical and laboratory signs of insulin production is diagnostic for an insulinoma 6. The presence of liver metastases and the course of the disease demonstrated the malignancy of the tumor.\n\nIn retrospect, the insulinoma should have been diagnosed during the patient's first hospital admission at age 43. The reason for the delayed diagnosis was partly a belief that insulinoma and T1DM could not co‐exist. Moreover, the fast was stopped too early (after 24 h) based on bedside blood glucose measurements that overestimated the degree of hypoglycemia. A prolonged fast (up to 72 h) has a sensitivity approaching 100% for detecting functioning insulinoma 14. In addition, the C‐peptide level at the end of the first fast was not assessed carefully enough. C‐peptide measurement can exclude exogenous insulin administration as cause of hyperinsulinism, and a concentration above 0.2 nmol/L in a patient with hypoglycemia is suggestive of insulinoma 5, 14.\n\nGiven that the prevalence of diabetes mellitus is 5–10% in industrial countries and that the incidence of insulinoma is 0.7–4 per 1,000,000 per year 1, co‐existence of the disorders should be more frequent than the literature indicates. It is possible that the presence of diabetes prevents the development of insulinoma or reduces the clinical symptoms. In addition, hypoglycemia in diabetic subjects is frequently observed and almost always caused by overtreatment with glucose‐lowering agents, making it easy to neglect alternative explanations for persistent hypoglycemia.\n\nThe demonstration of insulinoma in T1DM raises some interesting questions with regard to the underlying pathophysiology and origin of the tumor. The insulin‐producing malignant cells must have been able to avoid the autoimmune attack that otherwise had completely destroyed the beta cells of the patient. Notably, there was no evidence of an inflammatory response, neither in the resected tumor nor in the normal pancreatic tissue. Whether there was a lack of autoantigen expression in the insulinoma cells or they were able to escape immune surveillance in other ways will remain an open question. In this regard, it should be noted that although the large majority of insulinomas are benign 3, 8, the insulinomas of both the current and the two previously published T1DM patients were malignant 11, 12.\n\nIn some cases, such as in the MEN syndrome and in autoimmune chronic gastritis, neuroendocrine tumors may develop in the context of endocrine cell hyperplasia 15. In long‐standing T1DM, the pancreas has been depleted of normal beta cells (Fig. 5D). It is therefore difficult to envisage that the insulinoma of the present case developed from hyperplastic or normal beta cells. Instead, we propose that that the pluripotency of uncommitted stem cells is required to give rise to an insulin‐producing tumor in a patient who lacks normally functioning beta cells and where such cells are likely to be constantly attacked by the immune system.\n\nConclusion\nThis case report and previous publications show that insulinoma can occur in individuals with diabetes, even in patients with long‐standing T1DM. Thus, when hypoglycemic episodes persist in a diabetic subject despite reduction or discontinuation of hypoglycemic treatment, and other causes of low blood glucose level have been ruled out, the presence of an insulin‐producing tumor should be considered.\n\nAuthorship\nHKG: evaluated the patient's medical records, did the literature review, wrote the article draft, and made the figures. DH: operated the patient, provided the patient's consent, and contributed to the writing process. CSV: followed up on all pathology data and made critical revisions of the text and figures. JE: did the primary pathology evaluation of the surgical specimen and contributed to the writing process. JGC: performed the clinical evaluation of the patient and contributed to the writing process. AM: coordinated and supervised the writing process, performed critical revisions of the text and figures, and is the corresponding author. All authors approved the final manuscript version.\n\nConsent for Publication\nInformed and written consent were obtained from the patient.\n\nConflict of Interest\nThe authors have no conflict of interests to disclose.\n\nAcknowledgments\nThe authors are grateful to prof. Ingfrid S. Haldorsen, Department of Radiology, Haukeland University Hospital, Bergen, Norway, for discussion of the radiological images, to staff members who cared for the patient at Haukeland University Hospital, and to Helge K. Gjelberg for assistance with Figure 1.\n==== Refs\nReferences\n1 \n\nHalfdanarson , T. R. \n, \nJ. \nRubin \n, \nM. B. \nFarnell \n, \nC. S. \nGrant \n, and \nG. M. \nPetersen \n. 2008 \nPancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors . Endocr. Relat. Cancer \n15 :409 –427 .18508996 \n2 \n\nService , F. J. \n, \nM. M. \nMcMahon \n, \nP. C. \nO'Brien \n, and \nD. J. \nBallard \n. 1991 \nFunctioning insulinoma–incidence, recurrence, and long‐term survival of patients: a 60‐year study . Mayo Clin. Proc. \n66 :711 –719 .1677058 \n3 \n\nKrampitz , G. W. \n, and \nJ. A. \nNorton \n. 2013 \nPancreatic neuroendocrine tumors . Curr. Probl. Surg. \n50 :509 –545 .24206780 \n4 \n\nWhipple , A. O. \n, and \nV. K. \nFrantz \n. 1935 \nAdenoma of islet cells with hyperinsulinism: a review . Ann. Surg. \n101 :1299 –1335 .17856569 \n5 \n\nVezzosi , D. \n, \nA. \nBennet \n, \nJ. \nFauvel \n, and \nP. \nCaron \n. 2007 \nInsulin, C‐peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism . Eur. J. Endocrinol. \n157 :75 –83 .17609405 \n6 \n\nMathur , A. \n, \nP. \nGorden \n, and \nS. K. \nLibutti \n. 2009 \nInsulinoma . Surg. Clin. North Am. \n89 :1105 –1121 .19836487 \n7 \n\nTucker , O. N. \n, \nP. L. \nCrotty \n, and \nK. C. \nConlon \n. 2006 \nThe management of insulinoma . Br. J. Surg. \n93 :264 –275 .16498592 \n8 \n\nMehrabi , A. \n, \nL. \nFischer \n, \nM. \nHafezi \n, \nA. \nDirlewanger \n, \nL. \nGrenacher \n, \nM. K. \nDiener \n, et al. 2014 \nA systematic review of localization, surgical treatment options, and outcome of insulinoma . Pancreas \n43 :675 –686 .24921202 \n9 \n\nKane , L. A. \n, \nC. S. \nGrant \n, \nT. B. \nNippoldt \n, and \nF. J. \nService \n. 1993 \nInsulinoma in a patient with NIDDM . Diabetes Care \n16 :1298 –1300 .8404437 \n10 \n\nHoem , D. \n, \nD. \nJensen \n, \nS. \nSteine \n, \nT. E. \nThorsen \n, \nA. \nViste \n, and \nA. \nMolven \n. 2008 \nClinicopathological characteristics and non‐adhesive organ culture of insulinomas . Scand. J. Surg. \n97 :42 –49 .18450205 \n11 \n\nSvartberg , J. \n, \nM. \nStridsberg \n, \nE. \nWilander \n, \nD. E. \nAndersson \n, and \nB. \nEriksson \n. 1996 \nTumour‐induced hypoglycaemia in a patient with insulin‐dependent diabetes mellitus . J. Intern. Med. \n239 :181 –185 .8568488 \n12 \n\nLablanche , S. \n, \nM. \nChobert‐Bakouline \n, \nO. \nRisse \n, \nM. H. \nLaverriere \n, \nO. \nChabre \n, and \nP. Y. \nBenhamou \n. 2015 \nMalignant insulinoma may arise during the course of type 1 diabetes mellitus: a case report . Diabetes Metab. \n41 :258 –261 .25451188 \n13 \n\nOikawa , Y. \n, \nT. \nKatsuki \n, \nM. \nKawasaki \n, \nA. \nHashiguchi \n, \nK. \nMukai \n, \nK. \nHanda \n, et al. 2012 \nInsulinoma may mask the existence of Type 1 diabetes . Diabet. Med. \n29 :e138 –e141 .22356209 \n14 \n\nService , F. J. \n\n1995 \nHypoglycemic disorders . N. Engl. J. Med. \n332 :1144 –1152 .7700289 \n15 \n\nMete , O. \n, and \nS. L. \nAsa \n. 2013 \nPrecursor lesions of endocrine system neoplasms . Pathology \n45 :316 –330 .23478233\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "5(6)",
"journal": "Clinical case reports",
"keywords": "Chromogranin; diabetes; hypoglycemia; insulin secretion; insulinoma",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "761-768",
"pmc": null,
"pmid": "28588806",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": "19836487;8404437;8568488;25451188;18508996;7700289;16498592;24206780;17856569;1677058;24921202;17609405;22356209;18450205;23478233",
"title": "Hypoglycemia and decreased insulin requirement caused by malignant insulinoma in a type 1 diabetic patient: when the hoof beats are from a zebra, not a horse.",
"title_normalized": "hypoglycemia and decreased insulin requirement caused by malignant insulinoma in a type 1 diabetic patient when the hoof beats are from a zebra not a horse"
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"abstract": "Enteroviruses are a frequent source of infection and among the most common central nervous system viral pathogens. Enteroviruses - in particular, the Coxsackie B viruses - are a known cause of myocarditis. Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. Many reports in the literature suggest a higher risk of infection following repeated rituximab therapy, including viral infection. However, observations of enterovirus-related myocarditis in the context of rituximab treatment are scarce. The authors describe the case of a patient with neuromyelitis optica spectrum disorder who developed severe and fatal enterovirus-related myocarditis after rituximab therapy with a difficult differential diagnosis of autoimmune or giant-cell myocarditis. This case highlights the importance of complete diagnostic workup in difficult cases of myocarditis, including endomyocardial biopsies.",
"affiliations": "Department of Internal Medicine and Clinical immunology, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille Lille, France.;Centre for Anaesthesia and Resuscitation, CHU Lille Lille, France.;Laboratory of Virology, CHU Lille, Lille University, EA3610 Lille, France.;Department of Cardiology, CHU Lille Lille, France.;Institute of Immunology, CHU Lille Lille, France.;CRC-SEP, CHU Lille Lille, France.;Department of Cardiovascular Radiology, CHU Lille Lille, France.;Department of Cardiovascular Radiology, CHU Lille Lille, France.;Department of Cardiology, CHU Lille Lille, France.;Department of Cardiology, CHU Lille Lille, France.;Department of Cardiology, CHU Lille Lille, France.;Regional Centre of Pharmacovigilance, CHU Lille Lille, France.;Department of Internal Medicine and Clinical immunology, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille Lille, France.;Department of Anatomy and Pathology, CHU Lille Lille, France.;Department of Internal Medicine and Clinical immunology, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille Lille, France.;Department of Infectious Diseases, CHU Lille Lille, France.;Department of Internal Medicine and Clinical immunology, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille Lille, France.",
"authors": "Diarra|Ava|A|;Gantois|Guillaume|G|;Lazrek|Mouna|M|;Verdier|Basile|B|;Elsermans|Vincent|V|;Zephir|Hélène|H|;Longère|Benjamin|B|;Gkizas|Xristos|X|;Goeminne|Céline|C|;Lemesle|Gilles|G|;Juthier|Francis|F|;Bene|Johana|J|;Launay|David|D|;Dubois|Romain|R|;Morell-Dubois|Sandrine|S|;Vuotto|Fanny|F|;Piton|Anne-Laure|AL|",
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"doi": "10.15420/cfr.2020.33",
"fulltext": "\n==== Front\nCard Fail Rev\nCard Fail Rev\nCFR\nCardiac Failure Review\n2057-7540\n2057-7559\nRadcliffe Cardiology\n\n10.15420/cfr.2020.33\nClinical Syndromes\nFatal Enterovirus-related Myocarditis in a Patient with Devic’s Syndrome Treated with Rituximab\nDiarra Ava 1\nGantois Guillaume 2\nLazrek Mouna 3\nVerdier Basile 4\nElsermans Vincent 5\nZephir Hélène 6\nLongère Benjamin 7\nGkizas Xristos 7\nGoeminne Céline 4\nLemesle Gilles 4\nJuthier Francis 4\nBene Johana 8\nLaunay David 1,9,10\nDubois Romain 11\nMorell-Dubois Sandrine 1\nVuotto Fanny 12\nPiton Anne-Laure 1\n1. Department of Internal Medicine and Clinical immunology, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille Lille, France\n2. Centre for Anaesthesia and Resuscitation, CHU Lille Lille, France\n3. Laboratory of Virology, CHU Lille, Lille University, EA3610 Lille, France\n4. Department of Cardiology, CHU Lille Lille, France\n5. Institute of Immunology, CHU Lille Lille, France\n6. CRC-SEP, CHU Lille Lille, France\n7. Department of Cardiovascular Radiology, CHU Lille Lille, France\n8. Regional Centre of Pharmacovigilance, CHU Lille Lille, France\n9. Institute for Translational Research in Inflammation (INFINITE – U1286) Lille, France\n10. Inserm Lille, France\n11. Department of Anatomy and Pathology, CHU Lille Lille, France\n12. Department of Infectious Diseases, CHU Lille Lille, France\nDisclosure: The authors have no conflicts of interest to declare.\n\nCorrespondence: Ava Diarra, CHU Lille, Département de médecine interne et immunologie clinique, Centre de référence des maladies autoimmunes systémiques rares du Nord et Nord-Ouest de France (CeRAINO), F-59000 Lille, France. E: ava.diarra@gmail.com\n12 5 2021\n3 2021\n7 e0923 12 2020\n15 1 2021\nCopyright © 2021, Radcliffe Cardiology\nhttps://creativecommons.org/licenses/by-nc/4.0/ This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.\nEnteroviruses are a frequent source of infection and among the most common central nervous system viral pathogens. Enteroviruses – in particular, the Coxsackie B viruses – are a known cause of myocarditis. Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. Many reports in the literature suggest a higher risk of infection following repeated rituximab therapy, including viral infection. However, observations of enterovirus-related myocarditis in the context of rituximab treatment are scarce. The authors describe the case of a patient with neuromyelitis optica spectrum disorder who developed severe and fatal enterovirus-related myocarditis after rituximab therapy with a difficult differential diagnosis of autoimmune or giant-cell myocarditis. This case highlights the importance of complete diagnostic workup in difficult cases of myocarditis, including endomyocardial biopsies.\n\nDevic’s syndrome\nenterovirus\nmyocarditis\nrituximab\n==== Body\nDevic’s syndrome (or neuromyelitis optica spectrum disorder; NMOSD) is a rare autoimmune disorder involving the central nervous system. The disease spectrum includes longitudinally extensive transverse myelitis and optic neuritis. Treatment relies on high-dose steroids and maintenance immunosuppressant therapy, such as rituximab.[1] Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. It causes depletion of CD20+ B cells and decreased immunoglobulin production.\n\nMany reports in the literature suggest a higher risk of infection – including viral infection – following repeated rituximab therapy.[2] Human enteroviruses are a group of viruses related to the picornavirus family. They are a known cause of myocarditis – in particular Coxsackie B viruses.[3] Reports of enterovirus-related myocarditis due to rituximab are scarce.[4,5] Cases of acute fatal viral myocarditis are mostly described among neonatal and young patients, in contrast to chronic forms of heart failure and dilated cardiomyopathy, which are more common in the adult population.[6]\n\nHere, we describe the case of a patient with NMOSD who developed a severe and fatal enterovirus-related myocarditis after rituximab therapy. The differential diagnosis included autoimmune or giant-cell myocarditis. This case highlights the importance of the complete diagnosis workup in difficult cases of myocarditis, including endomyocardial biopsies.\n\nIn accordance with French legislation, written information was provided and consent was obtained from the patient. French legislation does not require that written consent is obtained for this type of study.\n\nCase Report\n\nWe report a 29-year-old patient with NMOSD associated with anti-aquaporin-4-antibodies. She experienced multiple retrobulbar optic neuritis despite corticosteroid therapy. Since 2012, she received prednisone pulses and plasma exchange for the management of these optical attacks. Since the introduction of rituximab in 2012, prednisone and plasma exchange were not repeated. A 1 g dose of rituximab was administered on day 1, repeated on day 15, then followed by rituximab maintenance therapy of 1 g every 6 months for 7 years. The eleventh and final rituximab infusion was performed in September 2019, thus a total dose of 11 g had been administered with three missed administrations over the years of treatment due to pregnancies.\n\nPrior to rituximab initiation, the patient’s immunoglobulin level was normal (gammaglobulin 9.6 g/l; normal range 8.0–13.5 g/l) along with CD4 cell count (755/mm3; normal range 400–1,300/mm3). After rituximab treatment, CD19 depletion was complete. Immunoglobulin G (IgG) level in the remission phase of the disease was low, reaching 6.2 g/l.\n\nIn November 2019, 2 months after the last rituximab infusion, the patient suddenly developed cyanotic acute respiratory failure and loss of consciousness while resting. When the rescue team found the patient, she was in cardiac arrest. Transthoracic echocardiogram revealed a left ventricle ejection fraction of 35% (compared with a normal value of 65%during a previous assessment in 2012). Cardiac MRI revealed global hypokinesia with concentric left ventricle hypertrophy and significant increase of T2 mapping values, suggesting a diffuse myocardial oedema. CT coronary angiography revealed no significant stenosis.\n\nA subcutaneous defibrillator was implanted on day 22 post cardiac arrest. The patient was eventually discharged without a clear final diagnosis. On day 47, 10 days after discharge, she was re-admitted to the intensive cardiac care unit with recurrent ventricular tachycardia, despite treatment with amiodarone and lidocaine, resulting in severe cardiogenic shock. With the working hypothesis of giant cell myocarditis, she received prednisone pulses before further results.\n\nMyocardial biopsy was performed on day 51. It revealed acute inflammatory myocardial lymphocytic infiltrate with no signs of giant cells or eosinophilic infiltration. We completed the diagnostic workup, including exhaustive serology and molecular testing. This revealed a positive enterovirus reverse-transcriptase polymerase chain reaction (RT-PCR) on blood, identified as Coxsackie type B4. The first positive enterovirus RT-PCR on blood was reported on day 47. Retrospectively, the analysis of blood sample and pectoral biopsies dating from days 12 and 22 were also positive for enterovirus. Enterovirus RT-PCR was also strongly positive on myocardial tissue. Stool and throat samples were negative, suggesting a long-term enteroviral infection.\n\nBased on these results, the final diagnosis was acute enterovirus-related myocarditis in an immunocompromised patient receiving rituximab. In the absence of specific antiviral treatment, she received IV immunoglobulin 0.4 g/kg/day over 5 days from day 53 to day 57 along with blood PCR monitoring. Enterovirus viral load dramatically decreased from the initiation of IV immunoglobulin therapy. Heart transplantation would have been the best therapeutic option in this situation. However, our patient had high panel reactive alloantibodies and no desensitisation strategies allowing access to heart transplantation in safe conditions. She was finally implanted with a biventricular extracorporeal total artificial heart (Berlin Heart) as a bridge to transplant.\n\nNonetheless, after 6 weeks of intensive resuscitation the patient deteriorated despite maximum therapy and ultimately died on day 91.\n\nDiscussion\n\nWe describe the case of a patient with NMOSD who developed a severe and fatal enterovirus-related myocarditis after rituximab therapy.\n\nBecause of the multiple possible causes of myocarditis in this context, we considered the following hypotheses. First, we explored the possibility of a cardiac manifestation of the underlying autoimmune condition. To our knowledge, no cardiac symptoms have been described so far with NMOSD. Second, in light of the severe presentation and rhythmic disorders, we considered giant cell myocarditis. This particular myocarditis affects younger patients with an autoimmune disorder in 20% of cases, causing rapidly progressive and heart failure that is frequently fatal.[7] Because of the patient’s severe presentation, we decided to start immediate corticosteroids and consider rapid immunosuppression. However, we were concerned by the immunocompromised status of the patient. Moreover, although guidelines are scarce, official guidelines of the European Society of Cardiology advocates the role of endomyocardial biopsies in the management of patients with viral PCR both on blood and myocardium.[8] Thus, before starting immunosuppression, we performed a thorough diagnostic workup including myocardial biopsies.\n\nIn our patient, RT-PCR for enterovirus was positive both in blood and in myocardium, establishing the diagnosis of enterovirus-related myocarditis. Interestingly, the PCR was positive for samples taken during herfirst admission, allowing us to consider retrospectively that the patient had this diagnosis since the first event.\n\nSevere enterovirus infections, including meningoencephalitis and myocarditis, are usually described among neonates. Among adults, patients with primary humoral immune deficiencies such as Bruton’s X-linked agammaglobulinaemia are more likely to develop chronic enterovirus meningoencephalitis. Low immunoglobulin count increases sensitivity toward enteroviral infections. Our patient was clearly immunocompromised as a result of the rituximab treatment, having low levels of IgG, immunoglobulin (IgM) and CD19.\n\nRituximab induces B-cell depletion via different mechanisms, including complement- and antibody-dependent cellular cytotoxicity along with induced apoptosis. CD20-expressing cells remain undetectable for approximately 6 months post first administration.[9] Repeated cycles of rituximab are associated with low IgM and, to a lesser degree, low IgG, especially in patients with an underlying B-cell maturation defect. However, data concerning the risk of infection associated with rituximab are contradictory, varying according to the population studied and the accompanying treatments.\n\nSome studies do not find significant increase in the risk of infection under rituximab therapy, despite decreased immunoglobulin levels, whereas multiple reports have identified a link between rituximab regimen therapy and the occurrence of severe infection.[9] Moreover, in a recent study, our team showed that the 1- and 2-year incidences of serious infections were 17.3 (12.0–22.5) and 11.3 (8.1–14.5) per 100 person-years, respectively. Identified risk factors of severe infections were age, history of diabetes, history of cancer, concomitant steroid treatment and low CD4 lymphocyte count at rituximab initiation. Immunoglobulin replacement therapy was started in 22 rituximab courses (8%).[10]\n\nAcute and chronic enterovirus meningoencephalitis have been described among patients under rituximab therapy for B-cell malignancies or auto-immune disorders. Chronic enteroviral myocarditis is more frequent among adults, resulting in dilated cardiomyopathy.[11–13] However, rituximab-related enterovirus myocarditis observations are very scarce. Only one report of a child receiving rituximab treatment for nephrotic syndrome and one report of an adult treated for lymphoma were found in the literature.[4,5]\n\nIn terms of treatment, by the time the diagnosis of enterovirus had been made, the patient’s clinical status was already severely compromised. Therapeutic options are scarce. Pleconaril, pirodavir, and vapendavir are capsid-binding agents that are theoretically active on enteroviruses with modest antiviral activity, unapproved in the therapeutic arsenal of enterovirus infections. Interferon beta has been tested in phase 2 trials for cases of persistent left ventricle dysfunction linked to chronic enteroviral infection, but without success. In the absence of availability of specific treatments, we started IV immunoglobulin therapy, based on protocols used in paediatric and immunocompromised populations. Of note, following IV immunoglobulin therapy, the enteroviral RNA load rapidly dropped to zero, yet without any obvious effect on clinical status and myocardium recovery.\n\nOur case is a red flag for physicians about the possible association between rituximab and life-threatening enteroviral myocarditis in other immunocompromised patients. It also highlights the importance of a correct diagnostic workup including endomyocardial biopsies and viral PCR. Without them, we could have wrongly concluded on autoimmune myocarditis or giant cell myocarditis. In our case, despite a fatal course of evolution, the administration of IV immunoglobulin was highly effective on enterovirus RNA viral load, yet without leading to clinical improvement in an already severe patient. Earlier administration – when the patient was first admitted – may have changed the course and the patient’s outcome.\n==== Refs\n1. Patterson SL Goglin SE Neuromyelitis optica. Rheum Dis Clin N Am 2017 43 579 91 10.1177/1352458513495939 23846353\n2. Kimby E Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005 31 456 73 10.1016/j.ctrv.2005.05.007 16054760\n3. Fairley CK Ryan M Wall PG The organisms reported to cause myocarditis and pericarditis in England and Wales. J Infect 1996 32 223 5 10.1016/s0163-4453(96)80023-5 8793712\n4. Sellier-Leclerc A-L Belli E Guérin V Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome. Pediatr Nephrol 2013 28 1875 9 10.1007/s00467-013-2485-9 23700173\n5. Alonso JJ Cánovas A Rubio G Lethal enterovirus myocarditis associated with rituximab and chemotherapy for follicular lymphoma. Med Clínica (Barc) 2013 141 459 60 [in Spanish]. 10.1016/j.medcli.2013.03.001 23622890\n6. Kim -S Hufnagel G Chapman NM Tracy S The group B coxsackieviruses and myocarditis. Rev Med Virol 2001 11 355 68 10.1002/rmv.326 11746998\n7. Kasouridis I Majo J MacGowan G Clark AL Giant cell myocarditis presenting with acute heart failure. BMJ Case Rep 2017 bcr-2017-219574 10.1136/bcr-2017-219574 28536222\n8. Caforio ALP Pankuweit S Arbustini E Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013 34 2636 48 10.1093/eurheartj/eht210 23824828\n9. Cooper N Arnold DM The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases. Br J Haematol 2010 149 3 13 10.1111/j.1365-2141.2010.08076.x 20151975\n10. Stabler S Giovannelli J Launay D Serious infectious events and immunoglobulin replacement therapy in patients with autoimmune diseases receiving rituximab: a retrospective cohort study. Clin Infect Dis 2021 72 727 37 10.1093/cid/ciaa127 32067031\n11. Kim K-S Hufnagel G Chapman NM Tracy S The group B coxsackieviruses and myocarditis. Rev Med Virol 2001 11 355 68 10.1002/rmv.326 11746998\n12. Rose NR Viral myocarditis. Curr Opin Rheumatol 2016 28 (4) 383 9 10.1097/BOR.0000000000000303 27166925\n13. Liu Z Yuan J Yanagawa B Qiu D McManus BM Yang D Coxsackievirus-induced myocarditis: new trends in treatment. Expert Rev Anti Infect Ther 2005 3 (4) 641 50 10.1586/14787210.3.4.641 16107202\n\n",
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"medline_ta": "Card Fail Rev",
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"references": "23700173;16107202;20151975;29061244;23622890;11746998;16054760;27166925;8793712;23824828;32067031;28536222",
"title": "Fatal Enterovirus-related Myocarditis in a Patient with Devic's Syndrome Treated with Rituximab.",
"title_normalized": "fatal enterovirus related myocarditis in a patient with devic s syndrome treated with rituximab"
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"abstract": "Systemic lupus erythematosus (SLE) is a hypercoagulable state due to a variety of mechanisms. Herein, we discuss the case of a 40-year-old gentleman who presented with cerebral venous sinus thrombosis (CVST) as the first manifestation of underlying SLE. On initial presentation, he did not endorse any other signs and symptoms to suggest the presence of an autoimmune condition. Work-up revealed an absence of antiphospholipid antibodies. Further evaluation uncovered the underlying etiology of the CVST as SLE-induced nephrotic syndrome. The existing literature on CVST suggests that there are only two other biopsy-proven cases of lupus nephritis leading to nephrotic range proteinuria as the etiology for CVST. Given the rarity of this presentation, there are no clearly delineated treatment strategies.",
"affiliations": "Department of Internal Medicine, University of Connecticut Health Center, Farmington, USA.;Division of Rheumatology and Clinical Immunology, University of Pittsburgh Medical Center, Pittsburgh, USA.",
"authors": "Chandra|T|T|https://orcid.org/0000-0001-8667-1195;Tilstra|J S|JS|",
"chemical_list": "D000925:Anticoagulants; D008775:Methylprednisolone",
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"issue": "29(2)",
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"keywords": "SLE; cerebral venous sinus thrombosis; lupus nephritis",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D006801:Humans; D007668:Kidney; D008181:Lupus Nephritis; D008279:Magnetic Resonance Imaging; D008297:Male; D008775:Methylprednisolone; D008854:Microscopy, Electron; D012851:Sinus Thrombosis, Intracranial",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral venous sinus thrombosis as the initial presentation of systemic lupus erythematosus.",
"title_normalized": "cerebral venous sinus thrombosis as the initial presentation of systemic lupus erythematosus"
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"abstract": "BACKGROUND\nImmunotherapy may lead to durable remissions in patients with relapsed and refractory acute lymphoblastic leukemia (R/R ALL). Patients receiving immunotherapy with a lower disease burden tend to have improved long-term outcomes and less toxicity. Thus, an induction protocol to achieve lower disease burden is required. Bortezomib added to a 4-drug induction was shown to lead to high rates of remission in R/R ALL patients. Inclusion of anthracyclines in this protocol may preclude most patients, having maximized the cumulative dose of anthracyclines. Thus, our goal was to evaluate anthracycline-free bortezomib-based induction for patients with R/R ALL.\n\n\nMETHODS\nWe conducted a retrospective analysis of patients treated with bortezomib-based protocols for R/R ALL between 2011 and 2019 at our center. Data regarding toxicity and response rate was collected and analyzed.\n\n\nRESULTS\nEighteen children with R/R ALL were treated with bortezomib-based induction, 13 of them without anthracyclines. Eleven patients did not complete the induction course: 6 due to toxicity, and 5 due to physician decision to proceed to immunotherapy early. Two events of treatment-related mortality occurred. There was no significant difference in toxicity between patients who treated with anthracycline and those who were not. Ten patients achieved complete remission, with 4 patients having polymerase-chain-reaction minimal residual disease below 10-4. Fifteen patients proceeded directly to immunotherapy: 11 patients received CD19 chimeric-antigen receptor-T-cells, 2 blinatumomab and 2 hematopoietic stem cell transplant.\n\n\nCONCLUSIONS\nAnthracyclines can be safely omitted from bortezomib-based therapies in patients with R/R ALL, when planning to proceed to immunotherapy.",
"affiliations": "Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat-Gan Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Dadi|Gal|G|;Jacoby|Elad|E|;Toren|Amos|A|;Beilorai|Bella|B|",
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"title": "Bortezomib-based Anthracycline-free Induction for Pediatric Relapsed ALL as a Bridge to Immunotherapy.",
"title_normalized": "bortezomib based anthracycline free induction for pediatric relapsed all as a bridge to immunotherapy"
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"abstract": "Paroxysmal autonomic instability with dystonia (PAID) is a syndrome commonly related to traumatic brain injury (TBI) and rarely to anoxia associated with symptoms of dystonia, tachycardia, tachypnea, and diaphoresis. This is a case of a 20-year-old man who was stabbed in the heart. He underwent surgical repair of a ventricular septal defect and mitral valve replacement. Postoperatively, he developed dystonia with tachycardia and tachypnea consistent with PAID syndrome, secondary to prolonged hypoxia. Traditionally, this poorly understood syndrome is treated with morphine, clonazepam, and nonselective β-blockers. Second-line medications commonly used are baclofen, dantrolene, and gabapentin, which are aimed at the dystonia itself. In this case, both first- and second-line agents were ineffective. A 72-hour dexmedetomidine infusion resulted in complete resolution of symptoms. This is the first case of anoxia-induced PAID syndrome to be effectively treated with dexmedetomidine, which was previously used in a case induced by TBI.",
"affiliations": "Department of Internal Medicine, Rutgers University, New Jersey Medical School, Newark, NJ. Electronic address: johnkerndo@gmail.com.;Department of Internal Medicine, Rutgers University, New Jersey Medical School, Newark, NJ.;Department of Internal Medicine, Rutgers University, New Jersey Medical School, Newark, NJ.;Department of Internal Medicine, Rutgers University, New Jersey Medical School, Newark, NJ.",
"authors": "Kern|John|J|;Bodek|Daniel|D|;Niazi|Osama Tariq|OT|;Maher|James|J|",
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"keywords": "autonomic function; cardiac arrest; neurology; trauma",
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"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D001341:Autonomic Nervous System; D001342:Autonomic Nervous System Diseases; D006348:Cardiac Surgical Procedures; D020927:Dexmedetomidine; D004421:Dystonia; D004562:Electrocardiography; D006801:Humans; D000860:Hypoxia; D007262:Infusions, Intravenous; D008297:Male; D011183:Postoperative Complications; D013577:Syndrome; D055815:Young Adult",
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"title": "Refractory Case of Paroxysmal Autonomic Instability With Dystonia Syndrome Secondary to Hypoxia.",
"title_normalized": "refractory case of paroxysmal autonomic instability with dystonia syndrome secondary to hypoxia"
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"companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2016GMK023571",
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"abstract": "A 51-year-old man, homosexual, recently diagnosed with ocular neurosyphilis, presented to the emergency room with a 1-day history of fevers and chills. His vital signs were significant for a temperature of 102.8°F and tachycardia of 125 bpm. The patient had experienced blurred vision in his left eye and was diagnosed with ocular neurosyphilis 10 days prior to the current presentation. He was treated with a 14-day course of high-dose intravenous penicillin and oral prednisone. His laboratory studies were significant for transaminitis, with an aspartate aminotransferase of 1826 U/L, alanine aminotransferase of 1743 U/L, total bilirubin of 1.2 mg/dL and alkaline phosphatase of 68 U/L. After ruling out viral aetiologies and toxin-induced hepatic injury, penicillin was discontinued on the day following admission and transaminases promptly improved with resolution of symptoms. The patient's vision returned to normal within 2 weeks after discharge from hospital.",
"affiliations": "Royal College of Surgeons in Ireland, Dublin, Ireland.;Department of Medicine, Galway University Hospital, Galway, Ireland.;Internal Medicine, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania, USA.",
"authors": "Wilkinson|Janelle|J|;Zainal|Abir|A|;Naqvi|Syed Yaseen|SY|",
"chemical_list": "D000900:Anti-Bacterial Agents; D010406:Penicillins",
"country": "England",
"delete": false,
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"mesh_terms": "D000900:Anti-Bacterial Agents; D056486:Chemical and Drug Induced Liver Injury; D005128:Eye Diseases; D006801:Humans; D008099:Liver; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009494:Neurosyphilis; D010406:Penicillins",
"nlm_unique_id": "101526291",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24099021;9059967;7742464;4366005;22447259",
"title": "Penicillin-induced liver injury during treatment for ocular neurosyphilis.",
"title_normalized": "penicillin induced liver injury during treatment for ocular neurosyphilis"
} | [
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"activesubstancename": "VANCOMYCIN"
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"abstract": "Topical calcineurin inhibitors are widely used to treat inflammatory dermatoses for their steroid-sparing advantage. Herein, we report a patient with chronic lip dermatitis who developed multiple labial melanotic macules after application of tacrolimus 0.1% ointment and pimecrolimus 1% cream. Prior and current reports raise concerns for potential development of pigmented lesions associated with topical calcineurin inhibitor use. These reports highlight the need for careful risk-benefit assessment when prescribing topical calcineurin inhibitors for inflammatory dermatoses, especially when used on sun-exposed sites.",
"affiliations": "University of California, Davis.",
"authors": "Shi|Vivian Y|VY|;Joo|Jayne S|JS|;Sharon|Victoria R|VR|",
"chemical_list": "D065095:Calcineurin Inhibitors; C117268:pimecrolimus; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus",
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"mesh_terms": "D000279:Administration, Cutaneous; D000328:Adult; D001706:Biopsy; D065095:Calcineurin Inhibitors; D003876:Dermatitis, Atopic; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007911:Lentigo; D008047:Lip Diseases; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus",
"nlm_unique_id": "9610776",
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"pmid": "25148283",
"pubdate": "2014-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple labial melanotic macules occurring after topical application of calcineurin inhibitors.",
"title_normalized": "multiple labial melanotic macules occurring after topical application of calcineurin inhibitors"
} | [
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"drug... |
{
"abstract": "Early and accurate diagnosis remains crucial in the therapeutic management of invasive central nervous system fungal infections. Different molds have intrinsic resistance to antifungal agents; thus, morphologic differentiation is helpful to clinicians.\nUsing three examples, we present a guide on how to approach neuropathology specimens where hyphae are identified on initial histologic examination.\nHyphae can be classified into three basic groups: hyaline pauciseptated, hyaline septated, and pigmented or dematiaceous. The hyaline pauciseptated group includes the order of the Mucorales (previously Zygomyces) and is frequent in patients with decompensated diabetes and severe neutropenia. Aspergillus species constitutes the most frequently isolated mold in the hyaline septated group. However, other invasive hyaline septated molds include Fusarium species, which is frequently resistant to multiple antifungals, and Candida species Last, dematiaceous molds, although infrequent, can be found in neuropathology specimens, as happened during the outbreak of Exserohilum associated with manufacturing practices in a compound pharmacy.\nCategorizing hyphae into the three groups described allows pathologists to provide information that is useful for infectious disease treatment with an inclusive differential diagnosis of diverse fungal genera that share the same morphological features.",
"affiliations": "Department of Pathology and Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.",
"authors": "Chavez|Jesus A|JA|;Brat|Daniel J|DJ|;Hunter|Steven B|SB|;Velazquez Vega|Jose|J|;Guarner|Jeannette|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ajcp/aqx144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9173",
"issue": "149(2)",
"journal": "American journal of clinical pathology",
"keywords": "Dematiaceous; Histopathology; Hypha; Hyphae; Mold; Pauciseptated; Septate; Septated",
"medline_ta": "Am J Clin Pathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D020314:Central Nervous System Fungal Infections; D003937:Diagnosis, Differential; D006801:Humans; D025301:Hyphae; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D004718:Saccharomycetales",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "98-104",
"pmc": null,
"pmid": "29365030",
"pubdate": "2018-01-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Practical Diagnostic Approach to the Presence of Hyphae in Neuropathology Specimens With Three Illustrative Cases.",
"title_normalized": "practical diagnostic approach to the presence of hyphae in neuropathology specimens with three illustrative cases"
} | [
{
"companynumb": "US-UCBSA-2018016607",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo characterize the clinical and biological course, management and response to treatment in Systemic Lupus Erythematosus (SLE)-associated Pure Red Cell Aplasia (PRCA).\n\n\nMETHODS\nNationwide multicentre retrospective cohort study. From 2006 to 2018, we included adults with a diagnosis of PRCA supported by bone-marrow examination and SLE or biologic manifestations of SLE after ruling out parvovirus B19 infection.\n\n\nRESULTS\nWe enrolled 24 patients (20 women). SLE was diagnosed before PRCA for 14 patients (median delay 81 months). At PRCA diagnosis, mean age, haemoglobin level and reticulocyte and differential erythroblast count were 39.2 ± 13.2 years, 62 ± 20 g/L, 9.1 ± 7.6 x 109/L and 2.8 ± 2.5%, respectively. Eleven (45%) patients experienced multiple PRCA flares (median 6, range: 2-11). Corticosteroid therapy resulted in only three complete sustained responses, and 19 (79%) patients required immunosuppressive agents with highly variable regimens. After a median follow-up of 76 months (range 13-173), 17 (71%) patients showed complete response for PRCA, five (21%) partial response and two (8%) treatment failure. In total, 21 (87%) patients required red-blood-cell transfusion; five had a diagnosis of transfusion-related iron overload. Eighteen (75%) patients experienced severe infectious events requiring hospitalization.\n\n\nCONCLUSIONS\nSLE-associated PRCA is a severe condition. Repeated red-blood-cell transfusions and several lines of immunosuppressant therapy are mostly required with high risk of severe infectious events and iron overload. Despite sustained response for PRCA and SLE obtained in most patients, the best therapeutic strategy remains to be determined.",
"affiliations": "Service de Médecine Interne, Hôpital Estaing, Centre Hospitalier Universitaire de Clermont-Ferrand, France.;Service de Médecine Interne, Centre National de Référence des Cytopénies Auto-Immunes de l'Adulte, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.;Equipe mobile d'infectiologie, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.;Department of Clinical Immunology, Saint Louis University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Department of internal medicine, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Service de médecine interne 2, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.;Service de médecine interne, Hôpital Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.;Internal Medicine Department, Edouard Herriot University Hospital, Hospices Civils de Lyon, Lyon, France.;Service de médecine Interne, Centre Hospitalier Universitaire Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Service de Médecine Interne, Centre National de Référence des Cytopénies Auto-Immunes de l'Adulte, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.;Service de Médecine Interne, Centre National de Référence des Cytopénies Auto-Immunes de l'Adulte, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.",
"authors": "Lobbes|Hervé|H|;Mahévas|Matthieu|M|;Alviset|Sophie|S|;Galicier|Lionel|L|;Costedoat-Chalumeau|Nathalie|N|;Amoura|Zahir|Z|;Alric|Laurent|L|;Hot|Arnaud|A|;Durupt|Stéphane|S|;Michel|Marc|M|;Godeau|Bertrand|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keab363",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": null,
"journal": "Rheumatology (Oxford, England)",
"keywords": "bone marrow; immunosuppressant drugs; pure red cell aplasia; systemic lupus erythematosus",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": null,
"nlm_unique_id": "100883501",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33871586",
"pubdate": "2021-04-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pure red cell aplasia in systemic lupus erythematosus, a nationwide retrospective cohort and review of the literature.",
"title_normalized": "pure red cell aplasia in systemic lupus erythematosus a nationwide retrospective cohort and review of the literature"
} | [
{
"companynumb": "FR-ROCHE-3103506",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
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